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"abstract": "The present study aimed to compare the differences between the humanized CD19 chimeric antigen receptor (CAR)-T cell therapy and the murine CD19 CAR-T therapy in recurrent B-acute lymphoblastic leukemia (B-ALL). A 62-year-old male patient who had B-ALL (BCR/ABL+) for 4 years was diagnosed with relapsed central nervous system leukemia (CNSL). After several courses of high dose methotrexate combined with intrathecal chemotherapy, the patient received murine CD19 CAR-T therapy and achieved complete response (CR). The patient was diagnosed with relapsed CNSL again 15 months after his murine CD19 CAR-T therapy, and was therefore enrolled in the humanized CD19 CAR-T therapy. Subsequently, the present study aimed to compare murine and humanized CD19 CAR-T cells against Nalm-6 cells in vitro and in mice. The patient initially achieved CR from his murine CD19 CAR-T therapy with Grade 1 cytokine-release syndrome (CRS) and Grade 1 CAR-T cell-related encephalopathy syndrome (CRES). The patient then achieved CR again from his humanized CD19 CAR-T therapy with Grade 1 CRS and Grade 2 CRES. Peak levels of CD19 CAR-T cells were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy 7 days after infusion in the peripheral blood, in bone marrow and in cerebrospinal fluid (CSF). The cytokine levels were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy in the peripheral blood and in CSF. The cytotoxicity to Nalm-6 cells was higher in humanized CD19 CAR-T cells than that in murine CD19 CAR-T cells in vitro. In Nalm-6 BALB/c mice, the median survival time of mice in the murine CD19 CAR-T group was 35 days, while it was 43 days in the humanized CD19 CAR-T group. In conclusion, humanized CD19 CAR-T cell therapy had a better curative effect than that of murine CD19 CAR-T therapy, and may be used as a salvage treatment for recurrent B-ALL after treatment with murine CD19 CAR-T therapy.",
"affiliations": "Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China.;Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China.;Shanghai Genbase Biotechnology Co., Ltd., Tianjin 201210, P.R. China.;Shanghai Genbase Biotechnology Co., Ltd., Tianjin 201210, P.R. China.;Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China.;Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China.;Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China.;Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China.",
"authors": "Li|Xin|X|;Liu|Mei-Jing|MJ|;Mou|Nan|N|;Yang|Zhen-Xing|ZX|;Wang|Jia|J|;Mu|Juan|J|;Zhu|Hai-Bo|HB|;Deng|Qi|Q|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2021.13049",
"fulltext": "\n==== Front\nOncol Lett\nOncol Lett\nOL\nOncology Letters\n1792-1074\n1792-1082\nD.A. Spandidos\n\n10.3892/ol.2021.13049\nOL-0-0-13049\nArticles\nEfficacy and safety of humanized CD19 CAR-T as a salvage therapy for recurrent CNSL of B-ALL following murine CD19 CAR-T cell therapy\nLi Xin 1\nLiu Mei-Jing 12\nMou Nan 3\nYang Zhen-Xing 3\nWang Jia 1\nMu Juan 1\nZhu Hai-Bo 1\nDeng Qi 1\n1 Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China\n2 Department of Hematology, The First Central Clinical College of Tianjin Medical University, Tianjin 300192, P.R. China\n3 Shanghai Genbase Biotechnology Co., Ltd., Tianjin 201210, P.R. China\nCorrespondence to: Dr Qi Deng, Department of Hematology, Tianjin First Central Hospital, 24 Fukang Road, Nankai, Tianjin 300192, P.R. China, E-mail: kachydeng@126.com\n11 2021\n16 9 2021\n16 9 2021\n22 5 78808 7 2019\n19 2 2021\nCopyright: © Li et al.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This 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.\nThe present study aimed to compare the differences between the humanized CD19 chimeric antigen receptor (CAR)-T cell therapy and the murine CD19 CAR-T therapy in recurrent B-acute lymphoblastic leukemia (B-ALL). A 62-year-old male patient who had B-ALL (BCR/ABL+) for 4 years was diagnosed with relapsed central nervous system leukemia (CNSL). After several courses of high dose methotrexate combined with intrathecal chemotherapy, the patient received murine CD19 CAR-T therapy and achieved complete response (CR). The patient was diagnosed with relapsed CNSL again 15 months after his murine CD19 CAR-T therapy, and was therefore enrolled in the humanized CD19 CAR-T therapy. Subsequently, the present study aimed to compare murine and humanized CD19 CAR-T cells against Nalm-6 cells in vitro and in mice. The patient initially achieved CR from his murine CD19 CAR-T therapy with Grade 1 cytokine-release syndrome (CRS) and Grade 1 CAR-T cell-related encephalopathy syndrome (CRES). The patient then achieved CR again from his humanized CD19 CAR-T therapy with Grade 1 CRS and Grade 2 CRES. Peak levels of CD19 CAR-T cells were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy 7 days after infusion in the peripheral blood, in bone marrow and in cerebrospinal fluid (CSF). The cytokine levels were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy in the peripheral blood and in CSF. The cytotoxicity to Nalm-6 cells was higher in humanized CD19 CAR-T cells than that in murine CD19 CAR-T cells in vitro. In Nalm-6 BALB/c mice, the median survival time of mice in the murine CD19 CAR-T group was 35 days, while it was 43 days in the humanized CD19 CAR-T group. In conclusion, humanized CD19 CAR-T cell therapy had a better curative effect than that of murine CD19 CAR-T therapy, and may be used as a salvage treatment for recurrent B-ALL after treatment with murine CD19 CAR-T therapy.\n\nchimeric antigen receptor-T cells\nmurine\nhumanized\ncentral nervous system leukemia\ncytokine release syndrome\n==== Body\npmcIntroduction\n\nFor patients with acute lymphoblastic leukemia (ALL), the accompanying risk of central nervous system leukemia (CNSL) is more severe compared with that of patients with acute myeloid leukemia (1,2). CNSL is one of the primary causes of relapse in patients with acute leukemia and is associated with a less favorable prognosis (3). Initially, patients may achieve CNSL remission in the short term using established treatments, such as chemotherapy, intrathecal chemotherapy and radiation therapy (4).\n\nThe second generation of CD19-directed chimeric antigen receptors (CAR) results in a more pronounced activation and expansion of T cells to eliminate malignant B cells in vitro and in vivo (5). The use of anti-CD19 chimeric antigen receptor modified T (CAR-T) cells has achieved 70–88% CR and CRi in recurrent or refractory (R/R) B-ALL (6,7). Although for cases of R/R B-cell ALL, CD19 CAR-T therapy induces rapid and effective responses, it is associated with acute toxicity, including cytokine-release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES), which are severe or even fatal (8). CRS is characterized by a high fever, hypotension, hypoxia and/or multiorgan toxicity, whereas CRES is typically characterized by confusion, delirium and cerebral edema (9–12). Therefore, CRES is likely to be the more toxic side effect of CD19 CAR-T therapy in patients with CNSL arising from B-ALL.\n\nAt present, targeted CD19 CAR-T therapy for R/R B-cell malignant hematopathy is primarily attributed to the single-chain Fvs (scFvs) in CAR structures, which are derived from murine FMC63 or SJ25C1, which are the clone IDs for monoclonal antibodies targeting CD19 (6,13,14). In the majority of patients, immune responses are induced by the invasion of mouse-derived scFv structures to CD19 CAR-T cells following therapy (15). Although the effects are significant in the short term, survival of CAR-T cells in the peripheral blood following treatment for a short amount of time may assist the maintenance of the long term therapeutic effect (15). It has been reported that 93% of patients with R/R ALL exhibit a complete response (CR) to B cells following CD19 CAR-T cell therapy (7).\n\nIn a clinical study, 32 patients with ALL were treated with murine CD19 CAR-T therapy, and 5 patients relapsed; after receiving the second infusion, all of them did not respond to any curative effects after reinfusion of murine CD19 CAR-T cells (16). Immunogenicity may be an important factor affecting the survival of CAR-T cells in vivo and the curative effect of murine CD19 CAR-T therapy when used more than once (6). Therefore, humanized CD19 CAR-T cells have been constructed by isolation of anti-human CD19 scFvs from human DNA libraries and replaced with murine FMC63-derived scFv which possesses similar binding characteristics (17). A previous study has demonstrated that host immune responses can recognize the epitopes of the murine scFv and render subsequent infusions ineffective (18). Humanized CD19 CAR-T cells exhibit improved effects against tumor cell lines compared with murine CD19 CAR-T cells in vitro (19). Research on humanized CD19 CAR-T cells is being performed at several centers around the world; however, there are relatively few reports of humanized CD19 CAR-T therapy in clinical trials. The aim of the present study was to compare the differences between humanized CD19 and murine CD19 CAR-T cell therapy in recurrent B-ALL.\n\nMaterials and methods\n\nMedical history presentation\n\nHistory prior to murine CD19 CAR-T therapy: A 62-year-old male patient was admitted to Tianjin First Central Hospital (Tianjin, China) due to leukocytosis in September 2013. After bone marrow puncture and flow cytometry, the patient was diagnosed with B-ALL (BCR/ABL+). The patient received VDCP (vincristine, daunorubicin, cyclophosphamide and dexamethasone) chemotherapy and oral imatinib treatment. Subsequently, the first CR (CR1) was achieved in October 2013. In the following two courses of consolidation chemotherapy with VDCP, leukemia cells were found in the cerebrospinal fluid (CSF). The minimal residual disease and the BCR-ABL in the bone marrow was negative at this time. Therefore, the patient was diagnosed with CNSL and received two courses of high dose methotrexate (MTX) combined with intrathecal chemotherapy. CR2 was achieved in May 2014 and maintained with imatinib therapy for the following 17 months. In September 2016, the patient was readmitted with dizziness and tinnitus and diagnosed as relapsed CNSL. The patient received high dose MTX combined with several courses of intrathecal chemotherapy; however, CR was not achieved again.\n\nMurine CD19 CAR-T therapy as a first-time salvage therapy\n\nAccording to the examination, 57.51% of leukemia cells were found in the CSF, the patient's minimal residual disease in the bone marrow was 0.24% and P210 was 0.81% in February 2017. The patient was enrolled in a clinical trial at the Department of Hematology at Tianjin First Central Hospital (Tianjin, China) for treatment with autologous CAR-T 19 cells expressing murine anti-CD19 scFv and 4-1BB-CD3ζ costimulatory-activation domains (ChiCTR-ONN-16009862) following relapsed CNSL. Lymphodepleting chemotherapy with fludarabine (30 mg/m2) and cyclophosphamide (400 mg/m2) was administered daily between 4 and 2 days prior to initiation of the trial therapy. The patient received four courses of intrathecal chemotherapy to reduce the number of leukemia cells in the CSF from 57.51 to 5.26% prior to infusion of CAR-T 19 cells. Autologous murine CAR-T 19 cells were infused (1×106 cells/kg on day 1 and 6×106 cells/kg on day 2). The transduction efficiency of CD19 CAR and amplification of CD19 CAR-T cells were analyzed by flow cytometry (FCM) (data not shown).\n\nHumanized CD19 CAR-T therapy as a second-time salvage therapy\n\nThe patient maintained a stable condition for the following 15 months after treatment with murine CD19 CAR-T therapy combined with oral imatinib. In May 2018, the dizziness, tinnitus and deafness progressed, and the patient was diagnosed with relapsed CNSL again. The patient received high dose MTX combined with several courses of intrathecal chemotherapy as salvage therapy for 6 months. In November 2018, 79.28% leukemia cells were found in the CSF, while the patient's minimal residual disease in the bone marrow was 3.58% and P210 was 32.04%. The patient was given six courses of intrathecal chemotherapy, after which the patient was enrolled in a clinical trial for treatment with autologous CAR-T 19 cells expressing humanized anti-CD19 scFv and 4-1BB-CD3ζ costimulatory-activation domains (ChiCTR1800019622) as second-time relapsed CNSL. The patient received lymphodepleting chemotherapy in the same manner as the first time. After six courses of intrathecal chemotherapy, the quantity of leukemia cells in the CSF was reduced to 10.25% prior to CAR-T 19 cell infusion. Autologous CAR-T 19 cells were infused (5×105 cells/kg on day 1 and 5×105 cells/kg on day 2). Since the patient began to exhibit pyrexia 24 h after the first infusion, the total number of autologous humanized CAR-T 19 cells was reduced to 1×106 cells/kg compared with 7×106 cells/kg in the murine CD19 CAR-T therapy. The transduction efficiency of CD19 CAR and amplification of CD19 CAR-T cells were analyzed by FCM (data not shown).\n\nIsolation of peripheral blood mononuclear cells (PBMCs) and transduction of T cells with murine and humanized CD19 CAR\n\nPBMCs were isolated by Ficoll density gradient centrifugation at 400 ×g at 37°C for 20 min. CD3+ T cells were selected from the PBMCs by MACS using CD3 microbeads (Miltenyi Biotec, Inc.). CD3+ T cells were stimulated by anti-CD3/anti-CD28 mAb-coated Human T-Expander beads (cat. no. 11141D; Thermo Fisher Scientific, Inc.) and cultured in T-cell medium X–Vivo 15 (Lonza Group, Ltd.) supplemented with 250 IU/ml IL-2 (Proluekin; Novartis International AG). After the 4th day of culturing, at which point the CD19+ leukaemia cells could not be detected in the culture by FCM (BD Biosciences), T cells (3×106) were transduced with a lentiviral vector encoding CD19-CAR constructs [10 µg; lenti-CD19-2rd-CAR (murine/humanized); Shanghai Genbase Biotechnology Co., Ltd.] and cultured in medium containing recombinant human IL-2 (250 U/ml; Proleukin; Novartis International AG) at 37°C for 12 days. In the lentivirus packaging process, ~2.5–3.5 µg lentiviral vector was packaged in 293T cells (1×107). The multiplicity of infection (MOI) was 10 in murine CAR-T time and 1 in humanized CAR-T time. After 12 days of cultivation, the transduction efficiencies of anti-CD19 CAR (Shanghai Genbase Biotechnology Co., Ltd.) were analyzed by FCM. A total of 2×105 cells were added into each centrifuge tube, 100 µl biotin-labeled CD19 protein (cat. no. CD9-H8259; ACROBiosystems) was added into each tube, and then incubated at 4°C for 1 h. The final concentration of biotin-labeled CD19 protein was 10 µg/ml. After centrifugation at 300 × g at 37°C for 5 min, the supernatant was discarded and the cells were washed with PBS buffer once. A total of 100 µl diluted FITC-labeled streptavidin (cat. no. 405201; 1:500; BioLegend, Inc.) was added to each tube. After mixing, the tubes were incubated at 4°C for 1 h. After centrifugation at 300 × g at 37°C for 5 min, the supernatant was discarded and the cells were washed three times with PBS buffer. A total of 100 µl PBS suspension containing cells were added to each tube. All data were acquired using a BD Fortessa flow cytometer (BD Biosciences) and analyzed using FlowJo software (v10.0.7; FlowJo LLC). The CD19 CAR transfection rate was determined according to the instruction of CARTTEST-19 assay kit (Shanghai Genbase Biotechnology Co., Ltd.).\n\nPrimary cells and Nalm-6 cells (American Type Culture Collection) were cultured at 37°C in a humidified incubator with 4% CO2 in RPMI-1640 medium (Gibco; Thermo Fisher Scientific, Inc.) supplemented with 10% FBS (Gibco; Thermo Fisher Scientific, Inc.) and 50 IU/ml penicillin/streptomycin (Gibco; Thermo Fisher Scientific, Inc.). The human embryonic kidney 293T (Lenti-X-293T) cells (American Type Culture Collection) were maintained at 37°C in a humidified incubator with a 4% CO2 atmosphere in DMEM (Sigma-Aldrich; Merck KGaA) supplemented with 10% FBS and 50 UI/ml penicillin/streptomycin.\n\nMurine and humanized CD19 CAR-T cell proliferation\n\nAfter the CAR-T cells were harvested, the viability of murine and humanized CD19 CAR-T cells co-cultured with Nalm-6 cells (effect to target proportion was 1:1) in vitro was detected using a Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc.). A total of 100 µl cell suspension (5,000 cells/well) in a 96-well plate were cultured for 0, 24 and 48 h in a humidified incubator at 37°C. Subsequently, 10 µl CCK-8 solution was added to each well of the plate, and the plate was incubated for 4 h at 37°C. The absorbance was measured at 450 nm using a microplate reader. Optical density (OD)450 values were achieved using the Synergy H1 Hybrid Reader (BioTek China) after incubation and analyzed with Gen5 software.\n\nIn vitro cytotoxicity to Nalm-6 cells and cytokine-release assays\n\nTwo groups of CD19 CAR-T cells were co-cultured at 37°C with Nalm-6 cells at a ratio of 4:1 for 48 h in the absence of supplemented cytokines. Cytotoxicity was detected at 0, 24 and 48 h using a lactate dehydrogenase cytotoxicity test kit (cat. no. C0017; Beyotime Institute of Biotechnology) at according to the manufacturer's instructions at 490 nm. All assays were performed in duplicate or triplicate.\n\nThe release of TNF-α and IFN-γ from cells was detected using ELISA kits (cat. nos. 555268 and 550612, respectively; BD Biosciences). The absorbance value at 450 nm was detected at 0, 12, 24 and 48 h.\n\nMouse tumor model establishment and experiment\n\nThe mouse tumor model was established based on a previous study by Demehri et al (20). The method of euthanasia was carbon dioxide anesthesia. The animals were placed in a 10-liter euthanasia chamber with a carbon dioxide to oxygen ratio of 6:4. After the animals gradually lost consciousness, the chambers were filled with 100% carbon dioxide, and the flow rate was 2 l/min (20% carbon dioxide/min). Carbon dioxide was increased to 100% and kept for 10 min to determine the death of animals (21). Six to eight-week old female CAnN.Cg-Foxn1nu/CrlVR (BALB/c) mice weighing 20.31±1.39 g (n=30; Charles River Laboratories, Inc.) were used in the present study. BALB/c mice were raised in SPF conditions at 20–26°C, relative humidity 40–70% and light and dark alternated 10/14 h cycle. They were fed with food and water sterilized by high temperature and high pressure steam. Mice were injected subcutaneously with 5×106 Nalm-6 cells transduced with luciferase (AmyJet Scientific). Mice were monitored with bioluminescence imaging (BLI) for disease progression twice a week following intraperitoneal injection with D-luciferin (150 mg/kg) (AmyJet Scientific) 10 min before scanning. Before imaging, mice were anesthetized via a nose cone with 2% isoflurane medical oxygen (Zoetis) and maintained under continuous inhalational anesthesia. All mice were sacrificed wwhen the tumor volume exceeded 20 mm3 or when the experimental study has been completed. The mice were divided into three groups. The first group was given no treatment, the second group was given murine CD19 CAR-T, and the third group was given humanized CD19 CAR-T. The survival time of mice was assessed. The release of IFN-γ from peripheral blood was detected by ELISA (cat. no. E4593-100; AmyJet Scientific, Inc.). A total of 500 µl of blood was collected from the inner canthus of the three groups on days 7, 14, 21 and 28. Survival time of mice was the time when mice died or were killed for ethical reasons during the experiment.\n\nStatistical analysis\n\nAll experiments were performed independently at least three times and data are presented as the mean ± SD. Statistical analyses were performed using SPSS 18.0 software (SPSS, Inc.). Comparisons between two groups were made using the independent sample t-test. Comparisons among >2 groups were made using one-way ANOVA followed by Fisher's LSD post-hoc test. Survival curves were plotted using the Kaplan-Meier method, and the difference in OS survival rates was assessed using the log-rank test. P<0.05 was considered to indicate a statistically significant difference.\n\nResults\n\nExpansion of anti-CD19-CAR T-cells during therapy\n\nThe transduction efficiency of murine CD19 CAR was 25.88% (Fig. 1A). Peak levels of expansion of CAR-T cells were observed on day 7 in CSF accounting for 20.01% of cells, 9.07% in the peripheral blood and 8.00% in bone marrow (Fig. 1B). The time period before all murine CAR-T cells had disappeared was ~14 days in the CSF, 28 days in the peripheral blood and 42 days in the bone marrow (Fig. 2A-C).\n\nThe transduction efficiency of humanized CD19 CAR was 32.94% (Fig. 1A). Peak expansion of humanized CAR-T cells was observed on day 7 in the CSF accounting for 64.31% of cells, 30.64% in the peripheral blood and 25.57% in the bone marrow (Fig. 1C). The time period before all humanized CAR-T cells had disappeared was ~72 days in the peripheral blood and 72 days in the bone marrow. Humanized CAR-T 19 cells in the CSF were still present after 42 days of CAR-T 19 cell infusion (Fig. 2A-C).\n\nAdverse events following treatment\n\nThe infusions were well tolerated following murine CD19 CAR-T therapy. Notable adverse events were Grade 1 CRS and Grade 1 CRES (6,9). The adverse events manifested as pyrexia (39.7°C fever) with chills from days 3–5 following murine CAR-T 19 infusion, accompanied by a headache, dizziness, muscle ache, cognitive impairment, confusion and mild hypotension (Table I). Following murine CD19 CAR-T therapy, the levels of cytokines, including IL-2R, IL-6 and IL-10 were assessed. The highest level of IL-6 in serum was 86.2 pg/ml on day 7 after infusion (Fig. 3A). IL-2R, IL-8, IL-10 and TNF-α levels peaked on day 7 after infusion of murine CAR-T 19 cells (Fig 3B-E). The levels of cytokines in the CSF were detected by lumbar puncture on day 7 after infusion (Fig. 3). The level of cytokines increased gradually after CAR-T infusion, and the level of cytokines in CSF were higher compared with in peripheral blood from the fourth day after CAR-T infusion (Fig. 3). The patient was given an acetaminophen and diphenhydramine to overcome the adverse events.\n\nThe adverse events observed following humanized CAR-T cell therapy were Grade 1 CRS and Grade 2 CRES. Pyrexia (39.7°C fever) with chills from days 2–6 after infusion with humanized CD19 CAR-T cells, and headache, dizziness, muscle ache, fatigue, nausea, agitation, confusion and delirium were also experienced by the patient (Table I). The highest level of IL-6 in the serum was 125.3 pg/ml (on day 7 after infusion (Fig. 3A). The levels of IL-6, IL-8, IL-2R and IL-10 assessed peaked on day 7 after infusion of humanized CD19 CAR-T and were higher compared with murine CD19 CAR-T infusion. However, the change in TNF-α was not obvious. (Fig. 3B-E). The peak levels of all cytokines in the CSF on day 7 after infusion were lower compared with those in the peripheral blood. In the CSF, the cytokine levels at 7 days in the CSF when treated with humanized CD19 CAR-T therapy were higher compared with those for murine CD19 CAR-T therapy (Fig. 3).\n\nTherapeutic response to CD19-CAR-T cell therapy\n\nThe adverse events associated with murine CAR-T cell therapy were relieved after 10 days of infusion and the patient achieved CR after the murine CD19 CAR-T therapy. The disappearance time of leukemic cells from peripheral blood was 14 days after the treatment with murine CD19 CAR-T and 7 days after the treatment with humanized CD19 CAR-T (Fig. 2D). The disappearance time of leukemic cells from CSF was 72 days after the treatment with murine CD19 CAR-T and 14 days after the treatment with humanized CD19 CAR-T (Fig. 2E).\n\nThe patient was followed up in the outpatient department and underwent bone marrow biopsy every 2–3 months. He remained in CR condition for the following 18 months after treatment with humanized CD19 CAR-T therapy combined with oral imatinib. Subsequently, the patient relapsed again and declined further treatment.\n\nEffects of murine CD19 CAR-T and humanized CD19 CAR-T on proliferation and cytotoxicity in vitro\n\nThe proliferation of humanized CD19 CAR-T cells was higher compared with that of murine CD19 CAR-T cells (24 h, P=0.015; 48 h, P=0.002; Fig. 4A). The cytotoxicity of humanized CD19 CAR-T cells was higher compared with the murine CD19 CAR-T cells (24 h, P=0.001; 48 h, P=0.003; Fig. 4B).\n\nThere was no significant difference between the two groups in terms of the release of TNF-α and IFN-γ after 24 h. However, the release of TNF-α and IFN-γ following treatment with humanized CD19 CAR-T cells was higher compared with that following treatment with murine CD19 CAR-T cells after 48 h (TNF-α, 24 h, P=0.12 and 48 h, P=0.025; Fig. 4C; IFN-γ, 24 h, P=0.37 and 48 h, P=0.011; Fig. 4D).\n\nComparison between the murine and humanized CD19 CAR-T therapy in mice\n\nAll mice in the PBMCs group died at 7 days after therapy. Tumor fluorescence was barely present in the murine and humanized CD19 CAR-T groups at 7 days after infusion of CAR-T cells, and began to appear 14 days after infusion in the murine CD19 CAR-T group. In the humanized CD19 CAR-T group, fluorescence began to appear at 21 days after infusion. Tumor fluorescence in the murine CD19 CAR-T group rapidly increased in mice treated with murine CD19 CAR-T cells, and the mice began to die 21 days after infusion. Although the tumor fluorescence was also enhanced in the humanized CD19 CAR-T group, the mice survived until 35 days after infusion (Fig. 5A). The median survival time of mice in the murine CD19 CAR-T group was 35 days, and this was 43 days in the humanized CD19 CAR-T group (Fig. 5B). The release of IFN-γ in the humanized CD19 CAR-T cells group was increased compared with that in the murine CD19 CAR-T group (P<0.001; Fig. 5C)\n\nDiscussion\n\nThe present study investigated the safety and efficacy of humanized CD19 CAR-T therapy as a salvage treatment following murine CD19 CAR-T therapy. The transduction efficiency, proliferation, efficacy, survival time and the release of cytokines were compared between treatment with murine and humanized CD19 CAR-T cells in vitro and in mice.\n\nCRES is a severe and potentially fatal acute toxicity of CD19 CAR-T therapy for patients with R/R B-cell ALL, despite the promising results of the therapy (22). It has been reported that CAR-T cells are detectable in the CSF of patients who received CD19 CAR-T therapy, indicating severe neurotoxicity (13,23). Another study has demonstrated that the numbers of CAR-T cells in the CSF from patients with severe CRS or CRES were significantly higher compared with those in patients without neurotoxicity (8). The number of CAR-T cells in the peripheral blood also tends to be higher in patients who develop neurotoxicity compared with those who do not (13). In the present study, it was observed that the peak number of CAR-T cells in the CSF was higher compared with that in the peripheral blood or in bone marrow. Therefore, toxicity, and in particular neurotoxicity, may be a severe side effect of the process of CD19 CAR-T therapy for the treatment of patients with CNSL of B-cell ALL.\n\nFor patients with significant tumor burdens, particularly patients with ALL, the possibility of serious CRS or CRES is increased (8,11,24). Therefore, reducing the tumor burden may be an important means to prevent the manifestation of the more severe side effects. In the present study, the case of a patient who received several courses of high dose MTX combined with intrathecal chemotherapy to reduce the number of leukemia cells in the CSF before the infusion of CAR-T 19 cells is reported. The notable adverse events were Grade 1 CRS and Grade 2 CRES. Life threatening cerebral edema is the most serious neurotoxic symptoms observed in patients treated with CAR-T cell therapy (13,25–27), since there is a resultant increase to the permeability of the blood-brain barrier and increased levels of cytokines caused by the activation of central nervous system endothelial cells in CD19 CAR-T therapy (28,29). In studies using CAR-T, neurologic adverse events were reported in 40% of children and young adults with ALL (13% severe) and 50% of adults with ALL (50% severe) (16,30). Therefore, reducing the tumor burden prior to initiation of CD19 CAR-T therapy may be an effective method for the prevention of life-threatening cerebral edema. For the patient reported on in the present study, there was no cerebral edema reported for treatment with CD19 CAR-T therapy due to the several courses of high dose MTX combined with intrathecal chemotherapy prior to administration of CD19 CAR-T therapy.\n\nAlthough the most notable therapeutic effect is observed following application of CD19 CAR-T therapy for R/R B cell malignancies, the remission achieved by this therapy is a reflection of its specificity, potency and the persistence of CAR-T cells (26,31). Human leukocyte antigen restricts the T-cell-mediated immune response to epitopes derived from the murine scFv, which may affect the survival time of CAR-T cells in vivo (32). It has been reported that patients treated with murine CD19 CAR-T therapy develop an immune response specific to the murine scFv, and thus exhibit subsequent failure to respond to murine CD19 CAR-T therapy (15). Taking advantage of humanized scFvs may reduce the immunogenicity of murine CD19 CAR-T cells and improve the longevity of CAR-T cells in patients (17,33–35). In the present study, humanized CD19 CAR-T cells exhibited higher efficiency towards tumor cell lines in vitro and in mice compared with murine CD19 CAR-T cells. Additionally, the transduction efficiency, proliferation, cytotoxicity to Nalm-6 cells and cytokine-release of humanized CAR-T cells were higher compared with those of murine CAR-T cells in vitro and in mice. Based on the aforementioned experimental results, the number of CD19 CAR-T cells infused in the second therapy was reduced. The total number of autologous humanized CAR-T 19 cells infused was 1×106 cells/kg in the second therapy compared with 7×106 cells/kg in the murine CD19 CAR-T therapy. The second therapy had a complete curative effect and the severity of side effects was the same as for the first therapy. Another promising result observed in the present study was that the survival times of humanized CAR-T 19 cells in the CSF, peripheral blood and bone marrow were longer compared with those of murine CAR-T 19 cells. At this point, the patient remained in remission for >9 months after treatment with humanized CD19 CAR-T therapy. Longer remission was achieved and the risk of recurrence was reduced with the humanized CD19 CAR-T therapy. After successfully treating the patient and following recurrence, the patient was entered into another clinical trial for CD19 CAR-T therapy (ChiCTR1800019622). To establish a salvage therapy based on humanized CD19 CAR-T cell therapy for treatment of R/R B-cell hematologic malignancy to prolong survival, including patients who failed to respond or relapsed when treated with murine CD19 CAR-T therapy. The advantage of humanized CD19 CAR-T over murine CD19 CAR-T is due to a different humanized scFv sequence, the reversed order of heavy chain and light chain, and/or incorporation of the selective short peptide, which might have contributed to a change in the three-dimensional configuration of the antigen-recognizing domain of CAR (18).\n\nIn conclusion, the present study investigated the efficacy of humanized CD19 CAR-T as a salvage therapy for recurrent CNS B-ALL following murine CD19 CAR-T therapy. The prevention of life-threatening neurotoxicity, such as cerebral edema, following treatment with humanized CD19 CAR-T therapy may be achieved by reducing the initial tumor burden prior to initiation of treatment.\n\nAcknowledgements\n\nNot applicable.\n\nFunding\n\nNo funding was received.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\n\nQD conceived and designed the study. XL, ZXY and NM performed the experiments. MJL and JM contributed to acquisition of data. HBZ and JW contributed to analysis and interpretation of data. XL wrote, reviewed and revised the manuscript. XL and QD confirmed the authenticity of all the raw data. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nEthics approval and consent to participate\n\nThe present study was approved by the Ethics Committee of Tianjin First Central Hospital (Tianjin, China), and written informed consent was obtained from the enrolled patient. Additionally, the patient data were treated in accordance with the local privacy regulations. All animal procedures were approved by the institutional animal and care use committee of Tianjin First Central Hospital (Tianjin, China).\n\nPatient consent for publication\n\nThe patient provided written informed consent.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nFigure 1. Peak expansion of CAR-T cells in CSF, peripheral blood and bone marrow. The peak expansion of CAR-T cells was observed on day 7. (A) Murine CD19 CAR transduction efficiency was 25.88%, humanized CD19 CAR transduction efficiency was 32.94%. (B) Peak expression of CD19 CAR-T cells in this murine CD19 CAR-T cell therapy was 20.01% in CSF, 9.07% in peripheral blood and 8.00% in bone marrow. (C) Peak expression of CD19 CAR-T cells in this humanized CD19 CAR-T cell therapy was 64.31% in CSF, 30.64% in peripheral blood and 25.57% in bone marrow. APC, allophycocyanin; CAR-T, CD19 chimeric antigen receptor modified T; CSF, cerebrospinal fluid.\n\nFigure 2. Duration monitoring of CD19 CAR T cells in CSF, peripheral blood and bone marrow. (A-C) The vanishing time of murine CAR-T cells was ~14 days in CSF, 28 days in peripheral blood and 42 days in bone marrow. The vanishing time of humanized CAR-T cells was 42 days in CSF, 72 days in peripheral blood and 72 days in bone marrow. (D and E) In murine CD19 CAR-T therapy, leukemia cells disappeared at day 72 in CSF and day 14 in peripheral blood. In humanized CD19 CAR-T therapy, leukemia cells disappeared at day 14 in CSF and day 7 in peripheral blood. CAR-T, CD19 chimeric antigen receptor modified T; CSF, cerebrospinal fluid.\n\nFigure 3. Levels of cytokines including IL-2R, IL-6 and IL-10 and TNF-α were observed during the first and second round of therapy. (A) The highest level of IL-6 in serum on day 7 after infusion was 86.2 pg/ml in murine CAR-T cell therapy and 125.3 pg/ml in humanized CAR-T cell therapy. (B) The highest level of IL-2R in serum on day 7 after infusion was 6,520 pg/ml in murine CAR-T cell therapy and 7,500 pg/ml in humanized CAR-T cell therapy. (C) The highest level of IL-8 in serum on day 7 after infusion was 368.4 pg/ml in murine CAR-T cell therapy and 435.5 pg/ml in humanized CAR-T cell therapy. (D) The highest level of IL-10 in serum on day 7 after infusion was 256.4 pg/ml in murine CAR-T cell therapy and 392.2 pg/ml in humanized CAR-T cell therapy. (E) The highest level of TNF-α in serum on day 7 after infusion was 29.4 pg/ml in murine CAR-T cell therapy and 32.5 pg/ml in humanized CAR-T cell therapy. CAR-T, CD19 chimeric antigen receptor modified T; CSF, cerebrospinal fluid; TNF, tumor necrosis factor.\n\nFigure 4. Murine and humanized CD19 CAR-T cell transduction efficiency and proliferation. (A) Proliferation of humanized CD19 CAR-T cells was higher than that of murine CD19 CAR-T cells (P24h=0.015; P48h=0.002). (B) Cytotoxicity of humanized CD19 CAR-T cells was higher than that of murine CD19 CAR-T cells (P24h=0.001; P48h=0.003). There was no difference between the two groups at 24 h in terms of the release of (C) TNF-α and (D) IFN-γ. However, the release of TNF-α and IFN-γ in the humanized CD19 CAR-T cell group was increased compared with that in the murine CD19 CAR-T cell group at 48 h (TNF-α, P24h=0.120 and P48h=0.025; IFN-γ, P24h=0.370 and P48h=0.011). CAR-T, CD19 chimeric antigen receptor modified T.\n\nFigure 5. Curative effects of murine and humanized CD19 CAR-T cells in a mouse tumor model. (A) Tumor fluorescence almost disappeared in the murine and humanized CAR-T groups at 7 days after infusion. The tumor fluorescence disappeared 7 days after CA19 CAR-T infusion. The tumor fluorescence began to reappear at 14 days after infusion in the murine CAR-T group, while it began to reappear at 21 days after infusion in the humanized CAR-T group. The mice in the murine CAR-T group died quickly after 21 days of infusion, whereas the mice in the humanized CAR-T group were alive at 35 days after infusion. (B) Median survival of mice in the murine CAR-T group was 35 days compared with 43 days for mice in the humanized CAR-T group. (C) Release of IFN-γ in the humanized CAR-T group was higher than that in the murine CAR-T group (ANOVA F=5.591, P<0.01). CAR-T, CD19 chimeric antigen receptor modified T; PBS, blank control group.\n\nTable I. Adverse events in murine and humanized CD19 CAR-T cell therapy.\n\nEvent\tMurine CD19 CAR-T\tHumanized CD19 CAR-T\t\nFever\tGrade 1-CRS\tGrade 1-CRS\t\nChills\tGrade 1-CRS\tGrade 1-CRS\t\nNeutropenia\tNo\tNo\t\nLymphopenia\tNo\tNo\t\nAnemia\tNo\tNo\t\nThrombocytopenia\tNo\tNo\t\nFatigue\tGrade 1-CRS\tGrade 1-CRS\t\nHeadache\tGrade 1-CRS\tGrade 1-CRS\t\nDizziness\tGrade 1-CRES\tGrade 1-CRES\t\nNausea\tNo\tGrade 2-CRS\t\nVomiting\tNo\tNo\t\nSomnolence\tNo\tNo\t\nAgitation\tNo\tGrade 2-CRS\t\nConscious disturbance\tGrade 1-CRES\tGrade 2-CRES\t\nDiminished attention\tNo\tNo\t\nLanguage disturbance\tNo\tNo\t\nSeizures\tNo\tNo\t\nAtaxia\tNo\tGrade 2-CRS\t\nAnorexia\tNo\tNo\t\nDyspnea\tNo\tNo\t\nDelirium\tNo\tGrade 2-CRES\t\nMuscle soreness\tGrade 1-CRS\tGrade 1-CRS\t\nMuscle weakness\tGrade 1-CRS\tGrade 1-CRS\t\nHypotension\tGrade 1-CRS\tGrade 1-CRS\t\nHypoxemia\tNo\tNo\t\nHypoalbuminemia\tNo\tNo\t\nTransaminase increased\tNo\tNo\t\nBlood bilirubin increased\tNo\tNo\t\nSerum creatinine increased\tNo\tNo\t\nThe adverse events that occurred in the humanized CAR-T cell therapy were similar to those that occurred in the murine CAR-T cell therapy. CAR-T, CD19 chimeric antigen receptor modified T; CRES, CAR-T cell-related encephalopathy syndrome; CRS, cytokine-release syndrome.\n==== Refs\nReferences\n\n1 Rozovski U Ohanian M Ravandi F Garcia-Manero G Faderl S Pierce S Cortes J Estrov Z Incidence of and risk factors for involvement of the central nervous system in acute myeloid leukemia Leuk Lymphoma 56 1392 1397 2015 10.3109/10428194.2014.953148 25110819\n2 Aoki J Ishiyama K Taniguchi S Fukuda T Ohashi K Ogawa H Kanamori H Eto T Iwato K Sakamaki H Outcome of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with central nervous system involvement Biol Blood Marrow Transplant 20 2029 2033 2014 10.1016/j.bbmt.2013.12.079 25196856\n3 Krishnan S Wade R Moorman AV Mitchell C Kinsey SE Eden TO Parker C Vora A Richards S Saha V Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985–2001 Leukemia 24 450 459 2010 10.1038/leu.2009.264 20016529\n4 Jin MW Xu SM An Q Central nervous disease in pediatric patients during acute lymphoblastic leukemia (ALL): A review Eur Rev Med Pharmacol Sci 22 6015 6019 2018 30280785\n5 Irving BA Weiss A The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways Cell 64 891 901 1991 10.1016/0092-8674(91)90314-O 1705867\n6 Davila ML Riviere I Wang X Bartido S Park J Curran K Chung SS Stefanski J Borquez-Ojeda O Olszewska M Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia Sci Transl Med 6 224ra25 2014 10.1126/scitranslmed.3008226 24553386\n7 Lee DW Kochenderfer JN Stetler-Stevenson M Cui YK Delbrook C Feldman SA Fry TJ Orentas R Sabatino M Shah NN T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial Lancet 385 517 528 2015 10.1016/S0140-6736(14)61403-3 25319501\n8 Neelapu SS Tummala S Kebriaei P Wierda W Gutierrez C Locke FL Komanduri KV Lin Y Jain N Daver N Chimeric antigen receptor T-cell therapy - assessment and management of toxicities Nat Rev Clin Oncol 15 47 62 2018 10.1038/nrclinonc.2017.148 28925994\n9 Lee DW Gardner R Porter DL Louis CU Ahmed N Jensen M Grupp SA Mackall CL Current concepts in the diagnosis and management of cytokine release syndrome Blood 124 188 195 2014 Erratum in: Blood 128: 1533, 2016 10.1182/blood-2014-05-552729 24876563\n10 Brudno JN Kochenderfer JN Toxicities of chimeric antigen receptor T cells: Recognition and management Blood 127 3321 3330 2016 10.1182/blood-2016-04-703751 27207799\n11 Maude SL Barrett D Teachey DT Grupp SA Managing cytokine release syndrome associated with novel T cell-engaging therapies Cancer J 20 119 122 2014 10.1097/PPO.0000000000000035 24667956\n12 Hu Y Sun J Wu Z Yu J Cui Q Pu C Liang B Luo Y Shi J Jin A Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy J Hematol Oncol 9 70 2016 10.1186/s13045-016-0299-5 27526682\n13 Lamers CH Willemsen R van Elzakker P van Steenbergen-Langeveld S Broertjes M Oosterwijk-Wakka J Oosterwijk E Sleijfer S Debets R Gratama JW Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells Blood 117 72 82 2011 10.1182/blood-2010-07-294520 20889925\n14 Grupp SA Kalos M Barrett D Aplenc R Porter DL Rheingold SR Teachey DT Chew A Hauck B Wright JF Chimeric antigen receptor-modified T cells for acute lymphoid leukemia N Engl J Med 368 1509 1518 2013 10.1056/NEJMoa1215134 23527958\n15 Mulazzani M Fräßle SP von Mücke-Heim I Langer S Zhou X Ishikawa-Ankerhold H Leube J Zhang W Dötsch S Svec M Long-term in vivo microscopy of CAR T cell dynamics during eradication of CNS lymphoma in mice Proc Natl Acad Sci USA 116 24275 24284 2019 10.1073/pnas.1903854116 31712432\n16 Turtle CJ Hanafi LA Berger C Gooley TA Cherian S Hudecek M Sommermeyer D Melville K Pender B Budiarto TM CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients J Clin Invest 126 2123 2138 2016 10.1172/JCI85309 27111235\n17 Sommermeyer D Hill T Shamah SM Salter AI Chen Y Mohler KM Riddell SR Fully human CD19-specific chimeric antigen receptors for T-cell therapy Leukemia 31 2191 2199 2017 10.1038/leu.2017.57 28202953\n18 Song DG Ye Q Poussin M Liu L Figini M Powell DJ Jr A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity Oncotarget 6 21533 21546 2015 10.18632/oncotarget.4071 26101914\n19 Zhao Y Liu Z Wang X Wu H Zhang J Yang J Zhang F Liu L Long J Lu P Treatment with humanized selective CD19CAR-T cells shows efficacy in highly treated B-ALL patients who have relapsed after receiving murine-based CD19CAR-T therapies Clin Cancer Res 25 5595 5607 2019 10.1158/1078-0432.CCR-19-0916 31300451\n20 Demehri S Corbin A Loriaux M Druker BJ Deininger MW Establishment of a murine model of aggressive systemic mastocytosis/mast cell leukemia Exp Hematol 34 284 288 2006 10.1016/j.exphem.2005.11.015 16543062\n21 Tsukahara T Ohmine K Yamamoto C Uchibori R Ido H Teruya T Urabe M Mizukami H Kume A Nakamura M CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models Biochem Biophys Res Commun 438 84 89 2013 10.1016/j.bbrc.2013.07.030 23872144\n22 Liu D Zhao J Cytokine release syndrome: Grading, modeling, and new therapy J Hematol Oncol 11 121 2018 10.1186/s13045-018-0653-x 30249264\n23 Maude SL Frey N Shaw PA Aplenc R Barrett DM Bunin NJ Chew A Gonzalez VE Zheng Z Lacey SF Chimeric antigen receptor T cells for sustained remissions in leukemia N Engl J Med 371 1507 1517 2014 10.1056/NEJMoa1407222 25317870\n24 Kochenderfer JN Dudley ME Carpenter RO Kassim SH Rose JJ Telford WG Hakim FT Halverson DC Fowler DH Hardy NM Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation Blood 122 4129 4139 2013 10.1182/blood.V122.21.151.151 24055823\n25 Turtle CJ Hay KA Hanafi LA Li D Cherian S Chen X Wood B Lozanski A Byrd JC Heimfeld S Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor modified T cells after failure of ibrutinib J Clin Oncol 35 3010 3020 2017 10.1200/JCO.2017.72.8519 28715249\n26 Johnson LA June CH Driving gene-engineered T cell immunotherapy of cancer Cell Res 27 38 58 2017 10.1038/cr.2016.154 28025979\n27 Lowe KL Mackall CL Norry E Amado R Jakobsen BK Binder G Fludarabine and neurotoxicity in engineered T-cell therapy Gene Ther 25 176 191 2018 10.1038/s41434-018-0019-6 29789639\n28 Jain MD Bachmeier CA Phuoc VH Chavez JC Axicabtagene ciloleucel (KTE-C19), an anti CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B cell non Hodgkin's lymphoma Ther Clin Risk Manag 14 1007 1017 2018 10.2147/TCRM.S145039 29910620\n29 Gust J Hay KA Hanafi LA Li D Myerson D Gonzalez-Cuyar LF Yeung C Liles WC Wurfel M Lopez JA Endothelial activation and bloodbrain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR T cells Cancer Discov 7 1404 1419 2017 10.1158/2159-8290.CD-17-0698 29025771\n30 Gardner RA Finney O Annesley C Brakke H Summers C Leger K Bleakley M Brown C Mgebroff S Kelly-Spratt KS Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults Blood 129 3322 3331 2017 10.1182/blood-2017-02-769208 28408462\n31 Brentjens RJ Rivière I Park JH Davila ML Wang X Stefanski J Taylor C Yeh R Bartido S Borquez-Ojeda O Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias Blood 118 4817 4828 2011 10.1182/blood-2011-04-348540 21849486\n32 Mirzaei HR Pourghadamyari H Rahmati M Mohammadi A Nahand JS Rezaei A Mirzaei H Hadjati J Gene-knocked out chimeric antigen receptor (CAR) T cells: Tuning up for the next generation cancer immunotherapy Cancer Lett 423 95 104 2018 10.1016/j.canlet.2018.03.010 29544719\n33 Johnson LA Scholler J Ohkuri T Kosaka A Patel PR McGettigan SE Nace AK Dentchev T Thekkat P Loew A Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma Sci Transl Med 7 275ra22 2015 10.1126/scitranslmed.aaa4963 25696001\n34 Alonso-Camino V Sánchez-Martín D Compte M Nuñez-Prado N Diaz RM Vile R Alvarez-Vallina L CARbodies: Human antibodies against cell surface tumor antigens selected from repertoires displayed on T cell chimeric antigen receptors Mol Ther Nucleic Acids 2 e93 2013 10.1038/mtna.2013.19 23695536\n35 Zhao Y Wang QJ Yang S Kochenderfer JN Zheng Z Zhong X Sadelain M Eshhar Z Rosenberg SA Morgan RA A herceptin-based chimeric antigen receptor with modified signaling domains leads to 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "22(5)",
"journal": "Oncology letters",
"keywords": "central nervous system leukemia; chimeric antigen receptor-T cells; cytokine release syndrome; humanized; murine",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "788",
"pmc": null,
"pmid": "34584566",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "27526682;28408462;30280785;21849486;26101914;1705867;31300451;28202953;28025979;16543062;25110819;30249264;20016529;28925994;29025771;29544719;31712432;24055823;24876563;23695536;29910620;24553386;28715249;25196856;25317870;29789639;25319501;25696001;24667956;23872144;19843940;27111235;20889925;27207799;23527958",
"title": "Efficacy and safety of humanized CD19 CAR-T as a salvage therapy for recurrent CNSL of B-ALL following murine CD19 CAR-T cell therapy.",
"title_normalized": "efficacy and safety of humanized cd19 car t as a salvage therapy for recurrent cnsl of b all following murine cd19 car t cell therapy"
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"abstract": "Pediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient's symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.",
"affiliations": "Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.",
"authors": "Koganesawa|Masaya|M|;Matsuno|Ryosuke|R|;Sugishita|Yumiko|Y|;Kaneko|Ryota|R|https://orcid.org/0000-0001-8158-6338;Kawabata|Naoko|N|;Fujita|Sachio|S|;Akiyama|Kosuke|K|;Toyama|Daisuke|D|;Yamamoto|Shohei|S|https://orcid.org/0000-0003-1582-7062",
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"doi": "10.1177/2050313X211013225",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211013225\n10.1177_2050313X211013225\nCase Report\nAnticoagulation treatment and prophylactic edoxaban for cerebral sinus venous thrombosis in an adolescent with acute lymphoblastic leukemia\nKoganesawa Masaya\nMatsuno Ryosuke\nSugishita Yumiko\nhttps://orcid.org/0000-0001-8158-6338\nKaneko Ryota\nKawabata Naoko\nFujita Sachio\nAkiyama Kosuke\nToyama Daisuke\nhttps://orcid.org/0000-0003-1582-7062\nYamamoto Shohei\nDepartment of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan\nShohei Yamamoto, Department of Pediatrics, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama 227-8501, Japan. Email: shohei-y@tsc.u-tokai.ac.jp\n29 4 2021\n2021\n9 2050313X21101322529 11 2020\n7 4 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nPediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient’s symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.\n\nAcute lymphoblastic leukemia\nadolescent and young adults\ncerebral sinus venous thrombosis\nedoxaban\nL-asparaginase\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nTreatments for acute lymphoblastic leukemia (ALL) that include L-asparaginase (L-ASP) and steroids are associated with a high risk of venous thromboemboli (VTE).1–5 The central nervous system is one of the locations at which VTE most commonly occurs.3 Although cerebral sinus venous thrombosis (CSVT) is a common complication of ALL therapy in pediatric patients, adolescent and young adult (AYA) patients are at greater risk of developing CSVT than pediatric patients.2,4,6,7 The standard treatment for L-ASP-related VTE is unfractionated heparin or low-molecular-weight heparin (LMWH) followed by warfarin.8 However, some severe cases involving thrombosis of the internal cerebral veins require immediate local thrombolytic treatment.9,10 A recent study reported that the direct oral anticoagulant (DOAC) edoxaban was non-inferior to LMWH as a treatment for cancer-associated VTE.11 Herein, we report the case of an 18-year-old male with ALL, who developed CSVT during induction therapy and received edoxaban as a prophylactic anticoagulation therapy during the remaining ALL treatment, which included L-ASP and steroids. This case highlights the potential effectiveness of edoxaban as a prophylaxis for coagulation-related complications in AYA with ALL.\n\nCase\n\nAn 18-year-old male, who presented with migrating arthralgia, had taken prednisolone and certolizumab pegol, an anti-tumor necrosis-alpha antibody, for 9 months for rheumatoid arthritis. The patient was transferred to our hospital due to his peripheral blood test results, which showed leukocytosis with blasts and thrombocytopenia. On admission, the patient had pain in both knees, hepatomegaly, and a low-grade fever (37.9°C). Bone marrow aspiration revealed a blast frequency of 98%, and the blasts were positive for CD10, CD19, CD34, cy-CD79a, CD99, terminal deoxynucleotidyl transferase, and human leukocyte antigen-DR. Chromosomal analysis of the patient’s bone marrow cells revealed the following karyotype: 46, XY, t(2;11)(p11.2;p11.2). Magnetic resonance imaging (MRI) demonstrated necrosis of the femoral head, which seemed to be associated with prolonged prednisolone treatment. The patient was diagnosed with B-precursor ALL, and induction therapy, including prednisolone (60 mg/m2 daily for 4 weeks), vincristine (1.5 mg/m2 on days 8, 15, 22, and 29), daunorubicin (40 mg/m2 on days 8, 15, 22, and 29), L-ASP (5000 U/m2 on days 12, 15, 17, 21, 24, 27, 30, and 33), and triple intrathecal therapy (methotrexate, cytarabine, and hydrocortisone; 12.5, 25, and 25 mg, respectively, on days 1, 12, and 33). On day 20 of the induction therapy (after three courses of L-ASP), the patient developed left-sided paralysis and anarthria. A neurological examination revealed reduced movement in his left upper arm and left lower leg, together with loss of the deep tendon reflex. The Manual Muscle Test results for the left upper arm and left lower leg were both 1/5. Coagulation tests revealed the following: activated partial thromboplastin time, 191.6 s (normal = 26–36 s); prothrombin time, 17.9 s (normal = 10–15 s); prothrombin time-international normalized ratio, 1.46 (normal = 0.9–1.1); fibrinogen level = 50 mg/dL (normal = 175–430 mg/dL); antithrombin III (AT) activity level, 74% (normal = 80%–120%); and protein C activity level, 67% (normal = 79%–140%). The patient was considered to be in a hypercoagulable state, as he exhibited decreased fibrinogen levels, and the repeated administration of AT-III concentrate was required to maintain an AT-III activity level of >70% due to the effects of L-ASP. Although the patient’s brain MRI findings were normal, it was considered that CSVT had probably occurred due to hypercoagulation. The induction therapy was stopped, and anticoagulation therapy with unfractionated heparin was initiated. MRI performed on day 21 after the initiation of ALL treatment showed a CSVT in the superior sagittal sinus (Figure 1(a) and (b)). The patient’s neurological symptoms improved 3 days after the initiation of anticoagulation therapy. A course of L-ASP was skipped, and the remaining residual induction therapy, which included L-ASP, was restarted 16 days after the interruption (the first dose of L-ASP was a half dose, but full doses were administered thereafter). The unfractionated heparin was switched to LMWH 14 days later. The patient achieved complete remission after the completion of the induction therapy, and the follow-up brain MRI performed at the end of the induction therapy showed that the CSVT had been ameliorated (Figure 1(c) and (d)). As a prophylaxis against CSVT, the patient was switched from LMWH to oral edoxaban 2 months later. The edoxaban treatment was continued for about 12 months, and it was stopped about 4 months after the last round of consolidation therapy, which included L-ASP and steroids. During this time, there were no coagulation abnormalities associated with L-ASP or steroids. The patient was successfully treated with all of the therapies that were deemed necessary at admission, except the one and a half doses of L-ASP skipped during the induction therapy, and oral maintenance treatment was subsequently started.\n\nFigure 1. (a and b) Brain magnetic resonance imaging showed cerebral sinus venous thrombosis (arrows) in the superior sagittal sinus. (a) Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-DTPA)-enhanced T1-weighted imaging and (b) diffusion-weighted imaging. (c and d) Brain magnetic resonance imaging performed at the end of the induction therapy showed a cerebral sinus venous thrombosis. The arrow indicates a residual lesion. (c) T1-weighted imaging and (d) fluid attenuated inversion recovery (FLAIR) imaging.\n\nDiscussion\n\nThe cure rate of pediatric ALL is better than that of adult ALL. A recent study of AYA ALL patients revealed that patients who were treated with pediatric regimens exhibited better event-free and overall survival rates than those who were treated with adult regimens,12,13 and AYA patients are commonly treated with pediatric regimens. One proposed reason for the above-mentioned finding is differences in the dosages of chemotherapeutics, especially L-ASP. In the Japanese pediatric induction therapy regimen for ALL, the total dose of L-ASP is 90,000 U/m2, whereas in the adult ALL induction therapy regimen, it is 48,000 U/m2. Therefore, the adult ALL regimen is more intense, which is associated with improved outcomes in adult ALL patients.1,14 However, there is a possibility that this approach might increase the risk of VTE, including CSVT, in adult and AYA patients.\n\nA review of 17 prospective studies reported that the risk of thrombosis was 5.2% in pediatric ALL cases and that CSVT comprised 28.6% of all thrombotic events, most of which occurred during induction therapy.3 The NOPHO ALL 2008 study found that CSVT was associated with the use of steroids and L-ASP2 and that older age was associated with a higher risk of thrombosis.15 In addition, the UKALL 2003 trial also reported age to be a risk factor for CSVT and revealed that the median age of ALL patients with CSVT was 11 years.6 Furthermore, a comparison between pediatric and adult ALL patients who were treated at the Dana-Farber Cancer Institute revealed that age was the only significant predictor of VTE, especially among those aged >30 years.16 Interestingly, Imamura et al.17 reported the cases of two adolescent patients who were treated with L-ASP-containing regimens and emphasized the importance of decreased coagulation factor levels and increased D-dimer levels. Kasischke et al.10 reported various risk factors associated with cerebral vein thrombosis (CVT), such as a young age, female sex, estrogen-based contraceptive use, procoagulant drugs, steroids, prothrombotic conditions, inflammatory disease, infections, obesity, immobility, anatomical variants, and dehydration in addition to L-ASP. In our patient, the coagulation test results obtained on admission were within normal limits, and prolonged use of prednisolone for rheumatoid arthritis was an additional risk factor for CSVT in the current patient. Although pediatric ALL regimens include high doses of L-ASP, the optimal L-ASP dose for AYA patients remains unclear.18 Given that a reduction in the L-ASP dosage might increase the risk of relapse, further investigation is warranted to determine the optimal balance between the efficacy and complications of L-ASP.\n\nIn the current case, the acute CSVT was treated with unfractionated heparin and LMWH for 2 months, and induction therapy including L-ASP was restarted in combination with these anticoagulation therapies. After 2 months, edoxaban, a direct oral factor Xa inhibitor, was used for CSVT prophylaxis. Systematic reviews recommend LMWH, vitamin K antagonists, and warfarin for the management of thrombosis and supplementation with antiplatelet therapy for thromboprophylaxis. Treatment and thromboprophylaxis with direct oral thrombin inhibitors and anti-Xa anticoagulants have also been suggested.18,19 Recently, DOACs—such as apixaban, rivaroxaban, dabigatran etexilate, and edoxaban—have been added as options for CVT prophylaxis and treatment.20 Although there have not been any previous studies in which DOACs were used for CVT prophylaxis in ALL patients, the American Society of Clinical Oncology (ASCO) recommended thromboprophylaxis with apixaban, rivaroxaban, or LMWH for cancer patients who are at high risk of CVT.21 In addition, the ASCO also recommends treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months as a prophylaxis against recurrent CVT.21 The current patient took edoxaban for about 12 months while he was receiving L-ASP treatment, during which he exhibited normal coagulation values and did not experience any coagulopathic events. The development of novel oral anticoagulants has created an opportunity for chemotherapy-related thromboprophylaxis in patients receiving L-ASP.11 Unlike warfarin, these novel oral anticoagulants do not require monitoring of the patient’s coagulation status, such as the prothrombin time-international normalized ratio, and have few drug–drug interactions. Prophylaxis with edoxaban during chemotherapy might successfully prevent VTE associated with prednisolone and L-ASP. Furthermore, ALL patients who are at a high risk of VTE, such as AYA patients who are treated with pediatric regimens, might benefit from prophylactic edoxaban during induction therapy. Further investigation in prospective studies is necessary to determine the efficacy and safety of this approach.\n\nConclusion\n\nOur experience in the current case suggests that edoxaban may be an effective prophylaxis against chemotherapy-related VTE in AYA ALL patients.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iDs: Ryota Kaneko https://orcid.org/0000-0001-8158-6338\n\nShohei Yamamoto https://orcid.org/0000-0003-1582-7062\n==== Refs\nReferences\n\n1. Beinart G Damon L . Thrombosis associated with L-asparaginase therapy and low fibrinogen levels in adult acute lymphoblastic leukemia. Am J Hematol 2004; 77 (4 ): 331–335.15551293\n2. Ranta S Tuckuviene R Makipernaa A , et al . Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia—a multicentre study from the Nordic Society of Paediatric Haematology and Oncology. Br J Haematol 2015; 168 (4 ): 547–552.25288392\n3. Caruso V Iacoviello L Di Castelnuovo A , et al . Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108 : 2216–2222.16804111\n4. Ghanem KM Dhayni RM Al-Aridi C , et al . Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: risk factors and management. Pediatr Blood Cancer 2017; 64 (12 ): 26694.\n5. deVeber G Andrew M Adams C , et al . Cerebral sinovenous thrombosis in children. N Engl J Med 2001; 345 : 417–423.11496852\n6. Musgrave KM van Delft FW Avery PJ , et al . Cerebral sinovenous thrombosis in children and young adults with acute lymphoblastic leukaemia—a cohort study from the United Kingdom. Br J Haematol 2017; 179 (4 ): 667–669.27392277\n7. Toft N Birgens H Abrahamsson J , et al . Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia 2018; 32 (3 ): 606–615.28819280\n8. Payne JH Vora AJ . Thrombosis and acute lymphoblastic leukaemia. Br J Haematol 2007; 138 : 430–445.17608766\n9. Smith AG Cornblath WT Deveikis JP . Local thrombolytic therapy in deep cerebral venous thrombosis. Neurology 1997; 48 (6 ): 1613–1619.9191776\n10. Kasischke KA Peguero EN Sriaroon C , et al . Immediate transfer for clot-extraction in a young woman with leukemia and asparaginase-associated acute cerebral vein thrombosis. Neurohospitalist 2020; 10 (1 ): 58–63.31839868\n11. Raskob GE van Es N Verhamme P , et al . Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 : 615–624.29231094\n12. Ramanujachar R Richards S Hann I , et al . Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007; 48 (3 ): 254–261.16421910\n13. Stock W La M Sanford B , et al . What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; 112 : 1646–1654.18502832\n14. Huguet F Leguay T Raffoux E , et al . Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27 : 911–918.19124805\n15. Toft N Birgens H Abrahamsson J , et al . Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia. Eur J Haematol 2016; 96 (2 ): 160–169.25867866\n16. Grace RF Dahlberg SE Neuberg D , et al . The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol 2011; 152 (4 ): 452–459.21210774\n17. Imamura T Morimoto A Kato R , et al . Cerebral thrombotic complications in adolescent leukemia/lymphoma patients treated with L-asparaginase-containing chemotherapy. Leuk Lymphoma 2005; 46 (5 ): 729–735.16019511\n18. Koprivnikar J McCloskey J Faderl S . Safety, efficacy, and clinical utility of asparaginase in the treatment of adult patients with acute lymphoblastic leukemia. Onco Targets Ther 2017; 10 : 1413–1422.28331334\n19. Truelove E Fielding AK Hunt BJ . The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia 2013; 27 (3 ): 553–559.23099335\n20. Lurkin A Derex L Fambrini A , et al . Direct oral anticoagulants for the treatment of cerebral venous thrombosis. Crebrovacs Dis 2019; 48 : 32–37.\n21. Key NS Kharana AA Kuderer NM , et al . Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020; 38 : 496–520.31381464\n\n",
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"journal": "SAGE open medical case reports",
"keywords": "Acute lymphoblastic leukemia; L-asparaginase; adolescent and young adults; cerebral sinus venous thrombosis; edoxaban",
"medline_ta": "SAGE Open Med Case Rep",
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"references": "28660695;17608766;31480062;31381464;27392277;31839868;29231094;28819280;23099335;16421910;28331334;9191776;25867866;16804111;19124805;18502832;15551293;21210774;16019511;25288392;11496852",
"title": "Anticoagulation treatment and prophylactic edoxaban for cerebral sinus venous thrombosis in an adolescent with acute lymphoblastic leukemia.",
"title_normalized": "anticoagulation treatment and prophylactic edoxaban for cerebral sinus venous thrombosis in an adolescent with acute lymphoblastic leukemia"
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"abstract": "OBJECTIVE\nTo report globe salvage rates, patient survival and adverse events of ophthalmic artery chemosurgery (OAC) for International Classification of Retinoblastoma (ICRB) group D retinoblastoma (naive and after prior failures).\n\n\nMETHODS\nSingle institution retrospective review of all Group D eyes treated with OAC from 5/2006-12/2012. Patients were treated according to our previously-published techniques. Primary outcome was globe retention without need for external beam radiotherapy (EBRT). Demographics, prior treatments, OAC agents used, and adverse events were also recorded.\n\n\nRESULTS\n112 group D eyes (103 patients) that underwent OAC were included (average follow-up was 34 months, range: 2-110 months). 47 eyes were treatment-naïve, 58 eyes received prior treatments elsewhere, and 7 young infants (7 eyes) underwent our published \"bridge therapy\" (single agent intravenous carboplatin) until old enough to undergo OAC. Median number of OAC sessions/eye was 3 (range 1-9). 110/112 eyes received intra-arterial melphalan, but only 31 eyes received melphalan alone. 43 eyes received carboplatin, and 78 eyes received topotecan (never as a single agent). 80/112 eyes received >1 drug over their treatment course, and 39 eyes received all three agents. 24 eyes (16 pretreated, 7 treatment-naïve, 1 bridge) failed treatment and required enucleation during the study period. Enucleation and EBRT were avoided in 88/112 eyes (78.6%; including 40/47 [85.1%] treatment-naïve eyes, 42/58 [72.4%] previously-treated eyes, and 6/7 eyes [85.7%] among bridge patients). By Kaplan-Meier survival analysis, globe salvage rate was 74% at 110 months among all patients, and 85% at 110 months in the treatment-naïve subgroup. Transient grade 3/4 neutropenia was more common in patients receiving OAC bilaterally. No child died of metastatic disease.\n\n\nCONCLUSIONS\nOAC is effective for curing group D retinoblastoma, achieving rates of globe salvage many times higher than systemic chemotherapy (10-47%), even in eyes that previously failed other treatments. OAC can be performed multiple times, using multiple agents, on one or both eyes of patients.",
"affiliations": "Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States.;Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States.;Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States.;Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States.;Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York, United States.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, United States.;Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States.",
"authors": "Abramson|David H|DH|;Daniels|Anthony B|AB|;Marr|Brian P|BP|;Francis|Jasmine H|JH|;Brodie|Scott E|SE|;Dunkel|Ira J|IJ|;Gobin|Y Pierre|YP|",
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"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2675664310.1371/journal.pone.0146582PONE-D-15-39039Research ArticleIntra-Arterial Chemotherapy (Ophthalmic Artery Chemosurgery) for Group D Retinoblastoma Intra-Arterial Chemotherapy for Group D RetinoblastomaAbramson David H. 1Daniels Anthony B. 2345*Marr Brian P. 1Francis Jasmine H. 1Brodie Scott E. 6Dunkel Ira J. 78Gobin Y. Pierre 191 \nOphthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States2 \nDepartment of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States3 \nDepartment of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States4 \nDepartment of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States5 \nVanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States6 \nDepartment of Ophthalmology, Mount Sinai School of Medicine, New York, New York, United States7 \nDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, United States8 \nDepartment of Pediatrics, Weill Cornell Medical College, New York, New York, United States9 \nNeurosurgery / Interventional Radiology, Weill Cornell Medical College, New York, New York, United StatesVavvas Demetrios EditorMassachusetts Eye & Ear Infirmary, Harvard Medical School, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: DHA ABD. Performed the experiments: DHA BPM JHF SEB IJD YPG. Analyzed the data: ABD DHA. Contributed reagents/materials/analysis tools: DHA BPM JHF SEB IJD YPG. Wrote the paper: ABD DHA BPM JHF SEB IJD YPG.\n\n* E-mail: anthony.b.daniels@vanderbilt.edu12 1 2016 2016 11 1 e01465824 9 2015 18 12 2015 © 2016 Abramson et al2016Abramson et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Purpose\nTo report globe salvage rates, patient survival and adverse events of ophthalmic artery chemosurgery (OAC) for International Classification of Retinoblastoma (ICRB) group D retinoblastoma (naive and after prior failures).\n\nMethods\nSingle institution retrospective review of all Group D eyes treated with OAC from 5/2006-12/2012. Patients were treated according to our previously-published techniques. Primary outcome was globe retention without need for external beam radiotherapy (EBRT). Demographics, prior treatments, OAC agents used, and adverse events were also recorded.\n\nResults\n112 group D eyes (103 patients) that underwent OAC were included (average follow-up was 34 months, range: 2–110 months). 47 eyes were treatment-naïve, 58 eyes received prior treatments elsewhere, and 7 young infants (7 eyes) underwent our published “bridge therapy” (single agent intravenous carboplatin) until old enough to undergo OAC. Median number of OAC sessions/eye was 3 (range 1–9). 110/112 eyes received intra-arterial melphalan, but only 31 eyes received melphalan alone. 43 eyes received carboplatin, and 78 eyes received topotecan (never as a single agent). 80/112 eyes received >1 drug over their treatment course, and 39 eyes received all three agents. 24 eyes (16 pretreated, 7 treatment-naïve, 1 bridge) failed treatment and required enucleation during the study period. Enucleation and EBRT were avoided in 88/112 eyes (78.6%; including 40/47 [85.1%] treatment-naïve eyes, 42/58 [72.4%] previously-treated eyes, and 6/7 eyes [85.7%] among bridge patients). By Kaplan-Meier survival analysis, globe salvage rate was 74% at 110 months among all patients, and 85% at 110 months in the treatment-naïve subgroup. Transient grade 3/4 neutropenia was more common in patients receiving OAC bilaterally. No child died of metastatic disease.\n\nConclusions\nOAC is effective for curing group D retinoblastoma, achieving rates of globe salvage many times higher than systemic chemotherapy (10–47%), even in eyes that previously failed other treatments. OAC can be performed multiple times, using multiple agents, on one or both eyes of patients.\n\nThis work was supported by the Fund for Ophthalmic Knowledge, Inc. The sponsor or funding organization had no role in the design or conduct of this research (DHA). Data AvailabilityAll de-identified and tabulated data from which all analyses were derived is included as a Supplementary Table.Data Availability\nAll de-identified and tabulated data from which all analyses were derived is included as a Supplementary Table.\n==== Body\nIntroduction\nOver the past two decades, the introduction of systemic chemotherapy for the management of intraocular retinoblastoma has enabled globe retention for these children without the need for external beam radiation or enucleation.[1–3] Using primary systemic chemotherapy, most of the successes have been in children with International Classification of Retinoblastoma (ICRB) groups A, B and C eyes.[4] Success rates of systemic chemotherapy for group D eyes remain poor, with published rates of ocular survival of only 10–47%,[4–13] and group E eyes are nearly always enucleated.\n\nWe first began to perform intra-ophthalmic artery chemotherapy (ophthalmic artery chemosurgery, OAC) at Memorial Sloan Kettering Cancer Center (MSKCC) in 2006.[14] Since that time, we have performed the procedure over 1500 times, and OAC is now being performed in more than 45 countries worldwide. OAC allows many eyes, which previously would have required enucleation, to be saved, including many group E eyes.[15]\n\nSince the previous standard of care, systemic chemotherapy, had relatively poor success at saving group D eyes, we wanted to assess our success rates in treating these eyes using our OAC technique. In addition, intravenous chemotherapy is associated with many systemic side effects, including neutropenia during treatment and possibly secondary acute myelogenous leukemia (sAML) years later.[1, 5, 11, 16–18] However, complications related to OAC have likewise been reported by various authors.[19, 20] Here we report our success rates with OAC both as primary treatment, as well as for patients who had previously failed other forms of treatment, for group D retinoblastoma. We demonstrate rates of globe salvage with OAC that are much higher than those reported previously using other previous treatment modalities.\n\nMaterial and Methods\nPatients\nThis was a retrospective review of all patients treated at MSKCC from May 2006 until December 31, 2012. Inclusion criteria were patients with ICRB group D retinoblastoma in at least one eye at the time of presentation to MSKCC, who received OAC for the management of the group D eye. For all patients, records included the initial presentation and ICRB and Reese-Ellsworth classification, the presence or absence of subretinal or vitreous seeds, whether the patient had unilateral or bilateral disease or a positive family history of RB, the contralateral eye’s classification (for bilateral cases), the presenting ERG amplitude, whether or not any previous treatments had been given elsewhere, and the details of any prior treatments (see S1 Table). Ocular and patient outcomes and most recent ERG amplitude were also recorded. For patients prior to 2010 who were initially classified under the Reese-Ellsworth classification system, RetCam fundus photos and large-scale drawings in the patients charts were reviewed in assigning each patient an ICRB group. The Children’s Oncology Group (COG) version of the ICRB was used in all cases. Patients who were not treated with OAC due to patient/family refusal of this technique were not included.\n\nOAC Technique\nOAC was performed according to our published techniques.[14, 15, 21–25] Briefly, under general anesthesia and with the patient heparinized, a catheter was inserted into the femoral artery and advanced into the internal carotid and up to (but not in to) the os of the ophthalmic artery. Catheter tip position was confirmed by fluoroscopy, and care was taken to avoid placing the tip directly into the ophthalmic artery, to avoid wedge flow. Once position was confirmed, (each) drug was injected in a pulsatile fashion over ten minutes, as published previously.[26–28] For patients receiving bilateral sequential OAC (tandem therapy),[29] the catheter was then retracted and advanced to the os of the contralateral ophthalmic artery, position reconfirmed and drug re-injected. Cerebral angiography was performed at the end of the procedure to ensure no vascular flow anomalies were present in the brain. Intranasal epinephrine was used to reduce collateral blood flow to the nasal mucosa, and topical neosynephrine drops were used to minimize forehead hyperemia, rash and edema in the distribution of the supratrochlear artery.[30] Patients receiving bilateral treatments[29] or triple therapy with melphalan, carboplatin and topotecan[28] usually received IV steroids at the time of treatment, and an oral steroid taper thereafter. For patients with anomalous vascular anatomy, alternate techniques to infuse into the ophthalmic artery were used, according to our previously published techniques.[24] General starting doses were: melphalan 0.4 mg/kg (up to a starting dose of 5 mg), carboplatin 50 mg (which could be increased subsequently if the child’s vascular anatomy demonstrated an abnormal amount of collateral flow to extraocular structures), and topotecan 0.2–4 mg (patients treated earlier in the study tended to receive lower doses). These doses could be increased or decreased for subsequent infusions for each patient based on the judgment of the treating ocular oncologist and in real time by the interventional radiologist. The choice of drugs was decided by the treating ocular oncologist, but as a general rule, more severe tumors received a combination of multiple agents. For bilateral treatments, the worse eye usually received melphalan initially, and the contralateral eye received carboplatin. Parents were instructed to have a complete blood count with differential performed 7–10 days after the procedure. Patients were examined under anesthesia three to four weeks later, and treatments were performed as frequently as every three to four weeks, when necessary. Focal consolidation with transpupillary thermotherapy or cryotherapy was performed at the time of examination under anesthesia.\n\nDetails of all procedures were recorded, including catheter type, any vascular flow anomalies, drug regimens and dosing, any adverse events, and blood counts. Final outcome was recorded at most recent follow-up, up to the predetermined study end date (December 31, 2012). Success was defined as globe retention, without the need for external beam radiotherapy (EBRT), at the study end date.\n\nThe Memorial Sloan Kettering Cancer Center Institutional Review Board approved this study. This study was performed in accordance with the Declaration of Helsinki, and with the Health Insurance Portability and accountability Act (HIPAA). All patients provided written consent for all procedures described herein.\n\nStatistical Analyses\nStatistical analyses were performed using the R (Version 3.0.3) statistical software, with the assistance of biostatisticians Drs. Yu Shyr, Fei Yu and Liping Du of the Vanderbilt Center for Quantitative Sciences of the Vanderbilt Department of Biostatistics. Kaplan-Meier survival analysis curves were created using STATA.\n\nResults\nCharacteristics of Patients and Eyes Enrolled\nOur retrospective review included 112 group D eyes of 103 consecutive patients who received OAC for management of the group D eye. Follow-up was for an average of 34 months (range: 2–110 months). 53 patients (51%) were female and 50 (49%) were male. 63 patients (61%) had bilateral disease and 40 patients (39%) had unilateral disease. Of the 112 group D eyes, 56 (50%) were right eyes and 56 (50%) were left eyes. By Reese-Ellsworth classification, 85/112 (76%) eyes were group Vb, 17/112 (15%) were group Va, 3 (3%) were group IV, 4 (4%) were group III, 3 (3%) were group II, and none were group I. 85/112 (76%) of eyes had vitreous seeds. Among eyes in patients with bilateral disease, the contralateral eye’s ICRB classification could be determined in 58/72 (81%) of eyes. In 14 patients/eyes, the contralateral eye could not be classified due to prior enucleation of the other eye elsewhere, without adequate information to assign a classification. Of the 58 eyes for whom the contralateral eye could be classified, the contralateral eye was ICRB group A for 4 eyes, group B in 8 eyes, C in 15 eyes, D in 20 eyes and E in 11 eyes.\n\n47/112 eyes were treatment-naïve at the time they received OAC with us, 58 eyes had received prior treatment and 7 eyes received our previously-described “bridge” chemotherapy protocol.[31] The bridge approach was used in patients, usually under the age of 3 months. These infants received single agent intravenous (IV) carboplatin until they grew large enough to treat with OAC. The average age in the treatment-naïve group was 18.9 months (median age 10 months, range 3–111 months), and the average age in the pretreated group was 37.3 months (median age 24 months, range 5–252 months; p<0.001, Wilcoxon rank sum).\n\nPrevious Treatment Regimens\nAmong the 58 pretreated (non-bridge) eyes, 51/58 eyes (88%) had previously received IV chemotherapy, 15/58 (26%) had received prior EBRT, 9 eyes (16%) received periocular chemotherapy, 4 (7%) received plaque brachytherapy and 1 eye (2%) had only been treated previously with cryotherapy. 2 eyes (3%) had received and failed OAC at a different institution prior to being treated at MSKCC. Many patients had received combinations of treatments. Overall, the previous treatment strategies for the 58 pretreated patients were variable (most patients also received focal therapy with laser or cryotherapy in conjunction with the following). The most common treatment strategy was systemic chemotherapy (plus focal therapies) alone, utilized in 32/58 eyes (55%), usually with the standard vincristine/etoposide/carboplatin (VEC) regimen. The distribution of treatment strategies is shown in Fig 1.\n\n10.1371/journal.pone.0146582.g001Fig 1 Previous treatment strategies, by eye.\nOAC Treatments Received\nOn average, eyes received 3.7 OAC treatments (median 3, range 1–9). Treatment-naïve eyes received an average of 3.5 treatments (median 3, range 1–9), pretreated eyes received an average of 3.9 treatments (median 3, range 1–9), and eyes of patients that received bridge chemotherapy received an average of 3.1 OAC treatments (median 3, range 1–5; p = 0.25, Wilcoxon rank sum). Accounting for the fact that eyes could receive combinations of chemotherapy per infusion, treatment-naïve eyes received an average of 6.1 drug infusions (median 6, range 1–20), pretreated eyes received an average of 7.1 drug infusions (median 6, range 1–21), and eyes of patients that received bridge chemotherapy received an average of 4.6 OAC drug infusions (median 4, range 1–9; p = 0.29, Wilcoxon rank sum). 110/112 eyes (98%) received melphalan as a part of their OAC treatment at some point, but only 31/112 eyes (28%) received melphalan as the only agent used. 78 eyes (70%) received topotecan, but never as a single agent. 43 eyes received carboplatin, but only 1 eye received carboplatin alone. Over the course of their OAC treatments, 39 eyes (35%) received all three agents. Other combinations were used, and the distribution of OAC drug combination regimens is shown in Fig 2. No eye received intravitreous chemotherapy.\n\n10.1371/journal.pone.0146582.g002Fig 2 Distribution of eyes receiving different combinations of OAC chemotherapy agents.\nSuccess Rates with OAC\nOverall, enucleation and EBRT were both avoided in 88/112 (78.6%) of all group D eyes treated with OAC. Among treatment-naïve eyes, the success rate was 40/47 eyes (85.1%), among bridge-OAC patients, the success rate was 6/7 eyes (85.7%), and among eyes that had previously failed other treatments elsewhere, the success rate was 42/58 eyes (72.4%; Fig 3A). There was a trend toward a higher success rate in the OAC and bridge-OAC groups compared to the pretreated group (p = 0.1, Pearson) but this did not reach statistical significance. Kaplan-Meier survival analysis showed an overall globe salvage rate of 74% at 110 months (Fig 3B). For the treatment-naïve subgroup, this globe salvage rate was 85% at 110 months (Fig 3C).\n\n10.1371/journal.pone.0146582.g003Fig 3 OAC treatment success rates.\nSuccess was defined as globe salvage without the need for EBRT. A) OAC treatment success rates by treatment group. B) Kaplan-Meier survival analysis for all group D eyes receiving OAC, and C) by subgroup (prior treatment, treatment-naïve, and “bridge” chemotherapy).\n\nEssentially all patients (although not all tumors) who received OAC had focal consolidation with laser or cryotherapy. 33 eyes had some other form of treatment in addition to the OAC with focal consolidation. 3 eyes received periocular chemotherapy. 12 eyes had radioactive plaque brachytherapy (1 was in an eye that also received periocular chemotherapy). 2 eyes received systemic chemotherapy for treatment of the group D eye, and one of these eyes (which also received radioactive plaque brachytherapy) was able to avoid enucleation, 2 eyes (one pretreated and one treatment-naïve) received EBRT, but both ultimately required enucleation, as EBRT could not salvage either of the eyes that failed OAC. Overall, 24 eyes (7 treatment naïve, 1 bridge eye, and 16 eyes that had previously failed other treatments before receiving OAC) were ultimately enucleated. Of the 33 eyes that received additional treatment in conjunction with OAC, 10 were saved. Of the 10 eyes that received additional treatment and ultimately did not require enucleation, 9/10 received treatment for a focal lesion with plaque brachytherapy.\n\nAdverse Events\nOut of 103 patients treated with OAC, 39 patients developed grade 3/4 neutropenia. Of the 39 patients who developed grade 3/4 neutropenia, 27 were patients with bilateral retinoblastoma, and 17 received OAC for both eyes. Of the 76 patients that either had unilateral disease, or who only received OAC in one eye, only 22 developed grade 3/4 neutropenia at some point during their treatment course. In contrast, of the 27 patients who received bilateral OAC, 17 developed grade 3/4 neutropenia at some point during their treatment (OR = 4.2, p = 0.0026, Fisher exact). There was no significant association of grade 3 or 4 neutropenia with total number of treatments for the group D eye, with the total number of drug infusions the eye received, or with the number of triple agent (melphalan, carboplatin, plus topotecan) infusions that the eye received.\n\nIn addition, out of 103 patients treated with OAC, 44 experienced (usually mild) bronchospasm at some point during the actual OAC treatment. There was allergy-type reaction in 5 patients, grade 3 or 4 thrombocytopenia in 4, fever in 4, cardiorespiratory side effects in 3, injection site complications (such as thrombosis or bleeding) in 3, and epistaxis in 1 patient.\n\nOf 112 eyes treated with OAC, 44 (39%) experienced a local/regional adverse event at some point during their treatment course. The most common adverse event was eyelid edema or localized skin erythema (25), which was usually transient and self-limited. Other adverse events included madarosis (10), retinal or choroidal vascular occlusions (6), phthisis (5), vitreous hemorrhage (4), ptosis (4), optic nerve swelling (3), retinopathy (2), cranial nerve palsy (2), ophthalmic artery vessel injury or sclerosis (2), and suprachoroidal hemorrhage (1).\n\nThree patients, who were all in the treatment-naïve group, developed metastases over the course of their follow-up, but all three were successfully treated for their metastatic disease and all survived. One child developed (and died from) a second, non-ocular cancer (pineal gland). No patient developed a new intraocular tumor during treatment or follow-up, as we have previously reported for OAC.[32]\n\nDiscussion\nIn our study, we demonstrated high rates of successful globe salvage in eyes treated with OAC (without supplemental intravitreous chemotherapy), with an overall success rate of 78.6% (88/112 eyes saved). This was true across groups: in eyes that received OAC as primary treatment (40/47 eyes, 85.1%), in eyes that received carboplatin bridge to OAC because the infant was too young to receive OAC directly at the outset (6/7 eyes, 85.7%) as well as in eyes that had previously failed other treatments elsewhere (42/58 eyes, 72.4%).\n\nOur data also demonstrates that high success rates can be achieved with OAC even in eyes that have previously failed other treatment modalities. It is interesting that the success rate for the pretreated group is numerically (but not statistically significantly) lower than for the treatment-naïve group. There are at least two possible reasons why this might be so. The first hypothesis is that the eyes inherently do better if OAC is initiated from the outset.[21] By this argument, the time spent receiving other treatments in an attempt to cure the eye allows the tumor to progress to a stage that is inherently more resistant to treatment with subsequent OAC. This might happen, for example, by accumulating more mutations that allow for clonal escape from systemic chemotherapy, but also allows for cross-resistance to subsequent OAC that might otherwise have been curative. The alternative explanation is that these eyes, which failed prior alternative treatment strategies, therefore represent those eyes that are most difficult to cure from the outset. By this argument, the easiest-to-cure eyes were already cured by systemic chemotherapy (or another treatment modality), and therefore never entered into this study to receive OAC in the first place. Stated another way, our pretreated group is biased toward those eyes that are inherently more resistant to treatment. The success rate of 72.4% in the pretreated group therefore demonstrates the power of OAC to achieve cure even in these difficult to treat eyes that have failed other regimens previously.\n\nWe also found that our previously-described “bridge” strategy,[31] whereby patients who are too young and have femoral arteries too small to be safely accessed are treated with single agent systemic carboplatin as a bridge to planned OAC, do just as well as those who are old and large enough to receive OAC from the outset. Therefore, treating clinicians should not choose alterative chemotherapy approaches in young infants simply for fear that the couple month delay (usually until age 3 months) until OAC is possible in these infants might somehow lead to deleterious outcomes. It should be noted however, that in our bridge group the intention from the outset was to transition all patients to OAC as soon as it was technically feasible to do so. Therefore, patients should not be delayed and receive continued single agent carboplatin with intention to ultimately cure the child with intravenous monotherapy, rather, it should only be given until OAC is possible beginning at three months of age.\n\nThere is scant literature on treatment of Group D eyes after failed treatment because they are routinely enucleated.[2, 3, 11, 13] The best comparator to systemic chemotherapy success rates published in the literature is with our treatment-naïve group. The above rates of success are significantly higher than the success rates published in the literature for globe salvage with systemic chemotherapy in conjunction with focal consolidation (Fig 4). The published rates of globe salvage (without the need for EBRT) in the literature range from 10–47% (weighted average = 36.7% success) depending on the series and treating center (Table 1).[4–13] In comparison, our treatment-naïve group’s success rate was significantly higher (85.1%; Fig 4).\n\n10.1371/journal.pone.0146582.g004Fig 4 Comparison of our OAC success rates to previously-published success rates using systemic chemotherapy with or without focal consolidation.\nSuccess was defined as globe salvage without the need for EBRT. (Percent success +/- 95% confidence intervals).\n\n10.1371/journal.pone.0146582.t001Table 1 Comparison to published success rates of chemotherapy with or without focal consolidation or other local treatments.\nAuthors\tYear\tTreatment\tTotal # Group D Eyes\tEyes Successfully Treated\tSuccess Rate\t\nShields et al.\t2006\tChemo/Focal\t109\t48\t47%\t\nZage et al.\t2008\tChemo/Focal\t18\t4\t22%\t\nChung et al.\t2008\tChemo/Focal\t30\t8\t27%\t\nCohen et al.\t2008\tChemo/Focal\t18\t6\t33%\t\n+/- Plaque\t\nShin et al.\t2010\tChemo +/- Focal\t42\t15\t36%\t\nGao et al.\t2011\tChemo/Focal\t29\t9\t31%\t\nGunduz et al.\t2013\tChemo/Focal\t61\t23\t38%\t\n+/- Plaque\t\nBerry et al.\t2013\tChemo/Focal/ Periocular Chemo\t55\t26\t47%\t\nLim et al.\t2013\tChemo/Focal\t26\t6\t23%\t\nBartuma et al.\t2013\tChemo/Focal\t10\t1\t10%\t\n+/- Plaque\t\nWe decided on a strict cut off study follow-up end date of December 31, 2012, for all patients. Therefore, all primary end point (globe salvage) determinations are based on the last available follow-up information or the globe status on the above date, whichever is earlier. The reason for this study end date is that, beginning in early 2013, we began to use intravitreal melphalan widely, in conjunction with OAC, for the treatment of persistent vitreous seeds.[33–35] Most eyes that fail OAC treatment do so because of persistent vitreous seeds, and intravitreal melphalan appears to be particularly effective at treating vitreous seeds. Therefore, had we included follow-up into 2013, it would be hard to ascertain whether the success was from OAC or from the addition of intravitreal chemotherapy.\n\nEyes were treated with the minimum number of cycles of OAC necessary either to induce total regression of the tumor, or to shrink the tumor sufficiently that local consolidation with transpupillary thermotherapy or cryotherapy could be applied. Once no active tumor was noted on exam, OAC treatments were stopped. The large range of treatment sessions (3–9) derived from the variability in group D eyes. Eyes classified as Group D based on the presence of vitreous seeds tended to require more intensive treatment (either higher doses or multiple agents), as well as a greater number of treatments, than eyes that were classified as Group D based on extensive subretinal seeding, as subretinal seeds are quite easily treated with OAC. Similarly, more vitreous seeds tended to require more treatment sessions compared to eyes with fewer vitreous seeds, as this cohort was prior to the introduction of intravitreal chemotherapy at our institution.\n\nWe considered OAC treatment failure to be any eye that required enucleation or required EBRT. We considered EBRT to be treatment failure because EBRT has been shown to increase the risk of second cancers in patients with germline RB.[36, 37] Plaque brachytherapy, due to its localized radiation field, has not been associated with the subsequent development of second cancers, and so the addition of plaque brachytherapy was not considered to denote a failure of OAC, but rather the application of a focal treatment.[38] While several patients had received, and failed, EBRT prior to being referred to us for OAC, in our series, only two patients received post-OAC EBRT as salvage therapy, both of whom were treated with OAC early in this series, and both of whom received EBRT upon returning to their original referring institution. Interestingly, EBRT was not able to salvage the globe successfully in either of these two patients, and both required subsequent enucleation. In the past, there has been concern expressed about the radiation exposure due to the fluoroscopy required for OAC. We have previously published our various techniques that allow us to minimize radiation dose during OAC treatments.[39]\n\nOut of 112 group D eyes treated with OAC, 24 eyes were not salvaged. This included 7 treatment-naïve eyes, 16 eyes that had received prior treatment elsewhere, and 1 eye treated with bridge chemotherapy. Of the 16 previously treated eyes that ultimately required enucleation, 14 had been treated with IV chemotherapy previously, 6 had received EBRT prior to referral to us (5 of which had received both IV chemotherapy and EBRT). Of these 16 eyes, 1 received neither IV chemotherapy nor EBRT, but instead had been treated with plaque brachytherapy in combination with laser and cryotherapy.\n\nIn a multivariate analysis, we were not able to identify specific predictors of failure with OAC. This might be due to the overall high success rate with OAC. Put another way, there simply were not enough eyes that failed OAC to be able to tease out the factors that predicted that failure. Similarly, we could not find any statistically significant associations between prior treatment strategies and subsequent OAC failure, in part because of the low rate of failure even in the pretreated group and because almost all pretreated eyes received intravenous chemotherapy. This also raises the question of whether IV chemotherapy should ever be used as primary treatment,[40] or whether OAC as primary treatment might be a better strategy.[21]\n\nThe published literature on systemic chemotherapy for the treatment of RB often does not include a discussion of adverse events, either in the eye or for the patient systemically.[41] The main side effects associated with the systemic chemotherapy agents most commonly used are neutropenia and neutropenic fever,[1, 6, 11, 13] other forms of myelosuppression,[42, 43] thrombocytopenia,[43] ototoxicity,[44, 45] nephrotoxicity,[8] neurotoxicity, potential reduction in fertility, and the subsequent development of secondary acute myelogenous leukemia (sAML).[1, 5, 11, 16–18] Ramasubramanian et al. found no statistically significant reduction (p = 0.1) in the incidence of pineoblastoma between germline retinoblastoma patients treated with systemic chemotherapy and those not treated with systemic chemotherapy. In our study, 1/47 patients with bilateral retinoblastoma developed a pineoblastoma. This is not statistically different from the rate found by Ramasubramanian et al. in their systemic chemoreduction group (1/252 patients, p = 0.29, Fisher’s exact test).\n\nMurphree et al. have written that “transient myelosuppression occurs in virtually all cases [of retinoblastoma treated with systemic chemotherapy].”[42] Febrile neutropenia requiring hospitalization has been variably reported following systemic chemotherapy for RB in 12.7%,[11] 22.5%,[1] 28.6%,[6] 38%[13] and 80%[13] of patients, depending on the series and on the specific chemotherapeutic regimen utilized. In contrast, only 4/103 patients (3.9%) who received OAC in this study developed a fever. Reporting of reduction in fertility in these published studies is hampered by the fact that this would only become apparent decades later. Since systemic chemotherapy only became widely used in the early- to mid-1990s, these patients would only be beginning to try to establish families now. Therefore, the true rate of infertility associated with the use of systemic chemotherapy for RB has not yet become manifest. Similarly, while the development of secondary hematologic malignancies has been reported by multiple authors[1, 5, 11, 16–18] following systemic chemotherapy for RB, the total number of children who will develop sAML in the future remains to be seen. While nephrotoxicity has not been commonly reported, there have been reported deaths associated with chemotherapy-induced nephrotoxicity causing Fanconi syndrome.[8]\n\nWe did find that patients who received bilateral (tandem or sequential) OAC for the treatment of bilateral RB were more likely to develop grade 3 or 4 neutropenia at some point during their treatment course but few required transfusion. Patients with unilateral RB or bilateral RB patients who received OAC for only one eye were much less likely to develop neutropenia. Interestingly, there was no significant association between the development of neutropenia and the total number of OAC treatments the eye received, nor with the total number of drug infusions the eye received, nor with the number of triple agent (melphalan, carboplatin, plus topotecan) infusions that the eye received. Fever associated with neutropenia, or myelosuppression or cytopenias requiring hospitalization, were extremely rare following OAC in our study.\n\nConclusions\nIn conclusion, OAC is a very effective treatment for curing ICRB group D retinoblastoma, and appears to achieve rates of globe salvage many times higher than systemic chemotherapy (and, of course, higher than primary enucleation), without compromising patient survival. The procedure can be performed safely multiple times, using multiple intra-arterial chemotherapeutic agents, on one or both eyes of patients, and allows the vast majority of children to keep their eyes. It is well tolerated by patients with an acceptable side effect profile, consisting mostly of local side effects that are mild and transient (although rare sight threatening consequences do occur). High success rates can even be achieved in eyes that previously failed other treatment modalities, but our data suggest that beginning treatment primarily with OAC, rather than only using it as salvage therapy after failed systemic chemotherapy, might possibly be a better strategy. However, this is a single center, retrospective study, and a prospective randomized study would be required to answer this question definitively.\n\nSupporting Information\nS1 Table Complete de-identified data set used for analyses.\n(PDF)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Kunkele A , Jurklies C , Wieland R , Lohmann D , Bornfeld N , Eggert A , et al\nChemoreduction improves eye retention in patients with retinoblastoma: a report from the German Retinoblastoma Reference Centre . The British journal of ophthalmology . 2013 ;97 (10 ):1277 –83 . 10.1136/bjophthalmol-2013-303452 .23863458 \n2 Gunduz K , Gunalp I , Yalcindag N , Unal E , Tacyildiz N , Erden E , et al\nCauses of chemoreduction failure in retinoblastoma and analysis of associated factors leading to eventual treatment with external beam radiotherapy and enucleation . 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Ophthalmology . 2014 \n10.1016/j.ophtha.2014.03.028 .24819859 \n36 Wong FL , Boice JD Jr, Abramson DH , Tarone RE , Kleinerman RA , Stovall M , et al\nCancer incidence after retinoblastoma. Radiation dose and sarcoma risk . JAMA: the journal of the American Medical Association . 1997 ;278 (15 ):1262 –7 . .9333268 \n37 Abramson DH , Frank CM . Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk . Ophthalmology . 1998 ;105 (4 ):573 –9 ; discussion 9–80. 10.1016/S0161-6420(98)94006-4 .9544627 \n38 Francis JH , Barker CA , Wolden SL , McCormick B , Segal K , Cohen G , et al\nSalvage/adjuvant brachytherapy after ophthalmic artery chemosurgery for intraocular retinoblastoma . International journal of radiation oncology, biology, physics . 2013 ;87 (3 ):517 –23 . 10.1016/j.ijrobp.2013.06.2045 .23953635 \n39 Gobin YP , Rosenstein LM , Marr BP , Brodie SE , Abramson DH . Radiation exposure during intra-arterial chemotherapy for retinoblastoma . Archives of ophthalmology . 2012 ;130 (3 ):403 –4 ; author reply 4–5. 10.1001/archopthalmol.2011.2717 .22411679 \n40 Shields CL , Kaliki S , Al-Dahmash S , Rojanaporn D , Leahey A , Griffin G , et al\nManagement of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation . Retina . 2013 ;33 (10 ):2103 –9 . 10.1097/IAE.0b013e318295f783 .23873161 \n41 Rizzuti AE , Dunkel IJ , Abramson DH . The adverse events of chemotherapy for retinoblastoma: what are they? Do we know? \nArchives of ophthalmology . 2008 ;126 (6 ):862 –5 . 10.1001/archopht.126.6.862 .18541855 \n42 Murphree AL , Villablanca JG , Deegan WF 3rd, Sato JK , Malogolowkin M , Fisher A , et al\nChemotherapy plus local treatment in the management of intraocular retinoblastoma . Archives of ophthalmology . 1996 ;114 (11 ):1348 –56 . .8906025 \n43 Rodriguez-Galindo C , Wilson MW , Haik BG , Merchant TE , Billups CA , Shah N , et al\nTreatment of intraocular retinoblastoma with vincristine and carboplatin . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2003 ;21 (10 ):2019 –25 . 10.1200/JCO.2003.09.103 .12743157 \n44 Jehanne M , Mercier G , Doz F . Monitoring of ototoxicity in young children receiving carboplatin for retinoblastoma . Pediatric blood & cancer . 2009 ;53 (6 ):1162 \n10.1002/pbc.22124 .19479791 \n45 Jehanne M , Lumbroso-Le Rouic L , Savignoni A , Aerts I , Mercier G , Bours D , et al\nAnalysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma . Pediatric blood & cancer . 2009 ;52 (5 ):637 –43 . 10.1002/pbc.21898 .19148943\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(1)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000970:Antineoplastic Agents; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D009880:Ophthalmic Artery; D012175:Retinoblastoma; D016896:Treatment Outcome",
"nlm_unique_id": "101285081",
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"pmid": "26756643",
"pubdate": "2016",
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"references": "12743157;17613328;20844675;9544627;21826785;15465557;18342944;21670326;24465398;11992863;24819859;22694968;18541855;23244241;23863458;22411679;23028521;22863945;23953635;23177361;22611138;9333268;21383945;19479791;22332209;21681922;22368262;8906025;22442047;20714385;21320950;22997170;16996605;20212212;23991112;17729249;24119165;14609838;22053101;18650212;20381868;19148943;23873161;18703556;23937863",
"title": "Intra-Arterial Chemotherapy (Ophthalmic Artery Chemosurgery) for Group D Retinoblastoma.",
"title_normalized": "intra arterial chemotherapy ophthalmic artery chemosurgery for group d retinoblastoma"
} | [
{
"companynumb": "US-CORDEN PHARMA LATINA S.P.A.-US-2016COR000090",
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"abstract": "Minimally invasive glaucoma surgery (MIGS) provides a safe option for individuals with mild to moderate open-angle glaucoma to reduce their need for pharmacologic therapy or more extensive ab externo surgeries. In this report, we describe a surgical technique using both the Kahook Dual Blade and Gonioscopy-assisted transluminal trabeculotomy (GATT), to treat a 23-year-old active duty female with idiopathic uveitis and subsequent corticosteroid-induced glaucoma who presented with consistently elevated intraocular pressure (IOP) measurements despite maximal pharmacologic interventions. This combination was effective in consistently lowering intraocular pressure for at least 12 months in a young, phakic, active duty patient with uveitis and steroid-responsive open-angle glaucoma.",
"affiliations": "1st Marine Logistics Group, Camp Pendleton, CA.;Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA.",
"authors": "Widder|Jared R|JR|;Schmitz|Joseph W|JW|",
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"keywords": "Gonioscopy-Assisted Transluminal Trabeculotomy; Kahook Dual Blade; Uveitic glaucoma; minimally invasive glaucoma surgery (MIGS)",
"medline_ta": "Mil Med",
"mesh_terms": "D005260:Female; D005901:Glaucoma; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D008889:Military Personnel; D015641:Radiography, Interventional; D012189:Retrospective Studies; D014130:Trabeculectomy; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Combining Ab Interno Kahook Trabeculectomy with Gonioscopy-Assisted Transluminal Trabeculotomy Reduces Intraocular Pressure.",
"title_normalized": "combining ab interno kahook trabeculectomy with gonioscopy assisted transluminal trabeculotomy reduces intraocular pressure"
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"abstract": "A 61-year-old woman was treated with cisplatin and etoposide for ovarian carcinoma. After the second course of chemotherapy she developed acute encephalopathy which manifested itself as headache, fever, a partial seizure, confusion, and mild right hemiparesis, although no evidence of a central nervous system infection was found. Ten days after the onset of neurological symptoms, she experienced a sudden loss of vision in both eyes. Neurological findings were compatible with cortical blindness. Neurological symptoms subsided and visual acuity completely returned over the next months. The total cumulative dose of cisplatin was 325 mg/m2. She died of aspiration pneumonia on the 43rd day. Postmortem examination revealed severe nerve cell loss, gliosis and spongy changes in the bilateral occipital cortex including visual field, and slight to moderate demyelination in the subcortical white matter of the occipital cortex, Goll's tract, and dorsal root ganglia. As far as we know this encephalopathy is the second report in which the neuropathological changes associated with cisplatin therapy have been demonstrated by autopsy findings. The first was a case report of leukoencephalopathy, which differed significantly from our case in the primary lesions of the brain. We measured the platinum level in several parts of the cerebrum and cerebellum, optic nerve, spinal cord, and cauda equina by using an atomic absorption spectrophotometric technique. Platinum was detected in the bilateral occipital cortex, spinal cord, and cauda equina. These results were consistent with the distribution of pathological lesions. The mechanism of cisplatin-induced focal encephalopathy remains speculative.(ABSTRACT TRUNCATED AT 250 WORDS)",
"affiliations": "Department of Neurology, Gynecology, Saitama Medical School.",
"authors": "Nomura|K|K|;Ohno|R|R|;Hamaguchi|K|K|;Hata|T|T|;Hatanaka|H|H|;Matsuyama|H|H|",
"chemical_list": "D002945:Cisplatin",
"country": "Japan",
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"issn_linking": "0009-918X",
"issue": "35(1)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
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"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D001766:Blindness; D001927:Brain Diseases; D002945:Cisplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms",
"nlm_unique_id": "0417466",
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"references": null,
"title": "Clinicopathological report of cisplatin encephalopathy.",
"title_normalized": "clinicopathological report of cisplatin encephalopathy"
} | [
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"companynumb": "JP-TEVA-648277ISR",
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"abstract": "In anaplastic large cell lymphoma (ALCL), the anaplastic lymphoma kinase (ALK) gene is rearranged with diverse partners due to variant translocations/inversions. Case 1 was a 39-year-old man who developed multiple tumors in the mediastinum, psoas muscle, lung, and lymph nodes. A biopsy specimen of the inguinal node was effaced by large tumor cells expressing CD30, epithelial membrane antigen, and cytoplasmic ALK, which led to a diagnosis of ALK(+) ALCL. Case 2 was a 51-year-old man who was initially diagnosed with undifferentiated carcinoma. He developed multiple skin tumors eight years after his initial presentation, and was finally diagnosed with ALK(+) ALCL. He died of therapy-related acute myeloid leukemia. G-banding and fluorescence in situ hybridization using an ALK break-apart probe revealed the rearrangement of ALK and suggested variant translocation in both cases. We applied an inverse cDNA polymerase chain reaction (PCR) strategy to identify the partner of ALK. Nucleotide sequencing of the PCR products and a database search revealed that the sequences of ATIC in case 1 and TRAF1 in case 2 appeared to follow those of ALK. We subsequently confirmed ATIC-ALK and TRAF1-ALK fusions by reverse transcriptase PCR and nucleotide sequencing. We successfully determined the partner gene of ALK in two cases of ALK(+) ALCL. ATIC is the second most common partner of variant ALK rearrangements, while the TRAF1-ALK fusion gene was first reported in 2013, and this is the second reported case of ALK(+) ALCL carrying TRAF1-ALK.",
"affiliations": "Tenri Institute of Medical Research.",
"authors": "Takeoka|Kayo|K|;Okumura|Atsuko|A|;Honjo|Gen|G|;Ohno|Hitoshi|H|",
"chemical_list": "D018076:DNA, Complementary; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.54.225",
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"issue": "54(3)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": null,
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D018076:DNA, Complementary; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D017728:Lymphoma, Large-Cell, Anaplastic; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases; D014178:Translocation, Genetic",
"nlm_unique_id": "101141257",
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"references": null,
"title": "Variant translocation partners of the anaplastic lymphoma kinase (ALK) gene in two cases of anaplastic large cell lymphoma, identified by inverse cDNA polymerase chain reaction.",
"title_normalized": "variant translocation partners of the anaplastic lymphoma kinase alk gene in two cases of anaplastic large cell lymphoma identified by inverse cdna polymerase chain reaction"
} | [
{
"companynumb": "JP-BAXTER-2015BAX008110",
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"activesubstancename": "DOXORUBICIN"
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{
"abstract": "There is no pediatric overdose information available for perampanel. We present twocases involving children 2 years of age. A female ingested 0.77mg/kg perampanel anddeveloped drowsiness and ataxia within an hour, followed by bradycardia after 6 hours.She was admitted to the pediatric intensive care unit and given fluids and was thendischarged after 20 hours. The other case involved a male who ingested 0.25mg/kgperampanel and developed ataxia within an hour, eventually he was discharged after 6hour observation in the emergency department without any treatment.",
"affiliations": "California Poison Control System, 200 W. Arbor Drive, San Diego, CA 92103, USA. Electronic address: mqozi@calpoison.org.;California Poison Control System, 200 W. Arbor Drive, San Diego, CA 92103, USA. Electronic address: lcantrell@calpoison.org.",
"authors": "Qozi|Mariam|M|;Cantrell|F Lee|FL|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2020.04.039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "38(7)",
"journal": "The American journal of emergency medicine",
"keywords": "Overdose; Pediatric; Perampanel; Poisoning; Toxicity",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000927:Anticonvulsants; D001259:Ataxia; D001919:Bradycardia; D002675:Child, Preschool; D062787:Drug Overdose; D005221:Fatigue; D005260:Female; D006801:Humans; D008297:Male; D009570:Nitriles; D011728:Pyridones",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1545.e1-1545.e2",
"pmc": null,
"pmid": "32349889",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pediatric perampanel poisoning.",
"title_normalized": "pediatric perampanel poisoning"
} | [
{
"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2020-074236",
"fulfillexpeditecriteria": "2",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERAMPANEL"
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"drugadditional... |
{
"abstract": "Celiac disease is characterized by duodenal inflammation after exposure to gluten. Checkpoint inhibitors are antibodies that inhibit the inhibitory signals of the cytotoxic T lymphocytes to enhance antitumor responses. A 79-year-old man with an unknown history of celiac disease underwent treatment with pembrolizumab for recurrent left maxillary melanoma. He subsequently developed diarrhea and weight loss. Serology was positive for anti-tissue transglutaminase immunoglobulin A. Upper endoscopy revealed duodenal villous atrophy, which was confirmed on biopsy. A gluten-free diet was not tolerated, and symptoms resolved with withdrawal of pembrolizumab and steroid administration for another medical reason.",
"affiliations": "Department of Internal Medicine, UPMC McKeesport Hospital, McKeesport, PA.;Department of Internal Medicine, UPMC McKeesport Hospital, McKeesport, PA.;Department of Internal Medicine, UPMC McKeesport Hospital, McKeesport, PA.;Department of Gastroenterology, Hepatology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, PA.",
"authors": "Arnouk|Joud|J|;Mathew|Don|D|;Nulton|Ethan|E|;Rachakonda|Vikrant|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.0000000000000158",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD 31737699ACGCR-19-055010.14309/crj.000000000000015800022Case ReportSmall BowelA Celiac Disease Phenotype After Checkpoint Inhibitor Exposure: An Example of Immune Dysregulation After Immunotherapy Arnouk Joud MD1Mathew Don MD1Nulton Ethan DO1Rachakonda Vikrant MD21 Department of Internal Medicine, UPMC McKeesport Hospital, McKeesport, PA2 Department of Gastroenterology, Hepatology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, PACorrespondence: Joud Arnouk, MD, UPMC McKeesport Hospital, 1500 5th Avenue, Mckeesport, PA 15132 (arnoukj@upmc.edu).08 8 2019 8 2019 6 8 e0015814 11 2018 03 7 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nCeliac disease is characterized by duodenal inflammation after exposure to gluten. Checkpoint inhibitors are antibodies that inhibit the inhibitory signals of the cytotoxic T lymphocytes to enhance antitumor responses. A 79-year-old man with an unknown history of celiac disease underwent treatment with pembrolizumab for recurrent left maxillary melanoma. He subsequently developed diarrhea and weight loss. Serology was positive for anti-tissue transglutaminase immunoglobulin A. Upper endoscopy revealed duodenal villous atrophy, which was confirmed on biopsy. A gluten-free diet was not tolerated, and symptoms resolved with withdrawal of pembrolizumab and steroid administration for another medical reason.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nCeliac disease (CD) is a malabsorptive immune-mediated disease characterized by local inflammation in the duodenum due to intolerance of a gluten-rich diet in patients with a genetic predisposition.1 Immune checkpoint inhibitors (ICPIs) have been widely used in the management of many cancers by blocking the inhibitory receptors on cytotoxic T cells, leading to immune stimulation.2 Although colitis and hepatitis are known gastrointestinal toxicities related to immunotherapy, one case has described the association between CD and ipilimumab.2,3 We present the first case of a new-onset CD after exposure to pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor.\n\nCASE REPORT\nA 79-year-old man with a history of stage IIa left maxillary superficial melanoma developed local recurrence 2 years after initial resection. The patient had an unknown history of CD. He was treated with local radiation and 200 mg of intravenous pembrolizumab every 3 weeks. One week after initiating the therapy, he developed loss of appetite and episodic, twice daily, watery, and nonbloody diarrhea. His symptoms progressed after 4 months of therapy with abnormal laboratory findings of hemoglobin 10.4 g/dL, potassium 3.1 mEq/L, albumin 2.4 g/dL, vitamin D 25-OH 16 ng/mL, and zinc 54 mcg/dL.\n\nThe patient was referred to a gastroenterologist. Stool studies including fecal leukocytes, lactoferrin, stool cultures, and Clostridium difficile were normal. The patient underwent a colonoscopy, which demonstrated normal-appearing mucosa with normal random biopsies. An upper endoscopy to the second part of the duodenum revealed a small antral erosion and normal-appearing duodenal mucosa. A wireless capsule endoscopy performed 1 week later to rule out enteritis revealed villous blunting in the second part of the duodenum. This was overlooked in the upper endoscopy (Figure 1). As opposed to the upper endoscopy, capsule endoscopy revealed pronounced villi in the ileum (Figure 2). Duodenal biopsy, however, revealed lamina propria expansion, villous atrophy, flat mucosa, and increased intraepithelial lymphocytes classified as type IIIc as per Marsh classification (Figure 3).\n\nFigure 1. Capsule endoscopy image showing villous atrophy at the level of the second part of the duodenum.\n\nFigure 2. Capsule endoscopy image showing intact distal intestinal mucosa.\n\nFigure 3. Duodenal biopsy showing lamina propria expansion, villous atrophy, and increased intraepithelial lymphocytes.\n\nSerologies for CD revealed anti-tissue transglutaminase immunoglobulin A (IgA) of 59 U/mL, anti-gliadin IgA of 28 U/mL, and serum IgA of 213 mg/dL. A gluten-free diet was initiated; however, the patient was not able to afford it for more than 3 weeks because of the cost. Subsequently, his symptoms of weight loss and diarrhea worsened because of lack of adherence.\n\nAfter multiple hospital admissions, pembrolizumab was discontinued 4 months after the initial dose. The patient was concurrently started on systemic steroids (hydrocortisone 10 mg in the morning and 5 mg at night) for postural hypotension. While on steroids, his symptoms of diarrhea resolved, gaining 20 pounds in 1 month after initiating therapy. The patient was lost to follow up because of multiple hospitalizations, and no repeat serologic or endoscopic studies were performed.\n\nDISCUSSION\nCD is suggested by a combination of clinical characteristics and positive serology for celiac antibodies (tissue transglutaminase [TTG] antibody IgA is 95% sensitive and 95% specific). It is confirmed with villous blunting and mucosal inflammation on biopsy.1 CD has a wide variety of intraintestinal and extraintestinal manifestations; it can also be a silent disease in many patients.1,4 CD usually responds well to the elimination of gluten from the diet.1 However, patients may respond to systemic steroids when a gluten-free diet is not tolerated or in refractory cases.1\n\nDiarrhea can be the main presenting symptom of the gastrointestinal tract toxicity due to immunotherapy.5 It can be a self-limiting, infectious, or immune-related adverse event.5 The American Society of Clinical Oncology has classified ICPI-related diarrhea into 4 grades. Grade 1 is defined as < 4 stools over the baseline in 24 hours. Grade 2 is defined as 4–6 bowel movements over the baseline in 24 hours. Grade 3 is defined as more than 7 stools over the baseline in 24 hours. Diarrhea associated with life-threatening consequences is grade 4.2 The recommended management of diarrhea in those taking immunotherapy is based on the same grading system with symptomatic management for grade 1. For grade 2, stool studies, diagnostic endoscopies, and treatment with steroids are indicated. The stool studies routinely obtained are fecal leukocytes, lactoferrin, calprotectin, stool cultures, and C. difficile testing. Pembrolizumab would also be held temporarily for grade 2. Grade 3 may require hospitalization, corticosteroids administration (initial dose of 1–2 mg/kg/d prednisone or equivalent), and infliximab for nonsteroidal cases along with temporarily hold of pembrolizumab. It can be resumed if diarrhea returns to grade 1. Permanent discontinuation of pembrolizumab and tapering steroids or infliximab are indicated for grade 4 diarrhea.2\n\nPD-1 is a protein receptor expressed on T cells, and PD-1 ligands (PD-L1) are expressed on tumor cells.6 PD-1/PD-L1 blockade with pembrolizumab leads to interruption of the inhibitory signals and upregulate the stimulatory signals to reactivate the immune T cells.6,7 This activation may involve one or multiple organs, leading to serious adverse events known as immune-related toxicities.5 Multiple case reports have identified the association between ICPI toxicities and immune-related gastrointestinal diseases such as enteritis, esophagitis, hepatitis, and colitis.2,5,8-10 However, in this case, a new type of toxicity is reported, which will broaden the differential for any immunotherapy-related diarrhea in the future.\n\nIt is not clear whether pembrolizumab withdrawal or steroid administration or even both helped with the resolution of symptoms as both events happened concurrently. More studies are recommended to illustrate the exact mechanism.\n\nThe usage of ICPIs has quickly emerged and expanded to treat many cancers. Their complete safety and toxicity profile are still to be identified. The authors advise health care providers to take into consideration etiologies other than pembrolizumab-induced colitis or enteritis in the evaluation of diarrhea in the setting of new-onset immunotherapy.\n\nDISCLOSURES\nAuthor contributions: J. Arnouk wrote the manuscript and is the article guarantor. D. Mathew, E. Nulton, and V. Rachakonda edited the manuscript.\n\nFinancial disclosure: None.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Rubio-Tapia A Hill ID Kelly CP Calderwood AH Murray JA ; American College of Gastroenterology . ACG clinical guidelines: Diagnosis and management of celiac disease . Am J Gastroenterol . 2013 ;108 (5 ):656 –76 ; quiz 677.23609613 \n2. Brahmer JR Lacchetti C Schneider BJ \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline . J Clin Oncol. \n2018 ;36 (17 ):1714 –68 .29442540 \n3. Gentile NM D'Souza A Fujii LL Wu TT Murray JA \nAssociation between ipilimumab and celiac disease . Mayo Clin Proc. \n2013 ;88 (4 ):414 –7 .23541015 \n4. Qiao SW Sollid LM Blumberg RS \nAntigen presentation in celiac disease . Curr Opin Immunol. \n2009 ;21 (1 ):111 –7 .19342211 \n5. Wang Y Abu-Sbeih H Mao E \nImmune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: Retrospective review at MD Anderson . J ImmunoTherapy Cancer. \n2018 ;6 (1 ):37 .\n6. Wu Z Lai L Li M Zhang L Zhang W \nAcute liver failure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer . Medicine . 2017 ;96 (51 ):e9431 .29390572 \n7. Toor SM Syed Khaja AS Alkurd I Elkord E \nIn-vitro effect of pembrolizumab on different T regulatory cell subsets . Clin Exp Immunol . 2017 ;191 (2 ):189 –97 .28963773 \n8. Eigentler TK Hassel JC Berking C \nDiagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy . Cancer Treat Rev . 2016 ;45 :7 –18 .26922661 \n9. Onuki T Morita E Sakamoto N Nagai Y Sata M Hagiwara K \nSevere upper gastrointestinal disorders in pembrolizumab-treated non-small cell lung cancer patient . Respirol Case Rep. \n2018 ;6 (6 ):e00334 .30065841 \n10. Acero Brand FZ Suter N Adam JP \nSevere immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab . J Immunother Cancer . 2018 ;6 (1 ):22 .29548299\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2326-3253",
"issue": "6(8)",
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"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00158",
"pmc": null,
"pmid": "31737699",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "29747688;23541015;23609613;29442540;29548299;19342211;26922661;28963773;30065841;29390572",
"title": "A Celiac Disease Phenotype After Checkpoint Inhibitor Exposure: An Example of Immune Dysregulation After Immunotherapy.",
"title_normalized": "a celiac disease phenotype after checkpoint inhibitor exposure an example of immune dysregulation after immunotherapy"
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"activesubstancename": "PEMBROLIZUMAB"
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... |
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"abstract": "Colchicine has been proposed as a treatment for COVID-19 based on its anti-inflammatory actions. We aimed to evaluate the efficacy and safety of colchicine in patients admitted to hospital with COVID-19.\n\n\n\nIn this streamlined, randomised, controlled, open-label trial, underway at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Patients were eligible for inclusion in the study if they were admitted to hospital with clinically suspected or laboratory confirmed SARS-CoV-2 infection and had no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Eligible and consenting adults were randomly assigned (1:1) to receive either usual standard of care alone (usual care group) or usual standard of care plus colchicine (colchicine group) using web-based simple (unstratified) randomisation with allocation concealment. Participants received colchicine 1 mg after randomisation followed by 500 μg 12 h later and then 500 μg twice a day by mouth or nasogastric tube for 10 days in total or until discharge. Dose frequency was halved for patients receiving a moderate CYP3A4 inhibitor (eg, diltiazem), patients with an estimated glomerular filtration rate of less than 30 mL/min per 1·73m2, and those with an estimated bodyweight of less than 70 kg. The primary outcome was 28-day mortality, secondary endpoints included time to discharge, the proportion of patients discharged from hospital within 28 days, and, in patients not on invasive mechanical ventilation at randomisation, a composite endpoint of invasive mechanical ventilation or death. All analyses were by intention-to-treat. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.\n\n\n\nBetween Nov 27, 2020, and March 4, 2021, 11 340 (58%) of 19 423 patients enrolled into the RECOVERY trial were eligible to receive colchicine; 5610 (49%) patients were randomly assigned to the colchicine group and 5730 (51%) to the usual care group. Overall, 1173 (21%) patients in the colchicine group and 1190 (21%) patients in the usual care group died within 28 days (rate ratio 1·01 [95% CI 0·93 to 1·10]; p=0·77). Consistent results were seen in all prespecified subgroups of patients. Median time to discharge alive (10 days [IQR 5 to >28]) was the same in both groups, and there was no significant difference in the proportion of patients discharged from hospital alive within 28 days (3901 [70%] patients in the colchicine group and 4032 [70%] usual care group; rate ratio 0·98 [95% CI 0·94 to 1·03]; p=0·44). In those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (1344 [25%] in the colchicine group vs 1343 [25%] patients in the usual care group; risk ratio 1·02 [95% CI 0·96 to 1·09]; p=0·47).\n\n\n\nIn adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.\n\n\n\nUK Research and Innovation (Medical Research Council), National Institute of Health Research, and Wellcome Trust.",
"affiliations": null,
"authors": "|||",
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"country": "England",
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"doi": "10.1016/S2213-2600(21)00435-5",
"fulltext": "\n==== Front\nLancet Respir Med\nLancet Respir Med\nThe Lancet. Respiratory Medicine\n2213-2600\n2213-2619\nElsevier\n\nS2213-2600(21)00435-5\n10.1016/S2213-2600(21)00435-5\nArticles\nColchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial\nRECOVERY Collaborative Group†\n† The writing committee and trial steering committee are listed at the end of this manuscript and a complete list of collaborators in the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is provided in the appendix (pp 2–25).\n\n1 12 2021\n12 2021\n9 12 14191426\n© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nSummary\n\nBackground\n\nColchicine has been proposed as a treatment for COVID-19 based on its anti-inflammatory actions. We aimed to evaluate the efficacy and safety of colchicine in patients admitted to hospital with COVID-19.\n\nMethods\n\nIn this streamlined, randomised, controlled, open-label trial, underway at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Patients were eligible for inclusion in the study if they were admitted to hospital with clinically suspected or laboratory confirmed SARS-CoV-2 infection and had no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Eligible and consenting adults were randomly assigned (1:1) to receive either usual standard of care alone (usual care group) or usual standard of care plus colchicine (colchicine group) using web-based simple (unstratified) randomisation with allocation concealment. Participants received colchicine 1 mg after randomisation followed by 500 μg 12 h later and then 500 μg twice a day by mouth or nasogastric tube for 10 days in total or until discharge. Dose frequency was halved for patients receiving a moderate CYP3A4 inhibitor (eg, diltiazem), patients with an estimated glomerular filtration rate of less than 30 mL/min per 1·73m2, and those with an estimated bodyweight of less than 70 kg. The primary outcome was 28-day mortality, secondary endpoints included time to discharge, the proportion of patients discharged from hospital within 28 days, and, in patients not on invasive mechanical ventilation at randomisation, a composite endpoint of invasive mechanical ventilation or death. All analyses were by intention-to-treat. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.\n\nFindings\n\nBetween Nov 27, 2020, and March 4, 2021, 11 340 (58%) of 19 423 patients enrolled into the RECOVERY trial were eligible to receive colchicine; 5610 (49%) patients were randomly assigned to the colchicine group and 5730 (51%) to the usual care group. Overall, 1173 (21%) patients in the colchicine group and 1190 (21%) patients in the usual care group died within 28 days (rate ratio 1·01 [95% CI 0·93 to 1·10]; p=0·77). Consistent results were seen in all prespecified subgroups of patients. Median time to discharge alive (10 days [IQR 5 to >28]) was the same in both groups, and there was no significant difference in the proportion of patients discharged from hospital alive within 28 days (3901 [70%] patients in the colchicine group and 4032 [70%] usual care group; rate ratio 0·98 [95% CI 0·94 to 1·03]; p=0·44). In those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (1344 [25%] in the colchicine group vs 1343 [25%] patients in the usual care group; risk ratio 1·02 [95% CI 0·96 to 1·09]; p=0·47).\n\nInterpretation\n\nIn adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.\n\nFunding\n\nUK Research and Innovation (Medical Research Council), National Institute of Health Research, and Wellcome Trust.\n==== Body\npmcIntroduction\n\nInflammation is a key feature of severe COVID-19. Markedly raised concentrations of inflammatory markers, such as C-reactive protein (CRP), ferritin, interleukin-6 (IL-6), and other cytokines, are observed in severe cases and are associated with poor outcomes.1, 2, 3, 4, 5 Inflammation is particularly prominent in the lung and vascular endothelium, and is commonly associated with extensive alveolar damage and thrombosis of large and small pulmonary vessels.6 Corticosteroids and IL-6 inhibitors have both been shown to reduce mortality in patients with severe COVID-19; Janus kinase (JAK) inhibitors accelerate improvement in clinical status.7, 8, 9, 10 Together these results show that inflammation is modifiable and anti-inflammatory regimens can improve clinical outcomes.\n\nInflammasomes are a key part of the innate immune response to SARS-CoV-2 infection. These cytosolic pattern recognition receptor systems are activated in response to detection of pathogens in the cytosol and stimulate the release of proinflammatory cytokines.11 In COVID-19, the degree of inflammasome activation, particularly the nucleotide binding domain (NOD)-like pyrin domain 3 (NLRP3) inflammasome, correlates with disease severity.12 Colchicine, a readily available, safe, and inexpensive drug, has a wide range of anti-inflammatory effects, including inhibition of the NLRP3 inflammasome.13 In addition to its role in treating acute gout and pericarditis, evidence is emerging that colchicine might inhibit endovascular inflammation and provide clinical benefits in patients with coronary artery disease.14, 15, 16, 17 Given the activation of NLRP3 in COVID-19 and the presence of vascular endothelial inflammation, colchicine has been proposed as a treatment for SARS-CoV-2 associated inflammatory disease. However, only three small randomised trials have assessed the effects of colchicine in hospitalised patients with COVID-19, with a total of only seven deaths across these studies combined; none of the studies were adequately powered to identify any effect of the drug on mortality.18, 19, 20 Here we report the results of a large randomised controlled trial that aimed to evaluate the efficacy and safety of colchicine in patients hospitalised with COVID-19.\n\nResearch in context\n\nEvidence before this study\n\nWe searched medRxiv, bioRxiv, Medline, Embase, and the WHO International Clinical Trials Registry Platform from Sept 1, 2019, to April 1, 2021, for clinical trials evaluating the effect of colchicine treatment in patients hospitalised with COVID-19, using the search terms (“SARS-CoV-2.mp” OR “COVID.mp” OR “COVID-19.mp” OR “2019-nCoV.mp” OR “Coronavirus.mp” OR “Coronavirinae/”) AND (“colchicine.mp” OR “colchicine/”), using validated filters to select for randomised controlled trials. No language restrictions were applied.\n\nWe identified three relevant randomised trials that compared colchicine with usual care or placebo in patients hospitalised with COVID-19 (two at low risk of bias and one with some concerns because of limited information on randomisation process and poor clarity regarding the blinding in the study). Each trial suggested a potential favourable effect of colchicine on outcome measures of clinical improvement or duration of hospitalisation. The three trials combined included a total of 285 patients and seven deaths; even combined, these trials were not adequately powered to detect an effect on mortality.\n\nAdded value of this study\n\nThe RECOVERY trial is the first large, randomised trial to report results of the effect of colchicine in patients hospitalised with COVID-19. We found no significant effect of colchicine compared with usual care alone on 28-day mortality, the probability of discharge alive within 28 days, or the probability of progressing to the composite outcome of invasive mechanical ventilation or death in patients who were not receiving invasive mechanical ventilation at randomisation. We saw no evidence of benefit of colchicine in any patient subgroup.\n\nImplications of all the available evidence\n\nThere is no good evidence that colchicine treatment is of clinical benefit for adults hospitalised with COVID-19 compared with current usual care.\n\nMethods\n\nStudy design and participants\n\nThe RECOVERY trial is an investigator-initiated, streamlined, individually randomised, controlled, open-label, platform trial to evaluate the effects of potential treatments in patients hospitalised with COVID-19. Details of the trial design and results for other possible treatments (dexamethasone,7 hydroxychloroquine,21 lopinavir–ritonavir,22 azithromycin,23 tocilizumab,9 and convalescent plasma24) have been published previously. The trial is underway at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal (appendix pp 3–25). The trial is supported by the National Institute for Health Research Clinical Research Network, and is coordinated by the Nuffield Department of Population Health (University of Oxford, Oxford, UK), the trial sponsor. The trial was done in accordance with the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (20/EE/0101). The protocol, statistical analysis plan, and additional information are available online.\n\nPatients admitted to hospital were eligible for the study if they had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Children and pregnant women were not eligible to receive colchicine. Patients with severe liver impairment, significant cytopaenia, concomitant use of strong CYP3A4 (eg, clarithromycin, erythromycin, systemic azole antifungal, and HIV protease inhibitor) or P-glycoprotein inhibitors (eg, ciclosporin, verapamil, and quinidine), or hypersensitivity to lactose were excluded from the colchicine comparison (appendix p 81). Written informed consent was obtained from all patients, or a legal representative if patients were too unwell or unable to provide consent.\n\nRandomisation and masking\n\nBaseline data were collected using a web-based case report form that included demographics, level of respiratory support, major comorbidities, suitability of the study treatment for a particular patient, and treatment availability at the study site (appendix pp 32–34). Eligible and consenting, non-pregnant adult patients were randomly assigned (1:1) to receive either usual standard of care (usual care group) or usual standard of care plus colchicine (colchicine group), or one of the other available RECOVERY treatment groups, using web-based simple (unstratified) randomisation with allocation concealed until after randomisation (appendix pp 30–31). For some patients, colchicine was unavailable at the hospital at the time of enrolment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from the randomised comparison between colchicine and usual care. Patients received colchicine 1 mg after randomisation followed by 500 μg 12 h later and then 500 μg twice a day orally or by nasogastric tube for 10 days in total or until discharge, whichever occurred first. Dose frequency was halved for patients receiving a moderate CYP3A4 inhibitor (eg, diltiazem), those who had renal impairment (estimated glomerular filtration rate <30 mL/min per 1·73 m2), and patients with an estimated bodyweight of less than 70 kg (appendix p 81).\n\nAs a platform trial, and in a factorial design, patients could be simultaneously randomly assigned to other treatment groups: 1) convalescent plasma versus casirivimab and imdevimab versus usual care, 2) aspirin versus usual care, and 3) baricitinib versus usual care (appendix p 31). Until Jan 24, 2021, the trial also allowed a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia and a hyperinflammatory state) to receive usual care plus tocilizumab or usual care alone. Participants and local study staff were not masked to the allocated treatment. The trial steering committee, investigators, and all other individuals involved in the trial were masked to outcome data during the trial.\n\nProcedures\n\nA single online follow-up form was completed when participants were discharged, had died, or 28 days after randomisation, whichever occurred first (appendix pp 35–41). Information was recorded on adherence to allocated study treatment, receipt of other COVID-19 treatments, duration of admission, receipt of respiratory or renal support, and vital status (including cause of death). In addition, in the UK, routine health-care and registry data were obtained, including information on vital status (with date and cause of death), discharge from hospital, receipt of respiratory support, or renal replacement therapy.\n\nOutcomes\n\nOutcomes were assessed 28 days after randomisation, with additional analyses specified at 6 months. The primary outcome was all-cause mortality. Secondary outcomes were time to discharge from hospital alive within 28 days and, in patients not on invasive mechanical ventilation at randomisation, receipt of invasive mechanical ventilation (including extracorporal membrane oxygenation) or death. Prespecified subsidiary clinical outcomes were use of non-invasive respiratory support, time to successful cessation of invasive mechanical ventilation (defined as cessation of invasive mechanical ventilation within, and survival to, 28 days), use of haemodialysis or haemofiltration, cause-specific mortality, bleeding events, thrombotic events, and major cardiac arrhythmias. Information on suspected serious adverse reactions was collected in an expedited fashion to comply with regulatory requirements.\n\nStatistical analysis\n\nThe primary analysis for all outcomes was assessed according to the intention-to-treat principle by comparing patients randomly assigned to the colchicine group with those who were randomly assigned to the usual care group, but for whom colchicine was both available and a suitable treatment. For the primary outcome, all-cause 28-day mortality, the log-rank observed minus expected statistic and its variance were used to test both the null hypothesis of equal survival curves (ie, the log-rank test) and to calculate the one-step estimate of the average mortality rate ratio. We used Kaplan-Meier survival curves to display cumulative mortality over the 28-day period. We used the same method to analyse time to hospital discharge and successful cessation of invasive mechanical ventilation, with patients who died in hospital right-censored on day 29. Median time to discharge was derived from Kaplan-Meier estimates. For the prespecified composite secondary outcome of progression to invasive mechanical ventilation or death within 28 days in those not receiving invasive mechanical ventilation at randomisation, and the subsidiary clinical outcomes of receipt of ventilation and use of haemodialysis or haemofiltration, the precise dates were not available and so the risk ratio was estimated.\n\nPrespecified analyses were done for the primary outcome using the statistical test of interaction (test for heterogeneity or trend), in accordance with the prespecified analysis plan, defined by characteristics at randomisation: age, sex, ethnicity, level of respiratory support, days since symptom onset, and use of corticosteroids (appendix p 115). An exploratory analysis of the primary outcome by CRP concentration at randomisation was done using a similar approach.\n\nEstimates of rate ratios and risk ratios are shown with 95% CIs. All p values are two-sided and are shown without adjustment for multiple testing. The full database is held by the study team, which collected the data from study sites and did the analyses at the Nuffield Department of Population Health, University of Oxford (Oxford, UK).\n\nAs stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the COVID-19 pandemic (appendix p 55). As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that sufficient patients should be enrolled to provide at least 90% power at a two-sided significance level of 0·01 to detect a clinically relevant proportional reduction in 28-day mortality of 12·5% between the two groups.\n\nOn March 4, 2021, the independent data monitoring committee did a routine review of the available safety and efficacy data. The independent data monitoring committee notified the chief investigators that there was no convincing evidence that continued recruitment to the colchicine comparison would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup. Consequently, recruitment to the colchicine comparison was closed on March 5, 2021, and preliminary results were made available to the public.\n\nAnalyses were done using SAS (version 9.4) and (R version 3.4). The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.\n\nRole of the funding source\n\nThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.\n\nResults\n\nBetween Nov 27, 2020, and March 4, 2021, 11 340 (58%) of 19 423 patients enrolled into the RECOVERY trial were eligible to receive colchicine (ie, colchicine was available in the hospital at the time of their admission and the attending clinician was of the opinion that the patient had no known indication for or contraindication to colchicine; figure 1). 5610 (49%) patients were randomly assigned to the colchicine group and 5730 (51%) were randomly assigned to the usual care group (36 [<1%] patients were randomly assigned in Nepal and Indonesia). The mean age of study participants was 63·4 years (SD 13·8), and the median time since symptom onset was 9 days (IQR 6–12; table 1; appendix p 44) in both groups. At randomisation, 10 603 (94%) of patients were receiving corticosteroids.Figure 1 Trial profile\n\nOf the 11 340 patients randomly assigned to receive colchicine or usual care, 7091 (63%; 3505 [62%] of the colchicine group vs 3586 [63%] of the usual care group) patients were additionally randomised to receive convalescent plasma or REGN–COV2 or usual care; 7545 (67%; 3747 [67%] of the colchicine group vs 3798 [66%] of the usual care group) patients were additionally randomised to receive aspirin or usual care; and 1635 (14%; 802 [14%] of the colchicine group vs 833 [15%] of the usual care group) patients were additionally randomised to receive baricitinib or usual care. *Number recruited overall during period that adult participants could be recruited into colchicine comparison. †Colchicine unavailable and colchicine unsuitable groups are not mutually exclusive. ‡5122 (93%) of 5510 patients with completed follow-up at time of analysis received colchicine. §20 (<1%) of 5605 patients with completed follow-up at time of analysis received colchicine. ¶Includes 251 (4%) of 5610 patients in the colchicine group and 306 (5%) of 5730 patients in the usual care group allocated to receive tocilizumab.\n\nTable 1 Baseline characteristics\n\n\t\tColchicine group (n=5610)\tUsual care group (n=5730)\t\nAge, years\t63·3 (13·8)\t63·5 (13·7)\t\nAge groups, years\t\n\t<70\t3806 (68%)\t3850 (67%)\t\n\t70 to <80\t1139 (20%)\t1227 (21%)\t\n\t≥80\t665 (12%)\t653 (11%)\t\nSex\t\n\tMale\t3897 (69%)\t4012 (70%)\t\n\tFemale\t1713 (31%)\t1718 (30%)\t\nEthnicity\t\n\tWhite\t4344 (77%)\t4383 (76%)\t\n\tBlack, Asian, and minority ethnic\t758 (14%)\t813 (14%)\t\n\tUnknown\t508 (9%)\t534 (9%)\t\nNumber of days since symptom onset\t9 (6–12)\t9 (6–12)\t\nNumber of days since admission to hospital\t2 (1–3)\t2 (1–3)\t\nRespiratory support received\t\n\tNone or simple oxygen\t3815 (68%)\t3962 (69%)\t\n\tNon-invasive ventilation\t1527 (27%)\t1507 (26%)\t\n\tInvasive mechanical ventilation\t268 (5%)\t261 (5%)\t\nLaboratory measurements\t\n\tC-reactive protein, mg/L\t86 (44–145)\t87 (46–144)\t\n\tCreatinine, μmol/L\t78 (64–96)\t78 (65–96)\t\nPrevious diseases\t\n\tDiabetes\t1426 (25%)\t1470 (26%)\t\n\tHeart disease\t1189 (21%)\t1231 (21%)\t\n\tChronic lung disease\t1208 (22%)\t1206 (21%)\t\n\tTuberculosis\t16 (<1%)\t13 (<1%)\t\n\tHIV\t11 (<1%)\t20 (<1%)\t\n\tSevere liver disease*\t0\t0\t\n\tSevere kidney impairment†\t170 (3%)\t166 (3%)\t\n\tAny of the above\t2880 (51%)\t2963 (52%)\t\nUse of corticosteroids\t\n\tYes\t5243 (93%)\t5360 (94%)\t\n\tNo\t363 (6%)\t365 (6%)\t\n\tMissing\t4 (<1%)\t5 (<1%)\t\nUse of remdesivir\t1235 (22%)\t1251 (22%)\t\nSARS-CoV-2 PCR test result\t\n\tPositive\t5456 (97%)\t5553 (97%)\t\n\tNegative\t57 (1%)\t58 (1%)\t\n\tUnknown\t97 (2%)\t119 (2%)\t\nData are mean (SD), n (%), or median (IQR). No children or pregnant women were randomised.\n\n* Defined as requiring ongoing specialist care.\n\n† Defined as estimated glomerular filtration rate less than 30 mL/min per 1·73 m2.\n\nThe follow-up form was completed for 5510 (98%) patients in the colchicine group and 5605 (98%) patients in the usual care group. Of the patients with a completed follow-up form, 5122 (93%) in the colchicine group received at least one dose of colchicine. Of those assigned to the colchicine group who received at least one dose, 3823 (75%) received all (or nearly all, missing at most 1 day of treatment) of their scheduled doses during their hospital stay; 4576 (90%) received at least half of their scheduled doses (figure 1; appendix p 45). The median duration of treatment with colchicine was 6 days (IQR 3–9). Use of other treatments for COVID-19 was similar between patients in both groups, with 9675 (87%) receiving a corticosteroid, 2542 (23%) receiving remdesivir, and 1485 (13%) receiving tocilizumab or sarilumab (appendix p 45).\n\nPrimary outcome data are known for 11282 (99%) of the randomly assigned patients. There was no significant difference in the proportion of patients who died within 28-days between the two groups (1173 [21%] patients in the colchicine group vs 1190 [21%] patients in the usual care group; rate ratio 1·01 [95% CI 0·93–1·10]; p=0·77; figure 2). We observed similar results across all prespecified subgroups (figure 3) and in an exploratory analysis by baseline CRP concentration (appendix p 49). In an exploratory analysis restricted to the 11 009 (97%) patients with a positive SARS-CoV-2 test result, the result was virtually identical to the overall result (rate ratio 1·02 [0·94–1·10]; p=0·70).Figure 2 Effect of allocation to colchicine on 28-day mortality\n\nFigure 3 Effect of allocation to colchicine on 28-day mortality by baseline characteristics\n\nEthnicity, days since onset, and use of corticosteroids subgroups exclude those with missing data, but these patients are included in the overall summary.\n\nThe median time to discharge from hospital alive was 10 days (IQR 5 to >28) in both groups, and there was no significant difference in the probability of being discharged alive within 28 days between the two groups (3901 [70%] patients in the colchicine group and 4032 (70%) usual care group; rate ratio 0·98 [95% CI 0·94 to 1·03]; p=0·44; table 2). Of the patients not on invasive mechanical ventilation at baseline, the number of patients progressing to the prespecified composite secondary outcome of invasive mechanical ventilation or death was similar in both groups (1344 [25%] in the colchicine group vs 1343 [25%] patients in the usual care group; risk ratio 1·02 [95% CI 0·96 to 1·09]; p=0·47). Similar results were seen in all prespecified subgroups of patients (appendix pp 50–51).Table 2 Effect of allocation to colchicine on key study outcomes\n\n\t\tColchicine group (n=5610)\tUsual care group (n=5730)\tRR (95% CI)\tp value\t\nPrimary outcome\t\n28-day mortality\t1173 (21%)\t1190 (21%)\t1·01 (0·93–1·10)\t0·77\t\nSecondary outcomes\t\nMedian time to being discharged alive, days\t10 (5 to >28)\t10 (5 to >28)\t..\t..\t\nDischarged from hospital within 28 days\t3901 (70%)\t4032 (70%)\t0·98 (0·94–1·03)\t0·44\t\nReceipt of invasive mechanical ventilation or death*\t1344/5342 (25%)\t1343/5469 (25%)\t1·02 (0·96–1·09)\t0·47\t\n\tInvasive mechanical ventilation\t600/5342 (11%)\t591/5469 (11%)\t1·04 (0·93–1·16)\t0·48\t\n\tDeath\t1053/5342 (20%)\t1070/5469 (20%)\t1·01 (0·93–1·09)\t0·85\t\nPrespecified subsidiary clinical outcomes\t\nReceipt of ventilation†\t852/3815 (22%)\t941/3962 (24%)\t0·94 (0·87–1·02)\t0·14\t\nNon-invasive ventilation\t818/3815 (21%)\t904/3962 (23%)\t0·94 (0·86–1·02)\t0·14\t\nInvasive mechanical ventilation\t259/3815 (7%)\t228/3962 (6%)\t1·18 (0·99–1·40)\t0·06\t\nSuccessful cessation of invasive mechanical ventilation‡\t88/268 (33%)\t81/261 (31%)\t1·01 (0·75–1·37)\t0·93\t\nUse of haemodialysis or haemofiltration§\t212/5570 (4%)\t203/5683 (4%)\t1·07 (0·88–1·29)\t0·51\t\nData are n (%) or n/N (%). RR=rate ratio for the outcomes of 28-day mortality, hospital discharge, and successful cessation of invasive mechanical ventilation, and risk ratio for other outcomes.\n\n* Analyses exclude those on invasive mechanical ventilation at randomisation.\n\n† Analyses exclude those on any form of ventilation at randomisation.\n\n‡ Analyses restricted to those on invasive mechanical ventilation at randomisation.\n\n§ Analyses exclude those on haemodialysis or haemofiltration at randomisation.\n\nWe found no significant differences in the prespecified subsidiary clinical outcomes of cause-specific mortality (appendix p 46), use of ventilation, successful cessation of invasive mechanical ventilation, or need for haemodialysis or haemofiltration (table 2). The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was also similar in the two groups (appendix p 47). There were two reports of a serious adverse reaction believed related to colchicine: one patient had severe acute kidney injury and one had rhabdomyolysis.\n\nDiscussion\n\nIn this large, randomised trial involving more than 11 000 patients from three countries and more than 2000 deaths, use of colchicine was not associated with a reduction in mortality, duration of hospitalisation, or the risk of being ventilated or dying for those not on ventilation at baseline. These results were consistent across the prespecified subgroups of age, sex, ethnicity, duration of symptoms before randomisation, level of respiratory support at randomisation, and use of corticosteroids.\n\nThe benefit of dexamethasone in patients with COVID-19 requiring respiratory support shows the importance of inflammation in this patient group and colchicine was proposed as a treatment for COVID-19 based on its anti-inflammatory activity.25 However, in this large, well powered trial, we found no evidence of a benefit from colchicine, which suggests that the anti-inflammatory properties of colchicine are either insufficient to produce a meaningful reduction in mortality risk or are not affecting the relevant inflammatory pathways in moderate-to-severe COVID-19. The protocol included a maximum of 10 days of treatment with colchicine. It is possible that a longer duration of therapy might have provided benefit, but most participants had stopped colchicine before 10 days either because of death, discharge from hospital, or at the discretion of the treating clinician. Although, most patients in this study received concomitant corticosteroid therapy, we saw no evidence that colchicine was beneficial in those patients not receiving a corticosteroid.\n\nStrengths of this trial included that it was randomised, had a large sample size, broad eligibility criteria, was international, and more than 99% of patients were followed up for the primary outcome of all-cause mortality. However, there are some limitations. Detailed information on laboratory markers of inflammation and immune response and information on radiological features was not collected; therefore, it is not possible to assess if the effect of treatment varied between such subgroups of patients. Although this randomised trial is open-label, the outcomes are unambiguous and were ascertained without bias through linkage to routine health records.\n\nThree other randomised controlled trials have assessed the efficacy of colchicine for the treatment of patients hospitalised with COVID-19.18, 19, 20 A two day shorter duration of hospitalisation was reported in a trial of 100 patients with laboratory confirmed SARS-CoV-2 infection and pulmonary involvement—confirmed by CT—who were randomly assigned to receive either hydroxychloroquine plus colchicine or hydroxychloroquine plus placebo.18 A second trial reported a reduced duration of hospitalisation and oxygen therapy in 36 patients hospitalised with COVID-19 allocated colchicine compared with 36 patients allocated usual care, which included hydroxychloroquine, azithromycin, and methylprednisolone.19 Finally, the GRECCO-19 trial20 reported a lower rate of clinical deterioration in 55 patients randomly assigned to receive colchicine compared with 50 patients randomly assigned to receive usual care, which did not include corticosteroids.20 The total number of patients in all three of these trials combined was 285, with seven deaths during the follow-up period, meaning that, even combined, these three studies are not able to reliably assess the effects of colchicine on mortality. By contrast, the RECOVERY trial, with more than 11 000 participants and more than 2000 deaths, had excellent power to detect modest treatment benefits; none were observed.\n\nThe RECOVERY trial only studied patients who had been hospitalised with COVID-19; therefore, we are not able to provide any evidence on the safety and efficacy of colchicine used in other patient groups. In the COLCORONA trial26 of 4488 non-hospitalised patients with laboratory confirmed or clinically suspected COVID-19, fewer patients in the colchicine group died or were hospitalised within 30 days of randomisation than in the placebo group. However, the trial was stopped before the scheduled sample size had been fully enrolled due to logistical reasons, and the result was not statistically significant (odds ratio 0·79 [95% CI 0·61–1·03]; p=0·081).26 Thus, the role of colchicine in treatment of COVID-19 in patients not requiring hospitalisation remains uncertain. Future trials in this setting are ongoing.27\n\nIn summary, the results of this large, randomised trial do not support the use of colchicine in adults hospitalised with COVID-19.\n\nCorrespondence to: Prof Peter W Horby and Prof Martin J Landray, RECOVERY Central Coordinating Office, Oxford OX3 7LF, United Kingdom. recoverytrial@ndph.ox.ac.uk\n\nData sharing\n\nThe protocol, consent form, statistical analysis plan, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, and other relevant study materials are available online. As described in the protocol (appendix 2), the trial Steering Committee will facilitate the use of the study data and approval will not be unreasonably withheld. Deidentified participant data will be made available to bona fide researchers registered with an appropriate institution within 3 months of publication. However, the Steering Committee will need to be satisfied that any proposed publication is of high quality, honours the commitments made to the study participants in the consent documentation and ethical approvals, and is compliant with relevant legal and regulatory requirements (eg, relating to data protection and privacy). The Steering Committee will have the right to review and comment on any draft manuscripts prior to publication. Data will be made available in line with the policy and procedures described online. Those wishing to request access should complete the online form and sent to data.access@ndph.ox.ac.uk\n\nDeclaration of interests\n\nWe declare no competing interests.\n\nSupplementary Material\n\nSupplementary appendix\n\nAcknowledgments\n\nWe would like to thank the thousands of patients who participated in this trial. We would also like to thank the many doctors, nurses, pharmacists, other allied health professionals, and research administrators at 177 NHS hospital organisations across the whole of the UK, supported by staff at the National Institute of Health Research (NIHR) Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure Anonymised Information Linkage at University of Swansea, Swansea, UK, and the NHS in England, Scotland, Wales and Northern Ireland. The RECOVERY trial is supported by grants to the University of Oxford, Oxford, UK, from UK Research and Innovation and NIHR (MC_PC_19056), the Wellcome Trust (222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator, and by core funding provided by the NIHR Oxford Biomedical Research Centre, Oxford, UK, the Wellcome Trust, the Bill and Melinda Gates Foundation, the Foreign, Commonwealth and Development Office, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. TJ is supported by a grant from UK Medical Research Council (MC_UU_0002/14) and an NIHR Senior Research Fellowship (NIHR-SRF-2015-08-001). WSL is supported by core funding provided by NIHR Nottingham Biomedical Research Centre, Nottingham, UK. Combiphar (Jakarta, Indonesia) supplied colchicine free of charge for use in this trial in Indonesia. Tocilizumab was provided free of charge for this trial by Roche (Basel, Switzerland). REGN-COV2 was provided free of charge for this trial by Regeneron (Tarrytown, NY, USA). Convalescent plasma was collected by NHS Blood and Transplant, the Scottish National Blood Transfusion Service, Welsh Blood Service, Northern Ireland Blood Transfusion Service and funded by the Department of Health and Social Care through core funding and funding under COVID-19 and EU SoHo Grant. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health and Social Care.\n\nContributors\n\nThis manuscript was initially drafted by the PWH and MJL, developed by the Writing Committee, and approved by all members of the trial steering committee. PWH and MJL vouch for the data and analyses, and for the fidelity of this report to the study protocol and data analysis plan. PWH, JKB, MB, LCC, JD, SNF, TJ, EJ, KJ, WSL, AMo, AMu, KR, GT, MM, RH, and MJL designed the trial and study protocol. MM, MC, G P-A, LP, MW, LW, ST, BC, CW, CG, PH, BP, TG, and AW—the Data Linkage team at the RECOVERY Coordinating Centre—and the Health Records and Local Clinical Centre staff—listed in the appendix (pp 2–25)—collected the data. ES, NS, and JRE accessed and verified the data and did the statistical analysis. All authors contributed to data interpretation and critical review and revision of the manuscript. PWH and MJL had access to the study data and had final responsibility for the decision to submit for publication.\n\nWriting Committee (on behalf of the RECOVERY Collaborative Group)\n\nPeter W Horby, Mark Campbell, Enti Spata, Jonathan R Emberson, Natalie Staplin, Guilherme Pessoa-Amorim, Leon Peto, Martin Wiselka, Laura Wiffen, Simon Tiberi, Ben Caplin, Caroline Wroe, Christopher Green, Paul Hine, Benjamin Prudon, Tina George, Andrew Wight, J Kenneth Baillie, Buddha Basnyat, Maya Buch, Lucy C Chappell, Jeremy Day, Saul N Faust, Raph L Hamers, Thomas Jaki, Edmund Juszczak, Katie Jeffery, Wei Shen Lim, Alan Montgomery, Andrew Mumford, Kathryn Rowan, Guy Thwaites, Marion Mafham, Richard Haynes, and Martin J Landray. Peter W Horby, Mark Campbell, and Enti Spata contributed equally. Marion Mafham, Richard Haynes, and Martin J Landray contributed equally.\n\nData Monitoring Committee\n\nPeter Sandercock, Janet Darbyshire, David DeMets, Robert Fowler, David Lalloo, Mohammed Munavvar (from January 2021), and Ian Roberts (until December 2020), Janet Wittes.\n==== Refs\nReferences\n\n1 Huang C Wang Y Li X Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 2020 497 506 31986264\n2 Ruan Q Yang K Wang W Jiang L Song J Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Intensive Care Med 46 2020 846 848 32125452\n3 Wang JH Chen RD Yang HK Inflammation-associated factors for predicting in-hospital mortality in patients with COVID-19 J Med Virol 93 2021 2908 2917 33393678\n4 Thwaites RS Sanchez Sevilla Uruchurtu A Siggins MK Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19 Sci Immunol 6 2021 eabg9873 33692097\n5 McElvaney OJ McEvoy NL McElvaney OF Characterization of the inflammatory response to severe COVID-19 illness Am J Respir Crit Care Med 202 2020 812 821 32584597\n6 Dorward DA Russell CD Um IH Tissue-specific immunopathology in fatal COVID-19 Am J Respir Crit Care Med 203 2021 192 201 33217246\n7 RECOVERY Collaborative GroupHorby P Lim WS Dexamethasone in hospitalized patients with Covid-19 N Engl J Med 384 2021 693 704 32678530\n8 Sterne JAC Murthy S Diaz JV Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis JAMA 324 2020 1330 1341 32876694\n9 RECOVERY Collaborative Group Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial Lancet 397 2021 1637 1645 33933206\n10 Kalil AC Patterson TF Mehta AK Baricitinib plus remdesivir for hospitalized adults with Covid-19 N Engl J Med 384 2020 795 807 33306283\n11 Broz P Dixit VM Inflammasomes: mechanism of assembly, regulation and signalling Nat Rev Immunol 16 2016 407 420 27291964\n12 Rodrigues TS de Sa KSG Ishimoto AY Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients J Exp Med 218 2021 e20201707 33231615\n13 Dalbeth N Lauterio TJ Wolfe HR Mechanism of action of colchicine in the treatment of gout Clin Ther 36 2014 1465 1479 25151572\n14 Fiolet ATL Opstal TSJ Mosterd A Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials Eur Heart J 42 2021 2765 2775 33769515\n15 Martinez GJ Celermajer DS Patel S The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation Atherosclerosis 269 2018 262 271 29352570\n16 Imazio M Brucato A Cemin R A randomized trial of colchicine for acute pericarditis N Engl J Med 369 2013 1522 1528 23992557\n17 Tardif JC Kouz S Waters DD Efficacy and safety of low-dose colchicine after myocardial infarction N Engl J Med 381 2019 2497 2505 31733140\n18 Salehzadeh F Pourfarzi F Ataei S The impact of colchicine on the COVID-19 patients; a clinical trial study Research Square 2020 published online Sept 21. 10.21203/rs.3.rs-69374/v1 (preprint).\n19 Lopes MI Bonjorno LP Giannini MC Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial RMD Open 7 2021 e001455 33542047\n20 Deftereos SG Giannopoulos G Vrachatis DA Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial JAMA Netw Open 3 2020 e2013136 32579195\n21 RECOVERY Collaborative GroupHorby P Mafham M Effect of hydroxychloroquine in hospitalized patients with Covid-19 N Engl J Med 383 2020 2030 2040 33031652\n22 RECOVERY Collaborative Group Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial Lancet 396 2020 1345 1352 33031764\n23 RECOVERY Collaborative Group Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial Lancet 397 2021 605 612 33545096\n24 RECOVERY Collaborative Group Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial Lancet 397 2021 2049 2059 34000257\n25 Deftereos SG Siasos G Giannopoulos G The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design Hellenic J Cardiol 61 2020 42 45 32251729\n26 Tardif J-C Bouabdallaoui N L'Allier PL Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial Lancet Respir Med 9 2021 924 932 34051877\n27 University of Oxford PRINCIPLE COVID-19 treatments trial widens to under 50s and adds colchicine. 2021 https://www.principletrial.org/news/principle-covid-19-treatments-trial-widens-to-under-50s-adds-colchicine\n\n",
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"journal": "The Lancet. Respiratory medicine",
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"title": "Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.",
"title_normalized": "colchicine in patients admitted to hospital with covid 19 recovery a randomised controlled open label platform trial"
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"abstract": "Physiologic changes of pregnancy and cystic fibrosis pathology provide a unique set of circumstances. Pulmonary disease accounts for over 90% of the morbidity and mortality of patients with cystic fibrosis. These abnormalities create anesthetic challenges due to multiple organ systems being affected including the respiratory, gastrointestinal, cardiovascular, and genitourinary tracts, where patients present with chronic respiratory failure, pancreatic insufficiency, poor nutrition, and cardiac manifestations. We present the perianesthetic management of a parturient with cystic fibrosis who successfully underwent preterm cesarean delivery under neuraxial anesthesia with preemptive bilateral femoral venous sheaths placed for potential extracorporeal membrane oxygenation (ECMO) initiation.",
"affiliations": "Department of Anesthesiology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami 33136, FL, USA.;Department of Anesthesiology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami 33136, FL, USA.;Department of Anesthesiology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami 33136, FL, USA.;Department of Anesthesiology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami 33136, FL, USA.",
"authors": "Franklin Dos Santos|Thais|T|;Rabassa|Andrea|A|;Aljure|Oscar|O|;Zbeidy|Reine|R|https://orcid.org/0000-0002-6963-885X",
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"doi": "10.1155/2020/8814729",
"fulltext": "\n==== Front\nCase Rep Anesthesiol\nCase Rep Anesthesiol\nCRIA\nCase Reports in Anesthesiology\n2090-6382 2090-6390 Hindawi \n\n10.1155/2020/8814729\nCase Report\nPerioperative Management and Preemptive ECMO Cannulation of a Parturient with Cystic Fibrosis Undergoing Cesarean Delivery\nFranklin Dos Santos Thais Rabassa Andrea Aljure Oscar https://orcid.org/0000-0002-6963-885XZbeidy Reine rzbeidy@med.miami.edu Department of Anesthesiology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami 33136, FL, USA\nAcademic Editor: Anjan Trikha\n\n\n2020 \n4 12 2020 \n2020 881472920 5 2020 13 11 2020 24 11 2020 Copyright © 2020 Thais Franklin Dos Santos et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Physiologic changes of pregnancy and cystic fibrosis pathology provide a unique set of circumstances. Pulmonary disease accounts for over 90% of the morbidity and mortality of patients with cystic fibrosis. These abnormalities create anesthetic challenges due to multiple organ systems being affected including the respiratory, gastrointestinal, cardiovascular, and genitourinary tracts, where patients present with chronic respiratory failure, pancreatic insufficiency, poor nutrition, and cardiac manifestations. We present the perianesthetic management of a parturient with cystic fibrosis who successfully underwent preterm cesarean delivery under neuraxial anesthesia with preemptive bilateral femoral venous sheaths placed for potential extracorporeal membrane oxygenation (ECMO) initiation.\n==== Body\n1. Introduction\nCystic fibrosis (CF) is an autosomal recessive disease that currently affects at least 30,000 people in the United States [1]. Manifestations include severe pulmonary compromise, pancreatic insufficiency, diabetes mellitus, and poor nutrition, leading to increased mortality. Since the 1930s when CF was first described, advances in preventative measures and treatment significantly improved the poor prognosis and increased these patients' life expectancies from a median of 5 years to around 30 years old [1]. As a result, more women survive to an age where they can consider starting their own families [2].\n\nThe normal physiologic changes of pregnancy and CF pathology provide a unique set of circumstances. In CF, patients inherit a mutation on the long arm of chromosome 7 that encodes a chloride channel called the CF transmembrane regulator (CFTR). Defective CFTRs lead to a buildup of viscous secretions and pathologic changes to multiple organ systems including the respiratory, gastrointestinal, cardiovascular, and genitourinary tracts. Pulmonary disease is the source of over 90% of the morbidity and mortality of these patients [2]. In pregnancy, additional changes affect the lungs. The enlarged uterus displaces the diaphragm upwards, which decreases total lung capacity and residual volume. Cardiac output, blood volume, and minute ventilation increase [3]. One of the most important goals in anesthetic management is to prevent respiratory decompensation since this is the most common cause of death [2].\n\nThis case report describes a 21-year-old parturient with CF who presented with multiple predictors of a poor outcome including a severely decreased FEV1, frequent pulmonary infections, diabetes mellitus, and pancreatic insufficiency [2], undergoing cesarean delivery. It examines the cardiovascular implications of this increasing patient population focusing on perioperative ECMO use and backup noninvasive ventilation [4]. Written consent for this report has been obtained from the patient.\n\n2. Case Report\nA 21-year-old primigravida with cystic fibrosis presented for elective cesarean delivery at 34 weeks' gestation. Before becoming pregnant, she suffered recurrent chest infections requiring two to four courses of intravenous (IV) antibiotics per year and her sputum was chronically colonized with Pseudomonas aeruginosa, Stenotrophomonas, and MRSA. Her comorbidities included Class A1 diabetes mellitus, pancreatic insufficiency, and chronic hypoxemic respiratory failure on chronic prednisone 2.5 mg daily, requiring 4 L/min home oxygen at night with nasal cannula (NC). Throughout pregnancy, she required additional oxygen during the day at 2–3 L/min. Her baseline FEV1 was 27% of predicted. She denied any history of cardiac disease. She met lung transplantation criteria due to FEV1 <30% and recurrent exacerbations requiring IV antibiotics, which would be pursued following her delivery.\n\nShe was counselled at 11 weeks' gestation regarding the risk of serious worsening of her lung function but decided to continue with the pregnancy. At 24 weeks' gestation, she was admitted with deteriorating respiratory function (forced expiratory volume in one second (FEV1) 0.64 L, 21% of predicted) and shortness of breath. She was treated with IV antibiotics and intensive chest physiotherapy. On discharge, fifteen days later, her lung function had returned to baseline.\n\nA multidisciplinary meeting was organized with maternal-fetal medicine, obstetric anesthesiology, pulmonology, MICU, cardiac anesthesiology, cardiothoracic surgery, and NICU. Due to her poor lung function, pulmonology advised against normal vaginal delivery. The anesthetic plan was to prevent pulmonary decompensation and to avoid intubation because of the high likelihood of prolonged mechanical ventilation postoperatively. The patient would receive neuraxial anesthesia with general anesthesia as backup. A cardiac anesthesiologist would be available to assist with management and to perform intraoperative transthoracic or transesophageal echocardiogram if needed. Preemptive bilateral femoral sheath placement in preparation for possible cannulation for venovenous extracorporeal membrane oxygenation (ECMO) was also planned in case of intraoperative or postoperative decompensation. A low Pfannenstiel incision was planned and the MICU team arranged for postoperative ICU placement for close monitoring.\n\nA cesarean section was scheduled at 34 weeks of gestation, to avoid further deterioration in her lung function, because fetal growth began to slowdown and the mother started to lose weight. She was admitted six days before surgery weighing 53 kg. She received dexamethasone for fetal lung maturation, and a routine echocardiogram was performed at this stage which showed no evidence of pulmonary hypertension. Her diabetes was well controlled with insulin sliding scale. Chest physiotherapy continued 3 times a day. She was on amoxicillin/clavulanate for positive H. influenza sputum cultures, and she was switched to cefepime and aztreonam on admission and continued her home nebulization treatments with albuterol, dornase alfa, and acetylcysteine.\n\nOn the day of surgery, she received her bronchodilators and mucolytics and she was transferred to the OR after her hyperreactive airway symptoms subsided following chest physiotherapy. She was also premedicated with 30 mL of oral sodium citrate and 10 mg of IV metoclopramide. In the OR, a BiPAP machine, a high flow nasal cannula, and a bronchoscopy cart were readily available.\n\nMonitoring consisted of pulse oximetry, electrocardiogram, capnography, and direct intra-arterial blood pressure measurement after an arterial line was placed. Two 18-gauge peripheral cannulas were sited intravenously. A modified combined spinal-epidural was performed in the sitting position at L4-L5, with 9 mg of bupivacaine 0.75%, 15 mcg of fentanyl, and 100 mcg of preservative-free morphine given intrathecally. An epidural catheter was left in place. Only 9 mg of bupivacaine was administered aiming to slowly build a T5 sensory level with epidural medication and start placement of femoral sheaths simultaneously. Instead, the patient quickly developed a T2 sensory level but had nonlabored breathing on NC at 4 L/min and tolerated the anesthesia well. Phenylephrine (50 mcg/mL) infusion was started after injecting the intrathecal medications at a rate of 20 mcg/kg/min and titrated to keep MAP above 90. The patient was positioned laying on a wedge pillow, with her back up 30 degrees, because she could not tolerate lying supine. Oxygen was continued via a NC 4 L/min, and oxygen saturations were maintained above 95%. Arterial blood gas obtained after supine position showed pO2 of 104 mmHg, no acid-base imbalances, and hematocrit of 31%.\n\nBilateral femoral veins were cannulated with 16-gauge introducer sheaths, which would allow for rapid cannulation for ECMO if necessary. The patient received 2 g of cefazolin IV for surgical prophylaxis, and surgery was started. Shortly after incision, a female neonate was delivered with Apgar scores of 9 at 1, 5, and 10 minutes. Oxytocin infusion was started immediately after delivery and continued during the case. 15 minutes following delivery, the patient's oxygen saturation dropped to low 90 s and a Venturi mask at 10 L/min was temporarily required to improve her oxygen saturation, in addition to elevating the back of the bed. The patient received 1 g of acetaminophen and 30 mg of ketorolac IV as part of a multimodal pain regimen, and bilateral transversus abdominis plane (TAP) blocks with 266 mg of liposomal bupivacaine were performed in the OR following the end of surgery. Estimated blood loss was 600 mL. A final arterial blood gas again showed no acid-base disorders, pO2 was 114 mmHg, and hematocrit was 29%. The epidural catheter was removed at the end of the case, and the patient was transferred in stable condition on 4 L NC to a medical ICU for close monitoring.\n\nShe was placed on scheduled IV acetaminophen and ketorolac and reported excellent pain control with no supplemental opioids. Chest physiotherapy was resumed the same day. On postoperative day 1, the femoral sheaths were removed, subcutaneous heparin was started for deep venous thrombosis prophylaxis, the patient was ambulating, and she was transferred out of the ICU. While she remained inpatient, she continued to report significant improvement of the dyspnea. On the fifth postoperative day, she had no oxygen requirements on a six-minute walk test and her chest X-ray was stable, and on the following day, she was discharged home.\n\n3. Discussion\nImproved prognosis for CF patients means more women are surviving into their reproductive years. Both CF and pregnancy provide interesting physiologic and pathologic conditions. These changes negatively affect patients depending on several factors that predict poor outcome. The most reliable predictor is prepregnancy FEV1 [3, 5]. Although successful delivery is possible in a patient with the baseline FEV1 of 17% predicted [6], CF parturients with baseline FEV1 <60% are at higher risk for complications [3]. Other significant factors include frequent pulmonary infections, especially with Burkholderia cepacia, BMI <18 kg/m2, poor weight gain, pancreatic insufficiency, CF-related diabetes, pulmonary hypertension, and cor pulmonale [2, 3, 5]. These factors together may predispose patients to the most common cause of morbidity and mortality and respiratory deterioration [2, 7]. In addition to that, the increase in circulating blood volume and cardiac output that occur in pregnancy may lead to right heart strain and right heart failure in the setting of moderate to severe pulmonary disease [8].\n\nPregnant CF patients who may not tolerate the respiratory demands of labor or reaching full term may require scheduled cesarean section [2]. The choice for timing of delivery should balance the risks of respiratory complications to the mother and the risks of prematurity to the baby [9]. This decision should involve the mother and a multidisciplinary team. These patients should be managed in a tertiary center during the perinatal period by a maternal-fetal medicine team in consultation with pulmonology, cardiology, respiratory therapy, obstetric anesthesiology, and NICU for optimal care. Management of diabetes and nutritional deficiency, optimization of respiratory function, and management as well as prophylaxis of pulmonary exacerbations should be addressed during the prenatal period [10].\n\nAmong the cardiac complications in CF, cor pulmonale and pulmonary hypertension are the most concerning. Even pediatric CF patients have early signs of potential cardiac impairment, and in the Adult population, changes can be found in the left and right ventricular function. Inflammation and hypoxemia seem to play an important role in the development of these changes [11, 12]. Several studies suggest that cor pulmonale and pulmonary hypertension are absolute contraindications for pregnancy in CF women [4, 13]. Increased pressure in the right ventricle can cause right ventricular dysfunction, tricuspid regurgitation, and, in severe cases, death. Women with pulmonary hypertension before pregnancy may also have right ventricular hypertrophy or arrhythmias [14]. Strong data specifically linking cor pulmonale to poor outcomes in CF pregnant women could not be located. However, the mortality in parturients with pulmonary hypertension is around 30% [14–16]. A systematic review reported a mortality rate of 17–33% and recommended discussing termination with patients if pregnancy occurs [16]. Screening patients with CF with an echocardiogram during prenatal care is very important. This patient fortunately had a normal echocardiogram.\n\nThe common goal in the anesthetic care of all CF patients is to avoid pulmonary deterioration [2]. Regardless of the anesthetic technique, these patients should have recent pulmonary function tests and they should receive their usual treatment with inhalers and mucolytics as well as chest physical therapy in the preoperative period. Premedication with antacid and/or H2 blockers and prokinetic agents should be considered since gastroesophageal reflux is common in pregnancy and aspiration would be catastrophic in a CF patient.\n\nGeneral anesthesia should be avoided when possible due to its potential to worsen lung function [16]. CF patients are more prone to have obstructive physiology with air trapping and intrinsic PEEP, and they are at risk for barotrauma, bronchospasm, and pneumothorax with invasive mechanical ventilation (IMV) [17]. In the presence of cor pulmonale, positive pressure ventilation during induction and maintenance of anesthesia can have serious deleterious effects in hemodynamics. Clearance of secretions would also be a challenge during IMV in CF. In addition to that, IMV in the setting of acute respiratory failure in a CF patient could result in chronic dependency of mechanical ventilation. For all these reasons, neuraxial anesthesia was chosen for our patient.\n\nIn this case, a modified combined spinal-epidural neuraxial technique was preferred for slow titration of the anesthetic level. A goal sensory level of T6 instead of the routine goal of T4 was chosen due to its success in previous cases and in order to minimize the possible impact in intercostal musculature and thus in the ventilation dynamics [7, 18]. This anesthesia technique also had the advantage of allowing for administration of neuraxial morphine. Despite low dose of intrathecal hyperbaric bupivacaine, this patient developed a T2 level to cold, but her respiratory function did not significantly deteriorate. The patient was kept in a semi-sitting position to additionally increase respiratory compliance. Strategies to avoid intubation included having humidified Venturi mask, high-flow nasal cannula, and BiPAP available as alternatives to escalate noninvasive ventilation (NIMV). A bronchoscopy cart was also available for management of lower airway obstruction with secretions after intubation and IMV if needed. Arterial line placement should be considered for either neuraxial or general anesthesia for continuous monitoring and for frequent arterial blood gases. Having a cardiac anesthesiologist available to assist with management and with transesophageal echocardiogram if significant intraoperative clinical deterioration may be helpful.\n\nExtracorporeal membrane oxygenation (ECMO) can be a strategy used as a bridge to lung transplant or to recovery in a carefully selected CF population. ECMO continues to be considered a relative contraindication for lung transplant in CF patients [19]; however, there have been technical advances in this area and positive outcomes [20]. A retrospective review of the Extracorporeal Life Support Organization (ESLO) Registry reported that 52% of CF patients survived their ECMO run and there was no difference in survival when venovenous (VV) and venoarterial (VA) ECMO were compared [20, 21]. ECMO use in CF patients is more often discussed as a controversial bridge to transplantation when ventilatory support is insufficient [17, 20–23]. The respiratory indications for transplantation in CF are severe respiratory disease with FEV1 <30%, type 1 or 2 respiratory failure, and recurrent pneumothoraces or hemoptysis not responsive to treatment [23]. A retrospective analysis of the United Network for Organ Sharing database suggested that patients on ECMO with spontaneous breathing had improved survival compared with other bridging strategies [24]. ECMO is also associated with possible serious complications such as hemorrhage, vascular rupture, infection, and failure of other organs, and some studies argue that these risks and the high mortality rate associated with ECMO outweigh its benefits [20, 21].\n\nThe data on use of ECMO for the obstetric population with CF are extremely limited. These patients may present rapid deterioration due to exacerbations of their baseline pathology combined with the expected physiologic changes inherent to the peripartum period, and ECMO may play an important role in the acute respiratory failure phase. The selection of the type of ECMO should be considered ahead of time. VV ECMO could potentially be a better option if the need for ECMO is pure ventilatory secondary to progression of pulmonary disease. On the other hand, VA ECMO can be beneficial when cor pulmonale is present. In our case, the possibility of an emergency lung transplant was thoroughly discussed with the patient and cardiothoracic surgery was consulted to participate in her care. In this scenario, bilateral femoral venous sheaths were placed after neuraxial procedure and prior to starting surgery in preparation for potential cannulation and VV ECMO initiation. It was determined that this approach was less invasive than preemptive cannulation while providing access, so cannulation could be performed rapidly if needed.\n\nPain control is a major concern in the peripartum period of a CF patient. These patients should have optimal analgesia in order to continue chest physical therapy, to be able to cough and clear secretions, to maintain their respiratory dynamics, and to be able to mobilize early. A multimodal pain regimen as an opioid sparing strategy should be applied to reduce the risk of opioid-induced respiratory depression [2, 17]. Our patient received low-dose intrathecal morphine as it is the gold standard option for postcesarean analgesia with the benefit of providing less sedation and lower early postoperative total opioid consumption than systemic opioids [25]. Intraoperatively she received acetaminophen and ketorolac, and immediately after surgery she received bilateral TAP blocks with liposomal bupivacaine with the goal of prolonged postoperative analgesia and decreased overall opioid consumption. Using the epidural catheter would also be a good option as part of the regimen for postoperative analgesia, but this was not logistically feasible in our institution.\n\nThese patients should be closely monitored in the early postoperative phase in an ICU with availability of NIMV and IMV [18]. Maintenance of their respiratory treatment regimen, antibiotic regimen for treatment, or prophylaxis of infections as well as pain control and thromboprophylaxis are very important considerations. Our patient was immediately transferred to a medical ICU where she was followed by all the teams involved in her preoperative care, she maintained good saturations, she continued chest physical therapy with no problems, and she reported significant improvement of the dyspnea as well as excellent pain control with no supplemental opioids. She was discharged from the ICU on postoperative day 1, and she was later able to go home with no complications.\n\n4. Conclusion\nCF is a multifaceted, chronic, and life-threatening disease. With the advances in therapy, more CF patients are living until reproductive age, but the mortality remains very high [22]. Our case highlights the value of multidisciplinary management with optimization of the patient as well as thorough planning to prevent and manage complications and improve outcomes, in addition to screening for cardiovascular changes and the considerations for ECMO as a backup plan along with the limitations in the literature showing a need for further research in the area.\n\n5. Authors' Contribution\nThais Franklin Dos Santos helped manage the patient, conduct the background research, and write the manuscript. Andrea Rabassa helped manage the patient, conduct the background research, and write the manuscript. Oscar Aljure helped write and edit manuscript. Reine Zbeidy helped manage the patient, conduct the background research, and write the manuscript.\n\nAdditional Points\nCystic fibrosis is associated with multiple organ systems being affected including the respiratory, gastrointestinal, cardiovascular, and genitourinary tracts. Anesthetic challenges augmented in pregnant patients with cystic fibrosis. Multidisciplinary planning is needed for successful outcome in these patients.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\n1 Marshall B. C. Cystic Fibrosis Foundation Patient Registry 2018 Annual Data Report 2019 Bethesda, MD, USA Cystic Fibrosis Foundation \n2 Huffmyer J. L. Littlewood K. E. Nemergut E. C. Perioperative management of the adult with cystic fibrosis Anesthesia & Analgesia 2009 109 6 1949 1961 10.1213/ANE.0b013e3181b845d0 2-s2.0-73949084809 19923526 \n3 Geake J. Tay G. Callaway L. Bell S. C. Pregnancy and cystic fibrosis: approach to contemporary management Obstetric Medicine 2014 7 4 147 155 10.1177/1753495X14554022 2-s2.0-84911970578 27512443 \n4 Edenborough F. P. Borgo G. Knoop C. Guidelines for the management of pregnancy in women with cystic fibrosis Journal of Cystic Fibrosis 2008 7 S2 S32 10.1016/j.jcf.2007.10.001 2-s2.0-37449031999 18024241 \n5 Lau E. M. T. Moriarty C. Ogle R. Bye P. T. Pregnancy and cystic fibrosis Paediatric Respiratory Reviews 2010 11 2 90 94 10.1016/j.prrv.2010.01.008 2-s2.0-77952241136 20416544 \n6 Cameron A. J. D. Skinner T. A. J. Management of a parturient with respiratory failure secondary to cystic fibrosis Anaesthesia 2005 60 1 77 80 10.1111/j.1365-2044.2004.03973.x 2-s2.0-11444253707 15601277 \n7 Muammar M. Marshall P. Wyatt H. Skelton V. Caesarean section in a patient with cystic fibrosis International Journal of Obstetric Anesthesia 2005 14 1 70 73 10.1016/j.ijoa.2004.08.003 2-s2.0-14844337479 15627546 \n8 Elkus R. Popovich J. Respiratory physiology in pregnancy Clinics in Chest Medicine 1992 13 4 555 565 1478018 \n9 Bose D. Yentis S. M. Fauvel N. J. Caesarean section in a parturient with respiratory failure caused by cystic fibrosis Anaesthesia 1997 52 6 578 582 10.1111/j.1365-2222.1997.132-az0128.x 2-s2.0-0030918355 9203887 \n10 Mcardle J. R. Pregnancy in cystic fibrosis Clinics in Chest Medicine 2011 32 1 111 120 10.1016/j.ccm.2010.10.005 2-s2.0-79251491342 21277453 \n11 Giacchi V. Rotolo N. Amato B. Heart involvement in children and adults with cystic fibrosis: correlation with pulmonary indexes and inflammation markers Heart, Lung and Circulation 2015 24 10 1002 1010 10.1016/j.hlc.2015.03.006 2-s2.0-84942196561 \n12 Labombarda F. Saloux E. Brouard J. Bergot E. Milliez P. Heart involvement in cystic fibrosis: a specific cystic fibrosis-related myocardial changes? Respiratory Medicine 2016 118 31 38 10.1016/j.rmed.2016.07.011 2-s2.0-84978712534 27578468 \n13 Edenborough F. P. Mackenzie W. E. Stableforth D. E. The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977–1996 BJOG: An International Journal of Obstetrics and Gynaecology 2000 107 2 254 261 10.1111/j.1471-0528.2000.tb11697.x 2-s2.0-0033953750 10688510 \n14 Madden B. P. Pulmonary hypertension and pregnancy International Journal of Obstetric Anesthesia 2009 18 2 156 164 10.1016/j.ijoa.2008.10.006 2-s2.0-62149129343 19223169 \n15 Jaïs X. Olsson K. M. Barbera J. A. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era European Respiratory Journal 2012 40 4 881 885 10.1183/09031936.00141211 2-s2.0-84865577863 \n16 Bédard E. Dimopoulos K. Gatzoulis M. A. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? European Heart Journal 2009 30 3 256 265 10.1093/eurheartj/ehn597 2-s2.0-59749092944 19147605 \n17 King C. S. Brown A. W. Aryal S. Ahmad K. Donaldson S. Critical care of the adult patient with cystic fibrosis Chest 2019 155 1 202 214 10.1016/j.chest.2018.07.025 2-s2.0-85054084518 30077689 \n18 Deighan M. Ash S. Mcmorrow R. Anaesthesia for parturients with severe cystic fibrosis: a case series International Journal of Obstetric Anesthesia 2014 23 1 75 79 10.1016/j.ijoa.2013.10.006 2-s2.0-84893429610 24361190 \n19 Weill D. Benden C. Corris P. A. A consensus document for the selection of lung transplant candidates: 2014-an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation The Journal of Heart and Lung Transplantation 2015 34 1 1 15 10.1016/j.healun.2014.06.014 2-s2.0-84920055756 25085497 \n20 Snell G. Reed A. Stern M. Hadjiliadis D. The evolution of lung transplantation for cystic fibrosis: a 2017 update Journal of Cystic Fibrosis 2017 16 5 553 564 10.1016/j.jcf.2017.06.008 2-s2.0-85023626786 28711221 \n21 Hayes D. Kopp B. T. Preston T. J Survival of patients with cystic fibrosis on ECMO: analysis of the extracorporeal life support organization registry International Journal of Clinical and Experimental Medicine 2014 7 5 1370 2 24995097 \n22 Shah N. Perrin F. Extracorporeal membrane oxygenation (ECMO) in cystic fibrosis Paediatric Respiratory Reviews 2014 15 1 26 28 10.1016/j.prrv.2014.04.009 2-s2.0-84901611922 24846285 \n23 Sivam S. Dentice R. Reddy N. Use of extracorporeal membrane oxygenation in cystic fibrosis in an Australian cystic fibrosis centre Internal Medicine Journal 2018 48 3 340 343 10.1111/imj.13728 2-s2.0-85042943621 29512325 \n24 Schechter A. Matthew G. M. A. Englum R. Spontaneously breathing extracorporeal membrane oxygenation support provides the optimal bridge to lung transplantation Transplantation 2016 100 12 2699 2704 10.1097/TP.0000000000001047 2-s2.0-84959169700 26910331 \n25 Sutton C. D. Carvalho B. Optimal pain management after cesarean delivery Anesthesiology Clinics 2017 35 1 107 124 10.1016/j.anclin.2016.09.010 2-s2.0-85008922038 28131114\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6390",
"issue": "2020()",
"journal": "Case reports in anesthesiology",
"keywords": null,
"medline_ta": "Case Rep Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101581025",
"other_id": null,
"pages": "8814729",
"pmc": null,
"pmid": "33457018",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "18024241;9203887;30077689;25911142;27578468;15627546;26910331;19223169;24361190;19147605;27512443;21277453;24846285;10688510;22282544;19923526;28711221;24995097;1478018;15601277;20416544;28131114;25085497;29512325",
"title": "Perioperative Management and Preemptive ECMO Cannulation of a Parturient with Cystic Fibrosis Undergoing Cesarean Delivery.",
"title_normalized": "perioperative management and preemptive ecmo cannulation of a parturient with cystic fibrosis undergoing cesarean delivery"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP001238",
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{
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"activesubstancename": "CEFEPIME HYDROCHLORIDE"
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{
"abstract": "Posterior reversible encephalopathy syndrome(PRES)is a subacute neurological syndrome typically manifesting with headache, cortical blindness, and seizures. This syndrome is associated with risk factors such as malignant hypertension, eclampsia, and renal failure. Numerous case reports depict its occurrence in cancer patients. The direct causal mechanisms of PRES in cancer patients have not yet been identified. Cytotoxic chemotherapy may cause direct endothelial damage, which would impact the blood brain barrier. Angiogenesis inhibitors also cause elevation in blood pressure;this is significant, because PRES onset may be solely related to hypertension. An increased number of case reports involving new molecular targeted agent suggests that incidence of PRES as an oncological emergency may increase in the future.",
"affiliations": "Division of Neurosurgery, Shizuoka Cancer Center.",
"authors": "Mitsuya|Koichi|K|;Nakasu|Yoko|Y|;Hayashi|Nakamasa|N|;Yasui|Hirofumi|H|;Ikeda|Takashi|T|;Kuji|Shiho|S|;Onozawa|Yusuke|Y|;Endo|Masahiro|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11477/mf.1436203259",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2603",
"issue": "44(3)",
"journal": "No shinkei geka. Neurological surgery",
"keywords": null,
"medline_ta": "No Shinkei Geka",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D054038:Posterior Leukoencephalopathy Syndrome",
"nlm_unique_id": "0377015",
"other_id": null,
"pages": "211-9",
"pmc": null,
"pmid": "26965062",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Posterior Reversible Encephalopathy Syndrome Associated with Cancer Therapy.",
"title_normalized": "posterior reversible encephalopathy syndrome associated with cancer therapy"
} | [
{
"companynumb": "GXJP2016JP000705",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Sugammadex is a modified gamma cyclodextrin that encapsulates rocuronium. We report the successful use of sugammadex in the management of an elderly man with end-stage renal failure who sustained an infiltration of subcutaneous rocuronium during rapid sequence induction of general anesthesia. Given the erratic absorption of subcutaneous rocuronium from the tissue, sugammadex was chosen to reverse the neuromuscular block at the end of the procedure. This report demonstrates the efficacy of sugammadex to reverse neuromuscular block in elderly patients with poor renal function. Moreover, the duration of action for sugammadex was sufficient to neutralize the ongoing absorption of subcutaneous rocuronium.",
"affiliations": "From the Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota.",
"authors": "Navare|Sagar R|SR|;Garcia Medina|Oscar|O|;Prielipp|Richard C|RC|;Weinkauf|Julia L|JL|",
"chemical_list": "D000077122:Sugammadex; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000934",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "12(10)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D016099:Endoscopy, Gastrointestinal; D005764:Gastroesophageal Reflux; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D006435:Renal Dialysis; D000077123:Rocuronium; D000077122:Sugammadex; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "375-377",
"pmc": null,
"pmid": "30575607",
"pubdate": "2019-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sugammadex Reversal of a Large Subcutaneous Depot of Rocuronium in a Dialysis Patient: A Case Report.",
"title_normalized": "sugammadex reversal of a large subcutaneous depot of rocuronium in a dialysis patient a case report"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201911115",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
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... |
{
"abstract": "OBJECTIVE\nTo analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries.\n\n\nMETHODS\nThe primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients.\n\n\nRESULTS\nEighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years.\n\n\nCONCLUSIONS\ntAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.",
"affiliations": "Service des Maladies du Sang, Lille, France.",
"authors": "Beaumont|M|M|;Sanz|M|M|;Carli|P M|PM|;Maloisel|F|F|;Thomas|X|X|;Detourmignies|L|L|;Guerci|A|A|;Gratecos|N|N|;Rayon|C|C|;San Miguel|J|J|;Odriozola|J|J|;Cahn|J Y|JY|;Huguet|F|F|;Vekhof|A|A|;Stamatoulas|A|A|;Dombret|H|H|;Capote|F|F|;Esteve|J|J|;Stoppa|A M|AM|;Fenaux|P|P|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D014212:Tretinoin; D004250:DNA Topoisomerases, Type II",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2003.09.072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "21(11)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001530:Belgium; D001943:Breast Neoplasms; D002648:Child; D004250:DNA Topoisomerases, Type II; D005260:Female; D005602:France; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D007953:Leukemia, Radiation-Induced; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013030:Spain; D016896:Treatment Outcome; D014212:Tretinoin",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2123-37",
"pmc": null,
"pmid": "12775738",
"pubdate": "2003-06-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapy-related acute promyelocytic leukemia.",
"title_normalized": "therapy related acute promyelocytic leukemia"
} | [
{
"companynumb": "FR-PFIZER INC-2018152560",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "Intranasal drug abuse frequently leads to sinonasal complications, particularly sinus, nasal, and palatal necrosis. Classically, this type of necrosis has been linked to cocaine use, but the intranasal abuse of prescription narcotics and other pain medications can also lead to severe damage to the sinonasal tract. We describe a case of palatal and nasal septal necrosis resulting from intranasal acetaminophen abuse. The patient was a 34-year-old man with a remote history of polysubstance abuse who presented to the emergency department with worsening dysphagia and a recent history of exclusive intranasal acetaminophen abuse. He had an existing palatal fistula that was found to have dramatically increased in size. Examination revealed complete destruction of the soft palate and nasal septum and partial destruction of the hard palate. The areas of necrosis were surgically debrided. We describe the general clinical presentation and surgical outcome of this case.",
"affiliations": "Department of Otolaryngology, Virginia Commonwealth University, Richmond, VA, USA.",
"authors": "Hardison|Scott A|SA|;Marcum|Kristin K|KK|;Lintzenich|Catherine Rees|CR|",
"chemical_list": "D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-5613",
"issue": "94(10-11)",
"journal": "Ear, nose, & throat journal",
"keywords": null,
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D000082:Acetaminophen; D000281:Administration, Intranasal; D000328:Adult; D003646:Debridement; D006801:Humans; D008297:Male; D009300:Nasal Septum; D009336:Necrosis; D021362:Palate, Hard; D010160:Palate, Soft; D019966:Substance-Related Disorders",
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "E40-2",
"pmc": null,
"pmid": "26535831",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe necrosis of the palate and nasal septum resulting from intranasal abuse of acetaminophen.",
"title_normalized": "severe necrosis of the palate and nasal septum resulting from intranasal abuse of acetaminophen"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-132253",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"d... |
{
"abstract": "BACKGROUND\nStandard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial.\n\n\nMETHODS\nIn the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121.\n\n\nRESULTS\nBetween Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5).\n\n\nCONCLUSIONS\nR-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death.\n\n\nBACKGROUND\nNational Cancer Center and Ministry of Health, Labour and Welfare of Japan.",
"affiliations": "Department of Haematology, National Cancer Center Hospital, Tokyo, Japan; Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. Electronic address: twatanabe@doc.medic.mie-u.ac.jp.;Department of Haematology, National Cancer Center Hospital, Tokyo, Japan.;JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan.;Department of Haematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Haematology, Saitama Cancer Center, Saitama, Japan.;Department of Haematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Haematology and Oncology, Shiga General Hospital, Shiga, Japan.;Department of Haematology and Oncology, Mie University Graduate School of Medicine, Mie, Japan.;Division of Haematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.;Department of Haematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Molecular Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.;Department of Haematology, National Hospital Organization Kyusyu Cancer Center, Fukuoka, Japan.;Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama, Japan.;Center for Radiological Science, International University of Health and Welfare, Mita Hospital, Tokyo, Japan.;Screening Technology and Development Division, Research Center for Cancer Prevention and Screening, National Cancer Center Hospital, Tokyo, Japan; Department of Nuclear Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.;National Hospital Organization, Nagoya Medical Center, Nagoya, Japan.;Department of Haematology and Oncology Research, Nagoya Medical Center, Nagoya, Japan.;Department of Haematology, National Cancer Center Hospital East, Chiba, Japan.",
"authors": "Watanabe|Takashi|T|;Tobinai|Kensei|K|;Wakabayashi|Masashi|M|;Morishima|Yasuo|Y|;Kobayashi|Hirofumi|H|;Kinoshita|Tomohiro|T|;Suzuki|Takayo|T|;Yamaguchi|Motoko|M|;Ando|Kiyoshi|K|;Ogura|Michinori|M|;Taniwaki|Masafumi|M|;Uike|Naokuni|N|;Yoshino|Tadashi|T|;Nawano|Sigeru|S|;Terauchi|Takashi|T|;Hotta|Tomomitsu|T|;Nagai|Hirokazu|H|;Tsukasaki|Kunihiro|K|;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
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"medline_ta": "Lancet Haematol",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e520-e531",
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"pmid": "30389034",
"pubdate": "2018-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial.",
"title_normalized": "outcomes after r chop in patients with newly diagnosed advanced follicular lymphoma a 10 year follow up analysis of the jcog0203 trial"
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"abstract": "BACKGROUND\nFamilial Mediterranean fever (FMF) is an autosomal recessive disease characterized by self-limited recurrent attacks of fever and serositis. Patients may develop renal amyloidosis. Colchicine prevents attacks and renal amyloidosis. Five to 10 % of the patients with FMF are resistant or intolerant to colchicine.\n\n\nMETHODS\nHerein, we reported our experience with clinical-laboratory features and treatment responses of a pediatric FMF patient with amyloidosis treated with canakinumab. We observed a significant decrease in proteinuria and increase growth in the patient.\n\n\nRESULTS\nThe most serious complication of FMF is the development of AA type amyloidosis which is characterized by proteinuria. Colchicine is the prototype drug that decreases production of amyloidogenic precursor protein. Occasionally, colchicine inadequate patient is observed, as in our case. Canakinumab is a human anti-IL-1β monoclonal antibody. Previously, canakinumab efficacy were shown in a limited number of studies.\n\n\nCONCLUSIONS\nOur data, though limited to only one patient, emphasize that therapeutic intervention with canakinumab seems to be improve kidney function in colchicine-resistant FMF with renal amyloidosis.",
"affiliations": "Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Turkey. betulsozeri@yahoo.com.;Dr. Behcet Uz Children Diseases Teaching and Research Hospital Pediatric Immunology and Rheumatology, Izmir, Turkey.;Dr. Behcet Uz Children Diseases Teaching and Research Hospital Pathology, Izmir, Turkey.;Dr. Behcet Uz Children Diseases Teaching and Research Hospital Pediatric Nephrology, Izmir, Turkey.",
"authors": "Sozeri|Betul|B|;Gulez|Nesrin|N|;Ergin|Malik|M|;Serdaroglu|Erkin|E|",
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"country": "Germany",
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"doi": "10.1186/s40348-016-0058-2",
"fulltext": "\n==== Front\nMol Cell PediatrMol Cell PediatrMolecular and Cellular Pediatrics2194-7791Springer Berlin Heidelberg Berlin/Heidelberg 5810.1186/s40348-016-0058-2Case StudyThe experience of canakinumab in renal amyloidosis secondary to Familial Mediterranean fever Sozeri Betul betulsozeri@yahoo.com 1Gulez Nesrin 2Ergin Malik 3Serdaroglu Erkin 41 Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Turkey 2 Dr. Behcet Uz Children Diseases Teaching and Research Hospital Pediatric Immunology and Rheumatology, Izmir, Turkey 3 Dr. Behcet Uz Children Diseases Teaching and Research Hospital Pathology, Izmir, Turkey 4 Dr. Behcet Uz Children Diseases Teaching and Research Hospital Pediatric Nephrology, Izmir, Turkey 15 8 2016 15 8 2016 12 2016 3 1 3313 12 2015 19 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.Introduction\nFamilial Mediterranean fever (FMF) is an autosomal recessive disease characterized by self-limited recurrent attacks of fever and serositis. Patients may develop renal amyloidosis. Colchicine prevents attacks and renal amyloidosis. Five to 10 % of the patients with FMF are resistant or intolerant to colchicine.\n\nCase description\nHerein, we reported our experience with clinical-laboratory features and treatment responses of a pediatric FMF patient with amyloidosis treated with canakinumab. We observed a significant decrease in proteinuria and increase growth in the patient.\n\nDiscussion and evaluation\nThe most serious complication of FMF is the development of AA type amyloidosis which is characterized by proteinuria. Colchicine is the prototype drug that decreases production of amyloidogenic precursor protein. Occasionally, colchicine inadequate patient is observed, as in our case. Canakinumab is a human anti-IL-1β monoclonal antibody. Previously, canakinumab efficacy were shown in a limited number of studies.\n\nConclusions\nOur data, though limited to only one patient, emphasize that therapeutic intervention with canakinumab seems to be improve kidney function in colchicine-resistant FMF with renal amyloidosis.\n\nKeywords\nFamilial Mediterranean feverAmyloidosisChildCanakinumabissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nFamilial Mediterranean fever (FMF) is a genetic, autoinflammatory disease, characterized by acute episodes of serosal and cutaneous inflammation, expressed with pain, fever, neutrophilia, and intense acute-phase response, caused by activation of the innate immune system [1]. The FMF gene, named MEFV, is located on the short arm of chromosome 16 [2, 3]. It encodes a 781–amino acid protein called pyrin or marenostrin which is expressed mostly in neutrophils and acts in controlling inflammation by deactivating inflammatory peptides [4, 5]. Mutated forms of it may be involved in a series of reactions that ultimately enhance the overexpression of IL-1b and consequent inflammation [1].\n\nFMF has been associated with an increased risk for secondary amyloidosis, mainly affecting the renal and vascular function in untreated or insufficiently treated patients with FMF. Amyloidosis is a progressive destructive disorder that results in organ dysfunction due to extracellular deposition of N terminal fragments of serum amyloid A protein (SAA) in the form of insoluble amyloid fibrils [6]. Proteinuria is usually the earliest and most common clinical manifestation of AA amyloidosis in patients with inflammatory diseases [6].\n\nThe goal of therapy for FMF is the prevention of acute attacks, development, and progression of amyloidosis. Colchicine is the mainstay of therapy which decreases attack frequency and increases the quality of life in more than 60 % of patients [7]. It also prevents SAA secretion and slows the progression of amyloidosis in patients with FMF [7]. Approximately 40 % of FMF patients treated with colchicine have a partial remission showed in the Eurofever study [8]. Also, 5–10 % of the patients were reported to be resistant; suffering from either more than six typical FMF attacks per year or more than three typical FMF attacks within 4–6 months [9]. Several studies showed that the patients with FMF were successfully treated with agents blocking interleukin (IL)-1 activity due to the critical role of IL-1 in the pathogenesis FMF [10–14].\n\nCanakinumab is a high-affinity human anti-IL1 β monoclonal antibody of the IgG1/k isotype developed for the treatment of immune disorders, and it is highly specific for IL-1β and does not interfere with other IL-1-activated pathways.\n\nWe would like to share our experience of a patient with colchicine-resistant FMF and renal amyloidosis, whose treatment with canakinumab substantially improved renal functions and reduced proteinuria over a period of 26 months.\n\nCase presentation\nA 14-year-old male with colchicine-resistant FMF and amyloidosis was admitted for the first time in May 2013. He was born to parents of second-degree consanguineous marriage. He had taken regular colchicine therapy (2 g/day) and ramipril (5 mg/day) for proteinuria for a year.\n\nFrom his history, he had recurrent FMF attacks associated with severe abdominal pain, joint pain, and fever, which had begun at the age of four. However, he was hospitalized for the first time at the age of 7 years because of intermittent febrile episodes with chills, abdominal pain, and arthritis involving ankle joints. Splenomegaly was found a year later. His attacks continued once a month until he was diagnosed with FMF at 13 years old. At that time, he had proteinuria, splenomegaly, and growth retardation. He was homozygous for the M694V mutation in MEFV gene. Also, microhematuria and proteinuria (38 mg/m2/h) was found at his urinalysis. Serum creatinine level was 1.1 mg/dl, and creatinine clearance was 89 mL/min. Diagnosis of chronic kidney disease (CKD) with AA amyloidosis was established via renal biopsy (Fig. 1). Severe glomerular amyloidosis plus mild vascular and mild interstitial amyloidosis was found in his kidney biopsy. Colchicine therapy was started with a dose of 1 mg/day. In the first month of treatment, he was clinically normal and his C-reactive protein (CRP) level was within normal limits. At his 6-month follow up, the dose of colchicine had to be increased (2 g/day) due to an increased attack rate (5 attacks per 6 months) despite the regular use of drugs.Fig. 1 Renal amyloid deposition was diagnosed in glomerulus by two different staining\n\n\n\nThe laboratory findings on admission revealed an elevated CRP (184 mg/dL) and SAA (645 mg/dL) levels. Nephrotic range proteinuria was found in urine analysis (43 mg/m2/h). Because of his poor response to colchicine, severe growth retardation, and severe proteinuria due to amyloidosis, we decided to start canakinumab treatment (150 mg/month/sc) in June 2013. Informed consent about the potential side effects and the empirical aspects of the therapy was obtained. One month later, the patient was symptom-free and the inflammatory parameters almost normalized. After 26 months of follow-up, with canakinumab treatment, his complaints, inflammatory parameters (CRP; 0.03 mg/dl and SAA; 3.81 mg/dl) and proteinuria were decreased. Splenomegaly was decreased and also his growth rate returned to normal (Fig. 2), after canakinumab therapy. The mean height SDS before therapy was significantly lower than after canakinumab (−2.12 ± 0,11 vs −1.71 ± 0,14, P = 0,009) (Fig. 3). He was kept on 2 mg of colchicine daily. No side effects were noted.Fig. 2 Effect of canakinumab on proteinuria (miligrams/m2(per hour)\n\nFig. 3 Effect of canakinumab on growth parameters (height and weight)\n\n\n\nDiscussion and evaluation\nThe most serious complication of FMF is the development of AA type amyloidosis which is characterized by proteinuria and is typically progressive and leads to end-stage vital organ involvement, first diagnosed by Mamou and Cattan in 1952 [15]. Renal amyloidosis has been shown to cause mortality in FMF patients [16]. In the series reported by the Turkish FMF study group, the presenting clinical features of the patients with amyloidosis secondary to FMF were as follows: 32 % proteinuria, 40 % nephrotic syndrome, and 28 % chronic renal failure [17]. The M694V mutation has been shown to be a strong risk factor of developing amyloidosis in different ethnic groups [17]. The production of the precursor to SAA is the main step in the pathogenesis of amyloidosis, which is produced by inflammatory signals, IL-1β, tumor necrosis factor (TNF)-α, and IL-6 [18]. The “gold standard” for the diagnosis of amyloidosis remains a tissue biopsy demonstrating characteristic hematoxylin and eosin changes and Congo red birefringence or metachromatic pink-violet staining with methyl violet or crystal violet [19]. The patient’s renal biopsy was evaluated with the scoring system defined for renal amyloidosis and was found as severe glomerular amyloidosis plus mild vascular and mild interstitial amyloidosis. The scoring system proposed by Sen S et al. [20] in 2010 and compared to clinical parameters by Castano et al. [21]. They have demonstrated that the severity of glomerular amyloid deposition was correlated the risk of developing end-stage renal disease and increase the risk for premature death [21]. Also they have reported proteinuria, and serum albumin and serum creatinine levels were correlated with degree of amyloidosis [21]. Also, the degree of amyloidosis was measured through parameters such as SAA protein and serum amyloid P (SAP) scintigraphy [18, 22].\n\nHerein, we reported a FMF patient with biopsy-proven renal amyloidosis and growth retardation. He had various risk factors for amyloidosis including carrying the M694V allele, family history, and late diagnosis.\n\nPro-inflammatory cytokines may modulate growth patterns in children with inflammatory diseases through both systemic and local effects of the GH/IGF-1 axes [23]. It has been shown that FMF patients catch up to their growth with an effective colchicine treatment [24–26].\n\nThe aim of treatment in AA amyloidosis is the suppression, as complete as possible, of the inflammatory process responsible for the overwhelming SAA production. Colchicine is the prototype drug that decreases production of amyloidogenic precursor protein. Occasionally, colchicine inadequate patient is observed, as in our case. In such circumstances, anti IL-1 treatment options come into play. Anti- IL-1 drugs impact on amyloidosis is still unknown. Previously, there were reports of some adult cases with successful use of anti IL-1 therapy (anakinra) in renal transplant recipients [11, 12]. There are few data from pediatric patients in literature. Bilginer Y et al. [27] reported a patient who was diagnosed with FMF and Behçet’s disease and proteinuria, with normal kidney function after 18 months of anakinra treatment. Recently, Ozcakar et al. [28] showed one child patient with nephrotic syndrome in whom partial remission had been observed after 12 months of anakinra therapy.\n\nCanakinumab is a human anti-IL-1β monoclonal antibody. Its mode of action is based on the neutralization of IL-1β signaling which may result in the suppression of the inflammation process. To the best of our knowledge, about de novo canakinumab treatment in FMF patients with AA amyloidosis is limited. Topaloglu R et al. [29] reported a patient diagnosed amyloidosis was successful treated with canakinumab.\n\nCetin P et al. [12] reported experience in 20 cases of adult and pediatric FMF colchicine-resistant patients who were treated with anti-IL-1 agents. Twelve patients were receiving anakinra, and eight patients were treated with canakinumab. The number of monthly and yearly attacks after IL-1 treatment significantly decreased after the biologic agent (p < 0.05). Hashkes P et al. [13] conducted an open-label, single-arm study in seven children with colchicine-resistant FMF. Six participants met the primary outcome with ≥50 % reduction (range 76–100 %) in the FMF attack rate. The median 28-day time-adjusted attack rate decreased from 2.7 to 0.3 (89 %). Canakinumab was shown to be effective in treating pediatric patients with colchicine-resistant FMF in this study. Another study reported that in children with colchicine-resistant FMF, monthly canakinumab 150 mg subcutaneous injections prevented FMF attacks in patients with frequent attacks, and only one of nine patients experienced an attack during the treatment period [14].\n\nConclusions\nCanakinumab has demonstrated a sustained clinical response in the patient affected by colchicine-resistant FMF and biopsy-proven renal amyloid deposits, blocking and significantly reducing renal damage progression. Also, we observed the normalization of the markers of inflammation inc. SAA, and the reduction of proteinuria in an overall period. Moreover, his growth pattern was improved with therapy. No adverse events, namely infectious episodes, were reported in our patient during treatment with canakinumab. We did not consider making a repeat biopsy for proteinuria completely regressed.\n\nOur report emphasizes that the therapeutic intervention with canakinumab can treat colchicine-resistant FMF by suppressing inflammation and to prevent its most life-threatening complication, amyloidosis-related proteinuria. Further evaluations are needed in order to confirm the positive effect of canakinumab.\n\nAbbreviations\nCKD, chronic kidney disease; CRP, C-reactive protein; FMF, Familial Mediterranean fever; IL, interleukin; SAA, serum amyloid A protein; TNF, tumor necrosis factor\n\nAuthors’ contributions\nBS and NG were in charge of the patient’s treatment and care in hospital and drafted the manuscript. BS also supervised the management of patient and revised the final manuscript for submission. ME diagnosed the patient’s kidney biopsy. SE was in charge of the diagnosis of renal biopsy and helped in drafting the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nEthics approval and consent to participate\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 of this journal.\n==== Refs\nReferences\n1. Ben-Zvi I Livneh A Chronic inflammation in FMF: markers, risk factors, outcomes and therapy Nat Rev Rheumatol 2011 7 105 112 10.1038/nrrheum.2010.181 21060333 \n2. The International FMF Consortium Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever Cell 1997 90 797 10.1016/S0092-8674(00)80539-5 9288758 \n3. French FMF Consortium A candidate gene for familial Mediterranean fever Nat Genet 1997 17 25 10.1038/ng0997-25 9288094 \n4. Grattagliano I Bonfrate L Ruggiero V Scaccianoce G Palasciano G Portincasa P Novel therapeutics for the treatment of familial Mediterranean fever: from colchicine to biologics Clin Pharmacol Ther 2014 95 89 97 10.1038/clpt.2013.148 23867542 \n5. Ozen S Bilginer Y A clinical guide to autoinflammatory diseases: Familial Mediterranean fever and next-of-kin Nat Rev Rheumatol 2014 10 135 147 10.1038/nrrheum.2013.174 24247370 \n6. Merlini G Bellotti V Molecular mechanisms of amyloidosis N Engl J Med 2003 349 583 596 10.1056/NEJMra023144 12904524 \n7. Hentgen V Grateau G Kone-Paut I Livneh A Padeh S Rozenbaum M Amselem S Gershoni-Baruch R Touitou I Ben-Chetrit E Evidence-based recommendations for the practical management of Familial Mediterranean fever Semin Arthritis Rheum 2013 43 387 391 10.1016/j.semarthrit.2013.04.011 23742958 \n8. Ter Haar N Lachmann H Ozen S Woo P Uziel Y Modesto C Koné-Paut I Cantarini L Insalaco A Neven B Hofer M Rigante D Al-Mayouf S Touitou I Gallizzi R Papadopoulou-Alataki E Martino S Kuemmerle-Deschner J Obici L Iagaru N Simon A Nielsen S Martini A Ruperto N Gattorno M Frenkel J Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever/Eurotraps Projects Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review Ann Rheum Dis 2013 72 678 685 10.1136/annrheumdis-2011-201268 22753383 \n9. Lidar M Scherrmann JM Shinar Y Chetrit A Niel E Gershoni-Baruch R Langevitz P Livneh A Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization Semin Arthritis Rheum 2004 33 273 282 10.1053/S0049-0172(03)00137-9 14978665 \n10. Mitroulis I Skendros P Ritis K Targeting IL-1beta in disease; the expanding role of NLRP3 inflammasome Eur J Intern Med 2010 21 157 163 10.1016/j.ejim.2010.03.005 20493414 \n11. Moser C Pohl G Haslinger I Knapp S Rowczenio D Russel T Lachmann HJ Lang U Kovarik J Successful treatment of familial Mediterranean fever with Anakinra and outcome after renal transplantation Nephrol Dial Transplant 2009 24 676 678 10.1093/ndt/gfn646 19033248 \n12. Cetin P Sari I Sozeri B Cam O Birlik M Akkoc N Onen F Akar S Efficacy of interleukin-1 targeting treatments in patients with familial Mediterranean fever Inflammation 2015 38 27 31 10.1007/s10753-014-0004-1 25139580 \n13. Hashkes P Butbul Aviel Y Lubin S Ben-Dayan E Tseng L Brik R A76: long-term efficacy of canakinumab in childhood colchicine resistant familial mediterranean Fever Arthritis Rheumatol 2014 66 108 10.1002/art.38492 \n14. Gül A Ozdogan H Erer B Ugurlu S Kasapcopur O Davis N Sevgi S Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever Arthritis Res Ther 2015 17 243 10.1186/s13075-015-0765-4 26337145 \n15. Mamou H Cattan R La maladie periodique sur 14 cas personnels dont 8 compliqués de nephropathies Semaine hop Paris 1952 28 1062 14958422 \n16. Twig G Livneh A Vivante A Afek A Shamiss A Derazne E Tzur D Ben-Zvi I Tirosh A Barchana M Shohat T Golan E Amital H Mortality risk factors associated with Familial Mediterranean fever among a cohort of 1.25 million adolescents Ann Rheum Dis 2014 73 704 709 10.1136/annrheumdis-2012-202932 23505237 \n17. Tunca M Akar S Onen F Ozdogan H Kasapcopur O Yalcinkaya F Tutar E Ozen S Topaloglu R Yilmaz E Arici M Bakkaloglu A Besbas N Akpolat T Dinc A Erken E Turkish FMF Study Group Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study Medicine (Baltimore) 2005 84 1 11 10.1097/01.md.0000152370.84628.0c 15643295 \n18. Lachmann HJ Goodman HJ Gilbertson JA Gallimore JR Sabin CA Gillmore JD Hawkins PN Natural history and outcome in systemic AA amyloidosis N Engl J Med 2007 356 2361 237 10.1056/NEJMoa070265 17554117 \n19. Bennhold H spezifische Amyloidfarbung mit Kongorot Munch Med Wochenschr 1922 69 1537 1538 \n20. Sen S Sarsik B A proposed histopathologic classification, scoring, and grading system for renal amyloidosis: standardization of renal amyloid biopsy report Arch Pathol Lab Med 2010 134 532 544 20367305 \n21. Castano E Palmer MB Vigneault C Luciano R Wong S Moeckel G Comparison of amyloid deposition in human kidney biopsies as predictor of poor patient outcome BMC Nephrol 2015 16 64 10.1186/s12882-015-0046-0 25924613 \n22. Oner A Erdogan O Demircin G Bulbul M Memis L Efficacy of colchicine therapy in amyloid nephropathy of familial Mediterranean fever Pediatr Nephrol 2003 18 521 526 12698329 \n23. MacRae VE Wong SC Farquharson C Ahmed SF Cytokine actions in growth disorders associated with pediatric chronic inflammatory diseases (review) Int J Mol Med 2006 18 1011 1018 17089003 \n24. Zung A Barash G Zadik Z Barash J Familial Mediterranean fever and growth: effect of disease severity and colchicine treatment J Pediatr Endocrinol 2006 19 15 10.1515/JPEM.2006.19.2.155 \n25. Türkmen M Soylu OB Kasap B Güneş S Tüfekçi O Soylu A Erçal D Kavukçu S Growth in Familial Mediterranean fever: effect of attack rate, genotype and colchicine treatment J Pediatr Endocrinol Metab 2008 21 789 792 10.1515/JPEM.2008.21.8.789 18825879 \n26. Sozeri B Yilmaz E Mir S Berdeli A Effect of colchicine-resistant Familial Mediterranean fever on growth parameters Archives of Rheum 2011 26 1 5 \n27. Bilginer Y Ayaz NA Ozen S Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behçet’s disease Clin Rheumatol 2010 29 209 210 10.1007/s10067-009-1279-8 19774408 \n28. Ozçakar ZB Ozdel S Yılmaz S Kurt-Şükür ED Ekim M Yalçınkaya F Anti-IL-1 treatment in Familial Mediterranean fever and related amyloidosis Clin Rheumatol 2014 35 441 446 10.1007/s10067-014-2772-2 25213327 \n29. Topaloglu R Batu ED Orhan D Ozen S Besbas N Anti-interleukin 1 treatment in secondary amyloidosis associated with autoinflammatory diseases Pediatr Nephrol 2015 31 633 640 10.1007/s00467-015-3249-5 26563115\n\n",
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"abstract": "Herpesvirus colitis is a known cause of morbidity and mortality amongst immunosuppressed individuals. We present a case of HSV colitis following a diagnosis of Crohn's Disease and methylprednisolone therapy. Diagnosis was confirmed by immunohistochemical staining and supported by polymerase chain reaction (PCR) of cutaneous vesicles. The patient recovered following three weeks of acyclovir.",
"affiliations": "Department of Internal Medicine, McMaster University, Hamilton, ON, Canada.;Department of Internal Medicine, Division of Infectious Diseases, McMaster University, Hamilton, ON, Canada.;Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.;Department of Surgery, McMaster University, Hamilton, ON, Canada.;Department of Internal Medicine, McMaster University, Hamilton, ON, Canada.",
"authors": "Jafri|H|H|;Kalina|D R|DR|0000-0001-6588-9996;Aziz|T|T|;Serrano|P E|PE|;Haider|S|S|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/7591709Case ReportHerpes Simplex Virus Colitis in a Patient with Newly Diagnosed Crohn's Disease Jafri H. \n1\nhttp://orcid.org/0000-0001-6588-9996Kalina D. R. dale.kalina@medportal.ca\n2\nAziz T. \n3\nSerrano P. E. \n4\nHaider S. \n1\n\n2\n\n1Department of Internal Medicine, McMaster University, Hamilton, ON, Canada\n2Department of Internal Medicine, Division of Infectious Diseases, McMaster University, Hamilton, ON, Canada\n3Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada\n4Department of Surgery, McMaster University, Hamilton, ON, CanadaAcademic Editor: Thomas R. Chauncey\n\n2018 14 6 2018 2018 759170919 1 2018 22 4 2018 Copyright © 2018 H. Jafri et al.2018This 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.Herpesvirus colitis is a known cause of morbidity and mortality amongst immunosuppressed individuals. We present a case of HSV colitis following a diagnosis of Crohn's Disease and methylprednisolone therapy. Diagnosis was confirmed by immunohistochemical staining and supported by polymerase chain reaction (PCR) of cutaneous vesicles. The patient recovered following three weeks of acyclovir.\n==== Body\n1. Background\nThe management of inflammatory bowel disease (IBD) continues to evolve with the introduction of more toxic immunosuppressive therapies [1, 2]. Furthermore, paradigm shifts in management of IBD has resulted in earlier use of corticosteroids, thiopurine antimetabolites (6-MP, azathioprine), methotrexate, calcineurin inhibitors, and anti-TNF agents [2]. While these treatments are effective in managing IBD, they can result in severe acute microbial infections, loss of immunologic control of chronic viral infection (HIV and hepatitis B/C), reactivation of latent infections (HSV, EBV, and CMV), and malignancies resulting from oncogenic viruses (HPV and EBV) [3–5].\n\nHerpesvirus infections are common sequelae in the clinical course of patients being managed for IBD [2–5]. Although cytomegalovirus (CMV) is a common cause of tissue-invasive disease in these patients [1], herpex simplex virus (HSV) complicating the course of an IBD flare is a rare phenomenon. There have been only 4 published cases of HSV superinfection in the background of IBD [6–9].\n\n2. Case Report\nA 61-year-old female presented to hospital with a 2-week history of profound diarrhea and vomiting. The patient also complained of dull abdominal pain that temporarily resolved with bowel movements. She denied fevers, weight loss, exposure to sick contacts, external food sources, and a travel history. There were no extraintestinal manifestations of inflammatory bowel disease (IBD), such as arthralgias, uveitis, episcleritis, oral ulcers, and aphthous ulcers.\n\nShe was admitted with an initial diagnosis of viral gastroenteritis and treated with supportive therapy. Stool testing for Clostridium difficile, ova and parasites, viral PCR, and bacterial cultures were negative. A CT abdomen revealed diffuse edematous changes in the ascending colon, transverse colon, and descending colon, as well as hyperemia in the mesentery—indicating colitis.\n\nOn her second day of admission, the patient developed bloody diarrhea, prompting a colonoscopy by the gastroenterology service. The colonoscopy revealed severe inflammation with large (0.5–3 cm) deep punched-out ulcers, spontaneous bleeding, bridging mucosa, and patchy erythema affecting 80–90% of the mucosa from the cecum to the transverse colon, with rectal sparing. Several scattered aphthous ulcers were also noted.\n\nMultiple biopsy samples were taken from the colon—they revealed severe chronic colitis with focal areas of ulceration, focal cryptitis, and architectural distortion. Esophagogastroduodenoscopy (EGD) was normal. The results of the colonoscopy were consistent with Crohn's disease, and the patient was treated with intravenous methylprednisolone 80 mg for seven days.\n\nOn day 3 of admission, the patient developed fevers, chills, significant right-sided parotid swelling, erythema, and tenderness. Ultrasound of the right neck revealed parotitis with no abscess. Blood cultures revealed MSSA bacteremia, with parotitis being the presumed source. Transesophogeal echocardiogram was negative, and the patient was subsequently treated with supportive therapy and fourteen days of cefazolin.\n\nThe patient had a stable clinical course for the next thirteen days. However, on postadmission day 17, the patient developed severe abdominal pain and hemodynamic instability. On examination, the patient's abdomen was diffusely tender and rigid, suggesting peritonitis. Abdominal X-ray revealed features of colitis complicated by perforation. CT abdomen revealed bowel wall edema, pneumatosis, and focal perforation involving the anterior wall cecum/ascending colon, with extensive pneumoperitoneum. The patient was initially resuscitated and taken to the operating room the next day for a laparotomy. Findings in the operating room revealed microperforations of the cecum, large perforation at the splenic flexure, and fecal peritonitis. A subtotal colectomy was performed, as well as intra-abdominal and subphrenic abscesses were drained. The patient remained intubated postoperatively and was transferred to the intensive care unit (ICU). Concurrent blood cultures revealed Enterobacter cloacae bacteremia from an intra-abdominal source, and the patient was treated with intravenous ciprofloxacin. However, the patient remained intubated and required continued use of vasopressors in the ICU. Upon examination, the surgical wound demonstrated signs of infection, which along with the patient's clinical status suggested persistent intra-abdominal sepsis. On hospital day 25, the patient went to the operating room again for a washout of the abdomen and creation of a rectal stump mucous fistula. Tissue cultures revealed growth of Escherichia coli and Enterococcus faecium. Antimicrobical treatment with intravenous meropenem and intravenous metronidazole was commenced, for broad coverage of intra-abdominal abscess and sepsis.\n\nThe surgical biopsy from subtotal colectomy revealed extensive diffuse mucosal inflammation, acute ulceration, and mucosal and transmural ischemic changes from the ileum to the distal colon (Figure 1(a)). The ulcerated area exhibited granulation tissue that contained cells that diffusely exhibited intranuclear inclusions, morphologically and immunohistochemically consistent with herpes simplex virus (HSV-1 and HSV-2) (Figures 1(b)–1(d)). Immunohistochemistry for CMV was negative. The patient was started on treatment with intravenous acyclovir.\n\nUpon physical examination, the patient had developed lesions on the tongue, with visible dry blood. No lesions were seen on the lips. Furthermore, the patient had vesicular eruptions on the lower abdomen and inner thigh. The fluid from the tongue and abdominal lesions was also positive for HSV-2 DNA on a PCR-based assay, thus suggesting a disseminated HSV-2 infection. Viral PCR was negative for HSV-1 and varicella-zoster. The patient received treatment with intravenous acyclovir 10 mg/kg for three weeks.\n\nThe patient had a prolonged stay in the ICU spanning 42 days. She continued to make a recovery on the ward, as her hospital stay was further complicated by catheter- and line-related infections, as well as poor nutrition and muscle atrophy. The patient was discharged from the hospital on day 122.\n\n3. Discussion\nThe evolution of immunomodulatory therapies for the management of IBD has improved prognosis in this patient population, with the caveat of increased risk of infection with various microorganisms [2–5]. CMV colitis is a common complication in the clinical course of IBD—among IBD patients with acute colitis, the prevalence of CMV superinfection is 21–34% [1]. In contrast, HSV superinfection in the context of IBD has been rarely described in the literature [6, 10]. Along with the use of immunosuppressive agents, persistent inflammation is also a risk factor for developing HSV superinfection [4].\n\nWhile it is important to consider the possibility that HSV colitis was in fact a triggering condition rather than merely a superinfection, we consider this to be less likely in our presented case. Colonoscopic biopsies that had been taken two weeks prior to those showing evidence of HSV colitis showed evidence of colitis suggestive of inflammatory bowel disease in the absence of signs of HSV colitis. Given the relatively low specificity of serologic tests for HSV [11], especially in active infection [10], it is difficult to speculate if there had been increasing burden of viral disease leading to the development of the patient's IBD.\n\nIt is essential to recognize HSV colitis as a clinical entity in this patient population. A higher index of suspicion will lead to earlier diagnosis and management, which can significantly alter the clinical course and ultimately improve patient outcomes [12]. In such cases, the physical examination can be helpful as it was in our case—there was evidence of vesicular lesions indicating mucocutaneous manifestation of active HSV infection [7]. However, the most essential component in the diagnosis of HSV colitis is immunohistochemistry. The diagnosis can only be confirmed with adequate tissue samples sent for immunohistochemical analysis [7, 8, 13]. Similar to CMV colitis, HSV colitis can present with intranuclear eosinophilic inclusion bodies [7, 8, 13]. However, immunohistochemistry for CMV was negative in the colonic sample in our case, while it was positive for HSV. It is essential to appropriately test for all potential culprit microorganisms; otherwise, the diagnosis can be missed. Although CMV is the more common culprit, HSV must be ruled out immunohistochemically, especially if testing for CMV is negative.\n\nAlthough early diagnosis and treatment is the current clinical standard of care, future strategies may involve prophylactic treatments in patients receiving immunosuppressive therapies for IBD [5]. Prophylactic antiviral therapy may have a role in immunosuppressed patients with serological results consistent with latent viral infections or a history of complicated viral infections.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\nH. Jafri and D. R. Kalina contributed equally to this work.\n\nFigure 1 (a) Section from the ulcerated colonic mucosa with deep fissuring ulcer. Viral cytopathic changes are noted. (b, c) Giant cells within ulcer with characteristic intranuclear Cowdry type A inclusions of HSV-1 and HSV-2. Black arrows point to individual giant cells with Cowdry type A inclusions. (d) Immunohistochemistry study for HSV-2 antibody highlighted by the brown nuclear staining.\n==== Refs\n1 Kandiel A. Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease American Journal of Gastroenterology 2006 101 12 2857 2865 10.1111/j.1572-0241.2006.00869.x 2-s2.0-33845459588 17026558 \n2 Marehbian J. Arrighi H. M. Hass S. Tian H. Sandborn W. J. Adverse events associated with common therapy regimens for moderate-to-severe Crohn’s disease American Journal of Gastroenterology 2009 104 10 2524 2533 10.1038/ajg.2009.322 2-s2.0-70350513112 19532125 \n3 Stallmach A. Carstens O. Role of infections in the manifestation or reactivation of inflammatory bowel diseases Inflammatory Bowel Disease 2002 8 3 213 218 10.1097/00054725-200205000-00009 2-s2.0-0036111857 \n4 Toruner M. Loftus E. V. Harmsen W. S. Risk factors for opportunistic infections in patients with inflammatory bowel disease Gastroenterology 2008 134 929 936 10.1053/j.gastro.2008.01.012 2-s2.0-41349088375 18294633 \n5 Viget N. Vernier-Massouille G. Salmon-Ceron D. Yazdanpanah Y. Colombel J.-F. Infections in patients with inflammatory bowel disease: prevention and diagnosis Gut 2008 57 4 549 558 10.1136/gut.2006.114660 2-s2.0-41149119335 18178610 \n6 El-Serag H. Zwas F. R. Cirillo N. W. Eisen R. N. Fulminant herpes colitis in a patient with Crohn’s Disease Journal of Clinical Gastroenterology 1996 3 22 220 223 10.1097/00004836-199604000-00015 2-s2.0-0029887976 \n7 Phadke V. Friedman-Moraco R. J. Quigley B. C. Farris A. B. Norvell J. P. Concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis Medicine 2016 95 42 10.1097/md.0000000000005082 2-s2.0-84995603167 \n8 Schunter O. Walles T. Fritz P. Herpes simplex virus colitis complicating ulcerative colitis: a case report and brief review on superinfections Journal of Crohn’s and Colitis 2007 1 1 41 46 10.1016/j.crohns.2007.06.004 2-s2.0-37249038056 \n9 Smith J. Sterling R. K. Mills A. S. Herpes simplex virus colitis in a patient With Crohn’s Disease and Hepatitis B and D Cirrhosis Gastroenterology and Hepatology 2010 6 2 120 122 20567555 \n10 Chevaux J.-B. Peyrin-Biroulet L. Herpes simplex virus colitis complicating the course of a patient with Crohn’s Disease and Cirrhosis: an Underestimated Association? Gastroenterology and Hepatology 2010 6 2 122 124 20567556 \n11 Anderson N. W. Buchan B. W. Ledeboer N. A. Light microscopy, culture, molecular, and serologic methods for detection of herpes simplex virus Journal of Clinical Microbiology 2014 52 1 2 8 10.1128/jcm.01966-13 2-s2.0-84891418459 24131689 \n12 Rahier J. F. Magro F. Abreu C. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease Journal of Crohn’s and Colitis 2014 8 6 443 468 10.1016/j.crohns.2013.12.013 2-s2.0-84899719594 \n13 Shlien R. D. Meyers S. Lee J. A. Dische R. Janowitz H. D. Fulminant herpes simplex hepatitis in a patient with ulcerative colitis Gut 1988 29 2 257 261 10.1136/gut.29.2.257 3345937\n\n",
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"title": "Herpes Simplex Virus Colitis in a Patient with Newly Diagnosed Crohn's Disease.",
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"abstract": "The aim of this study was to evaluate whether indomethacin eye drops and intravitreal ranibizumab (IVR) injections would provide additional benefit over ranibizumab alone in the treatment of choroidal neovascularization (CNV).\nThis was a randomized, prospective pilot study of eyes with new-onset CNV. Fifty-eight patients were randomized 1:1 into a ranibizumab monotherapy (RM) group and a ranibizumab plus indomethacin (RI) group. All patients received monthly 0.5 mg IVR injections for 3 months, followed by monthly injections administered as needed. RI group patients also self-administered one drop of 0.5% indomethacin three times a day for 12 months. All patients were followed up for 12 months.\nAt 12 months, both groups showed significant improvement in best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was -0.12±0.04 LogMAR and -0.20±0.04 LogMAR in the RM and RI groups, respectively, with the degree of change being significantly different between the two groups (P=0.04). At 12 months, the mean CRT in the RM group (316±41.2 µm) was significantly higher than that in the RI group (287±31.5 µm; P=0.004). The mean required number of IVR injections was 7.38±0.78 and 6.34±0.67 in the RM and RI groups, respectively (P<0.001).\nCompared to IVR monotherapy, combination therapy with indomethacin eye drops and IVR provides superior anatomical and visual outcomes in patients with naive CNV lesions. Moreover, topical indomethacin might reduce the frequency of IVR injections, which is very beneficial considering the chronic and expensive nature of IVR therapy.",
"affiliations": "Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia.;Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia.;Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia.;Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia.;Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia.;Eye Clinic, Department of Health Sciences, University of Molise, Campobasso, Italy.;Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia.",
"authors": "Russo|Andrea|A|;Scaroni|Nicolò|N|;Gambicorti|Elena|E|;Turano|Raffaele|R|;Morescalchi|Francesco|F|;Costagliola|Ciro|C|;Semeraro|Francesco|F|",
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"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S159672opth-12-587Clinical Trial ReportCombination of ranibizumab and indomethacin for neovascular age-related macular degeneration: randomized controlled trial Russo Andrea 1Scaroni Nicolò 1Gambicorti Elena 1Turano Raffaele 1Morescalchi Francesco 1Costagliola Ciro 2Semeraro Francesco 1\n1 Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Brescia\n2 Eye Clinic, Department of Health Sciences, University of Molise, Campobasso, ItalyCorrespondence: Andrea Russo, Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedale Civili, 1, 25100 Brescia, Italy, Tel +39 33 8919 4364, Fax +39 30 309 9888, Email dott.andrea.russo@gmail.com2018 27 3 2018 12 587 591 © 2018 Russo et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nThe aim of this study was to evaluate whether indomethacin eye drops and intravitreal ranibizumab (IVR) injections would provide additional benefit over ranibizumab alone in the treatment of choroidal neovascularization (CNV).\n\nParticipants and methods\nThis was a randomized, prospective pilot study of eyes with new-onset CNV. Fifty-eight patients were randomized 1:1 into a ranibizumab monotherapy (RM) group and a ranibizumab plus indomethacin (RI) group. All patients received monthly 0.5 mg IVR injections for 3 months, followed by monthly injections administered as needed. RI group patients also self-administered one drop of 0.5% indomethacin three times a day for 12 months. All patients were followed up for 12 months.\n\nResults\nAt 12 months, both groups showed significant improvement in best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was −0.12±0.04 LogMAR and −0.20±0.04 LogMAR in the RM and RI groups, respectively, with the degree of change being significantly different between the two groups (P=0.04). At 12 months, the mean CRT in the RM group (316±41.2 µm) was significantly higher than that in the RI group (287±31.5 µm; P=0.004). The mean required number of IVR injections was 7.38±0.78 and 6.34±0.67 in the RM and RI groups, respectively (P<0.001).\n\nConclusion\nCompared to IVR monotherapy, combination therapy with indomethacin eye drops and IVR provides superior anatomical and visual outcomes in patients with naive CNV lesions. Moreover, topical indomethacin might reduce the frequency of IVR injections, which is very beneficial considering the chronic and expensive nature of IVR therapy.\n\nKeywords\ncentral retinal thicknesschoroidal neovascularizationindomethacininflammationranibizumab\n==== Body\nIntroduction\nAge-related macular degeneration (AMD) is still the primary cause of visual impairment and blindness in patients older than 60 years in developed countries.1 In the neovascular form of AMD, the choroidal neovascularization (CNV) beneath the macula leads to fibrous metaplasia, permanent loss of photoreceptors, and disciform scarring, which often results in the loss of central vision.2\n\nLarge-scale clinical trials have shown that monthly or bimonthly intravitreal injection of vascular endothelial growth factor (VEGF) antagonists prevents vision loss and may even improve visual acuity in patients with neovascular AMD.3,4 However, it is important to note that VEGF is not the only causative factor in CNV. In particular, free radicals and oxidized lipoproteins in the aging retina are major local triggers of parainflammation, which is the chronic status responsible for the initiation and progression of age-related chorioretinal damage.5,6 Thus, inflammation itself plays an important role in the pathogenesis of CNV and administration of a topical nonsteroidal anti-inflammatory drug (NSAID) has been shown to supplement the effectiveness of anti-VEGF agents in reducing central retinal thickness (CRT)7,8 and the rate of re-injection in CNV.9 A recent assessment of the vitreous penetration of NSAIDs and their effects on prostaglandin E2 (PGE2) revealed a significant reduction in vitreous PGE2 levels in response to indomethacin, bromfenac, and nepafenac.10 Considering these results, in this study, we prospectively evaluated whether the addition of 0.5% indomethacin eye drops three times a day (TID) to the standard treatment of intravitreal ranibizumab (IVR) injections would provide better efficacy than that achieved with ranibizumab alone in patients with CNV.\n\nParticipants and methods\nStudy design\nThis was an open-label, pilot study in eyes affected by new neovascular AMD. This study was conducted in the Ophthalmic Center of “Spedali Civili di Brescia”, according to the ethical principles of the Declaration of Helsinki. The institutional review board of the “Spedali Civili di Brescia” hospital approved the study protocol (registered with ClinicalTrials.gov, identifier NCT03261635). All study participants provided written informed consent.\n\nParticipants\nSixty consecutive participants were enrolled from September 2016 to March 2017 at the Spedali Civili Ophthalmic Center (Spedali Civili di Brescia) in Brescia, Italy. Patients were randomized (online statistical computing web programming www.graphpad.com/quickcalcs) at a 1:1 ratio into the following two groups: monotherapy with IVR injections (ranibizumab monotherapy [RM] group; n=29) and IVR injections plus off-label topical 0.5% indomethacin eye drops (ranibizumab plus indomethacin [RI] group; n=29). One patient per group was excluded because they moved to another eye clinic after the initial ranibizumab-loading phase.\n\nInclusion and exclusion criteria\nInclusion criteria were as follows: 1) provision of written informed consent, 2) age >40 years, and 3) presence of treatment-naive neovascular AMD, which was defined as neovascularization, fluid, or hemorrhage underneath the fovea. The presence of new active CNV was confirmed by the evidence of leakage on fluorescein angiography and fluid on spectral domain optical coherence tomography (OCT) (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). The diagnosis was made by one investigator (AR) and thereafter confirmed by the second investigator (EG).\n\nExclusion criteria were as follows: 1) any prior intravitreal or retinal laser treatment, 2) pathological myopia (>7 D), 3) any concomitant eye disease, and 4) corneal epithelial defects or any condition that would affect the cornea.\n\nStudy treatments\nParticipants in both groups received an initial loading phase of 3 monthly IVR. Retreatment criteria for further injections performed by a masked examiner were as follows: 1) any intraretinal or subretinal fluid on OCT, 2) new or persistent hemorrhage, and 3) decrease in visual acuity. In the case of the absence of fluid on OCT or visual acuity drop, a fluorescein leakage of >25% of the lesion circumference or the expansion of CNV was needed for retreatment in suspicious cases.\n\nPatients in the RI group were given a bottle of eye drops of 0.5% indomethacin ophthalmic solution for self-administration, which was provided free of charge by Alfa Intes Srl (Casoria, Italy). Over the 12-month study period, indomethacin was administered at a dose of one drop in the study eye TID. To verify and increase their compliance, patients were asked to bring their used bottles of indomethacin during each visit.\n\nClinical evaluation\nThe following examinations were performed at each visit by a blinded examiner: 1) measurement of best-corrected visual acuity (BCVA) as measured by the Early Treatment Diabetic Retinopathy study letter score, 2) fully dilated slit-lamp ophthalmic examination, 3) OCT (Spectral Domain Spectralis OCT) measurement of CRT, and 4) evaluation of adverse ocular events. Fundus photography (fluorescein and indocyanine green angiography) was performed at baseline, 3 months, and 12 months and at any monthly visit between 4 and 11 months on the basis of retreatment criteria.\n\nEndpoints and outcome measures\nOutcome measures were as follows: 1) mean change in study eye visual acuity; 2) mean change in CRT; 3) mean number of IVR injections over the 6-month period; and 4) adverse ocular events at 12 months.\n\nStatistical analyses\nTo determine if there was a significant difference in changes in BCVA and CRT, repeated measures of analysis of variance with Greenhouse–Geisser and Bonferroni corrections were performed. Independent samples t-tests were conducted to determine the statistical significance of differences in visual acuity, CRT, and number of injections between the RM and RI groups. All statistical analyses were performed using the SPSS software V.20 (IBM Corporation, Armonk, NY, USA). P-values <0.05 were considered significant, and all values are reported as mean ± standard deviation.\n\nResults\nBaseline demographic and clinical data of the participants are shown in Table 1. In general, the baseline demographics between the two groups were well matched, with no significant differences between the groups. All 58 patients completed the study.\n\nVisual acuity\nThe mean BCVA score improved significantly in both treatment groups, with the largest mean change observed in the RI group from baseline (Figure 1).\n\nThe mean change in BCVA from baseline to 12 months was −0.12±0.04 LogMAR in the RM group (P=0.04) and −0.20±0.04 LogMAR in the RI group (P=0.001), with the degree of change being significantly different between the two groups (P=0.04).\n\nAt 12 months, the mean BCVA in the RI group (0.35±0.14 LogMAR) was significantly higher than that in the RM group (0.45±0.18 LogMAR; P=0.04). Table 2 shows the changes in visual acuity at key time points.\n\nCRT\nA constant and significant reduction in mean CRT was observed in the RM group (−101±12.6 µm; P<0.0001) and in the RI group (−134±14.8 µm; P<0.0001) from baseline to 12 months. Figure 2 shows the changes in CRT in both groups over the 12-month treatment period. At 12 months, the mean CRT in the RM group (316±41.2 µm) was significantly higher than that in the RI group (287±31.5 µm; P=0.004). Changes in CRT over the 12-month treatment period are shown in Table 2.\n\nNumber of injections\nThe mean number of required IVR injections was 7.38±0.78 in the RM group and 6.34±0.67 in the RI group (P<0.001).\n\nSafety and adverse events\nNo serious adverse events were observed during the study period. There was no significant difference in the number of adverse ocular events described by either group. Mild burning/stinging was reported more frequently in the RI group, while pain was similar between groups. Adverse ocular events are reported in Table 3. No issues regarding compliance with the indomethacin therapy were recorded for any patient.\n\nDiscussion\nThe results of this prospective pilot study suggest that the topical administration of indomethacin, when used in combination with ranibizumab, may produce further improvements in BCVA, retinal thickness, and the number of required IVR injections.\n\nAlthough anti-VEGF agents constitute the first line of therapy against CNV in AMD, topical NSAIDs targeting specific inflammatory processes have recently been tested both experimentally11,12 and clinically and have been found to ameliorate AMD more effectively and synergistically.7–9,13 Moreover, these results are supported by the recent finding of significant vitreous penetration by NSAIDs, which reach therapeutic concentrations that allow a significant reduction in PGE2 and IL-8 vitreous production.10,14,15\n\nWe believe that the combination of IVR and indomethacin has the potential to reduce the burden associated with monthly IVR injections. Indeed, the results of this pilot study suggest that the addition of topical 0.5% indomethacin may result in a significant reduction in the 12-month CRT in patients with neovascular AMD, with a small but significant BCVA improvement over IVR monotherapy.\n\nThe anatomical and functional improvements shown in this study are consistent with the results of previous similar studies with other topical NSAIDs, including ketorolac,7,8 bromfenac,9,13 and nepafenac.16 Although a comparison between different studies is not feasible, the results coming from this study show a greater synergistic effect with topical 0.5% indomethacin. This might be explained by lower PGE2 vitreous levels after treatment with 0.5% indomethacin, compared to 0.09% bromfenac and 0.1% nepafenac in a prospective, investigator-masked, and randomized study.10\n\nInterestingly, we observed that the addition of indomethacin resulted in a significant reduction in the number of IVR injections, which could be a pivotal class effect with NSAIDs. Moreover, this finding is consistent with a previous report by Gomi et al,9 wherein patients who were prescribed bromfenac in combination with IVR required one less IVR injection during the first 6 months of therapy. Reduced frequency of IVR injections, although slight, is greatly beneficial in light of chronic and expensive (the mean national Medicare drug payment per anti-VEGF injection in the USA is reported to be $1,078 per injection)17 intravitreal therapy, which can be associated with serious adverse events such as endophthalmitis, retinal tears, and retinal detachment.\n\nNo serious adverse events were reported in our study. The results show that the treatments were well tolerated in all groups, with a safety profile comparable to that observed in previous studies. Furthermore, compliance with eye drop use was very high and the incidence of reported adverse events was mild to moderate.\n\nOur study has a few limitations: first, we included a limited number of patients in a pilot study design. Second, the evaluation of adverse events was limited to eye and headache symptoms. Third, we only assessed indomethacin TID. Further studies with a larger sample size, various dosing regimens, and more in-depth follow-up are warranted to validate the results of this pilot study, especially considering the substantial visual decline during the late stages of neovascular AMD.18\n\nConclusion\nThe results of this pilot study suggest that topical 0.5% indomethacin administered TID with IVR has an additive effect on CRT reduction in CNV. As previously reported, further larger studies are needed to confirm these data, especially evaluating the long-term efficacy of NSAIDs because AMD is a chronic disease with an inflammatory component. In particular, careful attention should be paid to the corneal complications associated with long-term use of topical NSAIDs.\n\nAcknowledgments\nThis study was presented in the AAO 2016 Meeting; Chicago, IL, USA. October 15, 2016 – October 18, 2016.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Change in visual acuity in both groups over 12 months of treatment.\n\nNotes: The red line indicates best-corrected visual acuity in patients treated with monthly 0.5 mg intravitreal ranibizumab and 0.5% indomethacin eye drops three times a day, and the blue line indicates best-corrected visual acuity in patients treated with monthly 0.5 mg intravitreal ranibizumab monotherapy. Mean values with standard error bars are shown for each time point.\n\nFigure 2 Change in central retinal thickness in both groups over 12 months of treatment.\n\nNotes: The red line indicates treatment with intravitreal ranibizumab and 0.5% indomethacin eye drops three times a day, and the blue line indicates intravitreal ranibizumab monotherapy. Mean values with standard error bars are shown for each time point.\n\nTable 1 Baseline patient characteristics\n\n\tRM group\n(n=29)\tRI group\n(n=29)\t\nSex, n (%)\t\t\t\n Male\t13 (44.8)\t12 (41.4)\t\n Female\t16 (55.2)\t17 (58.6)\t\nAge (years)\t\t\t\n Mean ± SD\t75.1±8.9\t75.0±7.1\t\n Range\t59–87\t58–83\t\nVisual acuity\t\t\t\n Mean ± SD (LogMAR)\t0.56±0.25\t0.56±0.29\t\n Range\t0.1–1\t0.1–1\t\nCRT (µm)\t\t\t\n Mean ± SD\t417±81.9\t422±73.6\t\nLesion composition, n (%)\t\t\t\n Classic/predominantly classic\t13 (44.8)\t12 (41.4)\t\n Minimally classic/occult\t16 (55.2)\t17 (58.6)\t\nNotes: RM group: monotherapy with monthly 0.5 mg intravitreal ranibizumab injections; RI group: monthly 0.5 mg intravitreal ranibizumab injections with topical indomethacin 0.5% eye drops three times a day.\n\nAbbreviations: CRT, central retinal thickness; RI, ranibizumab plus indomethacin; RM, ranibizumab monotherapy.\n\nTable 2 Changes in visual acuity and central retinal thickness over 12 months of treatment\n\n\tBaseline\t2 months\t4 months\t6 months\t8 months\t10 months\t12 months\t\nVisual acuity (mean ± SD)\t\n RM group\t0.56±0.25\t0.47±0.22*\t0.45±0.24*\t0.42±0.20*\t0.42±0.20*\t0.42±0.20*\t0.45±0.18*\t\n RI group\t0.56±0.29\t0.43±0.19*\t0.40±0.20*\t0.38±0.17*\t0.36±0.14*\t0.35±0.13*\t0.35±0.14*\t\n P-value\t0.83\t0.43\t0.39\t0.41\t0.18\t0.14\t0.04\t\nCRT (mean ± SD)\t\n RM group\t417±82\t338±50*\t335±49*\t327±52*\t322±39*\t326±38*\t316±41*\t\n RI group\t422±74\t327±37*\t309±43*\t300±43*\t293±36*\t290±33*\t287±32*\t\n P-value\t0.93\t0.35\t0.03\t0.03\t0.005\t<0.001\t0.004\t\nNotes:\nP-values presented are for the difference between the two groups. RM group: monotherapy with monthly 0.5 mg intravitreal ranibizumab injections; RI group: monthly 0.5 mg intravitreal ranibizumab injections with topical indomethacin 0.5% eye drops three times a day.\n\n* P<0.05 compared with baseline value for the same group.\n\nAbbreviations: CRT, central retinal thickness; RI, ranibizumab plus indomethacin; RM, ranibizumab monotherapy.\n\nTable 3 Ocular adverse events in the study eyes during the 12-month study period\n\n\tRM group, n (%)\tRI group, n (%)\t\nAbnormal sensation\t9 (31)\t12 (41)\t\nBurning/stinging\t14 (48)\t16 (55)\t\nEye pain\t4 (14)\t4 (14)\t\nItchy eye\t6 (21)\t8 (28)\t\nHeadache\t4 (14)\t3 (10)\t\nSore eyelid\t4 (14)\t4 (14)\t\nRetinal hemorrhage\t1 (3)\t0 (0)\t\nForeign body sensation\t10 (34)\t16 (55)\t\nConjunctivitis\t6 (21)\t4 (14)\t\nDry eye\t7 (24)\t9 (31)\t\nEye strain\t8 (28)\t9 (31)\t\nLight sensitivity\t12 (41)\t11 (38)\t\nFloaters\t15 (30)\t14 (48)\t\nNotes: RM group: monotherapy with monthly 0.5 mg intravitreal ranibizumab injections; RI group: monthly 0.5 mg intravitreal ranibizumab injections with topical indomethacin 0.5% eye drops three times a day.\n\nAbbreviations: RI, ranibizumab plus indomethacin; RM, ranibizumab monotherapy.\n==== Refs\nReferences\n1 Klein R Klein BEK Knudtson MD Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis Ophthalmology 2006 113 3 373 380 16513455 \n2 D’Amico DJ Diseases of the retina N Engl J Med 1994 331 2 95 106 8208273 \n3 Rosenfeld PJ Brown DM Heier JS Ranibizumab for neovascular age-related macular degeneration N Engl J Med 2006 355 14 1419 1431 17021318 \n4 Heier JS Brown DM Chong V Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration Ophthalmology 2012 119 12 2537 2548 23084240 \n5 Nita M Grzybowski A Ascaso FJ Huerva V Age-related macular degeneration in the aspect of chronic low-grade inflammation (pathophysiological parainflammation) Mediators Inflamm 2014 2014 930671 25214719 \n6 Lin T Walker GB Kurji K Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye Cytokine 2013 62 3 369 381 23601964 \n7 Semeraro F Russo A Delcassi L Treatment of exudative age-related macular degeneration with ranibizumab combined with ketorolac eyedrops or photodynamic therapy Retina 2015 35 8 1547 1554 25784358 \n8 Russo A Costagliola C Delcassi L Romano MR Semeraro F A randomised controlled trial of ranibizumab with and without ketorolac eyedrops for exudative age-related macular degeneration Br J Ophthalmol 2013 97 10 1273 1276 23873901 \n9 Gomi F Sawa M Tsujikawa M Nishida K Topical bromfenac as an adjunctive treatment with intravitreal ranibizumab for exudative age-related macular degeneration Retina 2012 32 9 1804 1810 22718152 \n10 Russo A Morescalchi F Vezzoli S Reduction of vitreous prostaglandin E2 levels after topical administration of indomethacin 0.5%, bromfenac 0.09%, and nepafenac 0.1 Retina Phila Pa 2016 36 6 1227 1231 \n11 Kim SJ Toma HS Inhibition of choroidal neovascularization by intravitreal ketorolac Arch Ophthalmol 2010 128 5 596 20457981 \n12 Schoenberger SD Kim SJ Nonsteroidal anti-inflammatory drugs for retinal disease Int J Inflamm 2013 2013 1 8 \n13 Flaxel C Schain MB Hamon SC Francis PJ Prospective randomized controlled trial of combination ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration: a pilot study Retina 2012 32 3 417 423 21862953 \n14 Schoenberger SD Kim SJ Sheng J Calcutt MW Reduction of vitreous prostaglandin E2 levels after topical administration of ketorolac 0.45% JAMA Ophthalmol 2014 132 2 150 154 24264034 \n15 Schoenberger SD Kim SJ Shah R Sheng J Cherney E Reduction of interleukin 8 and platelet-derived growth factor levels by topical ketorolac, 0.45%, in patients with diabetic retinopathy JAMA Ophthalmol 2014 132 1 32 37 24336915 \n16 Chen E Benz MS Fish RH Use of nepafenac (Nevanac) in combination with intravitreal anti-VEGF agents in the treatment of recalcitrant exudative macular degeneration requiring monthly injections Clin Ophthalmol 2010 4 1249 1252 21151329 \n17 Erie JC Barkmeier AJ Hodge DO Mahr MA High variation of intravitreal injection rates and medicare anti-vascular endothelial growth factor payments per injection in the United States Ophthalmology 2016 123 6 1257 1262 26976701 \n18 Rofagha S Bhisitkul RB Boyer DS Sadda SR Zhang K SEVEN-UP Study Group Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP) Ophthalmology 2013 120 11 2292 2299 23642856\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "12()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "central retinal thickness; choroidal neovascularization; indomethacin; inflammation; ranibizumab",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "587-591",
"pmc": null,
"pmid": "29628756",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "23084240;24264034;21151329;23601964;8208273;25214719;24336915;23873901;21862953;26976701;22718152;23642856;17021318;20457981;26562569;16513455;25784358",
"title": "Combination of ranibizumab and indomethacin for neovascular age-related macular degeneration: randomized controlled trial.",
"title_normalized": "combination of ranibizumab and indomethacin for neovascular age related macular degeneration randomized controlled trial"
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"activesubstancename": "RANIBIZUMAB"
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"abstract": "A 72-year-old woman was admitted for a routine elective total knee replacement. By day 1 postoperative, she became hyponatraemic following an Addisonian crisis, leading to an admission into the intensive therapy unit (ITU). It was later during this stay in the ITU and on a retrospective drug history review that she was found to have taken clobetasol, a high strength topical steroid cream over the past 2 years. The authors alert the reader to the importance of specially asking patients about their use of current or recent topical steroid creams as they may not always volunteer this information. Sudden withdrawal of steroid supplementation in these patients in the preoperative period may result in catastrophic consequences.",
"affiliations": "Department of Trauma and Orthopaedics, East Kent University Hospitals, Margate, UK.",
"authors": "Robati|Shibby|S|;Shahid|Mohammad Kamren|MK|;Vella|Adrian|A|;Vella|Adrien|A|;Rang|Simon|S|",
"chemical_list": "D005938:Glucocorticoids; D002990:Clobetasol",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2014()",
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"mesh_terms": "D000368:Aged; D019645:Arthroplasty, Replacement, Knee; D002990:Clobetasol; D017558:Elective Surgical Procedures; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007010:Hyponatremia; D011183:Postoperative Complications; D011300:Preoperative Care; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101526291",
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"pmid": "24632903",
"pubdate": "2014-03-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1125562;3656312",
"title": "Importance of a thorough drug history in presurgical patients.",
"title_normalized": "importance of a thorough drug history in presurgical patients"
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"companynumb": "GB-ACTAVIS-2015-04885",
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"activesubstancename": "LISINOPRIL"
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"abstract": "OBJECTIVE\nPrevious small studies have been reassuring regarding the pregnancy safety of hydroxychloroquine. One recent report found an increase in major birth defects at doses ≥400 mg/day. This study was undertaken to examine pregnancy outcomes following use of hydroxychloroquine.\n\n\nMETHODS\nPregnant women prospectively enrolled in MotherToBaby/OTIS Pregnancy Studies exposed to hydroxychloroquine were selected. Disease-matched and healthy comparison groups without hydroxychloroquine exposure were randomly selected from the same source using a 1:1 ratio. Data were collected through interviews, medical records, and dysmorphology examinations. Outcomes were major and minor birth defects, spontaneous abortion, preterm delivery and infant growth.\n\n\nRESULTS\nBetween 2004 and 2018, 837 pregnancies met criteria for inclusion, 279 exposed to hydroxychloroquine and 279 in each comparison group. Sixty pregnancies (7.2%) were lost-to-follow-up. Among live births, 20/232 (8.6%) with first-trimester hydroxychloroquine exposure had a major birth defect compared to 19/256 (7.4%) in the disease-matched group (Odds Ratio (OR) 1.18, 95% Confidence Interval (CI) 0.61, 2.26), and 13/239 (5.4%) in the healthy group (adjusted OR 0.76, 95% CI 0.28, 2.05). Risks did not differ at doses ≥400 mg/day. No pattern of birth defects was identified. There were no differences in rates of spontaneous abortion or preterm delivery. Growth deficiency measures did not differ in the hydroxychloroquine-exposed vs. disease-matched group, except birth head circumference (adjusted OR 1.85, 95% CI 1.07, 3.20).\n\n\nCONCLUSIONS\nWe found no evidence of an increased risk for structural defects or other outcomes with hydroxychloroquine, with the exception of birth head circumference. For women treated with hydroxychloroquine, these findings are reassuring.",
"affiliations": "Department of Pediatrics, University of California San Diego, La Jolla, CA.;Department of Pediatrics, University of California San Diego, La Jolla, CA.;Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, CA.;Department of Pediatrics, University of California San Diego, La Jolla, CA.;Department of Pediatrics, University of California San Diego, La Jolla, CA.;Department of Pediatrics, University of California San Diego, La Jolla, CA.;Department of Pediatrics, University of California San Diego, La Jolla, CA.;Department of Pediatrics, University of Washington, Seattle, WA.;Deparment of Pediatrics, Saint Louis University, St. Louis, MO.;Department of Pediatrics, State University of New York at Buffalo, Buffalo, NY.;Medical Genetics, University of Vermont Medical Center, Burlington, VT.;Department of Pediatrics, University of California San Diego, La Jolla, CA.",
"authors": "Chambers|Christina D|CD|https://orcid.org/0000-0003-4675-7722;Johnson|Diana L|DL|;Xu|Ronghui|R|;Luo|Yunjun|Y|;Felix|Robert|R|;Fine|Minh|M|;Lessard|Chloe|C|;Adam|Margaret P|MP|;Braddock|Stephen R|SR|;Robinson|Luther K|LK|;Burke|Leah|L|;Jones|Kenneth Lyons|KL|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/art.42015",
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"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
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"medline_ta": "Arthritis Rheumatol",
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"pmid": "34725951",
"pubdate": "2021-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Birth outcomes in women who have taken hydroxycholoroquine in pregnancy: a prospective cohort study.",
"title_normalized": "birth outcomes in women who have taken hydroxycholoroquine in pregnancy a prospective cohort study"
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"activesubstancename": "HYDROXYCHLOROQUINE"
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"abstract": "Poor delimitation from the viable brain, great genetic heterogeneity, lack of tumor vascularisation are factors that preclude intravenous chemotherapy. Interstitial chemotherapy could be a strategy to avoid a blood-brain barrier and to assure a minimal dose concentration of the chemotherapy agent. Doxorubicin might be devoid of neurotoxic effects and still efficient on remaining far-infiltrated tumor cells.",
"affiliations": "Neurosurgery Department Institute of Neurology Institute of Neurology and Neurosurgery Chisinau Moldova.;Neurosurgery Department Institute of Neurology Institute of Neurology and Neurosurgery Chisinau Moldova.;Biochemistry Department Nicolae Testemiţanu State University of Medicine and Pharmacy Chisinau Moldova.;Neurosurgery Department Institute of Neurology Institute of Neurology and Neurosurgery Chisinau Moldova.",
"authors": "Matcovschii|Valerii|V|;Lisii|Dan|D|https://orcid.org/0000-0002-1141-1441;Gudumac|Valentin|V|;Dorosenco|Stanislav|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2546",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2546CCR32546Case ReportCase ReportsSelective interstitial doxorubicin for recurrent glioblastoma MATCOVSCHII et al.Matcovschii Valerii \n1\nLisii Dan https://orcid.org/0000-0002-1141-1441\n1\nlisii.dan@gmail.com Gudumac Valentin \n2\nDorosenco Stanislav \n1\n\n1 \nNeurosurgery Department\nInstitute of Neurology\nInstitute of Neurology and Neurosurgery\nChisinau\nMoldova\n\n2 \nBiochemistry Department\nNicolae Testemiţanu State University of Medicine and Pharmacy\nChisinau\nMoldova\n* Correspondence\n\nDan Lisii, Institute of Neurology and Neurosurgery, Korolenco 2 street, Chisinau, MD 2022, Moldova.\n\nEmail: lisii.dan@gmail.com\n19 11 2019 12 2019 7 12 10.1002/ccr3.v7.122520 2525 15 4 2019 28 8 2019 29 8 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nPoor delimitation from the viable brain, great genetic heterogeneity, lack of tumor vascularisation are factors that preclude intravenous chemotherapy. Interstitial chemotherapy could be a strategy to avoid a blood‐brain barrier and to assure a minimal dose concentration of the chemotherapy agent. Doxorubicin might be devoid of neurotoxic effects and still efficient on remaining far‐infiltrated tumor cells.\n\nPoor delimitation from the viable brain, great genetic heterogeneity, lack of tumor vascularisation are factors that preclude intravenous chemotherapy. Interstitial chemotherapy could be a strategy to avoid a blood‐brain barrier and to assure a minimal dose concentration of the chemotherapy agent. Doxorubicin might be devoid of neurotoxic effects and still efficient on remaining far‐infiltrated tumor cells.\n\n\ndoxorubicinglioblastomainterstitial chemotherapyrecurrencestem cell culture source-schema-version-number2.0cover-dateDecember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:29.12.2019\n\n\nMatcovschii \nV \n, \nLisii \nD \n, \nGudumac \nV \n, \nDorosenco \nS \n. Selective interstitial doxorubicin for recurrent glioblastoma . Clin Case Rep . 2019 ;7 :2520 –2525 . 10.1002/ccr3.2546\n==== Body\n1 INTRODUCTION\nThe objective of this paper is to present two clinical cases of grade III and IV glioma patients that were treated with interstitial doxorubicin after undergoing two surgeries to remove a recurring tumor. Doxorubicin was tested in vitro in the primary cell culture that was obtained from the recurrent tumor. The patients presented with a recurrent frontal malignant glioma have undergone repeated surgeries. The drug was administered via a silicone catheter into the bed of the removed tumor in the interval between seven and 10 days postop, and both patients showed significant clinical improvements after three sessions of interstitial chemotherapy. After a month and a half, the first patient experienced sudden clinical decline which leads to a coma and ultimately, a lethal outcome. The morpho‐pathological analysis found small hemorrhagic lesions in the thalamus. There are no signs of the tumor recurrence in the second patient, 2 months post‐treatment. Doxorubicin could be an effective drug for treating glial brain tumors both in vitro and in a clinical setting. An interstitial chemotherapy with doxorubicin is possible if all the methodological steps are properly undertaken. In addition to that, micelles or liposomes need to be tested as potentially neurotoxicity‐free forms of doxorubicin.\n\nGlioblastoma is the most malignant tumor of the brain, characterized by high recurrence rates and a lethal outcome within 1.5‐2 years after surgical removal.\n\nSeveral controlled studies which focused on the survival rate and the length of a relapse‐free period indicated a lack of statistically significant improvements in patients that were administered the latest chemo and radiation therapy after surgery. Most commonly, the chemotherapy combination used is temozolomide, carmustine, and avastin. Currently, selective interstitial chemotherapy after the tumor removal entailing the implantation of a slowly absorbable carmustine wafers is gradually gaining interest.14\n\n\nSelective in situ chemotherapy, also called a convection method, is rarely proposed. In our cases, the drug was delivered via a silicone catheter into the bed of the removed tumor in the first seven to 10 days postsurgery. Substantial downsides of the systemic chemotherapy for case as of glioblastoma are as follows:\nThere is no evaluation of the sensitivity of the glioblastoma cells to the specific chemo treatment being administered.\n\nSystemic chemotherapy does not meet the requirements of selective targeting of glioblastoma cells and instead it attacks the entire immune system and the rapidly dividing intestinal epithelium cells, myelo and lymphopoietic bone marrow cells, gonads, and hair follicles.\n\nThe drug concentration in the tumoral tissue varies greatly, and it is noncytotoxic between the administration intervals. This method does not allow an effective dosage control in the tumors.\n\nThe drugs used during systemic chemotherapy are required to cross the blood‐brain barrier.\n\nThis type of therapy is conducive to the appearance of drug‐resistant glioblastoma cloned cells, which need to be targeted with a much higher chemotherapy dose.\n\n\n\n\nAs opposed to a systemic approach, selective interstitial chemotherapy has a number of advantages:\nThe highest concentration of the chemotherapeutic agent is delivered directly into the bed of the remaining tumor.\n\nWhen compared to a systemic approach, the dose of the administered drug decreases up to ten times, thus minimizing the potential of immunosuppressive side effects.\n\nThe choice of doxorubicin, which is a drug that does not pass the blood‐brain barrier, allows us to target the glioblastoma cells in a more precise manner, while avoiding systemic immunosuppressive and cytotoxic side effects.\n\nAn incremental administration allows for more frequent injections, which in turn allows to maintain the required concentration with less jumps.\n\nDecreased risk of infection, as doxorubicin is an anthracycline antibiotic\n\n\n\n\n2 CASE PRESENTATIONS\nWe present two female patients aged 46 and 64 (“A” and “B”, respectively), who were diagnosed with grade III and IV glial intracerebral tumors of the frontal lobes.\n\nPatient A (grade III glioma) undergone radiation therapy (60Gr) 1 month later. A CT performed after 4 months revealed a tumor recurrence with progressive growth. Clinically, she presented with partial Jackson seizures with secondary generalization, right‐sided leg hemiparesis and oligoaphasia.\n\nThe tumor regrowth was detected in patient B (grade IV glioma) after 3 months following the initial surgery, which then presented itself in the form of deep hemiplegia. Patient B was prescribed whole brain radiation therapy (Figure 1).\n\nFigure 1 The removal of the recurrent glioblastoma with the insertion of the port. A1, A2, MRI patient A and (B1, B2) MRI patient B, glioblastoma recurrence 1 y after initial surgery. A3 and B3, CT scan of patient A and B, respectively, after gross total resection and insertion of the port‐a‐cath., in the bed of the tumor\n\nBoth patients underwent another surgery, 1 year after the initial operation in the first case and only 5 months later in the second case. After obtaining approval from the ethics committee and getting the patients’ consent, a decision was made to perform selective interstitial chemotherapy following an internal protocol.\n\nThe operation of gross total resection was followed by subsequent installation of a “Celsite” port‐a‐catheter into the bed of the removed tumor (Figure 1).\n\n3 METHODS AND MATERIALS\nA sample of the tumor that was removed during the surgery served for glial stem isolation, in order to perform chemo‐sensitivity testing to doxorubicin. Initially, the tumor is mechanically dissociated with surgical blades. Then, fragments are passed twice through 1.5 and 0.5 mm cell diameter filters, prior to them being seeded in DMEM glucose media with 20% serum (taken from the patient's blood), gentamicin, and fluconazole (100 μg/mL). The cells were grown at a 3%‐5% CO2 level, 85% humidity, and a temperature of 37 degrees Celsius (Figure 2).\n\nFigure 2 Initial glioblastoma culture isolated from patient B (G4) (magnification ×200). B1, cell culture 1 wk after cultivation (arrow indicate the initial fragment of the tumor). B2, fibroblasts seen in the cell culture after 2 wks (arrows). B3, the cell culture at 4 wks after three passage (the arrows indicate the mitoses) \n\nAfter a period of growth lasting for 2‐3 weeks, the glioblastoma cells were selected through a several passages technique and then transferred onto a 24‐well cell culture plate. Each well contained anywhere from 50 up to 150 cells. Doxorubicin was added into each well at concentrations starting at 0.00002 mg/mL and up to 0.02 mg/mL. The cells status was verified microscopically at 1, 4, 24 hours, 3, 4, and 30 days. What was being taken into account were the number and the degree of damage of the glioblastoma cells depending on the exposure time to doxorubicin and the different concentrations. At 0.002 mg/mL, doxorubicin caused visible partial cell damage as early as a couple of hours; significant damage after 24 hours and full lysis after 3‐4 days. What is worth mentioning is that at lower concentrations (0.0002 mg/mL), the destruction of the glioblastoma cells starts later but reaches full lysis in the same 3‐ to 4‐day interval (Figure 3). In clinical settings, the recommended dose of doxorubicine administered intravenously is 25 mg/m2 per day, with the maximum amount per week reaching 100 mg. Considering the average volume of the removed tumor cavity, the sensitivity of doxorubicine in vitro and in order to avoid potential toxicity, the dosage that was used for the interstitial delivery was one of 0.1 mg/mL, which is ten times lower than the regular intravenous dose. The doxorubicin solution was prepared ex tempore, using 1 mg of the drug per 10 mL of water per injection.\n\nFigure 3 Glioblastoma sensitivity assay to Doxorubicin, patient B (magnification X200). A, 24 h after the injection of doxorubicin, cell damages shown by arrows (C = 0.002 mg/mL). B, An almost full glioblastoma cell lysis after 4 d since the addition of doxorubicin (C = 0.0002 mg/mL). C, Control cells, undamaged glioblastoma cells, day 7\n\nTen days after the second surgery, the patients were administered their first session of interstitial chemotherapy, with the first procedure carried out in the intensive care unit. The doxorubicin solution was injected through the port catheter using an electric syringe pump for thirty minutes, recorded on video and with the following metrics closely monitored: the patient's pulse, blood pressure, body temperature, neurological, and mental status. The patients were subjected to 3 sessions of 1 mg of doxorubicine introduced in the cavity of the removed tumor. The control CT performed after the 10 days of the procedure showed no signs of cerebral edema or any dislocation of the brain structures. Both patients were discharged in a satisfactory condition.\n\n4 RESULTS\n\nPatient A: A control MRI with a contrasting agent was performed on patient A 1 month after the second surgery, which showed a clear delimitation between the resected tumor and the brain tissue. No signs of the presence of the tumor were detected (Figure 4). Forty‐five days after the second surgery, patient A started experiencing severe headaches comparable to blows to the head and after a couple of hours, the patient became drowsy. The blood pressure dropped to 70/50 mm. HR. Art., the temperature dropped to 35.1 degrees C. The next day, the patient developed a coma (severity 1‐2), which lasted for 10 days, with a lethal outcome.\n\nFigure 4 A1, A2, A3, MRI of patient A and (B1, B2, B3) of patient B, respectively, control after the second surgery and 3 sessions of selective interstitial chemotherapy via the port‐catheter\n\nA pathological examination of the brain showed no macroscopic signs of the tumor. The findings comprised of massive glial necrotic changes to the brain tissue along the periphery of the removed cavity, as well as a small parenchymal hemorrhage in the posterior sections of the lateral walls of the third ventricle, over the mammary bodies in the posterior hypothalamus, around 10 mm in diameter. A histological examination of the areas of the cerebral cortex and partially white matter next to the border of the removed tumor revealed areas of massive necrosis and gliosis. An intense area of hemorrhage was found in the wall of the third ventricle in the hypothalamus region, with a large quantity of fibrins and lymphocytes.\n\n\nPatient B: Clinical examination of the patient during the follow‐up was characterized by a general improvement and a gradually reducing hemiparesis. A dose of 1 mg of doxorubicin was administered to her once a week in an outpatient setting. A control MRI once month after the surgery did not show any signs of the tumor (Figure 4).\n\n5 DISCUSSION\nFrom a surgical point of view, the implantation of the port‐catheter in the bed of the removed tumor is a simple and safe procedure. One potential complication is meningoencephalitis, due to the presence of a foreign body (the catheter). However, it could be reduced by administering a solution of dioxine through the catheter. Doxorubicin itself is a powerful wide‐spectrum antibiotic that prevents the development and spread of infection. In the early implementation of the treatment with carmustine, the reported occurrence of postoperative infection was significantly higher.3, 13 The overall incidence of serious intracranial infection was 2.2%, more common in the Gliadel than in placebo arm (3.6% and 0.89%, respectively).\n\nA slow delivery of doxorubicin with an electric syringe pump through the port‐catheter over the course of 30‐60 minutes did not result in clinical or vegetative reactions in the subjects. The lethal outcome in the first case occurred 45 days after the surgery and was caused by a small parenchymal hemorrhage in the posterior hypothalamus; which lead to distinct vegetative disorders, dramatic drops in blood pressure, hypothermia with the subsequent development of coma. One could explain such a delay in complications by a repetitive accumulation of the doxorubicin in the third ventricle, probably caused by the drain's proximity with the lateral cavity ventricle. Several reports showed that an inadvertently intrathecal use of doxorubicin caused disastrous effects on the spinal cord.1 In two cases, doxorubicin caused a severe myelitis with only a partial recovery. Still, in both cases the dose of doxorubicin was much higher, (×10) compared with the dose during interstitial delivery. 8, 11\n\n\nThree sessions of such therapy did not result in cerebral edema, thoroughly verified by a CT control scan; on the contrary, we noted a faster reduction of the brain edema after the doxorubicin perfusion. Repeated blood tests did not reveal any systemic hematopoietic changes. The dose delivered was determined through the cytotoxic sensitivity of the glioblastoma cells following the tumor culture in vitro assay. The quantity of the doxorubicin introduced into the bed of the tumor per session was around 1 mg.\n\nDoxorubicin is mostly indicated in lymphoma, leukemia, breast, and ovarian cancers, but has little clinical interest in cerebral malignant diseases.11 Several assays with doxorubicin in vitro, showed a quasi‐necrotic effect on glioblastoma cells with high selectivity at low doses.10 To date, there are no clinical data on doxorubicin administration in patients diagnosed with glioblastoma, either via systemic administration or interstitially. There are several essays on animals with promising results: significantly prolonging survival in bearing brain tumor in rats by delivering doxorubicin locally.10\n\n\nTargeting vascular drug delivery through brain‐blood barrier (BBB) modification represents a promising strategy for the treatment of glioblastoma.5, 7 In canines and rodents, BBB modification revealed a good penetration of the doxorubicin in the cerebrum. Alternatively, no drug was detected in the absence of BBB modification.5 For the same study, neuropathological examination gave the evidence of necrosis and hemorrhagic infarcts, pointing out significant neurotoxicity of doxorubicin at doses as small as of 0.1 mg/kg. A low passage of doxorubicin through BBB (blood‐brain barrier) explains its high general toxicity and low intratumoral dose levels. Local interstitial delivery could avert systemic complications.9, 15\n\n\nSome preferred doxorubicin forms are liposomes or micelles. The drug carrier system could provide neuroprotection effect, as stressed in assays with doxorubicin‐loaded monosialoganglioside micelles.4 Gangliosides (GM1) play neuroprotective and neurorestorative roles, as well as induce neurogenesis and promote cell differentiation.2, 6, 14\n\n\nThe same doxorubicin‐loaded micelles administered intravenously favor central nervous system doxorubicin accumulation. However, a preferential accumulation in central nervous system might not be enough to prevent systemic complications.12 The absence of patent vessels and infiltrative growth pattern of glial tumors represent a strong argument for local delivery versus systemic one.\n\n6 CONCLUSION\nLocal interstitial doxorubicin could be clinically relevant in treating recurrent glioblastomas. Further clinical and experimental studies are needed to assert the role of interstitial chemotherapy using a port‐catheter after glioblastoma removal. Interstitial doxorubicin might address the main issue of glioblastoma recurrences by increasing the length of a relapse‐free period and prolonging the life of the patients. Micelles or liposomes should be tested as potentially neurotoxicity‐free forms of doxorubicin.\n\nCONFLICT OF INTEREST\nNo potential conflict of interest was reported by the authors.\n\nAUTHOR CONTRIBUTIONS\nVM: involved in neurosurgical procedures and acquisition, analysis, interpretation of data of the work and revision. DL: involved in neurosurgical procedures and acquisition, analysis and interpretation of data of the work. VG: involved in stem cell isolation procedures and acquisition, analysis and revision of data. SD: involved in neurosurgical procedures and acquisition, analysis and interpretation of data of the work.\n==== Refs\nREFERENCES\n1 \n\nAricó \nM \n, \nNespoli \nL \n, \nPorta \nF \n, \nCaselli \nD \n, \nRaiteri \nE \n, \nBurgio \nGR \n. Severe acute encephalopathy following inadvertent intrathecal doxorubicin administration . Med Pediatr Oncol . 1990 ;18 (3 ):261 ‐263 .2329972 \n2 \n\nAriga \nT \n, \nMcDonald \nMP \n, \nYu \nRK \n. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease–a review . J Lipid Res . 2008 ;49 (6 ):1157 ‐1175 .18334715 \n3 \n\nBenjamin \nRS \n, \nRiggs \nCE \nJr\n, \nBachur \nNR \n. Pharmacokinetics and metabolism of doxorubicin in man . Clin Pharmacol Ther . 1973 ;14 (4 ):592 ‐600 .4723268 \n4 \n\nJoseph \nPJ \n, \nReyes \nMR \n. Dorsal column myelopathy following intrathecal chemotherapy for acute lymphoblastic leukemia . J Spinal Cord Med . 2014 ;37 (1 ):107 ‐113 .24090227 \n5 \n\nKanako \nI \n, \nTakahide \nA \n, \nMari \nH \n, et al. Interstitial pneumonitis induced by pegylated liposomal doxorubicin in a patient with recurrent ovarian cancer . Med Oncol . 2012 ;29 (2 ):1255 ‐1257 .21390517 \n6 \n\nLesniak \nMS \n, \nUpadhyay \nU \n, \nGoodwin \nR \n, \nTyler \nB \n, \nBrem \nH \n. Local delivery of doxorubicin for the treatment of malignant brain tumors in rats . Anticancer Res . 2005 ;25 (6B ):3825 ‐3831 .16312042 \n7 \n\nMeng \nY \n, \nSuppiah \nS \n, \nSurendrakumar \nS \n, \nBigioni \nL \n, \nLipsman \nN \n. Low‐intensity MR‐guided focused ultrasound mediated disruption of the blood‐brain barrier for intracranial metastatic diseases . Front Oncol . 2018 ;8 :338 .30211117 \n8 \n\nMerker \nPC \n, \nLewis \nMR \n, \nWalker \nMD \n, \nRichardson \nEP \nJr\n. Neurotoxicity of doxorubicin (doxorubicin) perfused through the cerebrospinal fluid spaces of the rhesus monkey . Toxicol ApplPharmacol . 1978 ;44 (1 ):191 ‐205 .\n9 \n\nNeuwelt \nEA \n, \nPagel \nM \n, \nBarnett \nP \n, \nGlassberg \nM \n, \nFrenkel \nEP \n. Pharmacology and toxicity of intracarotid doxorubicin administration following osmotic blood‐brain barrier modification . Cancer Res . 1981 ;41 (11 Pt 1 ):4466 ‐4470 .6796261 \n10 \n\nPerry \nJ \n, \nChambers \nA \n, \nSpithoff \nK \n, \nLaperriere \nN \n. Gliadel wafers in the treatment of malignant glioma: a systematic review . Curr Oncol . 2007 ;14 (5 ):189 ‐194 .17938702 \n11 \n\nRose \nPG \n. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer . Oncologist . 2005 ;10 :205 ‐214 .15793224 \n12 \n\nVoulgaris \nS \n, \nPartheni \nM \n, et al. Intratumoral doxorubicin in patients with malignant brain gliomas . Am J Clin Oncol . 2002 ;25 (1 ):60 ‐64 .11823699 \n13 \n\nWestphal \nM \n, \nHilt \nDC \n, \nBortey \nE \n, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (bcnu) wafers (Gliadel wafers) in patients with primary malignant glioma . Neuro‐oncol . 2003 ;5 :79 ‐88 .12672279 \n14 \n\nWestphal \nM \n, \nRam \nZ \n, \nRiddle \nV \n, \nHilt \nD \n, \nBortey \nE \n, on behalf of the Executive Committee of the \nGliadel \n Study Group \n. Gliadel wafer in initial surgery for malignant glioma: long‐term follow‐up of a multicenter controlled trial . Acta Neurochir . 2006 ;148 :269 ‐275 .16482400 \n15 \n\nZou \nD \n, \nWang \nW \n, \nLei \nD \n, et al. Penetration of blood‐brain barrier and antitumor activity and nerve repair in glioma by doxorubicin‐loaded monosialoganglioside micelles system . Int J Nanomedicine . 2017 ;12 :4879 ‐4889 .28744122\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "7(12)",
"journal": "Clinical case reports",
"keywords": "doxorubicin; glioblastoma; interstitial chemotherapy; recurrence; stem cell culture",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2520-2525",
"pmc": null,
"pmid": "31893093",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "28744122;2329972;24090227;18334715;97803;4723268;12672279;6796261;16482400;30211117;11823699;16312042;17938702;15793224;21390517",
"title": "Selective interstitial doxorubicin for recurrent glioblastoma.",
"title_normalized": "selective interstitial doxorubicin for recurrent glioblastoma"
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"abstract": "BACKGROUND\nAn increasing number of reports have documented the emergence of daptomycin-nonsusceptible Enterococcus in patients during daptomycin therapy. Even though several mechanisms for daptomycin-nonsusceptibility have been suggested, the potential genetic mutations which might contribute to the daptomycin-nonsusceptibility are not fully understood.\n\n\nMETHODS\nWe isolated a vancomycin-susceptible, daptomycin nonsusceptible Enterococcus faecium strain from a patient with acute lymphocytic leukemia who received high-dose daptomycin therapy for E. faecium endocarditis. Whole-genome sequencing analysis revealed mutations within genes encoding DNA repair proteins MutL and RecJ of the daptomycin-nonsusceptible Enterococcus strain which might have facilitated its emergence.\n\n\nCONCLUSIONS\nWe identified the mutations of DNA mismatch repair genes in a clinical isolate of daptomycin nonsusceptible E. faecium which emerged in spite of high-dose daptomycin therapy. The finding implicates the possible association of DNA repair mechanism and daptomycin resistance. Careful monitoring is necessary to avoid the emergence of daptomycin non-susceptible isolates of E. faecium and particularly in cases of long-term daptomycin use or in immunocompromised patients.",
"affiliations": "Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. kayokohayakawa@gmail.com.;Department of Hematology, National Center for Global Health and Medicine, Tokyo, Japan.;Department of Hematology, National Center for Global Health and Medicine, Tokyo, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Microbiology Laboratory, National Center for Global Health and Medicine, Tokyo, Japan.;Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.",
"authors": "Matono|Takashi|T|;Hayakawa|Kayoko|K|;Hirai|Risen|R|;Tanimura|Akira|A|;Yamamoto|Kei|K|;Fujiya|Yoshihiro|Y|;Mawatari|Momoko|M|;Kutsuna|Satoshi|S|;Takeshita|Nozomi|N|;Mezaki|Kazuhisa|K|;Ohmagari|Norio|N|;Miyoshi-Akiyama|Tohru|T|",
"chemical_list": "D017576:Daptomycin",
"country": "England",
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"doi": "10.1186/s13104-016-2003-9",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 200310.1186/s13104-016-2003-9Case ReportEmergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy Matono Takashi sincedec2012@gmail.com Hayakawa Kayoko 81-3-3202-7181kayokohayakawa@gmail.com Hirai Risen rhirai@ncgm.go.jp Tanimura Akira atanimura@ncgm.go.jp Yamamoto Kei kyamamoto@ncgm.go.jp Fujiya Yoshihiro yfujiya@ncgm.go.jp Mawatari Momoko mmawatari@ncgm.go.jp Kutsuna Satoshi skutsuna@ncgm.go.jp Takeshita Nozomi ntakeshita@ncgm.go.jp Mezaki Kazuhisa kmezaki@ncgm.go.jp Ohmagari Norio nohmagari@ncgm.go.jp Miyoshi-Akiyama Tohru takiyam@ri.ncgm.go.jp Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655 Japan Department of Hematology, National Center for Global Health and Medicine, Tokyo, Japan Microbiology Laboratory, National Center for Global Health and Medicine, Tokyo, Japan Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan 1 4 2016 1 4 2016 2016 9 1971 12 2015 22 3 2016 © Matono et al. 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\nAn increasing number of reports have documented the emergence of daptomycin-nonsusceptible Enterococcus in patients during daptomycin therapy. Even though several mechanisms for daptomycin-nonsusceptibility have been suggested, the potential genetic mutations which might contribute to the daptomycin-nonsusceptibility are not fully understood.\n\nCase presentation\nWe isolated a vancomycin-susceptible, daptomycin nonsusceptible Enterococcus faecium strain from a patient with acute lymphocytic leukemia who received high-dose daptomycin therapy for E. faecium endocarditis. Whole-genome sequencing analysis revealed mutations within genes encoding DNA repair proteins MutL and RecJ of the daptomycin-nonsusceptible Enterococcus strain which might have facilitated its emergence.\n\nConclusions\nWe identified the mutations of DNA mismatch repair genes in a clinical isolate of daptomycin nonsusceptible E. faecium which emerged in spite of high-dose daptomycin therapy. The finding implicates the possible association of DNA repair mechanism and daptomycin resistance. Careful monitoring is necessary to avoid the emergence of daptomycin non-susceptible isolates of E. faecium and particularly in cases of long-term daptomycin use or in immunocompromised patients.\n\nKeywords\nDaptomycinE. faeciumWhole-genome sequenceGrants for International Health Research26S-120Hayakawa Kayoko issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nDaptomycin (DAP) is a lipopeptide antibiotic that exhibits potent activity against gram-positive bacteria, including vancomycin-resistant enterococci (VRE); however, an increasing number of reports have documented the emergence of daptomycin-nonsusceptible Enterococcus (DNSE) in patients during DAP therapy [1–4]. Even though several mechanisms for daptomycin-non-susceptibility have been suggested [5, 6], the potential genetic mutations which might contribute to the daptomycin-nonsusceptibility are not fully understood. In this report, we describe vancomycin-susceptible, daptomycin non-susceptible Enterococcus (DNSE) faecium strain from a patient with acute lymphocytic leukemia who received high-dose DAP therapy. The whole-genome sequencing analysis revealed mutations within genes encoding DNA repair proteins MutL and RecJ.\n\nCase presentation\nA 32-year-old Japanese man with Philadelphia chromosome-positive acute lymphocytic leukemia (ALL) developed fever during chemotherapy with dasatinib and doxorubicin with dexamethasone for treatment of ALL relapse approximately 3 months after hematopoietic stem cell transplantation. The patient’s blood culture was positive for E. faecium, and, as he was allergic to vancomycin, teicoplanin therapy was initiated. Dasatinib and doxorubicin were discontinued immediately. The minimum inhibitory concentrations (MICs) of various antibiotics are listed in Table 1 (EFM01). Although the MIC of teicoplanin for the E. faecium strain was ≤2 mcg/ml, and the patient’s serum teicoplanin trough was maintained between 20 and 22 mcg/ml, E. faecium was consistently detected in his blood cultures for more than 3 weeks. In addition, the patient was neutropenic during this period, with neutrophil counts between 300 and 830 neutrophils/ml.Table 1 Susceptibility profile of resistance genes of Enterococcus faecium isolates\n\nIsolate\tResistance genes\tMinimum inhibitory concentrations (MIC) (μg/ml)/Interpretive criteriaa\n\t\n\nAac(6′)-Ii\n\t\nAnt(6)-Ia\n\t\nAph(3′)-III\n\t\nErmB\n\t\nMsrC\n\t\nTetM\n\tPCG\tABPC\tEM\tMINO\tVCM\tTEIC\tLVFX\tLZD\tDAP\t\nEFM01\t+\t+\t+\t+\t+\t+\t≥16/R\t≥16/R\t≥8/R\t8/I\t1/S\t≤2/S\t≥8/R\t≤2/S\t4/S\t\nEFM02\t+\t+\t+\t+\t+\t+\t≥16/R\t≥16/R\t≥8/R\t8/I\t1/S\t≤2/S\t≥8/R\t≤2/S\t256/–\t\n\nPCG penicillin G, ABPC ampicillin, MINO minocycline, VCM vancomycin, TEIC teicoplanin, LVFX levofloxacin, LZD linezolid, DAP daptomycin, S susceptible, I intermediate, R resistant\n\n\naMIC interpretive criteria, per the clinical and laboratory standards institute (CLSI; M100–S24) [20]\n\n\n\nAfter consulting the infectious disease service for recommendations on treating the persistent E. faecium infection, the treatment plan was modified to include gentamicin therapy (1.3 mg/kg every 12 h), and imaging studies and an endoscopy were ordered to identify the nidus of the persistent E. faecium bacteremia. A transthoracic echocardiogram subsequently revealed a vegetation, measuring a few millimeters in size, on the patient’s aortic valve. Meanwhile, chest and abdominal CT scans detected a thickened colon wall, but no other lesions, and a PET scan failed to identify a potential source of the infection. A colonoscopy, however, revealed erosion throughout the colonic mucosa, which was considered consistent with graft versus host disease and was considered the likely entry site of E. faecium into the bloodstream.\n\nAs the E. faecium bacteremia persisted for 2 weeks after initiation of the gentamicin therapy (gentamicin MIC was 16 mcg/ml) in combination with teicoplanin, the patient was switched to 10 mg kg−1 day−1 DAP [DAP; Etests indicated that the MIC of DAP for the E. faecium strain was 4 mcg/ml as in Table 1 (EFM01)]. After initiation of DAP therapy, the patient’s fever subsided and subsequent blood cultures were negative. As a result, after receiving the initial dose of DAP for 18 days, the dose was reduced to 6 mg kg−1 day−1. However, 1 day after reducing the dose, the patient developed fever again and his blood culture tested positive for E. faecium (DAP MIC, per Etest: 256 mcg/ml). The MICs for other antibiotics are listed in Table 1 (EFM02). DAP was therefore discontinued, and treatment with intravenous linezolid (600 mg every 12 h) was initiated. While blood cultures were negative after 2 days of linezolid therapy, the patient unfortunately passed away owing to exacerbation of the ALL at 26 days after initiation of treatment with linezolid.\n\nMolecular analysis of the daptomycin-susceptible (EFM01; isolated prior to the initiation of DAP) and daptomycin non-susceptible E. faecium (DNSE; EFM02) isolates was conducted in the Pathogenic Microbe Laboratory at the Research Institute of the National Center for Global Health and Medicine in Tokyo, Japan. The strains were cultured in brain heart infusion (BHI) broth overnight, and genomic DNA was purified using a DNeasy Blood & Tissue kit (Qiagen, Venlo, Netherlands). The genomes of the two isolates were then subjected to MiSeq sequencing using Nextera XT library kits (Illumina, Inc., San Diego, CA, USA), according to the manufacturer’s instructions. Approximately 1 million pair-end reads (301 base pairs [bp] × 2) were obtained from each genome and analyzed using CLC Genomics Workbench software (CLC bio, Aarhus, Denmark). The reads from each isolate were trimmed by screening for base quality (quality score limit = 0.05; reads that contained greater than two ambiguous nucleotides or that were less than 15 bp in length were removed), and then used to generate de novo genome assemblies, respectively. Meanwhile, the contigs were used as the reference genome. The reads from each isolate were then mapped to the reference genome, and variants were detected using CLC Genomics Workbench program that is based on the algorithm developed by Smith and Waterman (1981) [7]. For these analyses, the following detection parameters were used: 95 % coverage and more than 10 overlapping reads. Because the settings used can yield false-positive variants, each putative variant was manually confirmed by examining the mapping results. The resulting sequencing data were registered with the DNA Data Bank of JAPAN (DDBJ, accession number DRA03513). Furthermore, to annotate variants that were unique to the strains examined in this study, the genome sequence of E. faecium Aus0085 was used as a Ref. [8].\n\nThe MICs of multiple antimicrobials for the two E. faecium isolates, as well as the antimicrobial resistance genes encoded by these organisms, as identified by analysis of contigs using the ResFinder program [4], are summarized in Table 1. Comparison of the EFM01 and EFM02 genomes at SNP level based on whole genome sequencing indicated that EFM02 was derived from EFM01. While EFM02 contained 40 variants that were not present in EFM01, each of the variants identified in EFM01 were present in EFM02. The variants that resulted in amino acid substitutions within the genome of EFM02 compared to that of EFM01 are summarized in Table 2.Table 2 Nonsynonymous nucleotide mutations identified between the daptomycin non-susceptible Enterococcus faecium (EFM02) strain and the daptomycin-susceptible Enterococcus faecium (EFM01) strain\n\nGenes\t\nRecJ\n\t\nMutL\n\t\nFusA\n\t–\t\nHyuA\n\t\nDapB\n\t–\t\nManX\n\t\nYcaB\n\t\nEbpR\n\t\nlocus_tag\tEFAU085_01331\tEFAU085_00136\tEFAU085_00055\tEFAU085_00149\tEFAU085_00226\tEFAU085_00409\tEFAU085_00744\tEFAU085_00813\tEFAU085_01095\tEFAU085_01417\t\nPredicted gene products\tDNA repair protein\tDNA mismatch repair protein\tTranslation elongation factor G\tABC transporter\tHydantoinase/oxoprolinase\tDihydrodipicolinate reductase\tMembrane protein\tPTS system, Mannose/fructose/sorbose-specific IIAB component\tCalcium-translocating P-type ATPase, PMCA-type\tM protein trans-acting positive regulator\t\nPredicted amino acid change\tTyr434 Cys\tLeu286\tArg626 Cys\tGly190 Asp\tThr570 Ala\tAla190 Val\tPhe89 fs\tMet1\tAla108 fs\tPro199 Leu\t\nNucleotide mutation\t1301A > G\t1876C > T\t857T > A\t569G > A\t1708A > G\t569C > T\t260delT\t1A > G\t315delA\t596C > T\t\nPrevious reports on the same predicted proteins associated with DNSE\t\t\t\t[2]\t\t\t\t[2, 5, 21]\t\t\t\nGenes\t\nGlpQ\n\t–\t–\t–\t\nPspC\n\t–\t\nAmpC\n\t\nytpA\n\t–\t\nlocus_tag\tEFAU085_01796\tEFAU085_01902\tEFAU085_01910\tEFAU085_0195\tEFAU085_02050\tEFAU085_02219\tEFAU085_02548\tEFAU085_02618\tEFAU085_02818\t\nPredicted gene products\tGlycerophosphodiester phosphodiesterase family protein\tHypothetical protein\tHypothetical protein\tHD domain protein\tPspC domain protein\tHypothetical protein\tBeta-lactamase\tAlpha/beta hydrolase family protein\tHypothetical protein\t\nPredicted amino acid change\tIle283Phe\tTrp176\tAsn125 fs\tTrp118\nArg\tLys5 fs\tSer23 fs\tAsn265 fs\tGlu59Gly\tArg220 fs\t\nNucleotide mutation\t847A > T\t527G > A\t374delA\t352T > C\t14delA\t68delC\t794delA\t176A > G\t658delA\t\nPrevious reports on the same predicted proteins associated with DNSE\t\t\t\t[ 5], [21]\t[ 2], [5]\t\t\t\t\t\nReference strain: Enterococcus faecium Aus0085 [8]\n\n\nABC ATP-binding cassette, A adenine, Ala alanine, Arg arginine, Asn asparagine, Asp aspartic acid, C cytosine, Cys cysteine, del deletion, DNSE daptomycin non-susceptible Enterococcus, fs frameshift, G guanine, Glu glutamic acid, Gly glycine, Ile isoleucine, Leu leucine, Lys lysine, Met methionine, Phe phenylalanine, PMCA plasma membrance Ca2 + ATPase, Pro proline, PTS Phosphotransferase sytem, psPC phage shock protein C, Ser serine, Tyr tyrosine, T thymine, Thr threonine, Trp tryptophan, Val valine\n\n\n\nNotably, by comparing the genomes of the two E. faecium isolates, we detected mutations that were present in the genes encoding the DNA repair proteins MutL (mutL) and RecJ (recJ) of the DNSE strain, but not the DAP-susceptible parental strain. We, therefore, investigated whether the disruption of these genes affected the frequency of mutations in the E. faecium genome. For these analyses, each strain was cultured overnight in 2 ml of BHI broth. The following day, 2 μL of the resulting cultures was used to inoculate 2 ml of BHI broth, respectively. The cultures were again incubated overnight, diluted in fresh broth, and plated on BHI agar. Subsequently, 11 distinct colonies of each strain (EFM01 and EFM02) were harvested, and whole-genome sequencing of these isolates was conducted, as described above. The reads obtained from each isolate were mapped to the respective parental genome and analyzed for the presence of newly acquired variants. Because the settings used can yield false positive variants, any variants that were also present in the parental genome were excluded, and each putative variant was manually confirmed by examining the mapping results.\n\nThere was only one newly acquired variant identified after analysis of the genomes of the 11 daptomycin-susceptible E. faecium (EFM01) after the bacteria had undergone 9.2 generations. Conversely, analysis of the genomes of the 11 DNSE (EFM02) isolates detected 49 variants after the bacteria had undergone 9.4 generations. These findings indicate that the observed alterations to the mutL and recJ genes may have resulted in a significant increase in the frequency of mutations in the EFM02 genome.\n\nDiscussion\nIn this report, we characterized a strain of E. faecium with high level of DAP resistance (MIC = 256 mcg/ml) that was isolated from a patient with ALL following 20 days of exposure to high-dose DAP (10 mg kg−1 day−1) for treatment of E. faecium endocarditis. Subsequent genomic analyses indicated that this DNSE strain contained mutations within the known DNA repair genes mutL and recJ, which may have contributed to the acquisition of DAP resistance. Although dasatinib was reported to have effect on DNA repair pathways in human cancer cell lines [9], the association of DNA repair gene mutations of bacterial isolates with dasatinib or doxorubicin has not been reported to the best of our knowledge. In this case, dasatinib and doxorubicin were discontinued at the time of the first episode of E. faecium bacteremia, and thus, the patient was not receiving these drugs during DNSE emergence.\n\nIn a previous study of 42 cases of DNSE infection, which included five cases due to vancomycin-susceptible DNSE, only two VRE strains (4.2 %) exhibited DAP MICs ≥128 mcg/ml [10]. Meanwhile, the most common underlying disease associated with DNSE infection was hematologic malignancy (35 %), which was also present in the current case [10]. Indeed, immunosuppression and prior exposure to cephalosporins and metronidazole are considered independent predictors of infections caused by DNSE [11]. While in vitro analyses indicated that the acquisition of DAP resistance requires at least 6 days of exposure to DAP [6], the median duration of DAP exposure in previous case series of DNSE was 16–19 days [12, 13], which is similar to the duration of DAP treatment in the current case (20 days).\n\nIn recent reports of DNSE that developed during DAP therapy, patients received 6 mg/kg DAP [1–3, 14]. Meanwhile, separate studies demonstrated that ≥8 mg kg−1 day−1 of DAP resulted in improved clinical outcomes in cases of VRE blood stream infections, but that an even higher dose of DAP (≥10 mg kg−1 day−1) might be required to prevent the development of DAP resistance [6, 15]. In the current case, however, DNSE survived high-dose DAP therapy (10 mg kg−1 day−1). While recent studies suggest that increases in DAP MICs are associated with decreases in the MIC of beta-lactams [16], further investigation is required to assess whether the inclusion of beta-lactams such as ampicillin might help prevent the development of DNSE. Furthermore, a recent meta-analysis indicated that linezolid is more effective than is DAP for treatment of VRE bacteremia and that linezolid was associated with decreased rates of mortality [17]. However, the side effects associated with this antimicrobial, particularly adverse hematologic reactions, hinder its long-term use.\n\nThe mechanisms underlying DAP non-susceptibility in enterococci are not fully understood, but recent reports suggest the involvement of the cardiolipin synthase enzyme as well as several genetic pathways, including those associated with cell membrane phospholipid metabolism and the response of the bacterial cell-envelope to antibiotics [5]. We did not identify mutations that have been previously determined to confer daptomycin non-susceptibility in E. faecium, such as liaFSR, yycFGHIJ, cardiolipin synthetase, or ezrA [5]. However, we identified multiple amino acid changes predicting gene products which were reported previously in daptomycin non-susceptibile E. faecium isolates by whole-genome analyses, as shown in Table 2. In addition, we identified mutations within the DNA repair genes mutL and recJ that were unique to the DNSE strain and demonstrated that these mutations might have facilitated the emergence of spontaneous mutations during subculturing. We propose that this increased frequency of mutation might have led to the observed emergence of the DNSE phenotype. Contrary to this hypothesis, in a previous study, Willems et al. failed to detect demonstrable hypermutator phenotypes in oxazolidinone-resistant or -susceptible E. faecium isolates with mutations in the mutLS locus [18]. However, it is possible that the distinct phenotypes associated with alterations in the mutL gene could be due to differences in the genetic position of the individual mutL mutations [18]. Meanwhile, the recJ gene encodes a 5′-3′ single-stranded DNA-specific exonuclease that was reported to be associated with illegitimate recombination [19]. To the best of our knowledge, there have been no reports that have examined mutations in the recJ gene or the role of this protein in Enterococcus spp. Further studies are therefore are needed to reveal the association, if any, between mutations in recJ and the development of DNSE.\n\nConclusions\nIn conclusion, we isolated a strain of vancomycin-susceptible, DAP non-susceptible E. faecium, which survived exposure to high-dose (10 mg kg−1 day−1) DAP for treatment of E. faecium endocarditis. Whole-genome sequencing revealed mutations within the mutL and recJ genes of the DNSE strain, while in vitro analyses demonstrated that the DNSE strain exhibited higher rates of spontaneous mutation than did the parental strain. Our findings demonstrate that careful monitoring is necessary to avoid the emergence of DAP non-susceptible isolates of E. faecium, in spite of high-dose therapy, and particularly in cases of long-term DAP use or in immunocompromised patients such as those with hematological malignancy. Our study did not include the demonstration of the relationship of these DNA repair genes mutations with phenotypic changes, and we were unable to determine the exact mechanism of resistance. Further investigation is necessary to elucidate the mechanism by which E. faecium acquires DAP resistance, as well as the contribution of mutations in the DNA mismatch repair genes mutL and recJ to this process.\n\nAbbreviations\nDAPdaptomycin\n\nREvancomycin-resistant enterococci\n\nDNSEdaptomycin-nonsusceptible Enterococcus\n\nALLacute lymphocytic leukemia\n\nMICminimum inhibitory concentration\n\nBHIbrain heart infusion\n\nAuthors’ contributions\nTM and KH drafted the manuscript. KM carried out the microbiological analyses. TMA carried out the molecular genetic studies. RH, AT, KY, YF, MM, SK, NT and NO helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this is included with in the article.\n\nAcknowledgements and Funding\nThis study was supported by Grants for International Health Research (26S-120).\n\nCompeting interests\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. Arias CA Torres HA Singh KV Panesso D Moore J Wanger A Murray BE Failure of daptomycin monotherapy for endocarditis caused by an Enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster Clin Infect Dis 2007 45 10 1343 1346 10.1086/522656 17968832 \n2. Humphries RM Kelesidis T Tewhey R Rose WE Schork N Nizet V Sakoulas G Genotypic and phenotypic evaluation of the evolution of high-level daptomycin nonsusceptibility in vancomycin-resistant Enterococcus faecium Antimicrob Agents Chemother 2012 56 11 6051 6053 10.1128/AAC.01318-12 22948885 \n3. Kelesidis T Tewhey R Humphries RM Evolution of high-level daptomycin resistance in Enterococcus faecium during daptomycin therapy is associated with limited mutations in the bacterial genome J Antimicrob Chemother 2013 68 8 1926 1928 10.1093/jac/dkt117 23580562 \n4. Zankari E Hasman H Cosentino S Vestergaard M Rasmussen S Lund O Aarestrup FM Larsen MV Identification of acquired antimicrobial resistance genes J Antimicrob Chemother 2012 67 11 2640 2644 10.1093/jac/dks261 22782487 \n5. Diaz L Tran TT Munita JM Miller WR Rincon S Carvajal LP Wollam A Reyes J Panesso D Rojas NL Whole-genome analyses of Enterococcus faecium isolates with diverse daptomycin MICs Antimicrob Agents Chemother 2014 58 8 4527 4534 10.1128/AAC.02686-14 24867964 \n6. Werth BJ Steed ME Ireland CE Tran TT Nonejuie P Murray BE Rose WE Sakoulas G Pogliano J Arias CA Defining daptomycin resistance prevention exposures in vancomycin-resistant Enterococcus faecium and E. faecalis Antimicrob Agents Chemother 2014 58 9 5253 5261 10.1128/AAC.00098-14 24957825 \n7. Smith TF Waterman MS Identification of common molecular subsequences J Mol Biol 1981 147 1 195 197 10.1016/0022-2836(81)90087-5 7265238 \n8. Lam MM Seemann T Tobias NJ Chen H Haring V Moore RJ Ballard S Grayson LM Johnson PD Howden BP Comparative analysis of the complete genome of an epidemic hospital sequence type 203 clone of vancomycin-resistant Enterococcus faecium BMC Genom 2013 14 595 10.1186/1471-2164-14-595 \n9. Peng S Sen B Mazumdar T Byers LA Diao L Wang J Tong P Giri U Heymach JV Kadara HN Dasatinib induces DNA damage and activates DNA repair pathways leading to senescence in non-small cell lung cancer cell lines with kinase-inactivating BRAF mutations Oncotarget 2016 7 1 565 579 26623721 \n10. Wang G Kamalakaran S Dhand A Huang W Ojaimi C Zhuge J Yee LL Mayigowda P Surendraiah PK Dimitrova N Identification of a novel clone, ST736, among Enterococcus faecium clinical isolates and its association with daptomycin nonsusceptibility Antimicrob Agents Chemother 2014 58 8 4848 4854 10.1128/AAC.02683-14 24913170 \n11. Judge T Pogue JM Marchaim D Ho K Kamatam S Parveen S Tiwari N Nanjireddy P Bheemreddy S Biedron C Epidemiology of vancomycin-resistant enterococci with reduced susceptibility to daptomycin Infect Control Hosp Epidemiol 2012 33 12 1250 1254 10.1086/668438 23143365 \n12. Storm JC Diekema DJ Kroeger JS Johnson SJ Johannsson B Daptomycin exposure precedes infection and/or colonization with daptomycin non-susceptible enterococcus Antimicrob Resist Infect Control 2012 1 1 19 10.1186/2047-2994-1-19 22958379 \n13. Wudhikarn K Gingrich RD de Magalhaes Silverman M Daptomycin nonsusceptible enterococci in hematologic malignancy and hematopoietic stem cell transplant patients: an emerging threat Ann Hematol 2013 92 1 129 131 10.1007/s00277-012-1539-6 22869090 \n14. Kanafani ZA Federspiel JJ Fowler VG Jr Infective endocarditis caused by daptomycin-resistant Enterococcus faecalis : a case report Scand J Infect Dis 2007 39 1 75 77 10.1080/00365540600786465 17366018 \n15. Whang DW Miller LG Partain NM McKinnell JA Systematic review and meta-analysis of linezolid and daptomycin for treatment of vancomycin-resistant enterococcal bloodstream infections Antimicrob Agents Chemother 2013 57 10 5013 5018 10.1128/AAC.00714-13 23896468 \n16. Sakoulas G Nonejuie P Nizet V Pogliano J Crum-Cianflone N Haddad F Treatment of high-level gentamicin-resistant Enterococcus faecalis endocarditis with daptomycin plus ceftaroline Antimicrob Agents Chemother 2013 57 8 4042 4045 10.1128/AAC.02481-12 23689728 \n17. Balli EP Venetis CA Miyakis S Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia Antimicrob Agents Chemother 2014 58 2 734 739 10.1128/AAC.01289-13 24247127 \n18. Willems RJ Top J Smith DJ Roper DI North SE Woodford N Mutations in the DNA mismatch repair proteins MutS and MutL of oxazolidinone-resistant or -susceptible Enterococcus faecium Antimicrob Agents Chemother 2003 47 10 3061 3066 10.1128/AAC.47.10.3061-3066.2003 14506009 \n19. Shiraishi K Hanada K Iwakura Y Ikeda H Roles of RecJ, RecO, and RecR in RecET-mediated illegitimate recombination in Escherichia coli J Bacteriol 2002 184 17 4715 4721 10.1128/JB.184.17.4715-4721.2002 12169595 \n20. CLSI: The clinical and laboratory standards institute. performance standards for antimicrobial susceptibility testing; Twentieth Informational Supplement. Approved Standard M100-S24. Wayne: CLSI; 2014.\n21. Tran TT Panesso D Gao H Roh JH Munita JM Reyes J Diaz L Lobos EA Shamoo Y Mishra NN Whole-genome analysis of a daptomycin-susceptible Enterococcus faecium strain and its daptomycin-resistant variant arising during therapy Antimicrob Agents Chemother 2013 57 1 261 268 10.1128/AAC.01454-12 23114757\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "9()",
"journal": "BMC research notes",
"keywords": "Daptomycin; E. faecium; Whole-genome sequence",
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000328:Adult; D004260:DNA Repair; D017576:Daptomycin; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D016984:Enterococcus faecium; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "197",
"pmc": null,
"pmid": "27036708",
"pubdate": "2016-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12169595;23114757;24867964;23896468;17968832;22782487;22869090;24004955;22948885;26623721;23143365;24913170;24247127;23689728;14506009;23580562;24957825;22958379;17366018;7265238",
"title": "Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy.",
"title_normalized": "emergence of a daptomycin non susceptible enterococcus faecium strain that encodes mutations in dna repair genes after high dose daptomycin therapy"
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"abstract": "Pulmonary vein stenosis (PVS) is a rare, severe, and potentially fatal complication most often arising from pulmonary vein ablation for medication refractory, symptomatic, and permanent atrial fibrillation. At present, the optimal approach for the management of PVS remains to be defined. Here, we describe a unique case of bifurcation pulmonary venoplasty and stenting in a patient with recalcitrant PVS after surgical reconstruction of her pulmonary veins. To our knowledge, this is the first such report of its kind. <Learning objective: The optimal approach to managing complex pulmonary vein stenosis (PVS) is unclear. Our aim is to illustrate our successful approach for treating recalcitrant and complex PVS using dual transseptal access and kissing balloon bifurcation pulmonary venoplasty.>.",
"affiliations": "Loyola University Medical Center, Heart and Vascular Center, Chicago, IL, USA.;Northwestern Memorial Hospital, Chicago, IL, USA.;Loyola University Medical Center, Heart and Vascular Center, Chicago, IL, USA.;Loyola University Medical Center, Heart and Vascular Center, Chicago, IL, USA.;Loyola University Medical Center, Department of Surgery, Chicago, IL, USA.;Loyola University Medical Center, Heart and Vascular Center, Chicago, IL, USA.",
"authors": "Belin|Rashad J|RJ|;Leya|Marysa V|MV|;Bediako|Timothy|T|;Ronan|Adam P|AP|;Schwartz|Jeffrey|J|;Leya|Ferdinand|F|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "22(5)",
"journal": "Journal of cardiology cases",
"keywords": "Bifurcation angioplasty; Kissing balloon; Pulmonary vein ablation; Pulmonary vein stenosis; Stent",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "203-206",
"pmc": null,
"pmid": "33133309",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "19463436;24626996;24905444;21288274;22394418;27793993",
"title": "Bifurcation pulmonary venoplasty and stenting for recalcitrant pulmonary vein stenosis after surgical pulmonary vein reconstruction.",
"title_normalized": "bifurcation pulmonary venoplasty and stenting for recalcitrant pulmonary vein stenosis after surgical pulmonary vein reconstruction"
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"abstract": "BACKGROUND\nNeoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC.\n\n\nMETHODS\nWe conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade).\n\n\nRESULTS\nSeventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue.\n\n\nCONCLUSIONS\nNeoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.",
"affiliations": "Medical Oncology, University of Washington, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Medical Oncology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;eResearch Technologies, Inc., Pittsburgh, PA.;Medical Oncology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Medical Oncology, University of Illinois Cancer Center, Chicago, IL.;Medical Oncology, University of Washington, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Hematology and Oncology, University of California Davis, Sacramento, CA.;Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ.;Microsoft, Redmond, WA.;Clinical Cancer Genetics, Duke Cancer Institute, Durham, NC.;Seattle Cancer Care Alliance Network, Seattle, WA.;Hematology and Oncology, Stony Brook University, Stony Brook, NY.;Hematology and Oncology, University of New Mexico, Albuquerque, NM.;Medical Oncology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address: jspecht@uw.edu.",
"authors": "Symonds|Lynn|L|;Jenkins|Isaac|I|;Linden|Hannah M|HM|;Kurland|Brenda|B|;Gralow|Julie R|JR|;Gadi|Vijayakrishna V K|VVK|;Ellis|Georgiana K|GK|;Wu|Qian|Q|;Rodler|Eve|E|;Chalasani|Pavani|P|;Chai|Xiaoyu|X|;Riedel|Jinny|J|;Scca Network Investigators|||;Stopeck|Alison|A|;Brown-Glaberman|Ursa|U|;Specht|Jennifer M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2021.05.009",
"fulltext": null,
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"issn_linking": "1526-8209",
"issue": null,
"journal": "Clinical breast cancer",
"keywords": "Cyclophosphamide; Doxorubicin; HER2-negative; Inflammatory breast cancer; Locally advanced breast cancer (LABC); Neoadjuvant; Paclitaxel; Sunitinib",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": null,
"nlm_unique_id": "100898731",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34158245",
"pubdate": "2021-05-24",
"publication_types": "D016428:Journal Article",
"references": "19249675;12727920;30621641;18056680;19249680;2013044;27735826;22331954;26941473;20531297;22308314;19249681;17690708;12202664;24045439;10080586;20339913;16731761;11705867;21482989;18347007;11533692;14578466;27393622;15557593;15774788;31236813;15475452;9704717;27328945;18160686;31279611;26693900;21976315;8344219;20032126;28828583;19582160;26155975;33793299;26420402;1846728;19549711;21220618;21569994;9332513;16226705;11346684;29618617;23400797;22393532;17158757;17114668;14647449;27577069;15681523",
"title": "A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer.",
"title_normalized": "a phase ii study evaluating the safety and efficacy of sunitinib malate in combination with weekly paclitaxel followed by doxorubicin and daily oral cyclophosphamide plus g csf as neoadjuvant chemotherapy for locally advanced or inflammatory breast cancer"
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"abstract": "Sunitinib has become a standard treatment agent for metastatic renal cell carcinoma (RCC) for several years. However, various adverse events have been reported. We present a rare adverse effect of hyperammonemic encephalopathy induced by sunitinib. A 66-year-old woman with metastatic RCC referred to the emergency department with confusion that developed 14 days after the initiation of 50 mg/d of sunitinib. Her serum ammonia and thyroid-stimulating hormone levels were markedly elevated (146 μg/dL and 27.27 μIU/mL, respectively). Sunitinib was discontinued, and an enema with lactulose and L-thyroxine were administered. Her mental status and neurologic symptoms were normalized 7 days after the treatment. Serum ammonia level decreased to 61 μg/dL and thyroid stimulating hormone level decreased 22.34 μIU/mL. The incidence of sunitinib-induced hyperammonemia is rarely reported. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. Sunitinib-induced hyperammonemia is very rare, and to the best of our knowledge, this is fourth case hyperammonemia and first case hyperammonemic encephalopathy with hypothyroidism as an adverse effect. Therefore, it is important for clinicians to be aware of hyperammonemia that can occur in several days after the initiation of sunitinib treatment in metastatic RCC.",
"affiliations": "1Department of Medical Oncology, Faculty of Medicine, Bilim University, Istanbul, Turkey; Departments of 2Radiology, 3Medical Oncology, and 4General Surgery, Gayrettepe Florence Nightingale Hospital, Besiktas, Turkey; and 5Department of Pathology, Acıbadem Hospital, Istanbul, Turkey.",
"authors": "Pilanc|Kezban Nur|KN|;Elbüken|Filiz|F|;Ordu|Çetin|Ç|;Köksal|Gülistan|G|;Tekelioğlu|Mehmet Hakan|MH|;Okutur|Kerem|K|;Göksel|Süha|S|;Köksal|Ülkühan|Ü|;Akçal|Tark|T|;Tecimer|Coşkun|C|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib",
"country": "United States",
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"issn_linking": "1075-2765",
"issue": "23(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001927:Brain Diseases; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D007037:Hypothyroidism; D007211:Indoles; D007680:Kidney Neoplasms; D011758:Pyrroles; D000077210:Sunitinib",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e583-7",
"pmc": null,
"pmid": "24901901",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Rare Case of Sunitinib-Induced Hyperammonemic Encephalopathy and Hypothyroidism in Metastatic Renal Cell Carcinoma.",
"title_normalized": "a rare case of sunitinib induced hyperammonemic encephalopathy and hypothyroidism in metastatic renal cell carcinoma"
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"activesubstancename": "SUNITINIB MALATE"
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"abstract": "Diabetic ketoacidosis (DKA) can have an atypical presentation during pregnancy. In the case of euglycemic DKA, relatively normal blood glucose levels can hinder a quick diagnosis.\n\n\n\nA 34-year-old DM1 patient, 31 weeks pregnant, was admitted because of reduced fetal movements and nausea. She had reduced the amount of insulin that her insulin pump administered and had a severe euglycemic DKA. The CTG was abnormal and there was a threat of preterm birth. She was treated with insulin, glucose and bicarbonate. A month later the patient underwent an emergency cesarean section because of an abnormal CTG. A daughter was born that weighed 4820 grams, the Apgar score was 5/8/8, and the pH was 7.14. The girl required intravenous glucose for a week.\n\n\n\nEuglycemic DKA during pregnancy requires swift recognition and treatment but this remains challenging.",
"affiliations": "Ziekenhuis Gelderse Vallei, afd. Gynaecologie, Ede.;Ziekenhuis Gelderse Vallei, afd. Intensive Care, Ede.;Ziekenhuis Gelderse Vallei, afd. Gynaecologie, Ede.;Ziekenhuis Gelderse Vallei, afd. Intensive Care, Ede.;Ziekenhuis Gelderse Vallei, afd. Interne Geneeskunde, Ede.",
"authors": "Kamphof|Hester D|HD|;De Smet|Vivienne|V|;Jansen|Nicoline E|NE|;Tjan|Dave H T|DHT|;Heijligenberg|Rik|R|",
"chemical_list": "D001786:Blood Glucose; D007328:Insulin",
"country": "Netherlands",
"delete": false,
"doi": null,
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"issn_linking": "0028-2162",
"issue": "165()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D002585:Cesarean Section; D016883:Diabetic Ketoacidosis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin; D011247:Pregnancy; D047928:Premature Birth",
"nlm_unique_id": "0400770",
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"pages": null,
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"pmid": "34346591",
"pubdate": "2021-04-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Euglycemic diabetic ketoacidosis during pregnancy.",
"title_normalized": "euglycemic diabetic ketoacidosis during pregnancy"
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"abstract": "International guidelines consider quetiapine at medium doses (300-400 mg/day) as valid options for the treatment of bipolar depression for the supposed lower risk of a switch to hypomania/mania than antidepressants. Norquetiapine is an active metabolite with antidepressant action. We describe three cases of induced hypomania in bipolar type 2 subjects who received quetiapine extended-release monotherapy (300 mg/day) for a mild/moderate major depressive episode. Quetiapine and norquetiapine plasma concentrations were measured after 1 week of treatment. Hypomania appeared after 7-10 days of quetiapine extended-release monotherapy and all subjects had a quetiapine/norquetiapine plasma concentration ratio <1. We propose a ratio value <1 as a predictor of risk for a switch to hypomania in bipolar depressed subjects receiving quetiapine extended-release monotherapy. Future research should ascertain the validity of this laboratory parameter to assess the risk of quetiapine-induced hypomania in large samples of bipolar patients.",
"affiliations": "Department of Psychiatry, University of Milan, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.;Department of Psychiatry, University of Milan, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.;Department of Psychiatry, University of Milan, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.;Clinical Pharmacology Unit, ASST Fatebenefratelli-Sacco, Milan, Italy.;Clinical Pharmacology Unit, ASST Fatebenefratelli-Sacco, Milan, Italy.;Clinical Pharmacology Unit, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy.;Department of Psychiatry, University of Milan, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.;Department of Psychiatry, University of Milan, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy. massimiliano.buoli@hotmail.it.",
"authors": "Rovera|C|C|;Esposito|C M|CM|;Ciappolino|V|V|;Cattaneo|D|D|;Baldelli|S|S|;Clementi|E|E|;Altamura|A C|AC|;Buoli|M|M|",
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"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 290632175710.1007/s40800-017-0057-9Case SeriesQuetiapine-Induced Hypomania and its Association with Quetiapine/Norquetiapine Plasma Concentrations: A Case Series of Bipolar Type 2 Patients Rovera C. 1Esposito C. M. 1Ciappolino V. 1Cattaneo D. 2Baldelli S. 2Clementi E. 34 Altamura A. C. 1Buoli M. +39-02-55035983massimiliano.buoli@hotmail.itmassimiliano.buoli@unimi.it 11 Department of Psychiatry, University of Milan, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy 2 Clinical Pharmacology Unit, ASST Fatebenefratelli-Sacco, Milan, Italy 3 0000 0004 1757 2822grid.4708.bClinical Pharmacology Unit, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy 4 grid.420417.4E. Medea Scientific Institute, Bosisio Parini, Italy 23 10 2017 23 10 2017 12 2017 4 13© The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.International guidelines consider quetiapine at medium doses (300–400 mg/day) as valid options for the treatment of bipolar depression for the supposed lower risk of a switch to hypomania/mania than antidepressants. Norquetiapine is an active metabolite with antidepressant action. We describe three cases of induced hypomania in bipolar type 2 subjects who received quetiapine extended-release monotherapy (300 mg/day) for a mild/moderate major depressive episode. Quetiapine and norquetiapine plasma concentrations were measured after 1 week of treatment. Hypomania appeared after 7–10 days of quetiapine extended-release monotherapy and all subjects had a quetiapine/norquetiapine plasma concentration ratio <1. We propose a ratio value <1 as a predictor of risk for a switch to hypomania in bipolar depressed subjects receiving quetiapine extended-release monotherapy. Future research should ascertain the validity of this laboratory parameter to assess the risk of quetiapine-induced hypomania in large samples of bipolar patients.\n\nKeywords\nBipolar depressionHypomaniaQuetiapineissue-copyright-statement© The Author(s) 2017\n==== Body\nKey Points\n\nQuetiapine monotherapy is a therapeutic option for the treatment of depressive symptoms in bipolar type 2 patients.\t\nQuetiapine has a potential risk of induced hypomania owing to the antidepressant effect of its metabolite norquetiapine.\t\nA ratio of quetiapine/norquetiapine plasma concentrations <1 is thought to be a risk factor for developing quetiapine-induced hypomania.\t\n\n\n\nIntroduction\nBipolar disorder (BD) is a prevalent psychiatric condition (affecting up to 5–6% of the general population) [1] associated with high disability and a risk of chronicity if not promptly treated [2]. Approved in 1997 by the US Food and Drug Administration for the treatment of acute episodes of schizophrenia, quetiapine has been shown to be effective in a large number of neuropsychiatric disorders, including BD [3, 4]. Currently, both the European Medicines Agency and the US Food and Drug Administration recommend quetiapine for the treatment of major depressive and manic episodes as well as for the prevention of recurrences in BD. With regard to acute mood episodes, the World Federation of Societies of Biological Psychiatry guidelines consider quetiapine as a compound with high evidence of efficacy at the dosage of 600–800 mg/day for acute mania [5] and at the dosage of 300–600 mg/day for bipolar depression [6]. In addition, according to the Canadian Network for Mood and Anxiety Treatments [7], quetiapine is the only drug recommended as first-line treatment for major depressive episodes in BD type 2.\n\nQuetiapine appears to be one of the best options in terms of efficacy in bipolar depression and of risk of switching to hypomania/mania [8]. Quetiapine-induced hypomania or mania has been previously described [9, 10]; however, because the cases of quetiapine-induced hypomania are extremely rare in comparison with the antidepressant-induced cases [11, 12], quetiapine remains widely prescribed in the clinical practice for the treatment of bipolar depression [13].\n\nNorquetiapine, the most important active metabolite of quetiapine, has been shown to be associated with antidepressant, anxiolytic, and neurotrophic effects in humans [14]. In particular, norquetiapine facilitates dopamine release in the prefrontal cortex and inhibits dopamine reuptake [15, 16]. Moreover, norquetiapine potentiates serotoninergic and noradrenergic transmission through its high affinity for 5-HT1A, 5-HT2C, and 5-HT7 receptors and through noradrenaline reuptake inhibition [17, 18]. Previous studies have showed that the ratio of norquetiapine/quetiapine plasma concentrations was associated with an improvement of mood symptoms in bipolar patients [19, 20]. In the first study [19], bipolar patients showed a curvilinear relationship between the norquetiapine/quetiapine concentration ratio and the improvement of depressive symptoms after 3 months of treatment with quetiapine. In the second and more recent study [20], bipolar patients were found to have a significant correlation between improvement of depressive symptoms and the norquetiapine/quetiapine ratio, measured after 3 months of quetiapine treatment. In other studies, however, norquetiapine has been reported as possibly responsible for a switch to hypomania in bipolar subjects in treatment with quetiapine [9, 10], thus the measurement of norquetiapine plasma concentrations might be useful to evaluate the risk of a switch to hypomania in depressed bipolar subjects. In this article, we describe three cases of quetiapine-induced hypomania in subjects who were monitored for quetiapine and norquetiapine plasma concentrations.\n\nCase Series\nThree bipolar type 2 patients with a moderate major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Revision [21] had a switch to hypomania during quetiapine monotherapy. They were outpatients of the Department of Psychiatry, University of Milan. The patients provided consent to share their clinical data for research purposes. All patients underwent laboratory evaluations such as blood cell count, renal function tests, pancreatic and liver enzymes, and also safety assessments (neurological examination and electrocardiography). All the examination results were normal. All subjects were treated with 300 mg/day of quetiapine extended release (ER). After 1 week of treatment, quetiapine and norquetiapine plasma concentrations were measured, considering that steady state is usually achieved after 3 days of sequential doses [22]. Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and Brief Psychiatric Rating Scale (BPRS) were administered after 1 week (T1) and after 1 month of treatment (T2). Hypomania was defined not only according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Revision criteria, but also by an YMRS score ≥ 10 [23]. The patients did not receive other psychotropic drugs during the follow-up period. In addition, all the patients had discontinued autonomously the previous pharmacotherapy for at least 3 months. None of the subjects developed side effects except for induced hypomania. Changes in rating scale scores for the three patients are reported in Fig. 1.Fig. 1 Rating scale scores of the three patients during the 1-month follow-up period\n\n\n\n\nThe first case was a 28-year-old woman who had the first diagnosis of BD type 2 in 2007, while experiencing a hypomanic episode subsequent to a major depressive episode. In the last years, she experienced two further major depressive episodes and three hypomanic episodes. She has a family history of psychiatric disorders: her mother experienced a major depressive disorder, while one sister and one brother received a diagnosis of generalized anxiety disorder. Substance misuse was never reported by the patient, while she experienced Hashimoto thyroiditis (currently in remission and treated with hormone replacement therapy) and polycystic ovary syndrome (currently in remission and treated with a combined hormonal contraceptive). At the time of the first evaluation (T0), she presented with a mild major depressive episode (YMRS = 8; HAM-D = 17; HAM-A = 28; BPRS = 38). Pharmacotherapy with quetiapine ER 300 mg/day was prescribed and, after 1 week (T1), quetiapine and norquetiapine plasma concentrations were 113.9 and 178.1 ng/mL, respectively (ratio = 0.64). The scores of the clinical rating scales were the following: T1: YMRS = 11; HAM-D = 13; HAM-A = 25; BPRS = 36; T2: YMRS = 14; HAM-D = 8; HAM-A = 23; BPRS = 32. The clinical rating scale scores show the improvement of depressive symptoms, but also the early switch to hypomania (after 1 week of treatment).\n\nThe second case was a 45-year-old woman who first visited our outpatient clinic in 2005 because of a hypomanic episode followed by a major depressive episode. At that time, she had already presented with several mood episodes, starting from the age of 20 years, when she received a diagnosis of BD type 2, and she had been hospitalized three times for major depressive episodes. Her father had experienced a major depressive disorder, while her mother presented with a generalized anxiety disorder. No substance abuse was reported by the patient, while she had a head trauma following a road accident in 1998 at the age of 26 years, without any long-term consequences (no specific lesions were documented by a subsequent brain scan with computerized tomography). At baseline (T0), the patient presented with a mild major depressive episode (YMRS = 7; HAM-D = 16; HAM-A = 27; BPRS = 31) and pharmacotherapy with quetiapine ER 300 mg/day was prescribed. After 1 week (T1), quetiapine and norquetiapine plasma concentrations were respectively 5 and 10.1 ng/mL (ratio = 0.59). The rating scale scores were the following: T1: YMRS = 11, HAM-D = 13, HAM-A = 25, BPRS = 36; T2: YMRS = 13, HAM-D = 8, HAM-A = 21, BPRS = 32. The patient presented with an improvement of depressive symptoms, but also an early switch to hypomania (after 1 week of treatment).\n\nThe third case was a 25-year-old woman who developed obsessive-compulsive symptoms at the age of 12 years. She has a family history of psychiatric disorders: her father and her grandmother were affected by major depressive disorder, while her brother and an aunt experienced a generalized anxiety disorder. Neither substance abuse nor medical comorbidity was reported by the patient. When she started university at the age of 19 years, she showed a worsening of obsessive symptoms and received treatment with citalopram 25 mg/day for 1 year. There was an improvement of obsessive-compulsive symptoms, but also a switch to hypomania, followed by a major depressive episode. In the last 5 years, the patient presented with several episodes of mood alteration (including three spontaneous hypomanic episodes, two major depressive episodes, and one episode of antidepressant-induced hypomania) and has been followed up at our outpatient clinic with a diagnosis of BD type 2. The patient received only citalopram during major depressive episodes (the last two treatments in combination with a mood stabilizer or atypical antipsychotic different from quetiapine). At T0, she experienced a moderate major depressive episode (T0: YMRS = 7; HAM-D = 21; HAM-A = 27; BPRS = 32) and pharmacotherapy with quetiapine ER 300 mg/day was prescribed. The patient showed an amelioration of depressive symptoms, but also a switch to hypomania (after 10 days). The rating scale scores were the following: T1: YMRS = 10, HAM-D = 17, HAM-A = 25, BPRS = 30; T2: YMRS = 15, HAM-D = 7, HAM-A = 18, BPRS = 25. After 1 week (T1), quetiapine and norquetiapine plasma concentrations were found to be respectively, 33.7 and 42.5 ng/mL (ratio = 0.79).\n\nAfter the hypomanic switch, all three patients received higher doses of quetiapine, which were titrated up to 800 mg/day to have an anti-manic effect. However, no cytochrome P450 3A4 inhibitor was introduced in the treatment of these patients. During the period between T1 and T2, none of the patients satisfied the criteria for a major depressive episode with mixed features. In the next month after T2, patients showed an amelioration of hypomanic symptoms till the remission (YMRS < 7). No patients developed substantial depressive symptoms (HAM-D < 4). This is not surprising as a recent report showed quetiapine is a slow but effective anti-manic agent [24].\n\nDiscussion\nThe amelioration of depressive symptoms with quetiapine at the dosage of 300 mg/day in the three presented cases is in line with reports in the literature indicating that quetiapine ER at this dosage has antidepressant efficacy [8]. Despite the well-known metabolic side effects, this drug appears to also be a valid option for the treatment of major depressive episodes in bipolar type 2 patients with a supposed lower risk of hypomania with respect to antidepressants [25]. The novelty of the reported cases is that quetiapine is associated with a potential risk of hypomania, a situation not previously described. We also show that clinical biological/predictors may be useful to detect susceptibility to a mood switch in bipolar subjects receiving quetiapine monotherapy. The association between quetiapine monotherapy and mood switch is demonstrated by the fact that the medical and psychiatry comorbidities of the three bipolar subjects, if present, were in remission and the patients were not treated with other compounds with the exception of the first patient who received hormone replacement therapy. In addition, the patients had no history of rapid cycling and 7–10 days is too short a period to consider a spontaneous remission of depressive symptoms [26]. Rapid cycling was excluded according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Revision criteria (four or more mood episodes/year) [27]. Finally, the patients had mostly a clinical history characterized by hypomanic episodes that started during euthymic phases and some months after the remission of depressive symptoms. Although there can be no absolute certainty, it is reasonable to exclude that hypomania may be the result of the natural course of BD. Taking into consideration all the mentioned aspects, according to the Naranjo Adverse Drug Reaction Probability Scale, hypomania as an adverse reaction of the administration of quetiapine ER (300 mg/day) may be considered as probable in the light of a score of 6 [28].\n\nQuetiapine and norquetiapine plasma concentrations in the described bipolar subjects showed a high degree of variation, most likely owing to the inter-variability in cytochrome P450 functioning [29], as the patients did not take drugs with pharmacokinetic interactions with quetiapine or they were smokers. The patients took the therapy at 10 p.m. and compliance was checked by counting the pills in the blister. In addition, caregivers ensured treatment compliance.\n\nAs the efficacy of an antidepressant is mainly the result of the metabolite norquetiapine and there is a substantial variability of quetiapine/norquetiapine plasma concentrations after the same dose of quetiapine ER, the ratio of the plasma concentrations of quetiapine/norquetiapine may be a useful tool to predict the risk of mood destabilization [30]. Of note, a ratio < 1 is proposed as a pharmacological predictor for a switch to hypomania in bipolar subjects receiving medium doses of quetiapine. In a previous study published by our group, bipolar patients who had ameliorated the depressive symptoms without developing hypomania showed a quetiapine/norquetiapine ratio > 1 [20]. The results, however, are not totally comparable to those of the present case series as the evaluation of drug plasma concentration was done after 3 months of treatment and the sample consisted of both bipolar type 1 and 2 patients.\n\nProspective studies with large samples of bipolar patients are needed to confirm these preliminary results. In addition, clinicians should evaluate if a combined therapy (e.g., with valproate) may prevent the risk of quetiapine-induced hypomania and if the prophylactic efficacy overcomes the increased risk of side effects due to combined therapies [4].\n\nConclusions\nEven though quetiapine monotherapy (300 mg/day) is an option for the treatment of depressive symptoms of bipolar type 2 patients, clinicians should take into account the potential risk of induced hypomania. Some bipolar type 2 subjects may have a predisposition to a switch to hypomania when treated with low-medium doses of quetiapine monotherapy. Future studies need to assess the size of the risk and identify the risk factors of induced hypomania/mania. A ratio < 1 of quetiapine/norquetiapine plasma concentrations might be a useful predictor of the risk of a mood switch. The validation of this laboratory parameter should be examined by future research as well as the evaluation of the efficacy of a combined therapy (e.g., quetiapine plus valproate) in preventing the risk of a mood switch in bipolar depressed subjects receiving quetiapine monotherapy.\n\nCompliance with Ethical Standards\nFunding\nNo financial support was received for the conduct and preparation of this case series.\n\nConflict of interest\nProf. A. Carlo Altamura has served as a consultant for Merck and Astra Zeneca and has been on the speaker bureau for Sanofi, Lilly, and Pfizer. Dr. Massimiliano Buoli has served as a consultant for Lundbeck. Prof. Emilio Clementi, Drs. Chiara Rovera, Valentina Ciappolino, Dario Cattaneo, Sara Baldelli, and Ms Cecilia Maria Esposito have no conflicts of interest directly relevant to the content of this case series.\n\nInformed consent\nWritten informed consent was obtained from all three patients for the publication of this case report.\n==== Refs\nReferences\n1. Merikangas KR Jin R He JP Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative Arch Gen Psychiatry 2011 68 241 251 10.1001/archgenpsychiatry.2011.12 21383262 \n2. Altamura AC Serati M Buoli M Is duration of illness really influencing outcome in major psychoses? Nord J Psychiatry 2015 69 6 403 417 10.3109/08039488.2014.990919 25768662 \n3. Sanford M Quetiapine extended release: adjunctive treatment in major depressive disorder CNS Drugs 2011 25 803 813 10.2165/11207280-000000000-00000 21870891 \n4. Buoli M Serati M Altamura AC Is the combination of a mood stabilizer plus an antipsychotic more effective than mono-therapies in long-term treatment of bipolar disorder? A systematic review J Affect Disord 2014 152–154 12 18 10.1016/j.jad.2013.08.024 24041717 \n5. Grunze H Vieta E Goodwin GM The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania World J Biol Psychiatry 2009 10 85 116 10.1080/15622970902823202 19347775 \n6. Grunze H Vieta E Goodwin GM The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression World J Biol Psychiatry 2010 11 2 81 109 10.3109/15622970903555881 20148751 \n7. Yatham LN Kennedy SH Parikh SV The evolution of CANMAT bipolar disorder guidelines: past, present, and future Bipolar Disord 2013 15 1 58 60 10.1111/bdi.12038 23339676 \n8. Taylor DM Cornelius V Smith L Young AH Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis Acta Psychiatr Scand 2014 130 6 452 469 10.1111/acps.12343 25283309 \n9. Rachid F Bertschy G Bondolfi G Aubry JM Possible induction of mania or hypomania by atypical antipsychotics: an updated review of reported cases J Clin Psychiatry 2004 65 11 1537 1545 10.4088/JCP.v65n1116 15554769 \n10. Khalil RB Baddoura C Quetiapine induced hypomania: a case report and a review of the literature Curr Drug Saf 2012 7 3 250 253 10.2174/157488612803251333 22950378 \n11. Pacchiarotti I Bond DJ Baldessarini RJ The International Society for Bipolar Disorders (ISBD) Task Force report on antidepressant use in bipolar disorders Am J Psychiatry 2013 170 11 1249 1262 10.1176/appi.ajp.2013.13020185 24030475 \n12. Goodwin GM Haddad PM Ferrier IN Evidence-based guidelines for treating bipolar disorder: revised third edition recommendation from the British Association for Psychopharmacology J Psychopharmacol 2016 30 6 495 553 10.1177/0269881116636545 26979387 \n13. Osborne V Davies M Layton D Shakir SA Utilisation of extended release quetiapine (Seroquel XL™): results from an observational cohort study in England Eur Psychiatry 2016 33 61 67 10.1016/j.eurpsy.2015.12.004 26872067 \n14. Silverstone PH Lalies MD Hudson AL Quetiapine and buspirone both elevate cortical levels of noradrenaline and dopamine in vivo, but do not have synergistic effects Front Psychiatry 2012 3 82 10.3389/fpsyt.2012.00082 23049514 \n15. Mundo E Cattaneo E Zanoni S The use of atypical antipsychotics beyond psychoses: efficacy of quetiapine in bipolar disorder Neuropsychiatr Dis Treat 2006 2 139 148 10.2147/nedt.2006.2.2.139 19412458 \n16. Rasmussen H Ebdrup BH Aggernaes B Norquetiapine and depressive symptoms in initially antipsychotic-naive first-episode schizophrenia J Clin Psychopharmacol 2013 33 266 269 10.1097/JCP.0b013e318287acc9 23422401 \n17. Sümegi A Quetiapine in bipolar disorders Neuropsychopharmacol Hung 2008 10 281 291 19419014 \n18. Björkholm C Jardemark K Marcus MM Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine Eur Neuropsychopharmacol 2013 23 709 720 10.1016/j.euroneuro.2012.05.012 22732518 \n19. Altamura AC Moliterno D Paletta S Effect of quetiapine and norquetiapine on anxiety and depression in major psychoses using a pharmacokinetic approach: a prospective observational study Clin Drug Investig 2012 32 3 213 219 10.2165/11597330-000000000-00000 22299714 \n20. Rovera C Mauri MC Di Pace C Effect of N-desalkylquetiapine/quetiapine plasma level ratio on anxiety and depression in bipolar disorder: a prospective observational study Ther Drug Monit 2017 39 4 441 445 28486308 \n21. American Psychiatric Association Diagnostic and statistical manual of mental disorders, Fifth Revision 2013 Washington, DC American Psychiatric Press \n22. Li Q Su YA Liu Y Chen JX Pharmacokinetics and tolerability of extended-release quetiapine fumarate in Han Chinese patients with schizophrenia Clin Pharmacokinet 2014 53 5 455 465 10.1007/s40262-013-0127-9 24385309 \n23. McElroy SL Martens BE Creech RS Randomized, double-blind, placebo-controlled study of divalproex extended release loading monotherapy in ambulatory bipolar spectrum disorder patients with moderate-to-severe hypomania or mild mania J Clin Psychiatry 2010 71 5 557 565 10.4088/JCP.08m04854yel 20361901 \n24. Buoli M, Esposito CM, Godio M, Caldiroli A, Serati M, Altamura AC. Have antipsychotics a different speed of action in the acute treatment of mania? A single-blind comparative study. J Psychopharmacol. 2017:269881117705098. doi:10.1177/0269881117705098(Epub ahead of print).\n25. Selle V Schalkwijk S Vázquez GH Baldessarini RJ Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics Pharmacopsychiatry 2014 47 2 43 52 10.1055/s-0033-1363258 24549862 \n26. Ten Have M Penninx BWJH Tuithof M Duration of major and minor depressive episodes and associated risk indicators in a psychiatric epidemiological cohort study of the general population Acta Psychiatr Scand 2017 136 3 300 312 10.1111/acps.12753 28512767 \n27. Buoli M Serati M Altamura AC Biological aspects and candidate biomarkers for rapid-cycling in bipolar disorder: a systematic review Psychiatry Res. 2017 28864122 \n28. Hamilton HJ Gallagher PF O’Mahony D Inappropriate prescribing and adverse drug events in older people BMC Geriatr 2009 9 5 10.1186/1471-2318-9-5 19175914 \n29. Nikisch G Baumann P Oneda B Cytochrome P450 and ABCB1 genetics: association with quetiapine and norquetiapine plasma and cerebrospinal fluid concentrations and with clinical response in patients suffering from schizophrenia: a pilot study J Psychopharmacol 2011 25 7 896 907 10.1177/0269881110389208 21148022 \n30. Buoli M Dell’Osso B Caldiroli A Obesity and obstetric complications are associated with rapid-cycling in Italian patients with bipolar disorder J Affect Disord 2017 208 278 283 10.1016/j.jad.2016.10.010 27794251\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2199-1162",
"issue": "4(1)",
"journal": "Drug safety - case reports",
"keywords": "Bipolar depression; Hypomania; Quetiapine",
"medline_ta": "Drug Saf Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101674544",
"other_id": null,
"pages": "13",
"pmc": null,
"pmid": "29063217",
"pubdate": "2017-10-23",
"publication_types": "D016428:Journal Article",
"references": "24030475;24549862;28462607;20361901;20148751;28864122;26872067;19412458;27794251;19175914;21148022;22732518;15554769;25768662;19419014;25283309;28486308;22299714;26979387;23422401;23339676;22950378;28512767;19347775;24385309;24041717;21383262;23049514;21870891",
"title": "Quetiapine-Induced Hypomania and its Association with Quetiapine/Norquetiapine Plasma Concentrations: A Case Series of Bipolar Type 2 Patients.",
"title_normalized": "quetiapine induced hypomania and its association with quetiapine norquetiapine plasma concentrations a case series of bipolar type 2 patients"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1073141",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
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... |
{
"abstract": "BACKGROUND\nLung transplant patients experience a high risk of airway infections and microbial colonization of the lung due to constant exposure to the environment through inhaled microorganisms, denervation, reduced ciliary transport, and decreased cough.\n\n\nMETHODS\nIn this nationwide prospective study on Swedish lung transplant patients, we evaluated the microbiological panorama of bacteria, fungi, and virus found in bronchoalveolar lavage fluid (BALF) obtained the first year after lung transplantation (LTx). Differences in microbiological findings depending of concomitant signs of infection and background factors were assessed.\n\n\nRESULTS\nA total of 470 bronchoscopies from 126 patients were evaluated. Sixty-two percent (n = 293) of BALF samples had positive microbiological finding(s). Forty-six percent (n = 217) had bacterial growth, 29% (n = 137) fungal growth, and 9% (n = 43) were positive in viral PCR. In 38% of BALF samples (n = 181), a single microbe was found, whereas a combination of bacteria, fungi or virus was found in 24% (n = 112) of bronchoscopies. The most common microbiological findings were Candida albicans, Pseudomonas aeruginosa and coagulase negative Staphylococcus (in 42 (33%), 36 (29%), and 25 (20%) patients, respectively). Microbiological findings were similar in BALF from patients with and without signs of lung infection and the frequency of multidrug resistant (MDR) bacteria was low. No significant association was found between background factors and time to first lung infection.\n\n\nCONCLUSIONS\nThis study gives important epidemiologic insights and reinforces that microbiological findings have to be evaluated in the light of clinical symptoms and endobronchial appearance in the assessment of lung infections in lung transplant patients.",
"affiliations": "Division of Infection Medicine, Hospital of Helsingborg, Helsingborg, Sweden.;Department of Infectious Diseases, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.;Division of Infection Medicine, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden.;Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, Sweden.;Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, Sweden.;Department of Respiratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.;Department of Infectious Diseases, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.;Division of Infection Medicine, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden.;Division of Infection Medicine, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden.",
"authors": "Stjärne Aspelund|Anna|A|http://orcid.org/0000-0002-7391-268X;Hammarström|Helena|H|;Inghammar|Malin|M|;Larsson|Hillevi|H|;Hansson|Lennart|L|;Riise|Gerdt C|GC|;Friman|Vanda|V|;Christensson|Bertil|B|;Påhlman|Lisa I|LI|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "bronchoalveolar lavage fluid; lung infections; lung transplantation; microbiology",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D002176:Candida albicans; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D011446:Prospective Studies; D011550:Pseudomonas aeruginosa; D013210:Staphylococcus; D013548:Sweden; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12973",
"pmc": null,
"pmid": "30107073",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "20080440;28803455;28681941;19254327;18455028;16399537;26161017;7815807;21793988;30107073;24410732;27772669;17617864;20172345;20351205;18096473;7516251;8357286;19659672;12698153;26455730;22798321;28811074;21620113;17919621",
"title": "Microbiological findings in bronchoalveolar lavage fluid from lung transplant patients in Sweden.",
"title_normalized": "microbiological findings in bronchoalveolar lavage fluid from lung transplant patients in sweden"
} | [
{
"companynumb": "SE-ROCHE-2184511",
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"occurcountry": "SE",
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
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{
"abstract": "Patients with severe hepatic trauma requiring damage control laparotomy and perihepatic packing are at risk for venous thromboembolism (VTE). Prevention and treatment of VTE in this population is problematic, especially in children for whom adult guidelines are often adapted. The following case report describes two children who developed VTE with associated pulmonary embolism after damage control laparotomy and perihepatic packing for hepatic trauma. The first patient had hemodynamically significant pulmonary emboli. He received catheter-directed thrombolysis with subsequent improvement in ventilation and need for inotropic support. The second patient had a vena caval thrombus detected on surveillance ultrasound and later developed a pulmonary embolus, both of which were treated with heparin and enoxaparin. Our experience suggests that surveillance imaging of these patients may allow for prospective mobilization of specialized resources, such as interventional radiology support or cardiopulmonary bypass equipment, and that catheter-directed thrombolysis may be a viable treatment modality in these critically ill and injured children.",
"affiliations": "Division of Pediatric Critical Care Medicine, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Pediatric Critical Care Medicine, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Pediatric Critical Care Medicine, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Pediatric Surgery, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.",
"authors": "Claveria|Joanne K|JK|;Meyer|Michael T|MT|;Wakeham|Martin K|MK|;Sato|Thomas T|TT|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.3233/PIC-13061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2146-4626",
"issue": "2(3)",
"journal": "Journal of pediatric intensive care",
"keywords": "Pulmonary embolism; hepatic trauma; perihepatic packing; thrombolytic therapy; tissue plasminogen activator; venous thromboembolism",
"medline_ta": "J Pediatr Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101592756",
"other_id": null,
"pages": "127-130",
"pmc": null,
"pmid": "31214434",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pulmonary embolism in two patients after severe hepatic trauma.",
"title_normalized": "pulmonary embolism in two patients after severe hepatic trauma"
} | [
{
"companynumb": "US-ROCHE-1367405",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Women with evidence of myocardial infarction with non-obstructive coronary arteries (MINOCA) and ischemia with non-obstructive coronary arteries (INOCA), a condition associated with adverse cardiovascular outcomes, are becoming increasingly recognized. Underlying mechanisms of MINOCA, such as coronary microvascular spasm, represent a diagnostic and therapeutic challenge to clinicians as there is currently neither a uniform nor comprehensive diagnostic strategy for accurate risk stratification for these patients. Diagnostic tests such as invasive coronary reactivity testing (CRT) can be useful in the diagnosis of MINOCA. We present a challenging case of MINOCA due to microvascular coronary vasospasm. A 55-year-old female with a past medical history of hypertension was referred to our tertiary care center following a non-ST-elevation myocardial infarction. She was diagnosed with MINOCA secondary to coronary microvascular vasospasm by invasive CRT. This case presentation provides an example demonstrating that definitive diagnostic testing such as CRT used for the detection of vasospasm in coronary microvascular disease can be incorporated for routine assessment of MINOCA.",
"affiliations": "Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.;Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.;Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.;Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.;Emory School of Medicine, Emory University, Atlanta, GA, USA.;Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.;Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.;Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.",
"authors": "Marpuri|ReddySailaja|R|;Joung|Sandy|S|;Gadh|Adit|A|;Dhawan|Shivani|S|;Al-Badri|Ahmed|A|;Pacheco|Christine|C|;Wei|Janet|J|;Merz|C Noel Bairey|CNB|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.21037/cdt.2019.07.13",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2223-3652",
"issue": "9(4)",
"journal": "Cardiovascular diagnosis and therapy",
"keywords": "Ischemia with non-obstructive coronary arteries (INOCA); acute coronary syndrome; coronary microvascular dysfunction (CMD); coronary microvascular vasospasm; heart failure with preserved ejection fraction; myocardial infarction with non-obstructive coronary arteries (MINOCA); myocardial infraction",
"medline_ta": "Cardiovasc Diagn Ther",
"mesh_terms": null,
"nlm_unique_id": "101601613",
"other_id": null,
"pages": "400-405",
"pmc": null,
"pmid": "31555546",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "16458167;18687244;20031721;22322081;22721660;23816032;25801710;26245334;27081110;28158518;28616515;29498752;7829785",
"title": "Case report: assessment and management of myocardial infarction and non-obstructive coronary arteries (MINOCA): the role of microvascular coronary vasospasm.",
"title_normalized": "case report assessment and management of myocardial infarction and non obstructive coronary arteries minoca the role of microvascular coronary vasospasm"
} | [
{
"companynumb": "US-PFIZER INC-2019424860",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOPROLOL TARTRATE"
},
"drugadditional": "1",... |
{
"abstract": "Candida auris has become a global fungal public health threat. This multidrug-resistant yeast is associated with nosocomial intra- and interhospital transmissions causing healthcare-associated infections. Here, we report on two C. auris cases from Germany. The two patients stayed in Germany for a long time before C. auris was detected during their hospitalization. The patients were isolated in single rooms with contact precautions. No nosocomial transmissions were detected within the hospital. Both C. auris isolates exhibited high minimum inhibitory concentrations (MICs) of fluconazole and one isolate additionally high MICs against the echinocandins. Microsatellite genotyping showed that both strains belong to the South Asian clade. These two cases are examples for appropriate in-hospital care and infection control without further nosocomial spread. Awareness for this emerging, multidrug-resistant pathogen is justified and systematic surveillance in European health care facilities should be performed.",
"affiliations": "Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Klinikum Nürnberg, Paracelsus Medical University, 90419 Nuremberg, Germany.;Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Klinikum Nürnberg, Paracelsus Medical University, 90419 Nuremberg, Germany.;Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.;Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, 6532 SZ Nijmegen, The Netherlands.;Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.",
"authors": "Steinmann|Joerg|J|;Schrauzer|Thomas|T|;Kirchhoff|Lisa|L|0000-0003-2015-275X;Meis|Jacques F|JF|0000-0003-3253-6080;Rath|Peter-Michael|PM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jof7050380",
"fulltext": "\n==== Front\nJ Fungi (Basel)\nJ Fungi (Basel)\njof\nJournal of Fungi\n2309-608X\nMDPI\n\n10.3390/jof7050380\njof-07-00380\nCase Report\nTwo Candida auris Cases in Germany with No Recent Contact to Foreign Healthcare—Epidemiological and Microbiological Investigations\nSteinmann Joerg 12*\nSchrauzer Thomas 1\nhttps://orcid.org/0000-0003-2015-275X\nKirchhoff Lisa 2\nhttps://orcid.org/0000-0003-3253-6080\nMeis Jacques F. 34\nRath Peter-Michael 2\nRementeria-Ruiz Aitor D. Academic Editor\n1 Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Klinikum Nürnberg, Paracelsus Medical University, 90419 Nuremberg, Germany; thomas.schrauzer@klinikum-nuernberg.de\n2 Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; lisa.kirchhoff@uk-essen.de (L.K.); peter-michael.rath@uk-essen.de (P.-M.R.)\n3 Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, 6532 SZ Nijmegen, The Netherlands; jacques.meis@gmail.com\n4 Centre of Expertise in Mycology Radboudumc, Canisius-Wilhelmina Hospital, 6532 SZ Nijmegen, The Netherlands\n* Correspondence: joerg.steinmann@klinikum-nuernberg.de; Tel.: +49-911-3982-520; Fax: +49-911-398-3266\n12 5 2021\n5 2021\n7 5 38018 4 2021\n07 5 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nCandida auris has become a global fungal public health threat. This multidrug-resistant yeast is associated with nosocomial intra- and interhospital transmissions causing healthcare-associated infections. Here, we report on two C. auris cases from Germany. The two patients stayed in Germany for a long time before C. auris was detected during their hospitalization. The patients were isolated in single rooms with contact precautions. No nosocomial transmissions were detected within the hospital. Both C. auris isolates exhibited high minimum inhibitory concentrations (MICs) of fluconazole and one isolate additionally high MICs against the echinocandins. Microsatellite genotyping showed that both strains belong to the South Asian clade. These two cases are examples for appropriate in-hospital care and infection control without further nosocomial spread. Awareness for this emerging, multidrug-resistant pathogen is justified and systematic surveillance in European health care facilities should be performed.\n\nCandida auris\nresistance\nSTR typing\ninfection control\n==== Body\n1. Introduction\n\nCandida auris has become a worldwide public health threat [1]. This fungus is associated with multidrug resistance and a high mortality. Within a hospital C. auris can survive on inanimate surfaces for long periods and nosocomial transmissions were repeatedly reported from all over the world [2]. Compared to Asia, USA and South Africa the C. auris incidence in Europe is, despite outbreaks reported in Spain and UK [3,4], low. Between January 2018 and May 2019, 349 cases were reported in the European Union/European Economic Area [5]. In Germany only a few C. auris cases have been reported so far. In a series of seven German patients, six of these cases were previously hospitalized abroad or had contact to foreign healthcare [6]. Colonization with C. auris has been detected at various body sites, including nares, groin, axilla, ears and rectum [7]. Risk factors for colonization are among others elderly age, diabetes, indwelling medical devices, immunosuppression, hemodialysis/chronic renal disease and use of broad-spectrum antibiotics and/or antifungals [8]. Receiving carbapenems and systemic fluconazole in the prior 90 days, being on a ventilator and having ≥ 1 acute care hospital visit in the prior six months were shown to be associated with C. auris colonization in New York nursing facilities with ventilator units [9]. Furthermore, contact with C. auris positive patients or their environment is an additional risk factor in healthcare institutions. Recently, C. auris emerged in an Italian hospital in context with the COVID-19 pandemic [10]. In most of the European hospitals no clear screening strategies for C. auris are established [11]. However, UK guidelines recommend that all hospitals should establish a C. auris screening policy after local risk assessment of those patients most likely to be colonized [12]. In Germany, all admitted patients with a history of hospitalization in a country with a high prevalence of multidrug-resistant (MDR) gram-negative bacteria should be screened for MDR bacteria and placed in contact precautions in a private room [11]. In contrast, similar recommendations to screen for C. auris in Germany do not exist so far.\n\nHere we present the epidemiological, clinical, and mycological details of two C. auris cases in Germany highlighting that the time point of fungal pathogen acquisition remains open and infection control standards may prevent further transmission.\n\n2. Methods and Results\n\n2.1. Laboratory Investigations\n\nC. auris screening samples from patients and environmental swabs were cultured on chromogenic yeast medium (chromID, bioMèrieux, Nürtingen, Germany or Candida Brilliance, Thermo Fisher Scientific, Wesel, Germany) for 48 h at 37 °C. Identification of C. auris was done with MALDI TOF MS (Bruker, Bremen, Germany or VITEK MS, bioMèrieux, Marcy-l’Étoile, France) and confirmed by ITS sequencing as described previously [13]. Susceptibility testing was performed by broth microdilution according to CLSI, following M27-S4 [14] and one isolate was tested at the National Reference Centre for Invasive Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, Jena, Germany according to EUCAST. One C. auris isolate was selected for ERG11 and FKS1 gene amplification and sequencing [15]. Genotyping was performed by a recently developed short tandem repeat typing method [16].\n\n2.2. Cases\n\nCase 1: A middle-aged male patient with tetraparesis after fracture of the cervical vertebrae 4/5 in Iraq in 2015 came for further treatment to South Germany in 2018 and lived in a long-term care facility since 2019. In 2019 and 2020 the patient had several hospitalizations in Nuremberg, Germany because of pneumonia and recurrent urinary tract infections. He had an indwelling urinary catheter, decubitus ulcer and received several courses of broad-spectrum antibiotics. During his first hospital stay in February 2019, no C. auris was detected in screening swabs of rectum, groin and nose. In August 2019, C. auris was found for the first time in wound and urine screening samples at admission. During hospital stays in December 2019, April 2020 and September 2020, C. auris was found at several body sites including the ears. After C. auris was detected in August 2019, the patient was cared for in a single patient room throughout his hospitalizations. Based on results of clinical specimens there was no evidence of transmission of C. auris to other patients within the hospital. After patient discharge in April 2020 and subsequent cleaning of the patient room, inanimate surfaces close to the patient environment, e.g., bedrails, were examined for C. auris by taking a total of 20 swabs. Examining these swabs revealed no presence of yeasts. The patient never received antifungal treatment during hospitalizations. Susceptibility testing and microsatellite typing results are shown in Table 1 and Figure 1. The strain represents a new (sub)genotype within the South Asian clade.\n\nCase 2: A middle-aged male patient underwent lung transplantation in a tertiary hospital in Essen, Germany. Bronchial cultures of donor and recipient showed no fungal growth. After transplantation, antifungal prophylaxis with voriconazole was started. Regularly performed therapeutic drug monitoring showed trough levels of voriconazole within the therapeutic range (1–4 mg/L). The patient was nursed in a single patient room during the whole stay in the hospital due to colonization with MDR pathogens (Klebsiella pneumoniae with extended spectrum beta-lactamase phenotype and resistance to quinolones, vancomycin-resistant Enterococcus faecium, carbapenem-resistant Pseudomonas aeruginosa). Post-transplant the patient suffered from CMV pneumonia and recurrent septic episodes with Pseudomonas and Klebsiella as well as episodes of multi-organ failure. While routine microbiology tracheal aspirate samples showed colonization of bronchi with Candida albicans, urine samples showed no growth of pathogens. The patient died of cardiogenic-septic shock after a six week stay on an intensive care unit on day 290 after transplantation. He was not discharged home since transplantation.\n\nFive days before his death, yeasts were found in a urine culture without leucocyturia. At this time, only C. albicans and C. glabrata were cultured from screening samples from the respiratory tract and stool. Blood cultures always remained negative for fungi. The urine culture grew C. auris. Broth microdilution susceptibility testing showed that the C. auris isolate was resistant to fluconazole (>64 mg/L) and voriconazole (16 mg/L) (Table 1) [17]. The echinocandins micafungin and anidulafungin had an MIC of 2 mg/L. By sequencing the ERG11, an amino acid substitution was found at position 132 (Y132F). Further, the isolate was wild type at position 639 in the FKS1 gene. Immediately after identification of C. auris, all patients of the intensive care ward (n = 15) were assessed for C. auris (respiratory samples, stool, urine), but no further isolates were detected. Furthermore, C. auris was not found in routine screening or diagnostic samples of other patients on the wards where the patient stayed before. Genetically, the isolate belongs to the South Asian clade (Figure 1). The patient did not travel abroad for the last years and no other patients with C. auris could be identified, therefore the origin of this isolate remains elusive.\n\n3. Discussion\n\nThis report shows epidemiological and microbiological details of two C. auris cases from two distinct German tertiary hospitals without a recent exposure to foreign healthcare. C. auris is rarely detected in Germany and other European countries and was so far mainly introduced from patients with contact to healthcare systems from countries with higher prevalence [11,18,19,20]. Both patients had several risk factors for C. auris colonization. Epidemiological, phenotypical, and genotyping data showed that there was no link between the patients and/or isolates, indicating two different sources. Because there were no additional infected or colonized cases with C. auris identified and environmental sampling was negative, contact isolation precautions and appropriate infection control seemed to prevent further transmissions.\n\nEven though no C. auris case from Iraq was reported, it is possible that the first patient was already colonized with C. auris in Iraq years ago, but the fungus was never detected during previous hospital stays in Germany. C. auris may not have been detected on screening because the fungal load may have been below the limit of detection. A patient-to-patient transmission as the potential source of C. auris colonization in the long-term care facility in Germany cannot be excluded as the residents were not screened for C. auris. It has been shown earlier that C. auris can be highly prevalent in residents and in the environment of long-term care facilities in the USA [9].\n\nBoth patients were each nursed in single patient rooms during their hospital stay. Beyond basic hygiene, isolating colonized or infected patients with contact precautions, and regularly cleaning/decontaminating the environment is helpful to prevent further transmission [21,22]. The first patient was colonized with C. auris at several body sites, but no room contamination at high touch, inanimate surfaces could be found after terminal room cleaning. In addition, patient contact screening of direct contacts including those being discharged from the health care facility should be performed [22].\n\nAn open question remains whether both patients were already colonized with C. auris at hospital admission and detection was only possible due to selection factors (e.g., anti-infective therapy) during stay. There is only limited data from European hospitals on the prevalence of C. auris colonization at admission. In a study from London the prevalence of C. auris in admitted patients to the hospital was 0.04% (N = 1/2246) [3]. In a recent study from England, 921 patients from 998 admissions to eight ICUs in three major cities in 2017 to 2018 were screened for C. auris at admission [12]. No C. auris isolate was detected. It was concluded that widespread screening for C. auris in ICUs in England is not recommended and unlikely to be cost-effective. An admission screening strategy with focus on high-risk individuals based on local risk assessment was suggested [12]. Based on the current literature and our experience, a screening strategy for C. auris in patients with contact to foreign healthcare and with multiple risk factors including regional factors (e.g., outbreak in the area) can be considered in low prevalence countries. It is currently unclear, whether only an admission screening or additional repeated screening for C. auris should be conducted. A case-by-case decision may also be appropriate.\n\nOne isolate from Essen had elevated anidulafungin and micafungin MICs, but the patient never received antifungal therapy with echinocandins within the hospital. He received long treatment with voriconazole and the isolate exhibited high MICs against this tri-azole and also to fluconazole. In the USA, about 90% of C. auris isolates have been found to be resistant to fluconazole, about 30% resistant to amphotericin B, and less than 5% resistant to echinocandins [23]. We found an amino acid substitution in ERG11 at position 132 (Y132F). This substitution has been found previously in azole-resistant C. auris isolates. [15,24]. Additionally, the isolate was wildtype at position S639 in the FKS1 gene. A large study from Austria failed to find FKS1 mutations in C. albicans isolates with borderline echinocandin MICs [25]. The fact that our C. auris isolate had no mutation in the FKS1 region is congruent to observations that a mutation is mainly linked to high MICs above 4 mg/L [15]. EUCAST did not provide clinical breakpoints so far. The CDC reported tentative breakpoints for caspofungin with MICs of ≥2 mg/L as well as anidulafungin and micafungin of ≥4 mg/L [26]. A comparison of EUCAST and CLSI reference microdilution showed that six C. auris isolates, with elevated echinocandin MICs (4 mg/L), had the same results as measured by both methods for micafungin and anidulafungin (4.9%) [27].\n\nFour major clades of C. auris (I, II, III, and IV initially originating from South Asia, East Asia, South America, and South Africa, respectively) [26] and a fifth clade reported from Iran have been described to date [28]. Our isolates were from clade I as shown by short tandem repeat typing, a method which is comparable with whole-genome sequencing [7,16]. The two described isolates differ in three markers indicating that they are not related.\n\nThis case report has some limitations. The two reported cases were retrospectively investigated and not all screening samples were performed according to the recommendations. Furthermore, for both patients the time point of acquisition of C. auris cannot be definitely determined and it cannot be excluded that an undetected hospital transmission may have occurred.\n\nThese two potentially “endemic” German C. auris cases show the importance of awareness of C. auris in hospitals in Europe not only for patients with contact to foreign healthcare environments. European health care facilities should establish local guidelines for C. auris screening for patients with risk factors and implement strict infection control measures for positive cases.\n\nAcknowledgments\n\nWe thank Theun de Groot, Manja Schmidt and Dirk Schmidt for excellent technical assistance. We thank the National Reference Centre for Invasive Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, Jena, Germany for providing MIC results of isolate 1.\n\nAuthor Contributions\n\nConceptualisation, J.S., J.F.M. and P.-M.R.; laboratory investigations, J.F.M. and L.K., investigations, J.S., T.S. and P.-M.R.; writing—review and editing, J.S., T.S., J.F.M., L.K. and P.-M.R.; supervision, J.S. and P.-M.R. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nNot applicable.\n\nData Availability Statement\n\nData are available within the article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 STR genotypes of 27 C. auris isolates. In UPGMA dendrogram of STR genotypes, both German isolates (Essen and Nuremberg) are included.\n\njof-07-00380-t001_Table 1 Table 1 In vitro antifungal activities of the two C. auris isolates from Germany in mg/L.\n\n\tAMB\tFZ\tVRC\tPOS\tISA\tMCF\tANF\t\nIsolate 1\t1\t64\t1\t≤0.016\t≤0.016\tnd\t0.25\t\nIsolate 2\t2\t>64\t16\t0.25\t8\t2\t2\t\nAMB, amphotericin B; FZ, fluconazole; VRC, voriconazole POS, posaconazole; ISA, isavuconazole; MCF, micafungin; ANF, anidulafungin; nd, not determined.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Meis J.F. Chowdhary A. Candida auris: A global fungal public health threat Lancet Infect. Dis. 2018 18 1298 1299 10.1016/S1473-3099(18)30609-1 30293876\n2. Chowdhary A. Sharma C. Meis J.F. Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally PLoS Pathog. 2017 13 e1006290 10.1371/journal.ppat.1006290 28542486\n3. Schelenz S. Hagen F. Rhodes J.L. Abdolrasouli A. Chowdhary A. Hall A. Ryan L. Shackleton J. Trimlett R. Meis J.F. First hospital outbreak of the globally emerging Candida auris in a European hospital Antimicrob. Resist. Infect. Control. 2016 5 35 10.1186/s13756-016-0132-5 27777756\n4. Ruiz-Gaitán A. Moret A.M. Tasias-Pitarch M. Aleixandre-López A.I. Martínez-Morel H. Calabuig E. Salavert-Lletí M. Ramírez P. López-Hontangas J.L. Hagen F. An outbreak due to Candida auris with prolonged colonisation and candidaemia in a tertiary care European hospital Mycoses 2018 61 498 505 10.1111/myc.12781 29655180\n5. Plachouras D. Lötsch F. Kohlenberg A. Monnet D.L. Candida auris Survey Collaborative Group Candida auris: Epidemiological situation, laboratory capacity and preparedness in the European Union and European Economic Area*, January 2018 to May 2019. Eurosurveillance 2020 25 10.2807/1560-7917.ES.2020.25.12.2000240\n6. Hamprecht A. Barber A.E. Mellinghoff S.C. Thelen P. Walther G. Yu Y. Neurgaonkar P. Dandekar T. Cornely O.A. Martin R. Candida auris in Germany and Previous Exposure to Foreign Healthcare Emerg. Infect. Dis. 2019 25 1763 1765 10.3201/eid2509.190262 31223105\n7. Yadav A. Singh A. Wang Y. van Haren M.H. Singh A. de Groot T. Meis J.F. Xu J. Chowdhary A. Colonisation and Transmission Dynamics of Candida auris among Chronic Respiratory Diseases Patients Hospitalised in a Chest Hospital, Delhi, India: A Comparative Analysis of Whole Genome Sequencing and Microsatellite Typing J. Fungi 2021 7 81 10.3390/jof7020081 33530297\n8. Du H. Bing J. Hu T. Ennis C.L. Nobile C.J. Huang G. Candida auris: Epidemiology, biology, antifungal resistance, and virulence PLoS Pathog. 2020 16 e1008921 10.1371/journal.ppat.1008921 33091071\n9. Pacilli M. Kerins J.L. Clegg W.J. Walblay K.A. Adil H. Kemble S.K. Xydis S. McPherson T.D. Lin M.Y. Hayden M.K. Regional Emergence of Candida auris in Chicago and Lessons Learned from Intensive Follow-up at 1 Ventilator-Capable Skilled Nursing Facility Clin. Infect. Dis. 2020 71 e718 e725 10.1093/cid/ciaa435 32291441\n10. Di Pilato V. Codda G. Ball L. Giacobbe D.R. Willison E. Mikulska M. Magnasco L. Crea F. Vena A. Pelosi P. Molecular Epidemiological Investigation of a Nosocomial Cluster of C. auris: Evidence of Recent Emergence in Italy and Ease of Transmission during the COVID-19 Pandemic J. Fungi 2021 7 140 10.3390/jof7020140\n11. Vogelzang E.H. Weersink A.J.L. van Mansfeld R. Chow N.A. Meis J.F. van Dijk K. The First Two Cases of Candida auris in The Netherlands J. Fungi 2019 5 91 10.3390/jof5040091\n12. Sharp A. Muller-Pebody B. Charlett A. Patel B. Gorton R. Lambourne J. Cummins M. Alcolea-Medina A. Wilks M. Smith R. Screening for Candida auris in patients admitted to eight intensive care units in England, 2017 to 2018 Eurosurveillance 2021 26 1900730 10.2807/1560-7917.ES.2021.26.8.1900730 33632376\n13. Steinmann J. Schmidt D. Buer J. Rath P.-M. Discrimination of Scedosporium prolificans against Pseudallescheria boydii and Scedosporium apiospermum by semiautomated repetitive sequence-based PCR Med. Mycol. 2011 49 475 483 10.3109/13693786.2010.539630 21108573\n14. Clinical and Laboratory Standards Institute Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Fourth Informational Supplement M27-S4 CLSI Wayne, PA, USA 2012\n15. Chowdhary A. Prakash A. Sharma C. Kordalewska M. Kumar A. Sarma S. Tarai B. Singh A. Upadhyaya G. Upadhyay S. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: Role of the ERG11 and FKS1 genes in azole and echinocandin resistance J. Antimicrob. Chemother. 2018 73 891 899 10.1093/jac/dkx480 29325167\n16. De Groot T. Puts Y. Berrio I. Chowdhary A. Meis J.F. Development of Candida auris Short Tandem Repeat Typing and Its Application to a Global Collection of Isolates MBio 2020 11 02971-19 10.1128/mBio.02971-19 31911492\n17. Arendrup M.C. Friberg N. Mares M. Kahlmeter G. Meletiadis J. Guinea J. The Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST) How to interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST) Clin. Microbiol. Infect. 2020 26 1464 1472 10.1016/j.cmi.2020.06.007 32562861\n18. Dewaele K. Frans J. Smismans A. Ho E. Tollens T. Lagrou K. First case of Candida auris infection in Belgium in a surgical patient from Kuwait Acta Clin. Belg. 2020 75 221 228 10.1080/17843286.2018.1555114 30514182\n19. Pekard-Amenitsch S. Schriebl A. Posawetz W. Willinger B. Kölli B. Buzina W. Isolation of Candida auris from Ear of Otherwise Healthy Patient, Austria, 2018 Emerg. Infect. Dis. 2018 24 1596 1597 10.3201/eid2408.180495 30016243\n20. Riat A. Neofytos D. Coste A. Harbarth S. Bizzini A. Grandbastien B. Pugin J. Lamoth F. First case of Candida auris in Switzerland: Discussion about preventive strategies Swiss Med. Wkly. 2018 148 10.4414/smw.2018.14622\n21. Caceres D.H. Forsberg K. Welsh R.M. Sexton D.J. Lockhart S.R. Jackson B.R. Chiller T. Candida auris: A Review of Recommendations for Detection and Control in Healthcare Settings J. Fungi 2019 5 111 10.3390/jof5040111 31795175\n22. Kenters N. Kiernan M. Chowdhary A. Denning D.W. Pemán J. Saris K. Schelenz S. Tartari E. Widmer A. Meis J.F. Control of Candida auris in healthcare institutions: Outcome of an International Society for Antimicrobial Chemotherapy expert meeting Int. J. Antimicrob. Agents 2019 54 400 406 10.1016/j.ijantimicag.2019.08.013 31419480\n23. Candidiasis|Types of Diseases|Fungal Diseases|CDC Available online: https://www.cdc.gov/fungal/diseases/candidiasis/index.html (accessed on 16 February 2021)\n24. Healey K.R. Kordalewska M. Jiménez Ortigosa C. Singh A. Berrío I. Chowdhary A. Perlin D.S. Limited ERG11 Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole Susceptibility Antimicrob. Agents Chemother. 2018 62 01427-18 10.1128/AAC.01427-18\n25. Spettel K. Galazka S. Kriz R. Camp I. Willinger B. Do Candida albicans Isolates with Borderline Resistant Micafungin MICs Always Harbor FKS1 Hot Spot Mutations? J. Fungi 2021 7 93 10.3390/jof7020093\n26. Lockhart S.R. Etienne K.A. Vallabhaneni S. Farooqi J. Chowdhary A. Govender N.P. Colombo A.L. Calvo B. Cuomo C.A. Desjardins C.A. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses Clin. Infect. Dis. 2017 64 134 140 10.1093/cid/ciw691 27988485\n27. Arendrup M.C. Prakash A. Meletiadis J. Sharma C. Chowdhary A. Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight Antifungal Compounds for Candida auris and Associated Tentative Epidemiological Cutoff Values Antimicrob. Agents Chemother. 2017 61 00485-17 10.1128/AAC.00485-17\n28. Chow N.A. de Groot T. Badali H. Abastabar M. Chiller T.M. Meis J.F. Potential Fifth Clade of Candida auris, Iran, 2018 Emerg. Infect. Dis. 2019 25 1780 1781 10.3201/eid2509.190686 31310230\n\n",
"fulltext_license": "CC BY",
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"issue": "7(5)",
"journal": "Journal of fungi (Basel, Switzerland)",
"keywords": "Candida auris; STR typing; infection control; resistance",
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"title": "Two Candida auris Cases in Germany with No Recent Contact to Foreign Healthcare-Epidemiological and Microbiological Investigations.",
"title_normalized": "two candida auris cases in germany with no recent contact to foreign healthcare epidemiological and microbiological investigations"
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"abstract": "Brugada syndrome is an inherited arrhythmia that increases a patient's risk of sudden cardiac death. Certain pharmacologic agents may induce a transient Brugada pattern on surface electrocardiogram (EKG). One of these is loperamide, an over-the-counter agent commonly used to manage diarrhea. We report the case of a patient who experienced EKG changes that mimicked Brugada pattern after excessive intake of loperamide.",
"affiliations": "HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.;HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.;HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.;HOUSTON METHODIST DEBAKEY HEART AND VASCULAR CENTER, HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.;HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.;HOUSTON METHODIST DEBAKEY HEART AND VASCULAR CENTER, HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.;HOUSTON METHODIST DEBAKEY HEART AND VASCULAR CENTER, HOUSTON METHODIST HOSPITAL, HOUSTON, TEXAS.",
"authors": "Rojas|Stephanie Fuentes|SF|;Oglat|Ayah|A|;Bonilla|Hilda Mariana Gonzalez|HMG|;Jeroudi|Omar|O|;Sharp|Whitney|W|;Valderrábano|Miguel|M|;Schurmann|Paul Antonio|PA|",
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"keywords": "Brugada; arrhythmia; loperamide",
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"mesh_terms": "D000930:Antidiarrheals; D053840:Brugada Syndrome; D066126:Cardiotoxicity; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D008139:Loperamide; D008875:Middle Aged; D011237:Predictive Value of Tests",
"nlm_unique_id": "101508600",
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"pages": "e1-e3",
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"publication_types": "D002363:Case Reports",
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"title": "Loperamide Mimicking Brugada Pattern.",
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-206637",
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"abstract": "OBJECTIVE\nThe patients with hematological malignancies are a vulnerable group to COVID-19, due to the immunodeficiency resulting from the underlying disease and oncological treatment that significantly impair cellular and humoral immunity. Here we report on a beneficial impact of a passive immunotherapy with convalescent plasma to treat a prolonged, active COVID-19 infection in a patient with a history of nasopharyngeal diffuse large B-cell lymphoma treated with the therapy inducing substantial impairment of particularly humoral arm of immune system. The specific aim was to quantify SARS-CoV2 neutralizing antibodies in a patient plasma during the course of therapy.\n\n\nMETHODS\nBesides the standard of care treatment and monitoring, neutralizing antibody titers in patient's serum samples, calibrated according to the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin (human), were quantified in a time-dependent manner. During the immunotherapy period peripheral blood flow cytometry immunophenotyping was conducted to characterize lymphocyte subpopulations.\n\n\nRESULTS\nThe waves of clinical improvements and worsening coincided with transfused neutralizing antibodies rises and drops in the patient's systemic circulation, proving their contribution in controlling the disease progress. Besides the patient's lack of own humoral immune system, immunophenotyping analysis revealed also the reduced level of helper T-lymphocytes and immune exhaustion of monocytes.\n\n\nCONCLUSIONS\nTherapeutic approach based on convalescent plasma transfusion transformed a prolonged, active COVID-19 infection into a manageable chronic disease.",
"affiliations": "Special Hospital for Pulmonary Diseases, Rockefellerova 3, 10000 Zagreb, Croatia. Electronic address: dina.rnjak@gmail.com.;University of Zagreb, Centre for Research and Knowledge Transfer in Biotechnology, Rockefellerova 10, 10000 Zagreb, Croatia; Centre of Excellence for Virus Immunology and Vaccines, Zagreb, Croatia. Electronic address: sravlic@unizg.hr.;Special Hospital for Pulmonary Diseases, Rockefellerova 3, 10000 Zagreb, Croatia.;University of Zagreb, Centre for Research and Knowledge Transfer in Biotechnology, Rockefellerova 10, 10000 Zagreb, Croatia; Centre of Excellence for Virus Immunology and Vaccines, Zagreb, Croatia.;Special Hospital for Pulmonary Diseases, Rockefellerova 3, 10000 Zagreb, Croatia.;Special Hospital for Pulmonary Diseases, Rockefellerova 3, 10000 Zagreb, Croatia.;Croatian Institute of Transfusion Medicine, Zagreb, Croatia.;University Hospital for Infectious Diseases Dr. Fran Mihaljević, Zagreb, Croatia; Centre of Excellence for Virus Immunology and Vaccines, Zagreb, Croatia.;University of Zagreb, Centre for Research and Knowledge Transfer in Biotechnology, Rockefellerova 10, 10000 Zagreb, Croatia; Centre of Excellence for Virus Immunology and Vaccines, Zagreb, Croatia.;University Hospital for Infectious Diseases Dr. Fran Mihaljević, Zagreb, Croatia; Centre of Excellence for Virus Immunology and Vaccines, Zagreb, Croatia.;Srebrnjak Children's Hospital, Zagreb, Croatia.;University of Zagreb, Centre for Research and Knowledge Transfer in Biotechnology, Rockefellerova 10, 10000 Zagreb, Croatia.;Croatian Institute of Transfusion Medicine, Zagreb, Croatia.;Croatian Institute of Transfusion Medicine, Zagreb, Croatia.;Croatian Institute of Transfusion Medicine, Zagreb, Croatia.;Srebrnjak Children's Hospital, Zagreb, Croatia.;Special Hospital for Pulmonary Diseases, Rockefellerova 3, 10000 Zagreb, Croatia.",
"authors": "Rnjak|D|D|;Ravlić|S|S|;Šola|A-M|AM|;Halassy|B|B|;Šemnički|J|J|;Šuperba|M|M|;Hećimović|A|A|;Kurolt|I-C|IC|;Kurtović|T|T|;Mačak Šafranko|Ž|Ž|;Polančec|D|D|;Bendelja|K|K|;Mušlin|T|T|;Jukić|I|I|;Vuk|T|T|;Zenić|L|L|;Artuković|M|M|",
"chemical_list": "D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D012367:RNA, Viral; D000069283:Rituximab",
"country": "France",
"delete": false,
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"issue": "28(3)",
"journal": "Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine",
"keywords": "COVID-19; Convalescent plasma; Immunodeficiency; Infective virus-neutralization assay; Neutralizing antibody; SARS-CoV-2",
"medline_ta": "Transfus Clin Biol",
"mesh_terms": "D000818:Animals; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000971:Antineoplastic Combined Chemotherapy Protocols; D000086382:COVID-19; D000087123:COVID-19 Nucleic Acid Testing; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007116:Immunization, Passive; D016867:Immunocompromised Host; D016130:Immunophenotyping; D016131:Lymphocyte Subsets; D016403:Lymphoma, Large B-Cell, Diffuse; D008231:Lymphopenia; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D009305:Nasopharynx; D012367:RNA, Viral; D018714:Radiotherapy, Adjuvant; D000069283:Rituximab; D000086402:SARS-CoV-2; D014709:Vero Cells; D014776:Virus Cultivation",
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"pmc": null,
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"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "COVID-19 convalescent plasma as long-term therapy in immunodeficient patients?",
"title_normalized": "covid 19 convalescent plasma as long term therapy in immunodeficient patients"
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"companynumb": "HR-PFIZER INC-202101158100",
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"abstract": "We present a case of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) masquerading as a skin rash which progressively worsened over a year. After being treated for various dermatologic and infectious etiologies, he did not feel any relief and presented to our hospital. Imaging showed generalized lymphadenopathy. Later, lymph node biopsy and skin biopsy confirmed the diagnosis of CD30 + peripheral T-cell lymphoma. He was soon started on chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (CHOEP). However, because of the aggressive nature of his disease and advanced stage at presentation, he succumbed to complications and died of sepsis. This case highlights the importance of considering a rash as one of the early symptoms of an underlying life-threatening disease.",
"affiliations": "Internal Medicine, St. Vincent Hospital, Worcester, USA.;Internal Medicine, Rhode Island Hospital, Providence, USA.;Hematology and Oncology, St. Vincent Hospital, Worcester, USA.;Internal Medicine, St. Vincent Hospital, Worcester, USA.",
"authors": "Singh|Aditi|A|;Bhagat|Milind|M|;Siddiqui|Ahmad D|AD|;Thapa|Simant S|SS|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.3813",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3813DermatologyInternal MedicineOncologyPeripheral T-cell Lymphoma, Not Otherwise Specified: An Unusual Presentation of a Rare Lymphoma Muacevic Alexander Adler John R Singh Aditi 1Bhagat Milind 2Siddiqui Ahmad D 3Thapa Simant S 1\n1 \nInternal Medicine, St. Vincent Hospital, Worcester, USA \n2 \nInternal Medicine, Rhode Island Hospital, Providence, USA \n3 \nHematology and Oncology, St. Vincent Hospital, Worcester, USA \nAditi Singh aditisingh0215@gmail.com2 1 2019 1 2019 11 1 e381321 12 2018 2 1 2019 Copyright © 2019, Singh et al.2019Singh et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/16680-peripheral-t-cell-lymphoma-not-otherwise-specified-an-unusual-presentation-of-a-rare-lymphomaWe present a case of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) masquerading as a skin rash which progressively worsened over a year. After being treated for various dermatologic and infectious etiologies, he did not feel any relief and presented to our hospital. Imaging showed generalized lymphadenopathy. Later, lymph node biopsy and skin biopsy confirmed the diagnosis of CD30 + peripheral T-cell lymphoma. He was soon started on chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (CHOEP). However, because of the aggressive nature of his disease and advanced stage at presentation, he succumbed to complications and died of sepsis. \n\nThis case highlights the importance of considering a rash as one of the early symptoms of an underlying life-threatening disease.\n\nlymphomasrashperipheral t-cell lymphoma not otherwise specified (ptcl-nos)The 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\nPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) alludes to a heterogeneous group of mature T-cell lymphomas, features of which do not correspond to any of the other well-defined categories [1]. PTCL-NOS accounts for about one in four cases of PTCL. It is the most common subtype of PTCL in North America and Europe, as compared to natural killer (NK) T-cell lymphoma and adult T-cell leukemia/lymphoma, which are more common in Asia. It is more common in males, with a mean age of presentation around 60 years of age, and the majority presenting with an advanced stage [2]. PTCL directly involves the skin in only a minority of the cases [3-4].\n\nPTCL-NOS has a five-year survival of approximately 32% and five-year failure-free survival of 20% [5]. Considering that a majority of patients are at an advanced stage at the time of diagnosis and considering the overall aggressiveness of the tumor, a favorable prognosis is highly dependent on early diagnosis. \n\nOur patient presented with a very common dermatologic symptom (rash) which, although hiding in plain sight, can potentially result in the loss of valuable treatment time in arriving at the correct diagnosis. \n\nCase presentation\nA 54-year-old Caucasian man presented to the hospital with a rash of one year's duration. He had no significant past medical history, apart from moderate daily beer intake and one-pack-per-day cigarette smoking. A pruritic maculopapular rash first developed in his left lower extremity and later became generalized. He had been so far treated for scabies, dry skin, allergies, and cellulitis. He had visited multiple urgent care clinics, dermatologists, and infectious disease specialists without any solution to his predicament. Skin biopsies had only shown external trauma and excoriations. His ambiguous disease had now caused him dysphagia and weight loss. \n\nHis initial vital signs revealed a blood pressure of 115/78 mmHg, heart rate 120/m, sinus rhythm, respiratory rate of 18/m, temperature 98.1° F, and oxygenation saturation of 98% on room air. On examination, he was found to have a purulent nasal discharge, oropharyngeal thrush, tonsillar enlargement, foul breath, and maxillary sinus tenderness. He had generalized lymphadenopathy. Skin examination revealed a generalized rash involving the oral mucosa, face, palms, and soles. The rash was papulosquamous on his back. He had coin-shaped lesions on his legs and arms (Figure 1). The skin on the palm and soles was macerated. \n\nFigure 1 PTCL-NOS involvement in skin causing skin lesions seen on the legs and face\nPTCL-NOS: peripheral T-cell lymphoma, not otherwise specified\n\nInvestigation\n\nLaboratory studies revealed a normal complete blood count, basic metabolic panel, and liver function tests. Blood cultures were negative. The human immunodeficiency virus (HIV), rapid plasma reagin (RPR), herpes zoster culture, a fungal antigen, rheumatoid factor (RF), antinuclear antibody (ANA), cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA), perinuclear antineutrophil cytoplasmic antibody (P-ANCA), and atypical P-ANCA were all negative. \n\nComputed tomography scans of the chest, abdomen, and pelvis with contrast, obtained to further evaluate the generalized lymphadenopathy, showed the extensive burden of adenopathy in bilateral axillary regions, mediastinum, retroperitoneum, and both iliac chains into the inguinal regions. \n\nDuodenal compression at the third and fourth segment was seen with possible additional wall-thickening, raising concern for lymphomatous involvement.\n\nDiagnosis\n\nInguinal lymph node and skin biopsies were done. The inguinal lymph node biopsy revealed extensive tumor necrosis. Immunohistochemical stains were positive for CD3, CD30, and BCL2 and were negative for EMA, CD 20, CD45, and PAX5 (Figure 2). Flow cytometry showed a large population of abnormal T-cells which made up 88% of the total cells. These cells were moderately positive for CD2, CD3, and CD5, weakly positive for T-cell receptor (TCR) alpha/beta, and partially positive for CD11c, CD25, CD30, and CD57. They aberrantly lacked CD7 and were CD4 and CD8 dual-negative. CD56 was also negative. The CD3 positive normal T-cells was 9% of the total cells without the loss of pan-T-cell antigens. The CD4: CD8 ratio was 1.6:1. The CD19 and CD20 positive B-cells were 1% of total cells. It was consistent with CD30-positive peripheral T-cell lymphoma.\n\nFigure 2 Histopathology from the lymph node biopsy\nA) hematoxylin-eosin (H&E) peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) composed of pleomorphic medium to large cells with clear cytoplasm and nuclear irregularities admixed with reactive cells; B) tumor cells positive for CD3 immunostain with membranous staining; C) tumor cells positive for CD30 immunostain with membranous and Golgi-type staining.\n\nA skin biopsy from the right thigh showed atypical T-cell lymphoid infiltrate, including many CD30+ cells. Under the acanthotic and partially ulcerated epidermis, there was a dense monotonous lymphocyte infiltrate in the dermis. The lymphocytes showed significant cytologic atypia and perivascular accentuation. Immunostains showed the infiltrates were composed of mostly CD3+ T-lymphocytes with an increased CD4/CD8 ratio and reduced CD7 expression. Many of these lymphocytes were CD30+. There were also numerous CD1a+ dendritic cells in the epidermis and CD68+ histiocytes in the dermis. Only a few CD20+ B-lymphocytes and CD138+ plasma cells were present. Eosinophils were absent, and no evidence of vasculitis was seen. \n\nThe above histopathological findings and the immunophenotypical results, along with the patient's history of lymph node CD30+ lymphoma was consistent with the cutaneous involvement of CD30+ T-cell lymphoma. \n\nA bone marrow biopsy did not show the involvement of lymphoma. He was diagnosed with Stage IV PTCL-NOS. \n\nManagement\n\nThe patient was started on chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (CHOEP). He had improvement in the skin rash and lymphadenopathy after two cycles. His disease course was complicated by gastrointestinal bleeding from a duodenal perforation. He did not survive to finish the planned course of chemotherapy and succumbed to sepsis and respiratory failure. \n\nDiscussion\nPTCL-NOS as a category of lymphomas was first mentioned in 1994 in the Revised European-American Lymphoma (REAL) classification as PTCL-unspecified, which included various groups of mature T-cell lymphomas that did not fit into any of the established groups [6]. This has been updated to the currently known PTCL-NOS group in the World Health Organization (WHO) classification [6-7]. As a growing number of non-mycosis fungoides, cutaneous T-cell lymphomas have been recognized in recent years, the frequency of peripheral T-cell lymphoma (primary cutaneous or combined systemic and cutaneous) has been decreasing. We present a rare case with combined cutaneous and systemic features at diagnosis of PTCL-NOS with CD4- CD8- (double negative) (rarer) to examine the clinical and histopathological features of this disease.\n\nIn the prognostic analysis done by Tolkachjov et al., 15 out of 29 patients were found to have concurrent cutaneous and systemic involvement among those diagnosed to have PTCL-NOS. Clinical lesions of the dermatological presentation included plaques (10 patients), papules (three patients), nodules (three patients), tumors (one patient), and patches (two patients), with four patients having > 1 morphology. Ulceration of the lesions, B-symptoms at presentation, and multifocal lesions suggest concurrent systemic and cutaneous PTCL-NOS [8].\n\nThe proposed normal counterpart cells seen in PTCL-NOS are the CD4 central memory type T-lymphocytes. The cytology seen is often pleomorphic and seen as a mix of small and large cells with a high proliferation rate. It has been divided into three morphologic variants as per the WHO 2008 classification, namely, lymphoepitheloid (known as Lennert’s type), follicular, and T-zone. Lennert’s variant is mainly characterized by the predominance of reactive epithelial histiocytes. The follicular variant is so called because of its similarity to follicular lymphoma, has an occasional association with a t(5;9) (q33;q22) translocation, and is now classified as one of the nodal T-cell lymphomas with a T-follicular helper phenotype. The T-zone variant is so called due to its growth pattern in the T-zone of lymph nodes [7]. \n\nPhenotypically, PTCL-NOS shows expressivity for most of the T-cell antigens which include CD3, CD5, CD2, and CD7 with loss of any one antigen in four out of five cases. It originates usually from CD4 cells, but rare cases can be just CD8+, both CD4 and CD8+, or CD4- CD8- (as seen in this patient) [9].\n\nAn analysis done by Bekkenk et al. on 82 patients showed that peripheral T-cell lymphomas, unspecified, presenting in the skin have an unfavorable prognosis [8]. The prognostic marker used for PTCL-NOS is called the prognostic index for T-cell lymphoma, and it consists of age, elevated lactate dehydrogenase (LDH), poor performance status at baseline, and bone marrow involvement. The median survival for concurrent PTCL-NOS is around 2.1 years, and the time from symptom onset to diagnosis has been inversely associated with survival [10].\n\nThere is no consensus about optimal therapy for T- and NK-cell neoplasms. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is considered the standard therapy in PTCL-NOS [11]. The addition of etoposide, like in the index case, has not shown any significant improvement in overall survival cure rates. In some studies, the addition of etoposide to CHOP showed an improvement in event-free survival and progression-free survival [12-13].\n\nConclusions\nWe attempt to raise awareness about considering rash as a differential diagnosis for underlying malignancy, especially when the rash is of prolonged duration and the overall condition of patient deteriorates. A timely diagnosis of underlying aggressive malignancy, as in this case, can affect the subsequent outcome. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Peripheral T-cell lymphoma, not otherwise specified: A review of current disease understanding and therapeutic approaches Hematol Oncol Clin North Am Al-Zahrani M Savage KJ 189 207 31 2017 28340873 \n2 Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States Leuk Lymphoma Abouyabis AN Shenoy PJ Lechowicz MJ Flowers CR 2099 2107 49 2008 19021052 \n3 Peripheral T-cell lymphomas, unspecified (or not otherwise specified): a review Hematol Oncol Rodriguez-Abreu D Filho VB Zucca E 8 20 26 2008 18050364 \n4 Cutaneous manifestations of unspecified peripheral T-cell lymphoma may be indicative of disease activity and predict response to therapy J Clin Oncol Schowalter MK Akilov OE Story SK Geskin LJ 0 85 30 2012 \n5 Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project Blood Weisenburger DD Savage KJ Harris NL 3402 3408 117 2011 21270441 \n6 Clinical features of peripheral T-cell lymphomas in 78 patients diagnosed according to the Revised European-American lymphoma (REAL) classification Eur J Cancer Kim K Kim WS Jung CW 75 81 38 2002 11750843 \n7 The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood Swerdlow SH Campo E Pileri SA 2375 2390 127 2016 26980727 \n8 Cutaneous peripheral T-cell lymphoma, not otherwise specified: a single-center prognostic analysis J Am Acad Dermatol Tolkachjov SN Weenig RH Comfere NI 992 999 75 2016 27498959 \n9 International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes J Clin Oncol Vose J Armitage J Weisenburger D; International T-Cell Lymphoma Project 4124 4130 126 2008 \n10 Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients Blood Bekkenk MW1 Vermeer MH Jansen PM 2213 2219 102 2003 12750155 \n11 Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma) Br J Haematol Dearden CE Johnson R Pettengell R 451 485 153 2011 21480860 \n12 Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry Blood Ellin F Landström J Jerkeman M Relander T 1570 1577 124 2014 25006130 \n13 Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group Blood Schmitz N Trümper L Ziepert M 3418 3425 116 2010 20660290\n\n",
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"issue": "11(1)",
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"keywords": "lymphomas; peripheral t-cell lymphoma not otherwise specified (ptcl-nos); rash",
"medline_ta": "Cureus",
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"title": "Peripheral T-cell Lymphoma, Not Otherwise Specified: An Unusual Presentation of a Rare Lymphoma.",
"title_normalized": "peripheral t cell lymphoma not otherwise specified an unusual presentation of a rare lymphoma"
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"abstract": "BACKGROUND\nAtypical femoral fractures (AFF) can be present in patients with hip osteoarthritis (OA). This case highlights the opportunity to review the management of stress reactions, stress fractures and atypical femoral fractures, which depend on the activity of the fracture.\n\n\nMETHODS\nA 66-year-old female with a history of long-term bisphosphonate use underwent a total hip replacement for symptomatic osteoarthritis with a clinical presentation of right groin pain and radiographic signs of joint space narrowing and osteophyte formation. Radiographs before hip arthroplasty showed lateral cortical thickening in the ipsilateral femur in the subtrochanteric region. The patient developed a complete periprosthesic atypical femoral fracture a month after surgery at the level of the previously identified femoral cortical thickening.\n\n\nCONCLUSIONS\nGiven the high amount of elderly, osteoporotic patients presenting with groin/thigh pain undergoing hip replacement, surgeons should question them about the use of bisphosphonates in the past and look for the presence of AFF. These should receive bilateral imaging studies and a metabolic bone workup in order to define the status of the fracture and determine the appropriate management before considering any other surgical intervention.",
"affiliations": "Department of Orthopedic Surgery, Hospital for Special Surgery, New York - USA.;Department of Orthopedic Surgery, Hospital for Special Surgery, New York - USA.;Department of Orthopedic Surgery, Hospital for Special Surgery, New York - USA.;Department of Orthopedic Surgery, Hospital for Special Surgery, New York - USA.",
"authors": "Moya-Angeler|Joaquin|J|;Zambrana|Lester|L|;Westrich|Geoffrey H|GH|;Lane|Joseph M|JM|",
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"issue": "26(2)",
"journal": "Hip international : the journal of clinical and experimental research on hip pathology and therapy",
"keywords": null,
"medline_ta": "Hip Int",
"mesh_terms": "D000368:Aged; D019644:Arthroplasty, Replacement, Hip; D005260:Female; D005264:Femoral Fractures; D005269:Femur; D005593:Fracture Fixation, Internal; D015775:Fractures, Stress; D006621:Hip Joint; D006801:Humans; D015207:Osteoarthritis, Hip; D057068:Periprosthetic Fractures; D012086:Reoperation",
"nlm_unique_id": "9200413",
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"references": null,
"title": "Atypical femoral fracture post total hip replacement in a patient with hip osteoarthritis and an ipsilateral cortical thickening.",
"title_normalized": "atypical femoral fracture post total hip replacement in a patient with hip osteoarthritis and an ipsilateral cortical thickening"
} | [
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"abstract": "BACKGROUND\nCurrent first-line cisplatin-based combination chemotherapy regimens provide interesting response rates but limited impact on survival for patients with metastatic transitional cell carcinoma of the urothelium. Such results leave a significant patient population in need of salvage therapy.\n\n\nMETHODS\nAs the epidermal growth factor receptors 1 and 2 (EGFR and HER2) are frequently overexpressed in urothelial carcinoma, we explored the feasibility of a combination of paclitaxel (80 mg/m(2)/week) and lapatinib (1,500 mg orally daily) for six patients who were treated after failure of first-line platinum-based chemotherapy.\n\n\nRESULTS\nOnly one out of six patients was able to receive the full doses during the first six weeks of treatment, while grade 2 or 3 diarrhea events required lapatinib dose reduction (one patient) or discontinuation (five patients), despite loperamide support.\n\n\nCONCLUSIONS\nThis combination is not recommended for this population of patients.",
"affiliations": "Department of Medical Oncology, Henri Mondor Hospital, Créteil, France. stephane.culine@sls.aphp.fr",
"authors": "Culine|Stéphane|S|;Sellam|Zineb|Z|;Bouaita|Linda|L|;Assaf|Elias|E|;Delbaldo|Catherine|C|;Verlinde-Carvalho|Muriel|M|;Pouessel|Damien|D|",
"chemical_list": "D011799:Quinazolines; D000077341:Lapatinib; D017239:Paclitaxel",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D011799:Quinazolines; D016879:Salvage Therapy; D001749:Urinary Bladder Neoplasms; D014571:Urologic Neoplasms",
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"title": "Combining paclitaxel and lapatinib as second-line treatment for patients with metastatic transitional cell carcinoma: a case series.",
"title_normalized": "combining paclitaxel and lapatinib as second line treatment for patients with metastatic transitional cell carcinoma a case series"
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"abstract": "BACKGROUND\nCapecitabine (X) and docetaxel (T) have demonstrated a synergistic effect in preclinical models and a survival benefit in metastatic breast cancer. This study's purpose was to determine the efficacy of X and T followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) in the preoperative setting.\n\n\nMETHODS\nPatients with stage II/III breast cancer received four cycles of XT (capecitabine 1650 mg/m(2) on days 1-14 and docetaxel 60 mg/m(2) on day 8 every 3 weeks), followed by four cycles of FEC (5-fluorouracil 500 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 500 mg/m(2) on day 1 every 3 weeks). Primary end points were the pathological complete response (pCR) rate and adverse drug reactions.\n\n\nRESULTS\nSeventy-four patients were enrolled and 71 patients were assessable for clinical and pathological responses. The overall response rate was 91.5%. The pCR rate was 14.1% (10 of 71). Grade 3/4 neutropenia was observed in 32.4% of patients. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 11.3% of patients. With 29 months median follow-up, 2-year disease-free survival was estimated 85% for all patients.\n\n\nCONCLUSIONS\nThese data indicate that the sequential combination of XT followed by FEC is a well-tolerated, effective neoadjuvant treatment of stage II/III breast cancer.",
"affiliations": "Department of Surgery. Electronic address: jinno@sc.itc.keio.ac.jp.;Department of Surgery.;Department of Surgery.;Department of Surgery.;Department of Pathology, Keio University School of Medicine.;Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.;Department of Surgery.",
"authors": "Jinno|H|H|;Sakata|M|M|;Hayashida|T|T|;Takahashi|M|M|;Mukai|M|M|;Ikeda|T|T|;Kitagawa|Y|Y|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D015251:Epirubicin; D000069287:Capecitabine; D003520:Cyclophosphamide; D005472:Fluorouracil",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D002278:Carcinoma in Situ; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003841:Deoxycytidine; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D015412:Mastectomy, Segmental; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D057234:Preoperative Period; D043823:Taxoids; D016896:Treatment Outcome",
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"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase II trial of capecitabine and docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) as preoperative treatment in women with stage II/III breast cancer.",
"title_normalized": "a phase ii trial of capecitabine and docetaxel followed by 5 fluorouracil epirubicin cyclophosphamide fec as preoperative treatment in women with stage ii iii breast cancer"
} | [
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"companynumb": "JP-ROCHE-1847556",
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"abstract": "BACKGROUND\nMultiple myeloma is the second most common hematological neoplasm that also affects young patients. The progression-free survival after autologous stem cell transplant has improved with the introduction of several novel agents such as lenalidomide, which may, however, increase the risk of adverse events.\n\n\nMETHODS\nWe describe the case of a 54-year-old woman with relapse of multiple myeloma 3 years after myeloablative allogeneic stem cell transplant who developed abdominal pain and bloody diarrhea following 7 months of lenalidomide therapy.\n\n\nRESULTS\nAbdominal plain x-ray and magnetic resonance imaging (MRI) without intravenous contrast material showed left-sided and splenic flexure acute ischemic colitis with reperfusion phenomena. Continuous intravenous infusion of unfractionated heparin was given with metronidazole and meropenem and the patient improved within a few days. MRI performed 15 days later confirmed complete recovery of ischemic colitis.\n\n\nCONCLUSIONS\nTo our knowledge there have been no previously reported cases of ischemic colitis during lenalidomide therapy as a single agent in relapsed or refractory multiple myeloma, in particular promptly diagnosed by MRI.",
"affiliations": "Department of Medical, Surgical and Neuro Sciences, Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena - Italy.;Stem Cell Transplant and Cellular Therapy Unit, Azienda Ospedaliera Universitaria Senese, Siena - Italy.;Department of Medical, Surgical and Neuro Sciences, Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena - Italy.;Department of Diagnostic Imaging, Azienda Ospedaliera Universitaria Senese, Siena - Italy.;Department of Medical, Surgical and Neuro Sciences, Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena - Italy.;Department of Medical, Surgical and Neuro Sciences, Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena - Italy.",
"authors": "Guerrini|Susanna|S|;Bucalossi|Alessandro|A|;Cioffi Squitieri|Nevada|N|;Mazzei|Francesco G|FG|;Volterrani|Luca|L|;Mazzei|Maria Antonietta|MA|",
"chemical_list": "D000890:Anti-Infective Agents; D008795:Metronidazole; D013792:Thalidomide; D006493:Heparin; D000077269:Lenalidomide",
"country": "United States",
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"issue": "102(Suppl. 2)",
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"mesh_terms": "D000890:Anti-Infective Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017091:Colitis, Ischemic; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006493:Heparin; D006801:Humans; D000077269:Lenalidomide; D008279:Magnetic Resonance Imaging; D008795:Metronidazole; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "0111356",
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"pages": null,
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"pmid": "26350196",
"pubdate": "2016-11-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ischemic colitis diagnosed by magnetic resonance imaging during lenalidomide treatment in a patient with relapsed multiple myeloma.",
"title_normalized": "ischemic colitis diagnosed by magnetic resonance imaging during lenalidomide treatment in a patient with relapsed multiple myeloma"
} | [
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"abstract": "We report the first case of Ramsay Hunt syndrome (RHS) diagnosed after kidney transplantation in Korea. RHS is a disease caused by latent varicella-zoster characterized to involve geniculate ganglion of the seventh cranial nerve. Patients who have undergone kidney transplantation can be easily affected by viral infections because of their immune-compromised status. A 35-year-old man with hypertensive end-stage renal disease underwent kidney transplantation. Two months after surgery, the recipient was diagnosed with RHS and treated with antivirals and steroids. However, after using the antiviral agents for the recommended duration, facial paralysis occurred as a new presentation and he required further treatment. Otalgia and periauricular vesicles improved, but the facial palsy remained.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.",
"authors": "Park|Yoo Min|YM|;Kim|Da Rae|DR|;Park|Ji Yoon|JY|;Kim|Seul Ki|SK|;Kim|Se Yun|SY|;Kim|Jin Sug|JS|;Lee|Yu Ho|YH|;Kim|Yang-Gyun|YG|;Jeong|Kyung-Hwan|KH|;Moon|Ju-Young|JY|;Lee|Sang-Ho|SH|;Ihm|Chun-Gyoo|CG|;Lee|Tae-Won|TW|",
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"doi": "10.1016/j.krcp.2014.11.004",
"fulltext": "\n==== Front\nKidney Res Clin PractKidney Res Clin PractKidney Research and Clinical Practice2211-91322211-9140Elsevier S2211-9132(15)00055-810.1016/j.krcp.2014.11.004Case ReportA case of Ramsay Hunt syndrome diagnosed after kidney transplantation Park Yoo Min Kim Da Rae Park Ji Yoon Kim Seul Ki Kim Se Yun Kim Jin Sug Lee Yu Ho Kim Yang-Gyun Jeong Kyung-Hwan Moon Ju-Young Lee Sang-Ho Ihm Chun-Gyoo Lee Tae-Won wonkid12@hanmail.net∗Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea∗ Corresponding author. Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 45 Kyungheedae-gil, Dongdaemun-gu, Seoul 130-701, Korea. wonkid12@hanmail.net28 7 2015 12 2015 28 7 2015 34 4 241 244 30 6 2014 2 10 2014 5 11 2014 Copyright © 2015. The Korean Society of Nephrology. Published by Elsevier Ltd.2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report the first case of Ramsay Hunt syndrome (RHS) diagnosed after kidney transplantation in Korea. RHS is a disease caused by latent varicella-zoster characterized to involve geniculate ganglion of the seventh cranial nerve. Patients who have undergone kidney transplantation can be easily affected by viral infections because of their immune-compromised status. A 35-year-old man with hypertensive end-stage renal disease underwent kidney transplantation. Two months after surgery, the recipient was diagnosed with RHS and treated with antivirals and steroids. However, after using the antiviral agents for the recommended duration, facial paralysis occurred as a new presentation and he required further treatment. Otalgia and periauricular vesicles improved, but the facial palsy remained.\n\nKeywords\nKidney transplantationRamsay Hunt syndromeVaricella-zoster virusFacial palsy\n==== Body\nIntroduction\nLatent infection of varicella-zoster virus (VZV) is an issue in managing kidney transplant recipients. Because these patients are using various combinations of immunosuppressive agents, incidence of severe forms of viral infection is reported relatively high compared with that of normal immune status. Ramsay Hunt syndrome (RHS), also known as herpes oticus, is a rare manifestation of latent VZV infection and was first described by Ramsey Hunt [1]. This syndrome is caused by the reactivation of latent VZV in geniculate ganglion of the seventh cranial nerve and is characterized by otalgia, vesicle, and facial palsy of the affected side. RHS occurs more commonly in immunosuppressed individuals, such as kidney transplant recipients [2], [3], but it has not been reported previously in Korea. Here, we describe the first case of RHS diagnosed and treated with antiviral agents and glucocorticoids in a 35-year-old kidney transplant recipient in Korea.\n\nCase report\nA 35-year-old kidney transplant recipient presented to the nephrology outpatient clinic because of left otalgia and periauricular vesicles. He underwent deceased-donor kidney transplantation because of hypertensive end-stage renal disease about 2 months before the first symptoms appeared and had been using immunosuppressive medications. His regimen included tacrolimus 3 mg, mycophenolic acid 720 mg twice daily, and prednisolone 20 mg once daily. At the time of transplantation, we checked his viral markers as a protocol, and the patient did not recall his vaccination status. He underwent emergency surgery before we checked the final result of the viral markers. Later, we found out that his serum VZV immunoglobulin (Ig)-G was positive and IgM was negative (Fig. 1).\n\nInitial vital signs were stable. In addition to pain and vesicular rash around the left ear, he complained of numbness of the left half of his face, but neurologic examination revealed no abnormal findings. Routine laboratory tests were conducted and revealed a serum creatinine level of 1.9 mg/dL. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation, and the value was 48 mL/min. The tacrolimus level was measured immediately before ingestion, and the result was 4.8 ng/mL, which was slightly below the target range.\n\nIn addition, serum VZV IgG/IgM was measured, and serum VZV polymerase chain reaction (PCR) was performed (Fig. 2). However, his symptoms were sufficiently clear to make a diagnosis of RHS with or without serologic confirmation of VZV infection, and we were not reluctant to administer intravenous (i.v.) antiviral agents and steroids in this case. Acyclovir was administered at a dose of 500 mg i.v. (5 mg/kg, 95 kg) twice daily for 5 days. The preferred dose of acyclovir in patients with normal renal function is 5–12.4 mg/kg twice daily. However, considering his renal impairment, dose reduction was performed. To administer steroids via the i.v. route and considering an anti-inflammatory effect, methylprednisolone was chosen. Methylprednisolone 62.5 mg was given i.v. and then tapered out. Although serum VZV IgM was negative, a positive result was obtained on serum VZV PCR, so etiologic evidence was confirmed. As symptoms improved, the patient was discharged with oral antivirals and prednisolone. He was treated with famciclovir 750 mg once daily for an additional 10 days along with a maintenance dose of prednisolone (20 mg once daily). However, 3 days after cessation of famciclovir, he returned to the hospital because of a sudden onset of a severe spinning-type dizziness associated with nausea and left facial palsy. Neurologic examinations were conducted again, and nystagmus was observed at the primary position. When we evoked the nystagmus using the Dix–Hallpike test, left torsional nystagmus was observed in both eyes. In addition, on testing his facial paralysis, forehead blinking was decreased. These observations indicated that facial palsy was a result of peripheral nerve abnormality, but brain magnetic resonance imaging (MRI) was performed to exclude central vertigo and to evaluate the swelling of the facial nerve. In both T1- and T2-weighted images, microbleeding ∼9 mm in size was noted in the right pons. However, judging from its signal intensity, it was a chronic lesion rather than an acute lesion, and current dizziness was irrelevant. No swelling of the left facial nerve was seen. We restarted oral famciclovir 750 mg once daily with oral methylprednisolone for 7 days. This time we used oral methylprednisolone instead of i.v. because the patient complained of the i.v. catheter. The starting dose of oral methylprednisolone was 64 mg which was tapered every 2 days with a reduction of 16 mg each time. In addition, we lowered the dose of mycophenolate mofetil from 720 mg twice daily to 540 mg twice daily. We maintained the dose of tacrolimus because its serum level was at the lower limit of the therapeutic range. In addition to medical treatment, we encouraged self-facial massage and consulted for rehabilitation.\n\nThe patient was discharged with a slight improvement of facial paralysis. Electromyography was conducted 2 weeks after the onset to evaluate his facial motor and sensory nerves. This examination showed no abnormal spontaneous activity and neuropathy action potentials, but reduced recruitment of left frontalis, orbicularis oculi, nasalis, and orbicularis oris was noted. Otalgia and periauricular vesicles improved, but left facial palsy still remained. After 1 month, his facial palsy showed improvement.\n\nDiscussion\nRHS is a disease caused by latent VSV infection involving the geniculate ganglion of the seventh cranial nerve [1]. Kidney transplant patients can be easily affected by viruses and show severe extents of disease because of immunosuppressive medications that must be taken [2]. The incidence of VZV infection is ∼11.2% within 4 years after kidney transplantation [4], [5] but that of RHS has not been reported probably due to the rarity of the disease.\n\nMeasuring serum VZV IgG/IgM is essential before the transplant. A vaccination for seronegative candidates should be considered if the transplant is elective.\n\nThe patient described here showed the RHS symptom triad, and virologic confirmation was performed using VZV PCR. The disease was diagnosed easily, but treatment was challenging because he received a kidney from a donor with a high creatinine level (1.8 mg/dL). We considered his estimated glomerular filtration rate and had to reduce the dose of acyclovir. Typical brain MRI findings of RHS include enhancement of the affected facial nerve as a consequence of destruction of the blood–brain barrier [6]. In this case, facial nerve enhancement was not observed, but evidence of chronic pontine microbleeding was noted. We performed a brain MRI 14 days after the onset because his clinical signs and symptoms were compatible with typical peripheral vertigo. Because we used an antiviral agent and steroid for the 14 days, facial nerve swelling might have been improved at the time of the MRI. Preexisting bleeding in the central nervous system was thought to be a consequence of hypertension. RHS is treated with steroids to reduce the inflammation, and a starting dose of 50–60 mg of prednisolone is commonly used along with an i.v. antiviral agent to suppress virus replication [7], [8], [9]. Acyclovir is believed to reduce nerve damage, so its clinical usefulness is widely accepted [10]. In addition, adjunctive therapies, such as facial massage and acupuncture, can be useful, but there have been no systematic studies to evaluate the effectiveness of these treatments. However, unlike RHS in normal populations, there are several additional considerations in treating RHS in kidney transplant recipients. Posttransplant care for kidney recipients is difficult because care is required in the application of medications to protect renal function.\n\nTable 1 presents a literature review of RHS after kidney transplantation. Initial treatment using i.v. acyclovir and steroids (either i.v. or oral) was the same for all cases. All four cases of patients showed improvement after using acyclovir and steroids. However, time to achieve remission varied. It ranged from 10 days to 10 months.\n\nMaintaining the balance between rejection and the opportunistic infection is always troublesome after organ transplantation. In addition, in treating RHS, methylprednisolone is used for its anti-inflammatory effects, but steroid use can also suppress the host immunity simultaneously, so there is increased risk of virus infection. The duration of steroid use and the reduction of immunosuppressants are dependent on the clinician׳s decision. This case is worth reporting because it is the first case of RHS diagnosed after kidney transplantation in Korea.\n\nConflicts of interest\nThe authors have no conflicts of interest.\n\nFigure 1 Clinical course of the patient. Bid, twice a day; Day, days from the onset of otalgia; IV, intravenously; MPA, mycophenoleic acid; MPDL, methylprednisolone; PCR, polymerase chain reaction; qd, once a day; VZV, varicella-zoster virus.\n\nFigure 2 Result of varicella-zoster virus polymerase chain reaction from the serum of the patient.\n\nTable 1 Literature review of Ramsay Hunt syndrome after kidney transplantation\n\nNo.\tAge/sex\t1. Onset after KT\tImmunosuppressant\tTreatment\t\n2. Donor\t\n3. Cause of ESRD\t\n1 [3]\t36/F\tl. l mo\tl. MMF 1,500 mg\tIV Acyclovir (3 mg/kg, 3 times/d) Reduction of the MMF dose from 1,500 mg/d to 1,000 mg/d PO prednisolone 50mg for 3 days\t\n2. Living donor\t2. Tacrolimus 6 mg\t\n3. Polycystic kidney disease\t\t\n2 [2]\t41/M\tl. 4 yr\tl. MMF 1,500 mg\tIV Acyclovir (10 mg/kg, 3 times/d) Myringectomy with tube placement in the left middle ear Oral prednisone\t\n2. Living donor\t2. Tacrolimus 2.6 mg bid\t\n3. IgAN\t\t\nValacyclovir 1,000 mg 3 times/d\t\n3 [11]\t35/M\tl. 8 mo\tl. MPA 1,440 mg\tIV Acyclovir (250 mg, 3 times/d)\t\n2. Not mentioned\t2. Tacrolimus 2.5 mg/d\tIV Methylprednisolone (100 mg, 1 time/d)\t\n3. Unknown etiology\t\tReduction of the MMF dose from l,440 mg/d to 720 mg/d\t\n4 [12]\t27/M\tl. 18 mo\tl. MMF 2,000 mg\tIV Acyclovir 10 mg/kg/d, 3 times/d PO Acyclovir (400 mg. 5 times/d) Oral prednisolone dosage was tapered\t\n2. Living donor\t2. Cyclosporin\t\n3. Not mentioned\t\t\nBid, twice a day; ESRD, end-stage renal disease; IgAN, immunoglobulin-A nephropathy; IV, intravenously; KT, kidney transplantation; MMF, mycophenolate mofetil; MPA, mycophenolic acid; PO, oral.\n==== Refs\nReferences\n1 Hunt J.R. On herpetic inflammation of the geniculate ganglion: a new syndrome and its complications J Nerv Ment Dis 34 1907 73 96 \n2 Mortada RA El Fakih RO Assi M Unusual presentation of Ramsay Hunt syndrome in renal transplant patients: case report and literature review Transpl Infect Dis 11 2009 72 74 19000154 \n3 Otsuki K Kenmochi T Maruyama M Akutsu N Iwashita C Ito T Matsumoto I Asano T A case of Ramsay Hunt syndrome in living-kidney transplant recipient Transplant Proc 44 2012 307 308 22310640 \n4 Arness T Pedersen R Dierkhising R Kremers W Patel R Varicella zoster virus–associated disease in adult kidney transplant recipients: incidence and risk-factor analysis Transpl Infect Dis 10 2008 260 268 18086277 \n5 Insinga RP Itzler RF Pellissier JM Saddier P Nikas AA The incidence of herpes zoster in a United States administrative database J Gen Intern Med 20 2005 748 753 16050886 \n6 Suzuki F Furuta Y Ohtani F Fukuda S Inuyama Y Herpes virus reactivation and gadolinium-enhanced magnetic resonance imaging in patients with facial palsy Otol Neurotol 22 2001 549 553 11449115 \n7 Park JM Yu SJ Park AR Lee SM Treatment of Ramsay Hunt syndrome that is mistaken for trigeminal herpes zoster Korean J Pain 21 2008 237 240 \n8 McGrath N Anderson NE Croxson MC Powell KF Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome J Neurol Neurosurg Psychiatry 63 1997 321 326 9328248 \n9 Kinishi M Amatsu M Mohri M Saito M Hasegawa T Haseqawa S Acyclovir improves recovery rate of facial nerve palsy in Ramsay Hunt syndrome Auris Nasus Larynx 28 2001 223 226 11489365 \n10 Peterslund NA Seyer-Hansen K Ipsen J Esmann V Schonheyder H Juhl H Acyclovir in herpes zoster Lancet 2 1981 827 830 6116951 \n11 Ulusoy S Ozkan G Bektaş D Kaynar K Cansiz M Kazaz N Ramsay Hunt syndrome in renal transplantation recipient: a case report Transplant Proc 42 2010 1986 1988 20620563 \n12 Ozel L Toros SZ Unal E Kara M Eren PA Canbakan M Kucuk M Titiz I Ramsay Hunt syndrome with atypical progress in a renal transplant recipient: a case report Exp Clin Transplant 9 2011 413 416 22142050\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-9132",
"issue": "34(4)",
"journal": "Kidney research and clinical practice",
"keywords": "Facial palsy; Kidney transplantation; Ramsay Hunt syndrome; Varicella-zoster virus",
"medline_ta": "Kidney Res Clin Pract",
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"pages": "241-4",
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"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
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"title": "A case of Ramsay Hunt syndrome diagnosed after kidney transplantation.",
"title_normalized": "a case of ramsay hunt syndrome diagnosed after kidney transplantation"
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"abstract": "Small cell neuroendocrine carcinoma of the paranasal sinuses is an extremely rare and aggressive neoplasm. Despite aggressive management, the tumor carries a poor prognosis, with a high risk of local recurrence or distant metastases. The management strategy is based on that for pulmonary small cell cancer and includes platinum-based chemotherapy combined with radiotherapy. We are reporting a case of an 89-year-old female patient diagnosed with small cell carcinoma of right-sided ethmoid and sphenoid sinuses. The tumor was found to have invaded the right orbit and anterior cranial fossa. Metastases to cervical lymph nodes and bone were also found. Due to the extended stage and poor prognosis of the patient, the management plan is palliative chemoradiotherapy.",
"affiliations": "Presence Saint Joseph Hospital, Department of Internal Medicine, 2900 N. Lake Shore Drive, Chicago, IL 60657, USA.;Department of Medicine, Aga Khan University, Karachi, Sindh 74800, Pakistan.;Presence Saint Joseph Hospital, Department of Internal Medicine, 2900 N. Lake Shore Drive, Chicago, IL 60657, USA.;Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, MD 21287, USA.;Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, MD 21287, USA.;Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, MD 21287, USA.",
"authors": "Khan|Maliha|M|;Nizami|Sobia|S|;Mirrakhimov|Aibek E|AE|;Maughan|Benjamin|B|;Bishop|Justin A|JA|;Sharfman|William H|WH|",
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"doi": "10.1155/2014/874719",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/874719Case ReportPrimary Small Cell Neuroendocrine Carcinoma of Paranasal Sinuses Khan Maliha \n1\n*Nizami Sobia \n2\nMirrakhimov Aibek E. \n1\nMaughan Benjamin \n3\nBishop Justin A. \n3\nSharfman William H. \n3\n1Presence Saint Joseph Hospital, Department of Internal Medicine, 2900 N. Lake Shore Drive, Chicago, IL 60657, USA2Department of Medicine, Aga Khan University, Karachi, Sindh 74800, Pakistan3Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, MD 21287, USA*Maliha Khan: doc.maliha@gmail.comAcademic Editor: David W. Eisele\n\n2014 25 6 2014 2014 87471926 4 2014 3 6 2014 3 6 2014 Copyright © 2014 Maliha Khan 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.Small cell neuroendocrine carcinoma of the paranasal sinuses is an extremely rare and aggressive neoplasm. Despite aggressive management, the tumor carries a poor prognosis, with a high risk of local recurrence or distant metastases. The management strategy is based on that for pulmonary small cell cancer and includes platinum-based chemotherapy combined with radiotherapy. We are reporting a case of an 89-year-old female patient diagnosed with small cell carcinoma of right-sided ethmoid and sphenoid sinuses. The tumor was found to have invaded the right orbit and anterior cranial fossa. Metastases to cervical lymph nodes and bone were also found. Due to the extended stage and poor prognosis of the patient, the management plan is palliative chemoradiotherapy.\n==== Body\n1. Introduction\nSmall cell carcinoma (SCC) is a poorly differentiated neuroendocrine tumor that most commonly occurs in the lung [1]. Small cell neuroendocrine carcinoma (SNEC) of the paranasal sinuses is an extremely rare and aggressive tumor that demonstrates rapid expansion and early hematogenous spread [2]. Although the tumor is responsive to initial local therapy [1], it is associated with frequent local recurrence and new distant metastases, leading to poor prognosis [2]. Here we report the case of a patient diagnosed with small cell neuroendocrine carcinoma of the ethmoid/sphenoid sinuses with local intracranial extension, who was referred to our center for management.\n\n2. Case History\nAn 89-year-old female with a history of hypertension, hypercholesterolemia, glaucoma, and osteoarthritis presented with a history of headaches and facial pain over the right side of her face for one month. Other symptoms included decreased vision in the right eye, intermittent diplopia, difficulty in closing the right eye, and gait unsteadiness. She described having overall fatigue and lower back pain, worse on walking, for the past 3 months. There was no past history of cigarette smoking. Physical examination was positive for complete right eyelid closure, no overlying skin changes and no cervical lymphadenopathy. Brain CT and MRI scans revealed a large sinonasal mass involving the ethmoid/sphenoid sinuses and extending into the right orbit and anterior cranial fossa (Figures 1, 2, and 3). Fine-need aspiration of the nasal mass confirmed the tumor as small cell carcinoma (Figure 4(a)). A PET scan was done to look for distant disease as well as a possible lung primary, which showed multiple bone metastases but no lung mass. Immunohistochemical studies demonstrated tumor positivity for AE1/AE3 in a dot-like pattern (Figure 4(b)), synaptophysin (Figure 4(c)), and chromogranin and were negative for CD45, S100, and myogenin. The tumor was also positive for high-risk HPV by in situ hybridization (Figure 4(d)). The patient was diagnosed with extensive stage small cell carcinoma of the ethmoid/sphenoid sinuses. Due to disseminated disease, she was scheduled for palliative chemotherapy with 6 cycles of carboplatin and etoposide every 21 days [3].\n\nGiven the extent of her disease proximal to the orbit, she was started on chemotherapy urgently as inpatient for the first cycle. So far, she has completed 3 cycles of carboplatin/etoposide. Her complications have been mild but include fatigue that peaked with her second cycle of chemotherapy. The fatigue has improved with initiation of packed red blood cell transfusions to treat her chemotherapy induced anemia. Her baseline hemoglobin level was 12 g/dL and decreased to 9 g/dL prior to transfusions. She also developed acute renal insufficiency with a creatinine of 1.6 mg/dL, increased from a baseline of 1.0 mg/dL previously. This developed after the third cycle of chemotherapy. The creatinine returned to baseline with intravenous fluids. Regarding the presenting symptoms of headaches and vision disturbances, these have decreased but not entirely resolved. The headaches are less frequent and now only mildly impaired. A repeated head MRI was done after the third cycle that demonstrates a very good partial response at the site of the primary lesion. The ethmoid lesion has entirely resolved and around 50 percent reduction in the size of the inferior frontal lobe mass. There is still a slight enhancement noted on the orbital nerve but otherwise the lesion in that region has regressed. A restaging PET scan for systemic response is pending at this time.\n\n3. Discussion\nCarcinoma of the nasal cavity and paranasal sinuses is an uncommon tumor, with an incidence of less than 1 per 100,000 persons per year [4]. Extrapulmonary small cell neuroendocrine carcinomas (EPSNEC) are rare, making up 0.1–0.4% of all cancers [1]. Only 11% of EPSNC occur in the head and neck [1]. Among EPSNEC, primary SNEC arising in the nasal sinuses is extremely rare. It was first reported as a differentiated histological type in the paranasal sinuses by Raychowdhuri in 1965 [5]. In the past 45 years, 76 cases of small cell neuroendocrine carcinoma of nasal and paranasal region have been described in the medical literature [6].\n\nAccording to the World Health Organization criteria, small cell carcinomas are defined as malignant epithelial tumors consisting of small cells with scant cytoplasm, ill-defined borders, granular nuclear chromatin, absent nucleoli with extensive necrosis, and high mitotic count [7]. The tumor often stains positive for neuroendocrine markers such as synaptophysin, CD 56, and chromogranin A [8]. Small cell carcinomas of pulmonary and extrapulmonary origin all have similar morphologic, immunohistochemical, and ultrastructural features [9]. Due to the rarity of occurrence of EPSCC in the sinonasal tract, its initial workup must include searching for a primary tumor at a more likely site such as the lung [3].\n\nEPSCC of the sinonasal tract has a slight male predominance. It can occur in any age group, and the mean age at presentation is 51–58 years [2, 8]. Despite the biological similarities between pulmonary and extrapulmonary SCC, the risk factors are not identical. Although a history of tobacco use correlates strongly with pulmonary small cell carcinoma, it has not been reported as a risk factor for EPSCC [2].\n\nHuman papilloma virus (HPV) infection is a possible risk factor for small cell carcinoma in the sinonasal tract [10]. High-risk positivity for HPV infection was found in 1 out of 6 cases of sinonasal small cell carcinoma in one retrospective study by Bishop et al. [10] and was seen in our patient as well. However, it is unclear whether HPV has any role in the pathogenesis of sinonasal small cell lung cancer.\n\nFurthermore, paraneoplastic syndromes, seen in small cell lung cancer, are not common with EPSCC [11]. EPSCC can be classified as limited or extensive stage based on the extent of tumor spread. Local disease is defined as tumor confined to the primary site and regional lymph nodes, while tumors extending beyond locoregional boundaries are classified as extensive stage [8]. Despite aggressive management, the tumor carries a poor prognosis, with an overall 80% risk of local recurrence or distant metastases within 2 years after treatment [11]. The reported median survival for limited disease is 1.4 years, and for extensive disease it is 0.7 years [3]. The 5-year survival for limited disease is 25.4% and that for extensive disease is 0%. Occasionally, cases of limited stage sinus SCC have also been reported to be recurrence-free after 7–10 years of follow-up [11, 12].\n\nDue to the rarity of the disease, clinical trials to identify the optimal management for EPSCC have not been done. Retrospective studies and case reports consistently recommend that EPSCC be managed similar to pulmonary SCC [3]. This includes combination chemotherapy with at least 4 cycles of cisplatin and etoposide, along with radiotherapy of at least 50 Gy in 2 Gy fractions [3]. Surgical intervention is usually reserved for treatment-resistant cases [13], or cases where complete tumor resection can be achieved with minimal morbidity [3]. Keeping in mind the poor prognosis of extensive disease in our patient, the management plan is palliative platinum-based chemotherapy.\n\n4. Conclusions\nIn conclusion, the patient in this case was an 89-year-old female who presented with headaches and visual disturbances due to a sinonasal mass with intracranial extension. Biopsy revealed small cell carcinoma of the ethmoid and sphenoid sinuses of the right side, and further investigations demonstrated lymph node and multiple bone metastases. Due to the advanced stage and extensive spread of the tumor, the prognosis in this case is very poor, with an estimated survival of less than 2 years [3]. Therefore, the management for this patient is palliative chemotherapy with 6 cycles of carboplatin and etoposide.\n\nAcknowledgment\nThe authors gratefully acknowledge Dr. Satomi Kawamoto for her expert assistance with the radiological images.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Axial noncontrast brain CT (bone algorithm image) showing a large sinonasal mass involving the ethmoid/sphenoid minuses (arrows) with right orbital extension (arrowhead).\n\nFigure 2 Axial FLAIR T2-weighted brain MRI showing a sinonasal mass involving the ethmoid/sphenoid sinuses (white arrows) with extension into the right orbit (black arrowhead).\n\nFigure 3 Coronal T2-weighted brain MRI showing a sinonasal mass involving the ethmoid/sphenoid sinuses (white arrows) with extension into the right orbit (white arrow head) and anterior cranial fossa (black arrow).\n\nFigure 4 Hematoxylin and eosin staining showing nasal mass with small cell carcinoma (a), immunohistochemical staining showing tumor positivity for AE1/AE3 in a dot-like pattern (b), synaptophysin (c), and high-risk HPV by in situ hybridization (d). (a) The tumor consisted of a uniform population of small cells with minimal cytoplasm and hyperchromatic, angulated nuclei that demonstrated molding. The tumor exhibited high grade features including a high mitotic rate and necrosis (hematoxylin and eosin, ×400). (b) The neoplasm was positive for cytokeratin on a perinuclear, dot-like pattern (AE1/AE3 immunohistochemistry, ×400). (c) The tumor exhibited neuroendocrine differentiation in the form of diffuse staining for synaptophysin (synaptophysin immunohistochemistry, ×400). (d) HPV studies showed that the tumor harbored high-risk HPV DNA (high-risk HPV in situ hybridization, ×400).\n==== Refs\n1 Howard S O'Regan K Jagannathan J Krajewski K Giardino A Ramaiya N Extrapulmonary small cell carcinoma: a pictorial review The American Journal of Roentgenology 2011 197 3 W392 W398 2-s2.0-80052218182 21862764 \n2 Han G Wang Z Guo X Wang M Wu H Liu D Extrapulmonary small cell neuroendocrine carcinoma of the paranasal sinuses: a case report and review of the literature Journal of Oral and Maxillofacial Surgery 2012 70 10 2347 2351 2-s2.0-84866360419 22330330 \n3 Brennan SM Gregory DL Stillie A Herschtal A Manus MM Ball DL Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer 2010 116 4 888 895 2-s2.0-76249084084 20052730 \n4 Robin PE Powell DJ Stansbie JM Carcinoma of the nasal cavity and paranasal sinuses: incidence and presentation of different histological types Clinical Otolaryngology and Allied Sciences 1979 4 6 431 456 2-s2.0-0018724654 393432 \n5 Raychowdhuri RN Oat-cell carcinoma and paranasal sinuses The Journal of Laryngology and Otology 1965 79 253 255 2-s2.0-0001428280 14270662 \n6 Ma ATW Lei KIK Small cell neuroendocrine carcinoma of the ethmoid sinuses presenting with generalized seizure and syndrome of inappropriate antidiuretic hormone secretion: a case report and review of literature American Journal of Otolaryngology-Head and Neck Medicine and Surgery 2009 30 1 54 57 2-s2.0-56249144122 \n7 Travis WD Garg K Franklin WA Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 world health organization pathologic criteria Journal of Thoracic Oncology 2006 1 9 S13 S19 2-s2.0-34247890114 17409995 \n8 Brammer JE Lulla P Lynch GR Retrospective review of extra-pulmonary small cell carcinoma and prognostic factors International Journal of Clinical Oncology 2013 1 7 \n9 Frazier SR Kaplan PA Loy TS The pathology of extrapulmonary small cell carcinoma Seminars in Oncology 2007 34 1 30 38 2-s2.0-33846492298 17270663 \n10 Bishop JA Guo TW Smith DF Human papillomavirus-related carcinomas of the sinonasal tract The American Journal of Surgical Pathology 2013 37 2 185 192 2-s2.0-84872862169 23095507 \n11 Babin E Rouleau V Vedrine PO Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses The Journal of Laryngology and Otology 2006 120 4 289 297 2-s2.0-33747617543 16526967 \n12 Hosokawa S Okamura J Takizawa Y Mineta H Long-term survival of a patient with primary small cell neuroendocrine carcinoma of the maxillary sinus: a case report Journal of Oral and Maxillofacial Surgery 2013 71 8 e248 e252 2-s2.0-84880313801 23866955 \n13 Krishnamurthy A Ravi P Vijayalakshmi R Majhi U Small cell neuroendocrine carcinoma of the paranasal sinus National Journal of Maxillofacial Surgery 2013 4 1 111 113 24163566\n\n",
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"title": "Primary small cell neuroendocrine carcinoma of paranasal sinuses.",
"title_normalized": "primary small cell neuroendocrine carcinoma of paranasal sinuses"
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"abstract": "OBJECTIVE\nThis study compares 1-year intrauterine device (IUD) continuation among women presenting for emergency contraception (EC) and initiating the copper (Cu T380A) IUD or the levonorgestrel (LNG) 52 mg IUD plus 1.5 mg oral LNG.\n\n\nMETHODS\nThis cohort study enrolled 188 women who presented at a single family planning clinic in Utah between June 2013 and September 2014 and selected either the Cu T380A IUD or LNG 52 mg IUD plus oral LNG for EC. Trained personnel followed participants by phone, text or e-mail for 12 months or until discontinuation occurred. We assessed reasons for discontinuation and used Cox proportional hazard models, Kaplan-Meier estimates and log-rank tests to assess differences in continuation rates between IUDs.\n\n\nRESULTS\nOne hundred seventy-six women received IUDs; 66 (37%) chose the Cu T380A IUD and 110 (63%) chose the LNG 52 mg IUD plus oral LNG. At 1 year, we accounted for 147 (84%) participants, 33 (22%) had requested removals, 13 (9%) had an expulsion and declined reinsertion, 3 (2%) had a pregnancy with their IUD in place and 98 (67%) were still using their device. Continuation rates did not differ by IUD type; 60% of Cu T380A IUD users and 70% of LNG 52 mg IUD plus oral LNG users were still using their device at 12 months (adjusted hazard ratio 0.72, 95% confidence interval 0.40-1.3).\n\n\nCONCLUSIONS\nTwo-thirds of women who chose IUD placement at the EC clinical encounter continued use at 1 year. Women initiating Cu T380A IUD and LNG 52 mg IUD had similar 1-year continuation rates. These findings support same-day insertion of IUDs for women who are seeking EC and would like to use a highly effective reversible method going forward.\n\n\nCONCLUSIONS\nProviding IUD options for EC users presents an opportunity to increase availability of highly effective contraception.",
"affiliations": "Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132-2209, USA. Electronic address: Jessica.sanders@utah.edu.;Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132-2209, USA.;Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132-2209, USA.;Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132-2209, USA.;Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132-2209, USA.;Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Room 2B200, Salt Lake City, UT 84132-2209, USA.",
"authors": "Sanders|J N|JN|;Turok|D K|DK|;Royer|P A|PA|;Thompson|I S|IS|;Gawron|L M|LM|;Storck|K E|KE|",
"chemical_list": "D016912:Levonorgestrel",
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"keywords": "Continuation; Copper IUD; Emergency contraception; Levonorgestrel IUD",
"medline_ta": "Contraception",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D044363:Contraception, Postcoital; D005260:Female; D006801:Humans; D007435:Intrauterine Devices, Copper; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel; D011247:Pregnancy; D016896:Treatment Outcome; D055815:Young Adult",
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"pubdate": "2017-08",
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"title": "One-year continuation of copper or levonorgestrel intrauterine devices initiated at the time of emergency contraception.",
"title_normalized": "one year continuation of copper or levonorgestrel intrauterine devices initiated at the time of emergency contraception"
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"abstract": "We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy.",
"affiliations": "Department of Breast Surgical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Surgical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Ophthalmology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Surgical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Surgical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.",
"authors": "Yokoe|Takamichi|T|;Fukada|Ippei|I|;Kobayashi|Kokoro|K|;Shibayama|Tomoko|T|;Miyagi|Yumi|Y|;Yoshida|Atsushi|A|;Iwase|Takuji|T|;Ohno|Shinji|S|;Ito|Yoshinori|Y|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000477897",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000477897cro-0010-0605Case ReportCystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer: A Case Report and Literature Review Yokoe Takamichi ab*Fukada Ippei bKobayashi Kokoro bShibayama Tomoko bMiyagi Yumi aYoshida Atsushi cIwase Takuji aOhno Shinji abIto Yoshinori baDepartment of Breast Surgical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanbDepartment of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapancDepartment of Ophthalmology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan*Dr. Takamichi Yokoe, MD, Departments of Breast Surgical Oncology and Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Kotoku, Tokyo 135–8550 (Japan), E-Mail takamichi.yokoe@gmail.comMay-Aug 2017 11 7 2017 11 7 2017 10 2 605 612 30 5 2017 30 5 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy.\n\nKeywords\nCystoid macular edemaMacular edemaOptical coherence tomographyPaclitaxelBevacizumabBreast cancer\n==== Body\nIntroduction\nPaclitaxel is an anticancer agent classified as a taxane drug used for various types of solid malignant tumors, playing a key role in breast cancer treatment. Paclitaxel acts on microtubule mobility and inhibits mitosis. Adverse events such as myelosuppression, peripheral neuropathy, allergic reaction, arthralgia, and depilation are commonly seen in patients undergoing paclitaxel therapy. Ophthalmic adverse events can include visual loss due to optic neuropathy and cystoid macular edema (CME) [1, 2]. However, CME is thought to be a very rare adverse event since there has been no report about a case series of CME due to chemotherapy. There are several reports of taxane-related CME. Bevacizumab may reduce the degree of drug-induced CME. A few papers, however, reported CME induced by taxane with bevacizumab. We report a case of CME that occurred during treatment with paclitaxel and bevacizumab.\n\nCase Report\nA 47-year-old female was diagnosed with invasive left-breast cancer at stage IIB. The hormone receptors were positive and HER2 was negative (IHC 1+). Ki67 of the labeling index was high. She received 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2, day 1, every 3 weeks), followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m2. Neoadjuvant chemotherapy yielded partial response according to the response evaluation criteria in solid tumors (RECIST version 1.1). She underwent a partial mastectomy and axillary dissection at level II. The pathological finding showed residual invasive ductal carcinoma with surgical margin positive. Four out of 25 resected lymph nodes involved metastasis. She underwent postmastectomy radiation therapy and started hormonal therapy with tamoxifen. Two years after surgery, bone scintigraphy and positron emission tomography detected multiple bone metastases in her left 6th rib and thoracic vertebral bodies from the left 9th to 11th ribs. She was enrolled in a clinical trial (UMIN000009300), which evaluated efficacy and tolerance in maintenance treatment after paclitaxel plus bevacizumab. She received paclitaxel 90 mg/m2 on days 1, 8, and 15, and bevacizumab 10 mg/kg on days 1 and 15, every 4 weeks. She achieved partial durable response.\n\nAfter 31 cycles of paclitaxel plus bevacizumab, she complained of blurred vision and consulted an ophthalmologist. Her best corrected visual acuity was 1.2 in both eyes, and intraocular pressure was normal. Optical coherence tomography (OCT) revealed CME in both eyes (Fig. 1). There were large cystic spaces in the outer layer and small cystic spaces in the inner nuclear layer of both eyes. Retinal thickness was increased in the center of the macula due to the edema.\n\nWe suspected that paclitaxel was the causing agent and decided that it should be stopped, and bevacizumab alone was continued. Three weeks later, following ocular instillation of a nonsteroidal anti-inflammatory drug, bromfenac, the retinal thickness and cystic spaces decreased gradually on OCT scans (Fig. 2). Her blurred vision disappeared, and retinal thickness has been maintained in a normal state since that time.\n\nDiscussion\nThe present case showed bilateral CME during paclitaxel and bevacizumab treatment.\n\nCME induced by taxane chemotherapy is rare, but there are several articles reporting this adverse event (Table 1). A case has been reported of CME in both eyes secondary to paclitaxel at a dose of 175 mg/m2 after 10 months of use without any evidence of fluorescein leakage [3]. The treatment was changed from paclitaxel to capecitabine, and 6 weeks after discontinuing paclitaxel the patient's visual symptoms recovered, and fundus examination and OCT scans revealed resolution of CME. Four cases of CME associated with docetaxel therapy were documented [4, 5, 6]. Two authors reported CME due to albumin-bound paclitaxel, with resolution on discontinuation of the drug [7, 8]. In all these reports, the main complaint was decline in visual acuity.\n\nCME is a condition characterized by abnormal thickening of the retina associated with excess fluid accumulation within the macular retina. The precise pathogenesis of CME remains unclear. It is thought to occur following disruption of the blood-retinal barrier. Furthermore, Müller cells play an important role in dehydrating the macula by metabolic pumps. These conditions are induced by either microvascular occlusion or inflammatory disease [2].\n\nThe typical fluorescein angiographic appearance of CME consists of small focal leaks early on that increase in size and intensity, resulting in late pooling in a characteristic flower petal pattern with or without leakage surrounding the optic nerve [4]. For drug-induced CME, several papers have reported that CME was not associated with leakage on fluorescein angiography [3, 4, 5, 7, 9]. Therefore, the mechanisms of drug-induced CME may be different from those of CME associated with microvascular occlusion or inflammatory disease.\n\nThe pathogenesis of CME without fluorescein leakage is unclear. A subcategory of CME not associated with leakage on fluorescein angiography and therefore abnormal capillary permeability has been described and is associated with toxicity to niacin [4].\n\nNicotinic acid maculopathy was first described by Gass [10] in 1973. He reported 3 patients with decreased visual acuity and visual symptoms who were taking nicotinic acid for hypercholesterolemia. All patients were found to have CME by indirect biomicroscopy, but no leakage or alteration in the capillary bed was noted upon fluorescein angiography. Visual acuity returned to normal in all 3 patients following discontinuation of the drug, but 1 of the patients still had residual CME 4 months after discontinuing the nicotinic acid. Millay et al. [11] have hypothesized that the blood-retina barrier was intact and that the cystic changes were secondary to disturbed metabolism of the inner retinal neurons with intracellular fluid accumulation. Jampol [12] has proposed 2 possibilities for the etiology of the cystic changes in niacin retinopathy. The first is subclinical leakage in the extracellular space, stimulated by the release of prostaglandins by niacin. The other possibility is toxicity to Müller cells with subsequent swelling that was not sufficient to disrupt the blood-retina barrier.\n\nCME can be associated with many ocular conditions, including (1) microvascular occlusion such as diabetic macular disease, retinal vein occlusion, and retinal arteriolar macroaneurysm, (2) inflammatory disease such as uveitis, a condition following cataract surgery, and (3) other conditions such as retinitis pigmentosa and drug agents [2].\n\nCME can also be caused by various drugs such as taxanes, thiazolizine, tamoxifen, niacin, interferon, fingolimod, prostaglandin, epinephrine, timolol, and others. In taxanes, paclitaxel is commonly reported [1, 9, 13], followed by nanoparticle albumin-bound paclitaxel [7, 8] and docetaxel [4, 5, 6, 14].\n\nIn the case of the present patient, who had a history of medication with tamoxifen, it is possible that tamoxifen caused her CME. A common ocular adverse event of tamoxifen is bilateral yellow-white refractile crystalline deposits and pigmentary alterations in the macula. Macular edema and CME were reported in patients receiving high doses (>180 mg/day) of tamoxifen. Toxicity is not common at the usual dose of 20–40 mg/day. Moreover, CME will disappear with discontinuation of tamoxifen [15]. Therefore, we concluded that a history of tamoxifen usage did not evoke CME.\n\nThe characteristics of drug-induced CME are (1) often bilateral, (2) no leakage of contrast agent in fluorescein angiography [14], (3) a larger cystic space in the outer layer rather than the inner layer of the retina in OCT scans [8], and (4) spontaneous resolution and improvement of visual acuity after discontinuation of the cause [9]. In some cases with delayed diagnosis of CME, progression of macular degeneration occurred, and then visual acuity could not be reversed [16].\n\nTreatments for drug-induced CME are (1) cessation of the causing agent, (2) dorzolamide, (3) a nonsteroidal anti-inflammatory drug such as bromfenac sodium hydrate, (4) sub-Tenon injection of triamcinolone acetonide, which is a synthetic long-acting corticosteroid, and (5) injection of an anti-VEGF agent. Stopping the drug thought to be causing the condition is the first choice for treating drug-induced CME. When this is not enough to cure CME, drug-induced CME is treated the same as CME induced by vascular or inflammatory diseases [2]. There is no clear evidence for a treatment specific to drug-induced CME other than removing the cause. Some adverse events of injection such as endophthalmitis, cataracts, increased ocular pressure, and floaters are reported, and continuous follow-up is needed after treatment [2, 14]. Most taxane-related drug-induced CME was cured by discontinuation of the causing drugs only or by discontinuation plus ocular instillation of dorzolamide or acetazolamide.\n\nIn a case involving another antitumor agent, imatinib, CME associated with chronic myeloid leukemia and imatinib was treated with intravitreal injection of bevacizumab and triamcinolone [17]. Since injection of bevacizumab, an anti-VEGF agent, is used to treat CME, bevacizumab treatment for breast cancer might have reduced the degree of paclitaxel-induced CME. This issue should be investigated further as there is only 1 case report to support this idea [7].\n\nWe have presented a case of a patient with bilateral CME after receiving paclitaxel and bevacizumab. Complaining of blurred vision, the patient was diagnosed with drug-induced CME by paclitaxel. Following the cessation of paclitaxel and ocular instillation, CME was cured. Our observation confirmed that CME secondary to paclitaxel shows spontaneous resolution of visual complaint and macular edema by removing the causing agent [3].\n\nIn daily clinical practice, oncologists should ask patients about visual complaints. It is important for those with visual complaints during chemotherapy to consult an ophthalmologist promptly because decreased visual acuity may be irreversible if treatment is delayed. Another important issue is that chemotherapy may need to be halted in patients who develop CME. In the present case, since the metastatic lesion was only in her bones and metastatic disease was stable, we did not hesitate to cease paclitaxel and convert the treatment to therapy with bevacizumab alone.\n\nConclusion\nChemotherapy with paclitaxel may cause CME. Further research is necessary to clarify the mechanisms of drug-induced CME. Attention to possible ocular adverse events of paclitaxel is needed to avoid serious ocular problems such as decreased visual acuity. Oncologists need to draw information regarding treatment-related visual complaints from patients, and both doctors and patients need to discuss with ophthalmologists the risks and benefits of continuing paclitaxel.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nS. Ohno has received lecture fees from Chugai, Inc.; Y. Ito has received research funding fees from Chugai, Inc. No financial support was received for this submission. The authors have no financial or proprietary interest in any material or method mentioned. The material of this manuscript was not previously presented at a meeting.\n\nAuthor Contributions\nT.Y., I.F., K.K., Y.M., and A.Y. interacted with the patient. T.Y. and I.F. identified and acquired relevant reports. A.Y. diagnosed the patient by ophthalmological examination. T.Y. drafted the report. I.F., K.K., T.S., Y.M., A.Y., T.I., and S.O. critically reviewed the report. All authors read and approved the final submitted version.\n\nFig. 1 Ophthalmoscopy. Macular edema at the fovea is seen in both eyes.\n\nFig. 2 a–h Optical coherence tomography (OCT) scans of the macula densa of both eyes in time course. a, b OCT scans at diagnosis. Large cystic spaces are seen in the outer reticular layer and small cystic spaces in the inner nuclear layer. Retinal thickness is lower outside the perifoveal area. c, d OCT scans at 1 week following diagnosis, when paclitaxel was ceased. e, f One week after cessation of paclitaxel. g, h Three weeks after cessation of paclitaxel. Cystic spaces and retinal thickness gradually decreased.\n\nTable 1 Case reports of drug-induced macular edema caused by taxane\n\nCase (first author [ref.])\tAge, years\tAffected side\tSymptom\tTreatment\tTreatment time to recovery\tCausing agent\tBevacizumab\t\nJoshi [3]\t63\tbilateral\tdecreased\nvision\tcessation\t6 weeks\tPTX\tno\t\n\t\nHam [13]\t57\tbilateral\tdecreased\nvision\tcessation,\nintravitreal\nbevacizumab\t6 weeks\tPTX\tyes\t\n\t\nKuznetcova [9]\t64\tbilateral\tdecreased\nvision\tcessation\t4 weeks\tPTX\tyes\t\n\t\nMurphy [7] first case\t65\tbilateral\tdecreased\nvision\tcessation, NSAIDs,\ntopical steroids\t3 weeks\tnab-PTX\tyes\t\n\t\nMurphy [7] second case\t58\tbilateral\tdecreased\nvision\tcessation\t3 weeks\tnab-PTX\tyes\t\n\t\nSmith [8]\t56\tbilateral\tdecreased\nvision\tcessation\t4 weeks\tnab-PTX\tno\t\n\t\nMatsuoka [16]\t39\tbilateral\tdecreased\nvision\tSTTA, cessation\t11 months, not fully recovered\tnab-PTX\tno\t\n\t\nTeitelbaum [4]\t53\tbilateral\tblurred\nvision\tcessation\t6 weeks\tDTX\tno\t\n\t\nTelander [5]\t60\tbilateral\tdecreased\nvision\tcessation,\nacetazolamide\t16 weeks\tDTX\tno\t\n\t\nEnzsoly [6]\t45\tbilateral\tdecreased\nvision\tcessation, topical nepafenac\t5 weeks\tDTX\tno\t\nPTX, paclitaxel; nab-PTX, nanoparticle albumin-bound paclitaxel; DTX, docetaxel; NSAID, nonsteroidal anti-inflammatory drug; STTA, sub-Tenon triamcinolone acetonide injection.\n==== Refs\nReferences\n1 Hofstra LS de Vries EG Willemse PH Ophthalmic toxicity following paclitaxel infusion. Ann Oncol 1997 8 1053 \n2 Rotsos TG Moschos MM Cystoid macular edema. Clin Ophthalmol 2008 2 919 930 19668445 \n3 Joshi MM Garretson BR Paclitaxel maculopathy. Arch Ophthalmol 2007 125 709 710 17502517 \n4 Teitelbaum BA Tresley DJ Cystic maculopathy with normal capillary permeability secondary to docetaxel. Optom Vis Sci 2003 80 277 279 12692483 \n5 Telander DG Sarraf D Cystoid macular edema with docetaxel chemotherapy and the fluid retention syndrome. Semin Ophthalmol 2007 22 151 153 17763235 \n6 Enzsoly A Kammerer K Nemeth J Schneider M Bilateral cystoid macular edema following docetaxel chemotherapy in a patient with retinitis pigmentosa: a case report. BMC Ophthalmol 2015 15 32 25885440 \n7 Murphy CG Walsh JB Hudis CA Lake D Theodoulou M Cystoid macular edema secondary to nab-paclitaxel therapy. J Clin Oncol 2010 28 e684 e687 20805460 \n8 Smith SV Benz MS Brown DM Cystoid macular edema secondary to albumin-bound paclitaxel therapy. Arch Ophthalmol 2008 126 1605 1606 19001234 \n9 Kuznetcova TI Cech P Herbort CP The mystery of angiographically silent macular oedema due to taxanes. Int Ophthalmol 2012 32 299 304 22484725 \n10 Gass JD Nicotinic acid maculopathy. Am J Ophthalmol 1973 76 500 510 4743805 \n11 Millay RH Klein ML Illingworth DR Niacin maculopathy. Ophthalmology 1988 95 930 936 3174043 \n12 Jampol LM Niacin maculopathy. Ophthalmology 1988 95 1704 1705 \n13 Ham DS Lee JE Kim HW Yun ICH A case of cystoid macular edema associated with Paclitaxel chemotherapy. Korean J Ophthalmol 2012 26 388 90 23060727 \n14 Makri OE Georgalas I Georgakopoulos CD Drug-induced macular edema. Drugs 2013 73 789 802 23640687 \n15 Nayfield SG Gorin MB Tamoxifen-associated eye disease. A review. J Clin Oncol 1996 14 1018 1026 8622006 \n16 Matsuoka N Hasebe H Mayama T Fukuchi T Sub-Tenon injections of triamcinolone acetonide had limited effect on cystoid macular edema secondary to nanoparticle albumin-bound-paclitaxel (Abraxane). Case Rep Ophthalmol Med 2015 2015 181269 26366312 \n17 Newcott EK Ellabban AA Tavassoli S Sallam A Intravitreal bevacizumab and triamcinolone for treatment of cystoid macular oedema associated with chronic myeloid leukaemia and imatinib therapy. Case Rep Ophthalmol Med 2015 2015 713868 25722906\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "10(2)",
"journal": "Case reports in oncology",
"keywords": "Bevacizumab; Breast cancer; Cystoid macular edema; Macular edema; Optical coherence tomography; Paclitaxel",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "605-612",
"pmc": null,
"pmid": "28868019",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "20805460;23640687;25722906;17502517;8622006;25885440;22484725;23060727;4743805;3174043;19668445;17763235;3231439;26366312;12692483;9402182;19001234",
"title": "Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer: A Case Report and Literature Review.",
"title_normalized": "cystoid macular edema during treatment with paclitaxel and bevacizumab in a patient with metastatic breast cancer a case report and literature review"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1062293",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDespite the increased use of rituximab therapy in neuromyelitis optica spectrum disorder (NMOSD), the overall efficacy and safety of long-term rituximab treatment in a large group of patients is uncertain. Furthermore, the identification of a predictor of rituximab response is an important issue for assessing the individual risk-benefit of therapy and making treatment decisions.\n\n\nOBJECTIVE\nTo assess the long-term clinical efficacy and safety of rituximab treatment in patients with NMOSD and the influence of fragment c gamma receptor 3A (FCGR3A) polymorphisms on rituximab response.\n\n\nMETHODS\nA retrospective review of 100 patients with relapsing NMOSD treated with rituximab for at least 6 months, from February 1, 2006, to January 31, 2015, at the institutional referral center. After induction therapy, a single infusion of rituximab (375 mg/m2) as maintenance therapy was administered whenever a reemergence of CD27+ memory B cells among peripheral blood mononuclear cells occurred. Using an allele-specific polymerase chain reaction-based method, the gene polymorphisms FCGR3A-V158F were assessed.\n\n\nMETHODS\nThe primary end point was annualized relapse rate; disability (Expanded Disability Status Scale score), safety of rituximab treatment, event of insufficient memory B-cell depletion following rituximab, and time to retreatment of rituximab were secondary end points.\n\n\nRESULTS\nBy January 31, 2015, a total of 100 patients received repeated rituximab treatment during a median of 67 months. Of these patients, 41 had more than 5 years' follow-up and 24 had more than 7 years' follow-up. The annualized relapse rate was reduced significantly by 96% (mean [SD] annualized relapse rate of prerituximab vs postrituximab, 2.4 [2.0] vs 0.1 [0.6]) and disability improved or stabilized in 96% of patients. Rates of adverse events were generally stable. The FCGR3A-F allele was associated with a risk of relapse while receiving rituximab treatment (additive model, P < .05; recessive model, P = .04; maximum, P = .03) and insufficient memory B-cell depletion (additive model, P = .03; recessive model, P = .03; maximum, P = .03).\n\n\nCONCLUSIONS\nRepeated rituximab treatment for NMOSD was observed in an increasing number of patients and increasing duration of exposure and maintained good efficacy and a safety profile consistent with previous reports. The finding of a relationship between FCGR3A genetic polymorphisms and rituximab response suggests the importance of individualized rituximab treatment strategies in NMOSD.",
"affiliations": "Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Department of Laboratory Medicine and Hematologic Malignancy Branch, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Biometric Research Branch, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Biometric Research Branch, Research Institute and Hospital of National Cancer Center, Goyang, Korea.;Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.",
"authors": "Kim|Su-Hyun|SH|;Jeong|In Hye|IH|;Hyun|Jae-Won|JW|;Joung|AeRan|A|;Jo|Hyo-Jin|HJ|;Hwang|Sang-Hyun|SH|;Yun|Sooin|S|;Joo|Jungnam|J|;Kim|Ho Jin|HJ|",
"chemical_list": "C496030:AQP4 protein, human; D000906:Antibodies; D051401:Aquaporin 4; C496124:FCGR3A protein, human; D007155:Immunologic Factors; D017452:Receptors, IgG; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2015.1276",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "72(9)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000328:Adult; D000906:Antibodies; D051401:Aquaporin 4; D004185:Disability Evaluation; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009471:Neuromyelitis Optica; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG; D012189:Retrospective Studies; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "989-95",
"pmc": null,
"pmid": "26167726",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab.",
"title_normalized": "treatment outcomes with rituximab in 100 patients with neuromyelitis optica influence of fcgr3a polymorphisms on the therapeutic response to rituximab"
} | [
{
"companynumb": "KR-ROCHE-1644992",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to compare the characteristics of older and younger patients with suspected paracetamol toxicity.\n\n\nMETHODS\nA retrospective audit of the medical records of older (≥65 years, n = 25) and younger (20-30 years, n = 50) patients with a detectable paracetamol level at a Sydney hospital.\n\n\nRESULTS\nOlder patients showed a different clinical pattern of suspected paracetamol toxicity and were more likely than younger patients to have multifactorial elevation of liver function tests. Additionally, older age was more likely to be associated with chronic therapeutic paracetamol dosing (71% older, 6% younger, P < 0.001), or with accidental toxic exposure (90% older, 29% younger, P < 0.001), while younger patients were more likely to have a deliberate high-dose exposure (10% older, 71% younger, P < 0.001).\n\n\nCONCLUSIONS\nThe age-related differences in paracetamol exposure, paracetamol levels and liver function tests described in this population should be considered when ordering and interpreting paracetamol levels.",
"affiliations": "Kolling institute of Medical Research, University of Sydney and Royal North Shore Hospital, Sydney, New South Wales, Australia.",
"authors": "Kane|Alice|A|;Mitchell|Sarah J|SJ|;Carroll|Peter R|PR|;Matthews|Slade|S|;Hilmer|Sarah N|SN|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1741-6612.2012.00598.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1440-6381",
"issue": "31(3)",
"journal": "Australasian journal on ageing",
"keywords": null,
"medline_ta": "Australas J Ageing",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000367:Age Factors; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008099:Liver; D008297:Male; D008485:Medical Audit; D009517:New South Wales; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9808874",
"other_id": null,
"pages": "190-3",
"pmc": null,
"pmid": "22950592",
"pubdate": "2012-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Characteristics of older and younger patients with suspected paracetamol toxicity.",
"title_normalized": "characteristics of older and younger patients with suspected paracetamol toxicity"
} | [
{
"companynumb": "AU-JNJFOC-20120905828",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENZODIAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia for more than 3 decades. The clinical benefit of intensification of the daunorubicin dose to 90 mg/m2 has been supported by randomized trials. Based on these promising results, in 2010 we changed our induction protocol of acute myeloid leukemia, increasing the dose of daunorubicin.\n\n\n\nWe retrospectively analyzed the treatment outcome of patients treated with high-dose daunorubicin (90 mg/m2 on days 1-3) and cytosine arabinoside (200 mg/m2/day continuous infusion on days 1-7) compared with patients receiving 45 to 60 mg/m2 of daunorubicin. Twenty-six previously untreated patients younger than 60 years of age were included. Twelve received high-dose daunorubicin (HD) and 14 the low-dose (LD). Seventeen patients were in complete remission after 1 induction cycle.\n\n\n\nThere was no overall difference in complete remission rate between HD and LD (66% vs. 64%; P = 1.0). Thirty-day induction mortality was 15.3% overall, with a nonsignificant difference between groups (25% vs. 7.1%; P = .3). Relapses were observed in 9 (53%) patients: 3 (37.5%) in the HD group and in 6 (66.6%) in the LD group (P = .34). Invasive fungal disease (41.6% vs. 0%; P = .012), creatinine elevation (P = .001), abdominal pain (33% vs. 0%; P = .033), and need for intensive care unit admission (33.3% vs. 0%; P = .033) were more frequent in the HD group. Four patients in the HD group developed neutropenic enterocolitis (P = .033).\n\n\n\nThese data indicate that 90 mg/m2 of daunorubicin increased the toxicity compared with lower doses.",
"affiliations": "Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: doyle66@gmail.com.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.;Hematology Service, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.",
"authors": "Portugal|Rodrigo|R|;Lyrio|Renata|R|;Loureiro|Monique|M|;Urago|Kátia|K|;Bard|Johny|J|;Borchardt|Aline|A|;Garnica|Márcia|M|;Nucci|Márcio|M|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.06.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "17(8)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "AML; Anthracycline; High-dose; Remission; Survival",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000903:Antibiotics, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D003630:Daunorubicin; D018450:Disease Progression; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "527-531",
"pmc": null,
"pmid": "28842139",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Daunorubicin 90 mg/m2 in Acute Myeloid Leukemia Induction: Increased Toxicity in Young Patients.",
"title_normalized": "daunorubicin 90 mg m2 in acute myeloid leukemia induction increased toxicity in young patients"
} | [
{
"companynumb": "BR-MYLANLABS-2017M1064583",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 69-year-old retired miner with stage 4 non-small-cell lung cancer presented with a 2-month history of obstructive liver function tests following nivolumab immunotherapy. His case had not responded to high dose prednisolone or mycophenolate and he was admitted for investigation. MR cholangiopancreatography demonstrated areas of intrahepatic biliary tree beading and stricturing, in keeping with sclerosing cholangitis. Prednisolone and mycophenolate were stopped and ursodeoxycholic acid commenced with subsequent partial improvement of the patient's liver function tests.",
"affiliations": "Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK sam.talbot@ggc.scot.nhs.uk.;Clinical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK.;Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK.",
"authors": "Talbot|Sam|S|http://orcid.org/0000-0002-6988-732X;MacLaren|Vivienne|V|;Lafferty|Heather|H|",
"chemical_list": "D000077594:Nivolumab; D014580:Ursodeoxycholic Acid",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-241700",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "liver disease; lung cancer (oncology); radiology; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D015209:Cholangitis, Sclerosing; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D000077594:Nivolumab; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34049893",
"pubdate": "2021-05-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sclerosing cholangitis in a patient treated with nivolumab.",
"title_normalized": "sclerosing cholangitis in a patient treated with nivolumab"
} | [
{
"companynumb": "GB-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-058833",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nRoutine intraoperative ureteric stenting lowers the rate of urological complications after kidney transplantation. However, there is no consensus about the optimal stent design and duration. The aim of this prospective cohort study was to compare the influence of double J (JJ) stents and externally draining percutaneous (PC) stents on the early quality of recovery after living donor kidney transplantation.\n\n\nMETHODS\nA prospective cohort study was performed in two consecutive cohorts of 40 patients who underwent living donor kidney transplantation at the Radboud university medical center between April 2016 and October 2017. The first cohort of 40 patients received a 6-French externally draining PC stent. The second cohort of 40 patients received a 6-French/14 cm JJ stent. We compared the influence of the stent design on the quality of early post-operative recovery (measured by the Quality of Recovery-40 questionnaire) and the length of hospital stay.\n\n\nRESULTS\nPatients with a JJ stent scored significantly better on the Quality of Recovery score on the third and fifth postoperative day, when compared to patients with a PC stent. Furthermore, in comparison to patients with a PC stent, patients with a JJ stent were earlier mobilising and independent in daily activities, resulting in a shorter length of hospital stay. The number of postoperative urological complications was comparable between the two groups.\n\n\nCONCLUSIONS\nThe use of JJ stents during living donor kidney transplantations improves the postoperative recovery and shortens the length of hospital stay, when compared to PC stents without compromising the number of postoperative urological complications.",
"affiliations": "Department of Surgery, Radboud University Medical Center Nijmegen, the Netherlands; Department of Urology, Radboud University Medical Center Nijmegen, the Netherlands. Electronic address: Moira.Bruintjes@radboudumc.nl.;Department of Urology, Radboud University Medical Center Nijmegen, the Netherlands. Electronic address: Hans.Langenhuijsen@radboudumc.nl.;Department of Urology, Queen Beatrix Regional Hospital Winterswijk, the Netherlands. Electronic address: a.kusters@skbwinterswijk.nl.;Department of Nephrology, Radboud University Medical Center Nijmegen, the Netherlands. Electronic address: Luuk.Hilbrands@radboudumc.nl.;Department of Urology, Radboud University Medical Center Nijmegen, the Netherlands. Electronic address: Frank.dAncona@radboudumc.nl.;Department of Surgery, Radboud University Medical Center Nijmegen, the Netherlands. Electronic address: Michiel.Warle@radboudumc.nl.",
"authors": "Bruintjes|Moira H D|MHD|;Langenhuijsen|Johan F|JF|;Kusters|Anneke|A|;Hilbrands|Luuk B|LB|;d'Ancona|Frank C H|FCH|;Warlé|Michiel C|MC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ijsu.2019.09.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-9159",
"issue": "71()",
"journal": "International journal of surgery (London, England)",
"keywords": "Double J stent; Kidney transplantation; Length of hospital stay; Percutaneous stent; Postoperative recovery",
"medline_ta": "Int J Surg",
"mesh_terms": "D000328:Adult; D004322:Drainage; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011446:Prospective Studies; D015607:Stents; D016896:Treatment Outcome; D014513:Ureter",
"nlm_unique_id": "101228232",
"other_id": null,
"pages": "175-181",
"pmc": null,
"pmid": "31600570",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Double J stent is superior to externally draining ureteric stent in enhancing recovery after kidney transplantation - A prospective cohort study.",
"title_normalized": "double j stent is superior to externally draining ureteric stent in enhancing recovery after kidney transplantation a prospective cohort study"
} | [
{
"companynumb": "NL-ASTELLAS-2019US042932",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nCoronavirus disease (COVID-19) can lead to severe disease or death and is characterized by a wide range of mild to severe symptoms. In addition to the lungs, studies have reported the involvement of the stomach, intestine, and angiotensin-converting enzyme 2 receptors in the heart.\n\n\nMETHODS\nWe present a case of a patient with COVID-19 who died soon after developing multi-organ failure and myocardial injury due to COVID-19-associated pneumonia. A 71-year-old man who contracted COVID-19 was admitted to the hospital after presenting with fever for 7 days and developed dyspnea. Following treatment, his respiratory status worsened. Thus, he was transferred to our hospital for intensive care on day 11. Physical examination revealed fever, dyspnea, respiratory distress, and no chest pain. Invasive positive pressure ventilation was initiated for acute respiratory distress syndrome on day 14. On day 15, we observed renal, liver, and coagulation dysfunction, indicating multi-organ failure. Chest radiography did not show clear signs of an increased cardiothoracic ratio or pulmonary congestion. An electrocardiogram (ECG) showed signs of myocardial infarction, which was confirmed by elevated troponin I and creatine kinase levels. The patient's circulatory dynamics did not improve on medication, and he died on day 16.\n\n\nCONCLUSIONS\nWe report the case of a patient with severe COVID-19 who died from an exacerbation of myocardial injury. Clinicians should not only evaluate respiration but also assess the heart by performing a 12-lead ECG, echocardiogram, and myocardial injury marker examination. Together, these tools can help predict which patients will develop severe COVID-19.",
"affiliations": "Department of Emergency Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: yn0403@koto.kpu-m.ac.jp.;Department of Intensive Care, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: masaru@koto.kpu-m.ac.jp.;Department of Emergency Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: t-yamaki@koto.kpu-m.ac.jp.;Department of Intensive Care, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: kushihai@koto.kpu-m.ac.jp.;Department of Intensive Care, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: ayahiro@koto.kpu-m.ac.jp.;Department of Intensive Care, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: khayase@koto.kpu-m.ac.jp.;Department of Intensive Care, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: m-yama12@koto.kpu-m.ac.jp.;Department of Intensive Care, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: satoru@koto.kpu-m.ac.jp.;Department of Emergency Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo Ward, Kyoto City, Japan. Electronic address: b-ohta@koto.kpu-m.ac.jp.",
"authors": "Nakamura|Yuki|Y|;Shimizu|Masaru|M|;Yamaki|Taeka|T|;Kushimoto|Kohsuke|K|;Yamashita|Ayahiro|A|;Hayase|Kazuma|K|;Yamazaki|Masaki|M|;Hashimoto|Satoru|S|;Ohta|Bon|B|",
"chemical_list": "D019210:Troponin I; D003402:Creatine Kinase",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2020.09.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "27(2)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "ACE2 receptors; COVID-19; Multi-organ failure; Myocardial injury",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D003402:Creatine Kinase; D004562:Electrocardiography; D017809:Fatal Outcome; D006335:Heart Injuries; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D009203:Myocardial Infarction; D009206:Myocardium; D011859:Radiography; D012128:Respiratory Distress Syndrome; D000086402:SARS-CoV-2; D013909:Thorax; D019210:Troponin I",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "364-368",
"pmc": null,
"pmid": "33036894",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Myocardial injury in a patient with severe coronavirus disease: A case report.",
"title_normalized": "myocardial injury in a patient with severe coronavirus disease a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2021167449",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "In this case study, a nurse presents her reflections on the challenges of supporting a patient through his treatment journey for multidrug-resistant tuberculosis. The patient has significant comorbidities and social issues, such as diabetes and homelessness. There was also a language barrier. All these aspects made the management of his treatment challenging. The medication side effects and his lifestyle were also a barrier to full engagement. The same multidisciplinary team was involved with the patient and, despite the obstacles, he seemed willing to engage with treatment and the team.",
"affiliations": "Community nurse working in South West England.",
"authors": "Cornish|Ruth|R|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.12968/bjon.2018.27.14.806",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-0461",
"issue": "27(14)",
"journal": "British journal of nursing (Mark Allen Publishing)",
"keywords": "Comorbidities; Language barrier; Multidisciplinary team; Multidrug-resistant tuberculosis; Pulmonary TB; Under-served population",
"medline_ta": "Br J Nurs",
"mesh_terms": "D000428:Alcohol Drinking; D000995:Antitubercular Agents; D003144:Communication Barriers; D048909:Diabetes Complications; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D012944:Social Support; D018088:Tuberculosis, Multidrug-Resistant; D006113:United Kingdom",
"nlm_unique_id": "9212059",
"other_id": null,
"pages": "806-809",
"pmc": null,
"pmid": "30048191",
"pubdate": "2018-07-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case study of a patient with multidrug-resistant tuberculosis.",
"title_normalized": "a case study of a patient with multidrug resistant tuberculosis"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201911110",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN DETEMIR"
},
"drugadditional": nu... |
{
"abstract": "Castleman disease is a rare hematologic disorder, closely linked to the HHV-8, and most commonly observed in immunocompromised individuals. Thirteen months following a liver transplant for CPS-1 defect, a 15-month-old boy presented with fevers, anemia, and growth retardation. Abdominal CT scan showed splenomegaly and generalized lymphadenopathy. Histology of chest wall lymph nodes revealed a mixed CD3+ T-cell and CD20+ B-cell population with atretic germinal centers consistent with multicentric Castleman disease. Qualitative DNA PCR detected HHV-8 in the resected lymph node and in the blood, supporting the diagnosis. Immunosuppression was tapered, and he was transitioned from tacrolimus to sirolimus. His graft function remained stable, and repeat imaging showed regression of the lymphadenopathy. The child is living one yr after Castleman disease diagnosis with a well-functioning graft. Castleman disease is a potential complication of solid organ transplant and HHV-8 infection. Reduction in immunosuppression and switch to sirolimus may be an effective strategy to treat this condition.",
"affiliations": "Department of Surgery Pathology Pediatrics, Vanderbilt University Medical Center, Vanderbilt, Nashville, TN, USA.",
"authors": "Bonatti|Hugo J R|HJ|;Axt|Jason|J|;Hunter|Ellen Bailey|EB|;Lott|Sarah Louise|SL|;Frangoul|Haydar|H|;Gillis|Lynette|L|;Correa|Hernan|H|;Kelly|Beau|B|",
"chemical_list": "D018951:Antigens, CD20; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3046.2011.01570.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "16(6)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018951:Antigens, CD20; D001402:B-Lymphocytes; D017252:CD3 Complex; D005871:Castleman Disease; D006085:Graft Survival; D019288:Herpesvirus 8, Human; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D017093:Liver Failure; D016031:Liver Transplantation; D008206:Lymphatic Diseases; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020123:Sirolimus; D013163:Splenomegaly; D013601:T-Lymphocytes; D016559:Tacrolimus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E229-34",
"pmc": null,
"pmid": "22032720",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Castleman disease in a pediatric liver transplant recipient: a case report and literature review.",
"title_normalized": "castleman disease in a pediatric liver transplant recipient a case report and literature review"
} | [
{
"companynumb": "US-PFIZER INC-2019237877",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with reported prevalence in the United States of 1 in 59 children (approximately 1.7%). Core deficits are identified in 2 domains: social communication/interaction and restrictive, repetitive patterns of behavior. Children and youth with ASD have service needs in behavioral, educational, health, leisure, family support, and other areas. Standardized screening for ASD at 18 and 24 months of age with ongoing developmental surveillance continues to be recommended in primary care (although it may be performed in other settings), because ASD is common, can be diagnosed as young as 18 months of age, and has evidenced-based interventions that may improve function. More accurate and culturally sensitive screening approaches are needed. Primary care providers should be familiar with the diagnostic criteria for ASD, appropriate etiologic evaluation, and co-occurring medical and behavioral conditions (such as disorders of sleep and feeding, gastrointestinal tract symptoms, obesity, seizures, attention-deficit/hyperactivity disorder, anxiety, and wandering) that affect the child's function and quality of life. There is an increasing evidence base to support behavioral and other interventions to address specific skills and symptoms. Shared decision making calls for collaboration with families in evaluation and choice of interventions. This single clinical report updates the 2007 American Academy of Pediatrics clinical reports on the evaluation and treatment of ASD in one publication with an online table of contents and section view available through the American Academy of Pediatrics Gateway to help the reader identify topic areas within the report.",
"affiliations": "Golisano Children's Hospital, University of Rochester, Rochester, New York; susan_hyman@urmc.rochester.edu.;Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.;Geisinger Autism & Developmental Medicine Institute, Danville, Pennsylvania.",
"authors": "Hyman|Susan L|SL|;Levy|Susan E|SE|;Myers|Scott M|SM|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2019-3447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "145(1)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder; D002675:Child, Preschool; D000080536:Decision Making, Shared; D039721:Diagnostic and Statistical Manual of Mental Disorders; D006233:Disabled Persons; D006801:Humans; D007223:Infant; D015995:Prevalence; D013219:State Government; D060305:Transition to Adult Care; D014481:United States",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31843864",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Identification, Evaluation, and Management of Children With Autism Spectrum Disorder.",
"title_normalized": "identification evaluation and management of children with autism spectrum disorder"
} | [
{
"companynumb": "US-OTSUKA-2020_006885",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nWe aimed to investigate the clinical and magnetic resonance imaging (MRI) characteristics of uterine adenomyosis, in which there is an extensive area of high signal intensity in the myometrium on T2-weighted MRI.\n\n\nMETHODS\nThis retrospective radiographic study reviewed a case series of six patients (mean age, 36 years) with adenomyosis. These patients were selected because, unlike in classical adenomyosis, T2-weighted images showed a larger area of high signal intensity than that of low signal intensity in the myometrium. The morphology of the myometrial lesions, patterns of contrast enhancement (n=4), intramyometrial hemorrhaging, diffusion restriction (n=5), endometrial lesions, and imaging findings after treatment (n=3) were evaluated on MRI.\n\n\nRESULTS\nThe patients' clinical symptoms included vaginal bleeding and severe anemia. Four were administered hormonal therapy, one underwent hysterectomy, and one underwent enucleation. On T2-weighted images, all showed endometrial thickening and a high signal intensity area in the myometrium that was divided up by a mesh of low signal intensity bands, with an appearance reminiscent of a fish caught in a net. Other findings included gradual centripetal enhancement with contrast defects in multicystic areas (4/4), an intramyometrial hemorrhage (1/6), and increased diffusion (5/5). Following hormonal therapy, the uteruses decreased in size and were similar to those of classical adenomyosis on MRI (3/3). The lesions were diagnosed as adenomyosis with a proliferation of adenomyotic glandular tissue and a proliferative endometrial polyp.\n\n\nCONCLUSIONS\nThis case series suggests that there is a subgroup of uterine adenomyosis that shows a characteristic \"fish-in-a-net\" appearance on T2-weighted images.",
"affiliations": "Department of Radiology, The University of Tokyo School of Medicine, Tokyo, Japan;Department of Radiology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Radiology, The University of Tokyo School of Medicine, Tokyo, Japan.;Department of Radiology, Kobe University School of Medicine, Hyogo, Japan.;Department of Pathology, The University of Tokyo School of Medicine, Tokyo, Japan.;Department of Pathology, The University of Tokyo School of Medicine, Tokyo, Japan.;Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Radiology, Nippon Medical School Musashikosugi Hospital, Kanagawa, Japan.;Department of Radiology, The University of Tokyo School of Medicine, Tokyo, Japan.",
"authors": "Nakai|Yudai|Y|;Maeda|Eriko|E|;Kanda|Tomonori|T|;Ikemura|Masako|M|;Ushiku|Tetsuo|T|;Sasajima|Yuko|Y|;Isshiki|Saiko|S|;Abe|Osamu|O|",
"chemical_list": "D006728:Hormones",
"country": "Turkey",
"delete": false,
"doi": "10.5152/dir.2019.19252",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1305-3825",
"issue": "26(3)",
"journal": "Diagnostic and interventional radiology (Ankara, Turkey)",
"keywords": null,
"medline_ta": "Diagn Interv Radiol",
"mesh_terms": "D062788:Adenomyosis; D000328:Adult; D000740:Anemia; D049109:Cell Proliferation; D005260:Female; D006728:Hormones; D006801:Humans; D007044:Hysterectomy; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009215:Myometrium; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014592:Uterine Hemorrhage; D014594:Uterine Neoplasms; D014599:Uterus",
"nlm_unique_id": "101241152",
"other_id": null,
"pages": "153-159",
"pmc": null,
"pmid": "32209513",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10470920;19411035;20373443;11012741;28906310;4608783;18553239;22840719;9825847;28693952;21607841;23429961;19632664;20498539;9848728;20966706;28980163;17989068;22699695;17417087;26924986;19724949;21257936;20528202;2704819;10644098;11194912;15653584;21512093",
"title": "Uterine adenomyosis with extensive glandular proliferation: case series of a rare imaging variant.",
"title_normalized": "uterine adenomyosis with extensive glandular proliferation case series of a rare imaging variant"
} | [
{
"companynumb": "JP-TOLMAR, INC.-20JP022841",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "3"... |
{
"abstract": "Multimodal therapy, used for the treatment of patients with Hodgkin’s disease (HD), makes them prone to life-threatening infections, attributed mainly to febrile neutropenia. Herein, we present a case report of fatal combined bacterial and viral infection in a 49-year-old female patient, subject to polychemotherapy for HD. Rapid microbiological diagnosis performed by multiplex polymerase chain reaction elucidated the causes of the infection within hours. Listeria monocytogenes was detected in both the cerebrospinal fluid and blood samples. Nasopharyngeal swabs returned positive for two swine-derived strains of influenza A virus. We aimed to emphasize the importance of these pathogens and draw attention to their association in the aetiology of infections among patients receiving chemotherapy. In conclusion, better surveillance is needed to improve the early diagnosis of infectious complications in these patients.",
"affiliations": "Medical University of Plovdiv, Plovdiv, Bulgaria.;Medical University of Plovdiv, Plovdiv, Bulgaria.;Medical University of Plovdiv, Plovdiv, Bulgaria.;St George University Hospital, Plovdiv, Bulgaria.;Medical University of Plovdiv, Plovdiv, Bulgaria.",
"authors": "Kalchev|Yordan I|YI|0000-0001-8062-6799;Lengerova|Gergana B|GB|;Asif|Uswah|U|;Burnusuzov|Hasan A|HA|;Murdjeva|Marianna A|MA|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Bulgaria",
"delete": false,
"doi": "10.3897/folmed.61.e47811",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0204-8043",
"issue": "61(4)",
"journal": "Folia medica",
"keywords": "Hodgkin’s disease; Listeria monocytogenes; febrile neutropenia; influenza А virus; multiplex PCR",
"medline_ta": "Folia Med (Plovdiv)",
"mesh_terms": "D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008089:Listeria monocytogenes; D008088:Listeriosis; D008875:Middle Aged",
"nlm_unique_id": "2984761R",
"other_id": null,
"pages": "620-623",
"pmc": null,
"pmid": "32337875",
"pubdate": "2019-12-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fatal Chemotherapy-induced Combined Infection in a Hodgkin’s Disease Patient: a Case Report.",
"title_normalized": "fatal chemotherapy induced combined infection in a hodgkin s disease patient a case report"
} | [
{
"companynumb": "BG-BAXTER-2020BAX008162",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "A forensic method comprising solid phase extraction and HPLC analysis was developed for the detection and confirmation of atropine and scopolamine, the main toxic alkaloids of Datura stramonium and Datura ferox. This method allowed the direct coupling of an electrospray (ZMD) mass selective detector to the HPLC system. Under these conditions, atropine and scopolamine were well separated from other components and detected on the PDA (LOD = 1 microg/ml) and ZMD (LOD(atropine) = 10 pg/ml; LOD(scopolamine) = 100 pg/ml) detectors. Four geographically isolated populations of each of D. stramonium and D. ferox were analysed for seed alkaloids and it was found that the two species were diagnostically different in their atropine-scopolamine ratios. The optimised HPLC method was used to analyse three viscera samples of an adult Caucasian male whose death was ascribed to a fatal heart attack. Atropine and scopolamine were detected in the stomach and its contents, which contained Datura seeds. The chemical profile of the seeds found in the stomach contents was similar to those from four geographically different D. ferox plants.",
"affiliations": "Forensic Chemistry Laboratory, Department of Health, P.O. Box 1080, Johannesburg 2000, South Africa. fcljhb@icon.co.za",
"authors": "Steenkamp|P A|PA|;Harding|N M|NM|;van Heerden|F R|FR|;van Wyk|B-E|BE|",
"chemical_list": "D001285:Atropine; D012601:Scopolamine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2004.03.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "145(1)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D001285:Atropine; D002851:Chromatography, High Pressure Liquid; D032302:Datura; D005554:Forensic Medicine; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009203:Myocardial Infarction; D012601:Scopolamine; D012639:Seeds; D021241:Spectrometry, Mass, Electrospray Ionization; D013270:Stomach",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "31-9",
"pmc": null,
"pmid": "15374592",
"pubdate": "2004-10-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fatal Datura poisoning: identification of atropine and scopolamine by high performance liquid chromatography/photodiode array/mass spectrometry.",
"title_normalized": "fatal datura poisoning identification of atropine and scopolamine by high performance liquid chromatography photodiode array mass spectrometry"
} | [
{
"companynumb": "ZA-PFIZER INC-2016196058",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATROPINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Organ shortage and waiting list mortality have led to changes in the allocation policy in Eurotransplant.\n\n\n\nTo identify factors influencing the survival of liver transplanted patients with model for end-stage liver disease (MELD) score of 40.\n\n\n\nData of listed adult patients who reached a MELD score 40 in the period 12/2006-06/2010 were reviewed. Donor/graft and recipient characteristics, and operative details were analyzed. Statistical analysis encompassed Kaplan-Meier analysis/log-rank test as well as univariate and multivariable regression analyses.\n\n\n\nForty-eight patients achieved a MELD score 40. Thirty patients were transplanted, whereas 18 patients were not. Three-month, 1-year, and 5-year patient and graft survival for transplanted patients was 53, 50, and 47 %, respectively. Three-month and 1-year survival after listing was 11 and 6 % for not transplanted patients, respectively (p < 0.0001). Multivariable analysis revealed pre-operative dialysis (p = 0.0246) and portal vein thrombosis (PVT) (p = 0.0231) to be independent prognostic factors for post-transplant patient survival. A point scoring system was created, which reached statistical significance (p = 0.0007). One-year and 5-year survival for scores 0, 1, and 2 were 72 and 64, 42 and 42 and 0 %, respectively. There was no statistical difference in transplantation costs between patients who survived or died (p = 0.1578).\n\n\n\nAt our center, coexistence of pre-operative dialysis and PVT represents a clear contraindication for LT regarding MELD score 40 patients.",
"affiliations": "Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany. georgios.sotiropoulos@uni-due.de.;Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.;Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.;Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.;Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.;Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.",
"authors": "Sotiropoulos|Georgios C|GC|0000-0003-3236-6579;Vernadakis|Spyridon|S|;Paul|Andreas|A|;Hoyer|Dieter P|DP|;Saner|Fuat H|FH|;Gallinat|Anja|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-016-4274-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "61(11)",
"journal": "Digestive diseases and sciences",
"keywords": "Hospital mortality; Liver transplantation; MELD score; Sickest first policy; Survival benefit",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D015897:Comorbidity; D058625:End Stage Liver Disease; D005260:Female; D006085:Graft Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009026:Mortality; D015999:Multivariate Analysis; D018579:Patient Selection; D011169:Portal Vein; D011379:Prognosis; D006435:Renal Dialysis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D009927:Tissue and Organ Procurement; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "3346-3353",
"pmc": null,
"pmid": "27538409",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "19962165;24263317;21618688;15643990;22410005;22410023;21443420;20819196;11172350;25858520;23380865;1575628;20677285;21684210;25965438;20440776;19858705;19399732;26021233;12512033;23792527;10830225;20677291;25844060;25630462;21684209;24114826;22959095;22664005;27063579;26373873",
"title": "Single-Center Experience on Liver Transplantation for Model for End-Stage Liver Disease Score 40 Patients.",
"title_normalized": "single center experience on liver transplantation for model for end stage liver disease score 40 patients"
} | [
{
"companynumb": "DE-ROCHE-1900461",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Propylthiouracil (PTU)-associated vasculitis is a potentially life-threatening disease with a recent increase in the reported cases in the medical literature. This increase may suggest that some earlier cases have been unrecognized or assigned to an alternative nosology category. Although the skin can be the only organ affected by PTU-associated vasculitis, there are many reports with multiple-system involvement. Classically, the symptoms appear under a tetrad of fever, sore throat, arthralgia, and skin lesions. Cutaneous lesions in reported cases of PTU vasculitis have most commonly consisted of retiform acral, purpuric plaques, or nodules. We report a case of perinuclear antineutrophil cytoplasmic antibody-associated vasculitis developed during treatment with PTU for Grave's disease.",
"affiliations": "University of São Paulo, São Paulo, Brazil.;University of São Paulo, São Paulo, Brazil.;University of São Paulo, São Paulo, Brazil.;University of Toronto, Toronto, Ontario, Canada afsaneh.alavi@utoronto.ca.",
"authors": "Criado|Paulo Ricardo|PR|;Grizzo Peres Martins|Ana Claudia|AC|;Gaviolli|Camila Fatima|CF|;Alavi|Afsaneh|A|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D011441:Propylthiouracil",
"country": "United States",
"delete": false,
"doi": "10.1177/1534734614549418",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1534-7346",
"issue": "14(2)",
"journal": "The international journal of lower extremity wounds",
"keywords": "ANCA; hyperthyroidism; propylthiouracil; vasculitis",
"medline_ta": "Int J Low Extrem Wounds",
"mesh_terms": "D000328:Adult; D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D001706:Biopsy; D005260:Female; D006111:Graves Disease; D006801:Humans; D011441:Propylthiouracil; D014657:Vasculitis",
"nlm_unique_id": "101128359",
"other_id": null,
"pages": "187-91",
"pmc": null,
"pmid": "25256279",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Propylthiouracil-Induced Vasculitis With Antineutrophil Cytoplasmic Antibody.",
"title_normalized": "propylthiouracil induced vasculitis with antineutrophil cytoplasmic antibody"
} | [
{
"companynumb": "BR-ACTAVIS-2016-14350",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPYLTHIOURACIL"
},
"drugadditional": "1",
... |
{
"abstract": "This case report refers to a 31-year-old patient with an 11-year history of Crohn's disease. The patient presented with an edematous elevated lesion in the splenic flexure. Two histological analyses revealed no signs of obvious dysplasia, and the patient subsequently began infliximab treatment. Nine months later, a worsening of the stricture of the edematous elevated lesion was observed in the splenic flexure, and transverse colonic resection was performed. A histological investigation of the lesion in the splenic flexure revealed advanced adenocarcinoma. Six months after the surgery, computed tomography revealed recurrent carcinoma and peritoneal metastases. The patient was administered palliative chemotherapy.",
"affiliations": "Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan.",
"authors": "Matsueda|Katsunori|K|;Toyokawa|Tatsuya|T|;Sakata|Masahiro|M|;Fujita|Isao|I|;Horii|Jouichiro|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000069285:Infliximab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0583-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2952696410.2169/internalmedicine.0583-17Case ReportLarge Bowel Progressive Stricture after Infliximab Therapy for Crohn's Disease Matsueda Katsunori 1Toyokawa Tatsuya 1Sakata Masahiro 1Fujita Isao 1Horii Jouichiro 1\n1 Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, JapanCorrespondence to Dr. Katsunori Matsueda, rge43gs@yahoo.co.jp\n\n9 3 2018 1 8 2018 57 15 2179 2183 25 11 2017 8 1 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).This case report refers to a 31-year-old patient with an 11-year history of Crohn's disease. The patient presented with an edematous elevated lesion in the splenic flexure. Two histological analyses revealed no signs of obvious dysplasia, and the patient subsequently began infliximab treatment. Nine months later, a worsening of the stricture of the edematous elevated lesion was observed in the splenic flexure, and transverse colonic resection was performed. A histological investigation of the lesion in the splenic flexure revealed advanced adenocarcinoma. Six months after the surgery, computed tomography revealed recurrent carcinoma and peritoneal metastases. The patient was administered palliative chemotherapy. \n\nCrohn's diseasecolonic carcinomainfliximabTNFα blockade\n==== Body\nIntroduction\nThe efficacy of infliximab, a monoclonal antibody against tumor necrosis factor alpha (TNFα), is well documented for the treatment of Crohn's disease and it is generally well tolerated (1-3). However, there is legitimate concern regarding the impact of TNFα blockade on the incidence of infections, autoimmune disorders, and malignancy (1-5). Generally, a secondary neoplasm is one of the most concerning sequelae of immune system manipulation (6). However, it is unclear whether it is the immune-modulating therapy or the patients' disease that causes such malignancy. We herein report a case of transverse colonic carcinoma that was diagnosed in a patient with Crohn's disease who had previously been treated with infliximab.\n\nCase Report\nA 31-year-old man presented with an 11-year history of Crohn's disease manifesting as small bowel stricture. His family history was negative for cancer. The patient was a nonsmoker, and, with the exception of Crohn's disease, his medical history was unremarkable. His clinical course included segmental ileitis and colitis complicated by stenoses. He underwent surgical resection of the terminal ileum with ileoascending anastomosis and strictureplasty in 2009. After surgery, his Crohn's disease activity index (CDAI) score decreased to 164. Thereafter, therapy with mesalazine (3 g/day) was prescribed; however, due to patient noncompliance, he experienced episodic diarrhea and abdominal pain again, for which he did not seek further care.\n\nIn 2013, because of an acute exacerbation of symptoms, such as diarrhea and abdominal pain (CDAI score increased to 290), colonoscopy was performed. This revealed edema, friable mucosa, longitudinal ulcers in the left colon, and an edematous elevated lesion with a central reddish depression in the splenic flexure (Fig. 1A) where no ulcer, erosion, or elevated lesion had been observed before. Biopsies from the elevated lesion revealed polymorphic inflammatory infiltration with reactive or regenerative dysplasia. The anastomotic region and the small bowel follow-through showed no abnormality. Radiological enteroclysis revealed no significant findings, such as stricture or scars in the small intestine. Although we recommended immune-modulating therapies, such as infliximab or azathioprine, the patient refused them because of his young age. Furthermore, because the patient had been noncompliant with his drug therapy, we persuaded him to take mesalazine every day and carefully followed him up.\n\nFigure 1. Endoscopic findings. A: Colonoscopy revealed an edematous elevated lesion with a central reddish depression in the splenic flexure in 2013. B: A worsening of the stricture, caused by the edematous elevated lesion in the splenic flexure, was observed six months later. C, D: Nine months later, after the seventh infusion of infliximab, a further worsening of the stricture of the edematous elevated lesion was observed in the splenic flexure, which prevented the colonoscope from passing through.\n\nSix months later, the patient was admitted to the emergency department with obstructive symptoms consistent with occlusive ileus, which was treated conservatively. Abdominal computed tomography (CT) scan revealed ileus resulting from anastomotic stricture. Colonoscopy showed extensive ulcerations in the left colon interposed with areas of spared mucosa, exacerbation of the stenosis in the anastomotic region, and worsening of the stricture caused by the edematous elevated lesion in the splenic flexure (Fig. 1B). Histology showed inflammatory changes with no obvious sign of dysplasia in the edematous elevated lesion in the splenic flexure and ulceration with no signs of dysplasia. The patient's diarrhea and abdominal pain became frequent (CDAI scores increased to 314) although he continued taking mesalazine every day for six months; therefore, at that time, the patient started induction treatment with infliximab (5 mg/kg intravenous infusion at weeks one, two, and six and every eight weeks thereafter).\n\nNine months later, after the seventh infusion of infliximab, the obstruction in the anastomotic region recurred. The serum carcinoembryonic antigen (CEA) concentration was 1.10 μg/L, which was within the normal range (<5.0 μg/L). Colonoscopy showed an improvement in edema, friable mucosa, and longitudinal ulcers in the left colon, and his diarrhea and abdominal pain lessened (CDAI score decreased to 263) because of treatment with infliximab; however, a further worsening of the stricture of the edematous elevated lesion was observed in the splenic flexure, which prevented the colonoscope from passing through (Fig. 1C and D). Contrast radiography of the colon revealed indurated stenosis measuring 28 mm in length in the splenic flexure, but no prestenotic dilatation (Fig. 2). Due to suspicions that the lesion might be malignant and because ileus caused by stricture of the lesion was suspected, we performed transverse colon segmental resection and an anastomotic regional resection where ileuses had recurred. Gross examination of the resected specimen showed a well-defined ulcerative type lesion in the splenic flexure, measuring 25×12 mm (Fig. 3). Histological examination of this lesion revealed well-differentiated adenocarcinoma (Fig. 4) with extraserosal invasion. No lymphadenopathy was detected in the resected specimen. The tumor classification was pT4a (SE) N0 M0 L1 V0 Pn0 R0. The margins were clear, and the resection was radical. There was no other obvious dysplasia in the resected specimens. Because of the patient's poorly controlled Crohn's disease without infliximab therapy, adjuvant chemotherapy was deferred. Moreover, as the pathogenesis of the carcinoma contraindicated the use of infliximab, the infliximab treatment was discontinued. After surgery, the patient's diarrhea and abdominal pain remained stable (CDAI score decreased somewhat to 255); therefore, therapy with mesalazine was continued.\n\nFigure 2. Contrast radiography of the colon. Indurated stenosis in the splenic flexure with no prestenotic dilatation.\n\nFigure 3. Surgically resected specimen. A: Macroscopic view of the colon adenocarcinoma showed ulceration, and the tumor was considered to be a well-defined ulcerative type lesion. B: The sectioned surface of the lesion showed a tumor with extraserosal invasion.\n\nFigure 4. Pathological images of the surgically resected specimen. The pathological evaluation revealed well-differentiated adenocarcinoma infiltrating the colonic wall (Hematoxylin and Eosin staining, ×100).\n\nSix months after the surgery, CT detected two pelvic masses and one mass near the splenic flexure (Fig. 5). Positron emission tomography revealed a tracer uptake in these lesions, while colonoscopy revealed no mass. The serum CEA concentration was 1.17 μg/L. The CT findings indicated recurrent carcinoma. A biopsy of the mass was not indicated because of the risks associated with the procedure. The recurrent carcinoma was considered to be inoperable.\n\nFigure 5. Contrast-enhanced computed tomography scans of the abdomen. A, B: Two pelvic masses and one mass near the splenic flexure were observed (arrows) six months after the surgery, indicating recurrent carcinoma.\n\nDue to the existence of peritoneal metastasis, the patient was administered palliative chemotherapy. A combination of mFOLFOX6 (oxaliplatin with 5-fluorouracil/leucovorin) and panitumumab was initiated as a first-line therapy, which was well tolerated. After eight cycles of mFOLFOX6 and panitumumab, the patient achieved a partial response. However, after 10 cycles of the chemotherapy, an exacerbation of the patent's peripheral neuropathy, hypocalcemia, and hypomagnesemia occurred; therefore, oxaliplatin and panitumumab were discontinued. A combination of FOLFIRI (irinotecan with 5-fluorouracil/leucovorin) and bevacizumab was initiated as a second-line therapy. This standard frontline regimen was not considered as a first-line therapy for this patient because of the presence of diarrhea and the possibility of restenosis with the anastomotic region; however, after the severe adverse events of the first-line regimen, the irinotecan-based regimen was considered the therapy of last resort, despite the associated risks. The patient received three doses of this chemotherapy; it remained tolerated until the latest follow-up. Even after induction of chemotherapy, the patient's diarrhea did not worsen (CDAI score remained 250-280); therefore, the therapy with mesalazine was still continued.\n\nDiscussion\nThis case report describes a patient with Crohn's disease who had two previous diagnoses of inflammatory changes with reactive or regenerative dysplasia that could not be confirmed as obvious dysplasia. He also developed metastatic adenocarcinoma of the colon nine months after beginning infliximab therapy. The cancer was detected and rapidly progressed, showing a temporal association with the infliximab therapy.\n\nAlthough there is no definitive proof of a causal association between infliximab therapy and cancer, infliximab could inhibit the natural immune surveillance mechanism, allowing premalignant cells to transform into malignant cells and further enhance their ability to metastasize (7,8). There are only a few reports of tumors in patients treated with infliximab. Colombel et al. (8) reported nine cases of cancer in an institution-based cohort of 500 patients with Crohn's disease treated with infliximab; three of these cases (two lung cancers and one non-Hodgkin's lymphoma) were considered to possibly be related to the infliximab therapy. Furthermore, Brown et al. (9) described eight cases of lymphoma in patients treated with infliximab. Interestingly, tumor regression was observed in one patient after infliximab withdrawal in the absence of any other antitumor therapy.\n\nHowever, data from the TREAT Registry (10) indicate that the incidence of malignancy per 100 patient-years did not differ significantly between the patients who did and did not receive infliximab (relative risk 1.3, 95% confidence interval 0.36-5.03). This was the case for both all malignancies (0.58 vs. 0.53) and for lymphoma (0.06 vs. 0.05). The authors concluded that, despite having more severe Crohn's disease, patients who received infliximab had similar rates of mortality, neoplasm, and lymphoma as those who received other treatments. Conversely, there is a possibility that infliximab contributes to the progression of tumors that already exist. A previous experimental study (11) indicated that TNFα suppressors, such as infliximab, may enhance tumor growth. In that study, an impaired cytotoxic activity of lymphocytes and an enhanced in vivo tumor growth were observed in TNFα knockout mice.\n\nThe endoscopic and clinical findings of worsening stricture are not easily distinguishable between Crohn's exacerbation and malignant cancer; consequently, the diagnosis is often missed or only found during laparotomy for obstructive or perforated lesions, thus explaining why up to 35% of adenocarcinomas in Crohn's disease are diagnosed as stage IV disease with an unfavorable overall survival after diagnosis (12).\n\nIn our case, an elevated lesion with a central reddish depression in the splenic flexure was observed six months before the induction of infliximab. This lesion was accompanied by tense mucosa and it was retrospectively found to be different from Crohn's exacerbation. Because we put too much confidence in the two previous histopathological diagnoses of non-malignancy, we assumed that the worsening stricture resulted from a worsening of the edematous stricture associated with Crohn's disease. However, we should have noticed that the stricture progressed rapidly in only six months although there was no active ulceration associated with Crohn's disease, and we should have strongly suspected that the worsening stricture may have been caused by progressive malignant cancer.\n\nIn conclusion, infliximab might be associated with cancer, either as a causal factor or by indirectly enhancing the cancer risk in susceptible patients with potential malignancy. While this association is not clear, increased surveillance is warranted in patients treated with infliximab or other TNFα-blocking agents with regard to secondary neoplasms. This is particularly important in patients with a higher risk of cancer, such as those with longstanding, poorly managed Crohn's disease and worsening stricture. Furthermore, based on our experience, in all cases of large bowel progressive stricture associated with Crohn's disease, we recommend that a neoplastic workup should always be part of the differential diagnosis. Resection should also be considered to rule out malignancy, especially in patients who are scheduled for or who are currently receiving infliximab therapy.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Rutgeerts P , D'Haens G , Targan S , et al \nEfficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease . Gastroenterology \n117 : 761 -769 , 1999 .10500056 \n2. Hanauer SB , Feagan BG , Lichtenstein GR , et al \nMaintenance infliximab for Crohn's disease: the ACCENT I randomised trial . Lancet (London, England) \n359 : 1541 -1549 , 2002 .\n3. Sandborn WJ , Hanauer SB \nAntitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety . Inflamm Bowel Dis \n5 : 119 -133 , 1999 .10338381 \n4. Charles PJ , Smeenk RJ , De Jong J , Feldmann M , Maini RN \nAssessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials . Arthritis Rheum \n43 : 2383 -2390 , 2000 .11083258 \n5. Baeten D , Kruithof E , Van den , Bosch F , et al \nSystematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease? \nAnn Rheum Dis \n62 : 829 -834 , 2003 .12922954 \n6. First MR , Peddi VR \nMalignancies complicating organ transplantation . Transplant proc \n30 : 2768 -2770 , 1998 .9745563 \n7. Melichar B , Bures J , Dedic K \nAnorectal carcinoma after infliximab therapy in Crohn's disease: report of a case . Dis Colon Rectum \n49 : 1228 -1233 , 2006 .16845561 \n8. Colombel JF , Loftus EV Jr, Tremaine WJ , et al \nThe safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients . Gastroenterology \n126 : 19 -31 , 2004 .14699483 \n9. Brown SL , Greene MH , Gershon SK , Edwards ET , Braun MM \nTumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration . Arthritis Rheum \n46 : 3151 -3158 , 2002 .12483718 \n10. Lichtenstein GR , Feagan BG , Cohen RD , et al \nSerious infections and mortality in association with therapies for Crohn's disease: TREAT registry . Clin Gastroenterol Hepatol \n4 : 621 -630 , 2006 .16678077 \n11. Baxevanis CN , Voutsas IF , Tsitsilonis OE , Tsiatas ML , Gritzapis AD , Papamichail M \nCompromised anti-tumor responses in tumor necrosis factor-alpha knockout mice . Eur J Immunol \n30 : 1957 -1966 , 2000 .10940885 \n12. Dossett LA , White LM , Welch DC , et al \nSmall bowel adenocarcinoma complicating Crohn's disease: case series and review of the literature . Am Surg \n73 : 1181 -1187 , 2007 .18092659\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(15)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Crohn's disease; TNFα blockade; colonic carcinoma; infliximab",
"medline_ta": "Intern Med",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000911:Antibodies, Monoclonal; D003110:Colonic Neoplasms; D003424:Crohn Disease; D006801:Humans; D000069285:Infliximab; D008297:Male; D014057:Tomography, X-Ray Computed",
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"other_id": null,
"pages": "2179-2183",
"pmc": null,
"pmid": "29526964",
"pubdate": "2018-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10338381;12047962;11083258;10940885;18092659;10500056;14699483;9745563;12922954;12483718;16845561;16678077",
"title": "Large Bowel Progressive Stricture after Infliximab Therapy for Crohn's Disease.",
"title_normalized": "large bowel progressive stricture after infliximab therapy for crohn s disease"
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"abstract": "We present the case of an elderly female patient with rheumatoid arthritis (RA) treated with methotrexate. She was referred to our hospital with severe malaise. She was emaciated and had massive pleural effusion that induced atelectasis. Her blood tests revealed elevated CRP, leukopenia, and severe anaemia. She lost consciousness on the third day of hospital stay and passed away the following day. Her autopsy showed gelatinous transformation of the bone marrow that gave rise to bicytopoenia, whereas there were no other causes for severe anaemia. Bone marrow gelatinous transformation can cause impaired haematopoiesis in elderly RA patients.",
"affiliations": "Department of Rheumatology and Clinical Immunology, Sapporo City General Hospital, Hokkaido, Japan.;Department of Rheumatology and Clinical Immunology, Sapporo City General Hospital, Hokkaido, Japan.;Department of Rheumatology and Clinical Immunology, Sapporo City General Hospital, Hokkaido, Japan.;Department of Pathology, Sapporo City General Hospital, Hokkaido, Japan.;Department of Pathology, Sapporo City General Hospital, Hokkaido, Japan.;Department of Rheumatology and Clinical Immunology, Sapporo City General Hospital, Hokkaido, Japan.",
"authors": "Kataoka|Hiroshi|H|0000-0002-2502-8304;Tomita|Tomoko|T|0000-0001-9833-1534;Kondo|Makoto|M|0000-0003-4998-8630;Makita|Keishi|K|;Tsuji|Takahiro|T|0000-0001-9810-7305;Mukai|Masaya|M|0000-0002-4931-0910",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2021.1913278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2472-5625",
"issue": "5(2)",
"journal": "Modern rheumatology case reports",
"keywords": "Cytopoenia; elderly; gelatinous transformation; methotrexate; rheumatoid arthritis",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001344:Autopsy; D001853:Bone Marrow; D017809:Fatal Outcome; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D008727:Methotrexate; D012720:Severity of Illness Index",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "236-240",
"pmc": null,
"pmid": "33970059",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Autopsy of a case of rheumatoid arthritis with severe bicytopoenia due to gelatinous transformation of the bone marrow.",
"title_normalized": "autopsy of a case of rheumatoid arthritis with severe bicytopoenia due to gelatinous transformation of the bone marrow"
} | [
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"companynumb": "JP-TEVA-2021-JP-1924502",
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"activesubstancename": "CARPERITIDE"
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"abstract": "OBJECTIVE\nWe compared the efficacy, toxicity, and use of granulocyte colony-stimulating factor (g-csf) with tac (docetaxel-doxorubicin-cyclophosphamide) and fec-d (5-fluorouracil-epirubicin-cyclophosphamide followed by docetaxel) in women less than 50 years of age.\n\n\nMETHODS\nThe study included all women more than 18 years but less than 50 years of age with her2-negative, node-positive, stage ii or iii breast cancer diagnosed in Alberta between 2008 and 2012 who received tac (n = 198) or fec-d (n = 274).\n\n\nRESULTS\nThe patient groups were well-balanced, except that radiotherapy use was higher in the tac group (91.9% vs. 79.9%, p < 0.001). At a median follow-up of 49.6 months, disease-free survival was 91.4% for tac and 92.0% for fec-d (p = 0.76). Overall survival (os) was 96% with tac and 95.3% with fec-d (p = 0.86).The incidences of grades 3 and 4 toxicities were similar in the two groups (all p > 0.05). Overall, febrile neutropenia (fn) was reported in 11.6% of tac patients and 15.7% of fec-d patients (p = 0.26). However, use of g-csf was higher in the tac group than in the fec-d group (96.4% vs. 71.5%, p < 0.001). Hospitalization for fn was required in 10.5% of tac patients and 13.0% of fec-d patients (p = 0.41). In g-csf-supported and -unsupported patients receiving tac, fn occurred at rates of 11.1% and 33.3% respectively (p = 0.08); in patients receiving the fec portion of fec-d, those proportions were 2.9% and 8.1% respectively (p = 0.24); and in patients receiving docetaxel after fec, the proportions were 4.1% and 17.6% respectively (p < 0.001).\n\n\nCONCLUSIONS\nIn women less than 50 years of age receiving adjuvant tac or fec-d, we observed no differences in efficacy or other nonhematologic toxicities. Based on the timing and rates of fn, use of prophylactic g-csf should be routine for the docetaxel-containing portion of treatment; however, prophylactic g-csf could potentially be avoided during the fec portion of fec-d treatment.",
"affiliations": "Department of Oncology, University of Calgary, Calgary, AB;;CancerControl Alberta, Alberta Health Services, Calgary, AB;;Department of Oncology, University of Calgary, Calgary, AB;; CancerControl Alberta, Alberta Health Services, Calgary, AB;;Department of Oncology, University of Alberta, Edmonton, AB.",
"authors": "Lupichuk|S|S|;Tilley|D|D|;Kostaras|X|X|;Joy|A A|AA|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.23.3004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "23(3)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Efficacy; febrile neutropenia; g-csf; granulocyte colony–stimulating factor; hospitalization; systemic therapy; toxicity",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "164-70",
"pmc": null,
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"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "21655158;15930421;26026467;20842180;17116941;25870381;18505968;19305726;25559415;20519679;1246307;24868022;23246022;15894097;21911726;26169616;23970019",
"title": "Real-world adjuvant TAC or FEC-D for HER2-negative node-positive breast cancer in women less than 50 years of age.",
"title_normalized": "real world adjuvant tac or fec d for her2 negative node positive breast cancer in women less than 50 years of age"
} | [
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"companynumb": "CA-JNJFOC-20160702567",
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"occurcountry": "CA",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
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{
"abstract": "OBJECTIVE\nClinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during \"off-label use\" for vascular anomalies.\n\n\nMETHODS\nWe performed a retrospective, multicenter chart review for SAEs during \"off-label\" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow.\n\n\nRESULTS\nWe identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis.\n\n\nCONCLUSIONS\nMost SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.",
"affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Dermatology, Hospital Sant Joan de Deu, Barcelona, Spain.;Department of Dermatology, Hospital Sant Joan de Deu, Barcelona, Spain.;Department of Oncology, Hospital Sant Joan de Deu, Barcelona, Spain.;VASCERN VASCA European Reference Centre.;VASCERN VASCA European Reference Centre.;Department of Vascular Medicine, University Hospital of Montpellier, FAVA-MULTI Reference Centre for Lymphedema and Lymphatic Anomalies, University of Montpellier, Montpellier, France.;Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Pediatric Hematology and Oncology, Children's Hospital, Cologne, Germany.;Diakonie Klinikum, Children's Hospital, Schwäbisch Hall, Germany.;Pediatric Hematology and Oncology, University Hospital of Ulm, Ulm, Germany.;Department of Vascular Medicine, University Hospital of Montpellier, FAVA-MULTI Reference Centre for Lymphedema and Lymphatic Anomalies, University of Montpellier, Montpellier, France.;Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.",
"authors": "Rössler|Jochen|J|https://orcid.org/0000-0003-4022-4917;Baselga|Eulalia|E|;Davila|Victoria|V|;Celis|Veronica|V|;Diociaiuti|Andrea|A|;El Hachem|Maya|M|;Mestre|Sandrine|S|;Haeberli|Dario|D|;Prokop|Aram|A|;Hanke|Christof|C|;Loichinger|Wolfgang|W|;Quéré|Isabelle|I|;Baumgartner|Iris|I|;Niemeyer|Charlotte M|CM|;Kapp|Friedrich G|FG|https://orcid.org/0000-0002-2729-6177",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28936",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(8)",
"journal": "Pediatric blood & cancer",
"keywords": "severe adverse events; sirolimus; toxicity; vascular anomalies",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28936",
"pmc": null,
"pmid": "33580918",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe adverse events during sirolimus \"off-label\" therapy for vascular anomalies.",
"title_normalized": "severe adverse events during sirolimus off label therapy for vascular anomalies"
} | [
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"companynumb": "CH-PFIZER INC-2021227954",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
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... |
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"abstract": "The hyperosmolar hyperglycemic state (HHS), an acute complication of diabetes mellitus with plasma hyperosmolarity, promotes the secretion of anti-diuretic hormone (ADH) and reduces the storage of ADH. Magnetic resonance T1-weighted imaging reflects ADH storage in the posterior pituitary lobe, which disappears when the storage is depleted. Whether the HHS induces ADH depletion leading to clinical manifestations has been unclear.\nA 55-year-old Japanese woman was admitted to our center because of mental disturbance and hypotension. She had received lithium carbonate for bipolar disorder and presented with polydipsia and polyuria from 15 years of age. On admission, she had mental disturbance (Glasgow Coma Scale, E4V1M1), hypotension (systolic blood pressure, 50 mmHg), and tachycardia (pulse rate, 123/min). Plasma glucose was 697 mg/dL osmolality was 476 mOsm/kg•H2O, and bicarbonate was 23.7 mmol/L. The diagnoses of HHS and hypovolemic shock were made. During treatment with fluid replacement and insulin therapy, the urine volume continued to be approximately 3 to 4 L/day, and an endocrine examination revealed ADH insufficiency and nephrogenic diabetes insipidus. Desmopressin 10 μg/day and trichlormethiazide 2 mg/day were necessary and administered, and the endogenous ADH secretion improved gradually. The signal intensity of the pituitary posterior lobe, initially decreased on magnetic resonance T1 images, was also improved.\nThis patient had ADH insufficiency associated with ADH depletion due to hyperosmolarity and nephrogenic diabetes insipidus. Clinicians should be aware of the risk of the development of critical HHS and relative ADH insufficiency in patients being treated with lithium carbonate.",
"affiliations": "Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Diabetes and Endocrinology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Department of Psychiatry, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.;Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan.",
"authors": "Gobaru|Mizuki|M|;Sakai|Kentaro|K|;Sugiyama|Yuki|Y|;Kohara|Chiaki|C|;Yoshimizu|Akiko|A|;Matsui|Rei|R|;Sato|Yuichi|Y|;Tsukamoto|Tatsuo|T|;Ashida|Kenji|K|;Higashi|Harumichi|H|",
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"country": "United States",
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"doi": "10.1016/j.aace.2021.06.009",
"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(21)00082-1\n10.1016/j.aace.2021.06.009\nCase Report\nTransient Antidiuretic Hormone Insufficiency Caused by Severe Hyperosmolar Hyperglycemic Syndrome Based on Nephrogenic Diabetes Insipidus\nGobaru Mizuki MD 1\nSakai Kentaro MD ke-sakai@st-mary-med.or.jp\n1∗\nSugiyama Yuki MD 1\nKohara Chiaki MD 1\nYoshimizu Akiko MD 1\nMatsui Rei MD 1\nSato Yuichi MD 2\nTsukamoto Tatsuo MD 3\nAshida Kenji MD 4\nHigashi Harumichi MD 1\n1 Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan\n2 Department of Diabetes and Endocrinology, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan\n3 Department of Psychiatry, Our Lady of the Snow Social Medical Corporation, St. Mary's Hospital, Kurume, Japan\n4 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan\n∗ Address correspondence to Dr Kentaro Sakai, Department of Nephrology, Our Lady of the Snow Social Medical Corporation, St. Mary’s Hospital, 422 Tsubukuhon-machi, Kurume-shi, Fukuoka, 830-8543 Japan. ke-sakai@st-mary-med.or.jp\n18 6 2021\nNov-Dec 2021\n18 6 2021\n7 6 372375\n25 1 2021\n29 5 2021\n1 6 2021\n© 2021 AACE. Published by Elsevier Inc.\n2021\nAACE\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/).\nBackground\n\nThe hyperosmolar hyperglycemic state (HHS), an acute complication of diabetes mellitus with plasma hyperosmolarity, promotes the secretion of anti-diuretic hormone (ADH) and reduces the storage of ADH. Magnetic resonance T1-weighted imaging reflects ADH storage in the posterior pituitary lobe, which disappears when the storage is depleted. Whether the HHS induces ADH depletion leading to clinical manifestations has been unclear.\n\nCase Report\n\nA 55-year-old Japanese woman was admitted to our center because of mental disturbance and hypotension. She had received lithium carbonate for bipolar disorder and presented with polydipsia and polyuria from 15 years of age. On admission, she had mental disturbance (Glasgow Coma Scale, E4V1M1), hypotension (systolic blood pressure, 50 mmHg), and tachycardia (pulse rate, 123/min). Plasma glucose was 697 mg/dL osmolality was 476 mOsm/kg•H2O, and bicarbonate was 23.7 mmol/L. The diagnoses of HHS and hypovolemic shock were made. During treatment with fluid replacement and insulin therapy, the urine volume continued to be approximately 3 to 4 L/day, and an endocrine examination revealed ADH insufficiency and nephrogenic diabetes insipidus. Desmopressin 10 μg/day and trichlormethiazide 2 mg/day were necessary and administered, and the endogenous ADH secretion improved gradually. The signal intensity of the pituitary posterior lobe, initially decreased on magnetic resonance T1 images, was also improved.\n\nConclusion\n\nThis patient had ADH insufficiency associated with ADH depletion due to hyperosmolarity and nephrogenic diabetes insipidus. Clinicians should be aware of the risk of the development of critical HHS and relative ADH insufficiency in patients being treated with lithium carbonate.\n\nKey words\n\nnephrogenic diabetes insipidus\ncentral diabetes insipidus\nhyperglycemic hyperosmolar syndrome\nAbbreviations\n\nADH, antidiuretic hormone\nCDI, central diabetes insipidus\nDM, diabetes mellitus\nHHS, hyperosmolar hyperglycemic state\nMR, magnetic resonance\nNDI, nephrogenic diabetes insipidus\nT1WI, T1-weighted image\n==== Body\npmcIntroduction\n\nThe hyperosmolar hyperglycemic state (HHS) is an acute complication of diabetes mellitus (DM) characterized by hyperglycemia (>600 mg/dL) and plasma hyperosmolarity (>320 mOsm/kg•H2O). It is often observed in diabetic patients with diseases that increase counterregulatory hormones, but HHS can also be caused by dehydration alone in individuals who are unable to drink water freely.1 Antidiuretic hormone (ADH), synthesized in the hypothalamus, is stored in the posterior pituitary lobe and secreted in response to plasma hyperosmolality and hypovolemic conditions, such as HHS. ADH concentrates urine by activating arginine vasopressin receptor 2 in the renal collecting ducts.2 The high-intensity signal of the posterior lobe on magnetic resonance (MR) T1-weighted images (T1WIs) represents the storage of ADH secretory granules.3 When ADH storage is depleted or exhausted, the MR T1WI signal in the posterior lobe decreases or disappears. This is known as a “depleted posterior lobe.”4 ADH insufficiency complicated with HHS and “depleted posterior lobe” has not been reported in a way that links the status of ADH secretion and MR imaging findings at each time point.\n\nWe report a case of a patient with transient ADH insufficiency due to severe HHS and nephrogenic diabetes insipidus (NDI), including a detailed description of the patient’s course of treatment along with MR imaging findings. Clinicians should be aware of ADH insufficiency as posing a risk of a critical condition in patients with DM who have been treated with lithium carbonate.\n\nCase Report\n\nA 55-year-old Japanese woman was transferred to our center from a psychiatric hospital for the treatment of mental disturbance and hypotension. She had been treated with lithium carbonate for bipolar disorder from the age of 15 years. She had had polydipsia and polyuria, drinking approximately 5 L of water per day since she was 15 years of age. She had no familial history of diabetes insipidus and had not been examined for glucose impairment. She had been admitted to a psychiatric hospital with a diagnosis of severe depression approximately 1 month before her admission to our center. Appetite loss and drinking volume insufficiency due to depression had led to her 5.0-kg weight loss before this admission. Lithium carbonate had been discontinued 5 days before the patient’s present admission.\n\nOn admission, mental disturbance (Glasgow Coma Scale, E4V1M1) was observed, and her systolic blood pressure was 50 mmHg with a pulse rate of 123/min; the plasma glucose level was 697 mg/dL, plasma sodium level was 183.5 mEq/L, plasma osmolality was 476 mOsm/kg•H2O, and bicarbonate level was 23.7 mmol/L (Table 1). An abdominal ultrasound examination revealed that the inferior vena cava was collapsed.Table 1 Laboratory Examination Results\n\nTest\tValue\tReference range\t\nBlood chemistry\t\t\t\n AST, IU/L\t562\t13-30\t\n ALT, IU/L\t527\t8-36\t\n Total protein, g/dL\t5.9\t6.6-8.1\t\n Albumin, g/dL\t3.1\t4.1-5.1\t\n LDH, IU/L\t2045\t124-222\t\n GGT, IU/L\t47\t9-47\t\n BUN, mg/dL\t169.6\t8-20\t\n Creatinine, mg/dL\t4.77\t0.49-1.08\t\n Sodium, mEq/L\t183.5\t138-145\t\n Potassium, mEq/L\t4.87\t3.6-4.8\t\n Chloride, mEq/L\t143.1\t101-108\t\n Creatine kinase, IU/L\t1586\t45-216\t\n CRP, mg/dL\t12.9\t0.00-0.14\t\n Glucose, mg/dL\t697\t73-109\t\n HbA1c, NGSP; %\t7.0\t4.9-6.0\t\n Anti-GAD antibody\t<5.0\t\t\n ePosma, mOsm/Kg・H2O\t476.03\t\t\nArterial blood gas analysisb\t\t\t\n pH\t7.455\t7.35-7.45\t\n pCO2, mmHg\t34.2\t\t\n pO2, mmHg\t130\t\t\n HCO3−, mmol/L\t23.7\t\t\nUrinalysis\t\t\t\n SG\t1.019\t\t\n pH\t5.0\t\t\n Urinary protein\t1＋\t\t\n Occult blood\t±\t\t\nAbbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CRP = C-reactive protein; GAD = glutamic acid decarboxylase; GGT = γ-glutamyl transpeptidase; LDH = lactate dehydrogenase; SG = specific gravity.\n\na Estimated plasma osmolality as calculated as 2Na + glu/18 + BUN/2.8.\n\nb O2: 5 L/min.\n\nUnder the diagnosis of hypovolemic shock followed by HHS, a large amount of fluid replacement with 0.9% saline and continuous intravenous insulin infusion was administered. On day 10 after admission, the patient’s plasma sodium level was 150.9 mEq/L, and her ADH level was 2.0 pg/mL. ADH insufficiency was revealed (Fig. 1).5 On day 15, the high-intensity signal in the pituitary posterior lobe was diminished on MR T1WI (Fig. 2). Desmopressin (sublingual tablet) was administered from hospital day 17 with a gradual dose increase to 720 μg/day. The patient’s polyuria (approximately 3-4 L/day) was reduced to approximately 2 to 2.5 L/day, and her serum sodium level remained at 146.3 to 149.3 mEq/L (Fig. 3). Desmopressin was discontinued on day 31.Fig. 1 The patient’s ADH secretion against the plasma sodium level. The serum ADH level was relatively low on day 10 but had improved to normal secretion on hospital days 29 to 37 and then increased to hypersecretory levels. The two dashed areas represent the estimated values and standard error of the serum ADH level against the serum sodium level.6ADH = antidiuretic hormone.\n\nFig. 2 Magnetic resonance imaging findings. T1-weighted images (sagittal sections) are shown. A, A depleted high-intensity signal in the pituitary posterior lobe (arrow) was observed on hospital day 15. B, On hospital day 118, the high-intensity signal had recovered in the pituitary posterior lobe (arrow). The signal intensity of MR T1WI increased from 481.1 (SD, 15.4; 452-692) to 757.2 (SD, 126.2; 565-930).\n\nFig. 3 The treatment course of treatment of the patient, a 55-year-old woman. DDAVP = 1-desamino-8-d-arginine vasopressin.\n\nAfter the patient’s HHS and hypovolemic shock had improved, a water restriction test and a vasopressin loading test were performed. In the water restriction test, the urine osmolality remained at 244 to 256 mOsm/kg•H2O from 4 to 6 hours after the start of the test. The change in urine osmolality was within 30 mOsm/kg•H2O in 2 hours, which meet the criteria of water restriction.6 In response to a subcutaneous injection of 5 units of vasopressin, the change in urine osmolality was from 256 to 317 mOsm/kg•H2O. The urine osmolality change of 23.8% (reference value, >50%) indicated NDI.\n\nDesmopressin 10 μg/day (divided into 4 doses as nose drops) was initiated for ADH insufficiency. The patient’s urine volume, urine osmolality, and plasma osmolality improved to 1500 to 2680 mL/day, 107 to 196 mOsm/kg•H2O, and 293.8 to 297.8 mOsm/kg•H2O, respectively. Trichlormethiazide 2 mg/day was administered for NDI. Her urine volume improved to 800 to 1500 mL/day, urine osmolality improved to 172 to 294 mOsm/kg•H2O, and plasma osmolality improved to 281 to 291 mOsm/kg•H2O. The ADH secretion in response to the serum sodium level also relatively improved,5 and desmopressin was discontinued on hospital day 110. In addition, MR T1WI demonstrated the recovery of the high-intensity signal in the pituitary posterior lobe (Fig. 2). On hospital days 110 and 181, the serum sodium level and plasma osmolality were maintained in the normal range with preserved ADH secretion. The patient continued to be treated for her NDI using only trichlormethiazide 3 mg/day with stable laboratory findings including the ADH level.\n\nDiscussion\n\nTo our knowledge, this is the first case report of transient ADH insufficiency due to severe HHS based on lithium carbonate-induced NDI, including the total course of treatment along with MR imaging findings. Patients with NDI may be at risk of developing HHS and subsequent ADH insufficiency due to excessive ADH secretion. Clinicians should be aware of the possibility of ADH insufficiency complicated with NDI when they encounter patients with HHS who have been treated with an NDI-inducing drug (eg, lithium carbonate).\n\nCentral diabetes insipidus (CDI) is classically diagnosed by changes in urine osmolality in a water restriction test and a vasopressin loading test.6 A simple nomogram to diagnose the cause of disorders of plasma osmolality based on the relationship between plasma osmolality and urine osmolarity has also been reported.7 These diagnostic methods assume a normal urine-concentrating capacity. It was, thus, difficult to diagnose the present case as CDI. An estimated serum ADH level for the serum sodium level was proposed in healthy subjects and patients with CDI.6 In our patient’s case, the secretion of ADH in response to her plasma sodium level was initially decreased but improved during the treatment (Fig. 1).\n\nImpairment of the hypothalamic-pituitary system caused by pituitary stroke, traumatic brain injury, Sheehan syndrome, carbon monoxide poisoning, hypoxemia due to cardiopulmonary arrest, and brain edema caused by a rapid correction of hypernatremia can decrease the production of ADH. In our patient’s case, these factors were ruled out based on the interviewed history, MR imaging findings, and course of treatment. In patients with poorly controlled diabetes, ADH can be depleted by excessive secretion of ADH in response to dehydration.4 We ruled out all of the possible causes of ADH insufficiency and diagnosed the cause as decreased ADH storage. During the period of the patient’s treatment with desmopressin supplementation, her endogenous ADH secretion improved over time, and desmopressin supplementation was no longer necessary by day 110. The depleted posterior lobe on MR T1WI also improved to a normal appearance. This course of treatment and the changes in the MR imaging findings are consistent with a course of increased ADH storage and improved endogenous ADH secretion.\n\nWe confirmed that our present patient had NDI with a deficient response to vasopressin loading.6 Long-term lithium use with a prolonged history of polyuria may indicate occult persistent NDI. ADH secretion is increased in patients with NDI due to ADH resistance, but this generally does not lead to ADH depletion.8 However, it has been confirmed that under the influence of NDI, ADH secretion in response to increased plasma osmolality is also excessive.9 In this case, ADH was secreted in excess due to her NDI, and ADH storage resulted in a shortage due to the excessive secretion of ADH in response to the HHS.\n\nNDI was suggested to contribute to the development and exacerbation of the HHS due to free-water depletion.10,11 ADH insufficiency also reciprocally induces further high plasma osmolality. Patients with NDI may be at high risk of developing both the HHS and a subsequent ADH insufficiency due to excessive ADH secretion. It was reported that lithium carbonate caused NDI in approximately 10% to 20% of chronic lithium users.12 Lithium carbonate is frequently administered to patients with bipolar disorder, and this population has a significantly higher prevalence of DM than the general population.13 Clinicians should, therefore, be aware that occult NDI is a high-risk factor for the development of the HHS. ADH insufficiency should also be considered as an exacerbating factor for the HHS.\n\nThis case report has some limitations. We speculate that our patient’s ADH secretion was initially increased and then decreased as the storage decreased. However, we failed to measure the temporal changes in plasma ADH levels and plasma osmolality before and immediately after admission.\n\nConclusion\n\nWe presented the details of a case of transient ADH insufficiency due to a severe HHS based on lithium-induced NDI, and we included the patient’s course of treatment along with MR imaging findings. Patients with NDI are at high risk of the development of both the HHS and subsequent ADH insufficiency due to excessive ADH secretion. Clinicians should be aware of the relationships among NDI, HHS, and ADH insufficiency as critical factors in this type of patient.\n\nDisclosure\n\nThe authors have no multiplicity of interest to disclose.\n==== Refs\nReferences\n\n1 Kitabchi A.E. Umpierrez G.E. Miles J.M. Fisher J.N. Hyperglycemic crises in adult patients with diabetes Diabetes Care 32 7 2009 1335 1343 19564476\n2 Bankir L. Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects Cardiovasc Res 51 3 2001 372 390 11476728\n3 Christ-Crain M, Winzeler B, Refardt J. Diagnosis and management of diabetes insipidus for the internist: an update. J Intern Med. Published online March 2021. https://doi.org/10.1111/joim.13261\n4 Fujisawa I. Magnetic resonance imaging of the hypothalamic-neurohypophyseal system J Neuroendocrinol 16 4 2004 297 302 15089965\n5 Takagi H. Hagiwara D. Handa T. Diagnosis of central diabetes insipidus using a vasopressin radioimmunoassay during hypertonic saline infusion Endocr J 67 3 2020 267 274 31748430\n6 Miller M. Dalakos T. Moses A.M. Fellerman H. Streeten D.H. Recognition of partial defects in antidiuretic hormone secretion Ann Intern Med 73 5 1970 721 729 5476203\n7 Voets PJGM, Vogtländer NPJ, Kaasjager KAH. A novel clinical nomogram for the evaluation of disorders of plasma osmolality. Clin Kidney J. Published online June 2021. https://doi.org/10.1093/ckj/sfaa230\n8 Baylis P.H. Heath D.A. Water disturbances in patients treated with oral lithium carbonate Ann Intern Med 88 5 1978 607 609 646242\n9 Posner L. Mokrzycki M.H. Transient central diabetes insipidus in the setting of underlying chronic nephrogenic diabetes insipidus associated with lithium use Am J Nephrol 16 4 1996 339 343 8739289\n10 Azam H. Newton R.W. Morris A.D. Thompson C.J. Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus Postgrad Med J 74 867 1998 39 41 9538487\n11 MacGregor D.A. Baker A.M. Appel R.G. Ober K.P. Zaloga G.P. Hyperosmolar coma due to lithium-induced diabetes insipidus: report of a meeting of critical care physicians, Bowman Gray School of Medicine Lancet 346 8972 1995 413 417 7623573\n12 Bendz H. Aurell M. Drug-induced diabetes insipidus: incidence, prevention and management Drug Saf 21 6 1999 449 456 10612269\n13 Vancampfort D. Mitchell A.J. De Hert M. Prevalence and predictors of type 2 diabetes mellitus in people with bipolar disorder: a systematic review and meta-analysis J Clin Psychiatry 76 11 2015 1490 1499 26214054\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2376-0605",
"issue": "7(6)",
"journal": "AACE clinical case reports",
"keywords": "ADH, antidiuretic hormone; CDI, central diabetes insipidus; DM, diabetes mellitus; HHS, hyperosmolar hyperglycemic state; MR, magnetic resonance; NDI, nephrogenic diabetes insipidus; T1WI, T1-weighted image; central diabetes insipidus; hyperglycemic hyperosmolar syndrome; nephrogenic diabetes insipidus",
"medline_ta": "AACE Clin Case Rep",
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"nlm_unique_id": "101670593",
"other_id": null,
"pages": "372-375",
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"pmid": "34765734",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31748430;33713498;15089965;5476203;26214054;34276975;646242;19564476;11476728;10612269;9538487;8739289",
"title": "Transient Antidiuretic Hormone Insufficiency Caused by Severe Hyperosmolar Hyperglycemic Syndrome Based on Nephrogenic Diabetes Insipidus.",
"title_normalized": "transient antidiuretic hormone insufficiency caused by severe hyperosmolar hyperglycemic syndrome based on nephrogenic diabetes insipidus"
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"abstract": "Long-term survivors of hematopoietic stem cell transplantation are recognized as a risk group for malignization. Malignant oral neoplasms are increasingly being reported in the literature as a consequence of lesions of chronic graft-versus-host disease, and prolonged multidrug treatment to control its manifestations. This report describes a 43-year-old patient who, after allogeneic bone marrow transplantation, developed an oral squamous cell carcinoma secondary to the use of azathioprine, cyclosporine, prednisone, and tacrolimus, associated with multiorgan chronic graft-versus-host disease involving the oral mucosa, skin, eyes, and liver. This report aims to discuss the possible role of immunosuppressant therapy for chronic graft-versus-host disease on the development of oral squamous cell carcinoma, and the relevance of a close oral follow-up of patients to detect dysplastic or malignant alterations at an early stage.",
"affiliations": "Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.",
"authors": "de Araújo|Renata Lins Fuentes|RL|;Lyko|Karine de Fátima|Kde F|;Funke|Vaneuza Araújo Moreira|VA|;Torres-Pereira|Cassius Carvalho|CC|",
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"doi": "10.5581/1516-8484.20140016",
"fulltext": "\n==== Front\nRev Bras Hematol HemoterRev Bras Hematol HemoterRevista Brasileira de Hematologia e Hemoterapia1516-84841806-0870Sociedade Brasileira de Hematologia e Hemoterapia S1516-8484(14)50016-310.5581/1516-8484.20140016Case reportOral cancer after prolonged immunosuppression for multiorgan chronic graft-versus-host disease de Araújo Renata Lins Fuentes de Fátima Lyko Karine Funke Vaneuza Araújo Moreira Torres-Pereira Cassius Carvalho cassius@ufpr.br*Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil* Programa de Pós-Graduação em Odontologia e Departamento de Estomatologia, Universidade Federal do Paraná, Av. Lothário Meissner, 632, Jardim Botânico 80210-170, Curitiba, PR, Brazil. cassius@ufpr.br23 4 2014 Jan-Feb 2014 23 4 2014 36 1 65 68 10 6 2013 2 8 2013 © 2014 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.2014Associação Brasileira de Hematologia, Hemoterapia e Terapia CelularThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Long-term survivors of hematopoietic stem cell transplantation are recognized as a risk group for malignization. Malignant oral neoplasms are increasingly being reported in the literature as a consequence of lesions of chronic graft-versus-host disease, and prolonged multidrug treatment to control its manifestations. This report describes a 43-year-old patient who, after allogeneic bone marrow transplantation, developed an oral squamous cell carcinoma secondary to the use of azathioprine, cyclosporine, prednisone, and tacrolimus, associated with multiorgan chronic graft-versus-host disease involving the oral mucosa, skin, eyes, and liver. This report aims to discuss the possible role of immunosuppressant therapy for chronic graft-versus-host disease on the development of oral squamous cell carcinoma, and the relevance of a close oral follow-up of patients to detect dysplastic or malignant alterations at an early stage.\n\n© 2014 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.\n\nKeywords\nMouth neoplasmsBone marrow transplantationLeukemiaMyeloidGraft-versus-host disease\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a reciprocal translocation between chromosomes 9 and 22 (Philadelphia chromosome), which leads to the appearance of a new hybrid gene (BCR-ABL) with tyrosine kinase activity. Current initial therapy is the administration of the tyrosine kinase inhibitor, imatinib mesylate, but in some cases, particularly for refractory or advanced phase disease, hematopoietic stem cell transplantation (HSCT) can be indicated as a curative treatment. However, there is concern about late complications of this procedure, such as chronic graft-versus- host disease (cGVHD) and the development of malignancies secondary to radiotherapy, chemotherapy, and prolonged immunosuppressive treatment.1., 2.\n\nOne of the most common late complications after HSCT is graft-versus-host disease (GVHD). Studies demonstrate that patients who develop cGVHD have higher risk of developing solid tumors such as oral squamous cell carcinoma (SCC), mainly because of the immunosuppressive treatment, which generally includes cyclosporine, tacrolimus, and corticosteroids.2., 3.\n\nThe current report describes a patient with multiorgan cGVHD, who developed oral SCC after prolonged and combined immunosuppressant drug therapy.\n\nCase report\nIn 2008, a 43-year-old Caucasian male patient was referred for an oral medical consultation from a bone marrow transplantation unit, with the chief complaint of widespread oral pain, mainly of the palate, and difficulty to open his mouth. In 1999, the patient had been diagnosed with CML and started treatment with hydroxyurea to control the leukocyte count. Three years later he started taking imatinib mesylate, which was maintained for 14 months. As there was no response to high doses of imatinib or its association with cytarabine, the patient was submitted to a HSCT in 2003. The cell donor was his sister and they were fully matched. The patient progressed with acute GVHD (aGVHD), followed by extensive multiorgan cGVHD. In 2004, the CML relapsed, despite severe cGVHD. At that time, there was no other available option and the patient returned to imatinib therapy (400 mg/day), which was maintained until 2009, with an unexpected complete molecular response.\n\nAn extra oral examination revealed diffuse hypochromic and hyperchromic skin lesions (Figure 1), and palpable submandibular and cervical lymph nodes. The oral examination revealed a very poor hygiene status, scleroderma with a severe limitation of mouth opening, severe mucosal atrophy and ulcerations, absence of tongue papillae, a pseudomembrane on the anterior third part of the left buccal mucosa, and an indurated retrocomissural ulcerated nodule of approximately 1 cm in diameter (Figure 2). The panoramic radiographic image showed residual root fragments and loose teeth (Figure 3).\n\nThe patient was taking imatinib mesylate (400 mg/day), prednisone (20 mg) on alternate days, trimethoprim and sulfamethoxazole (TMP/SMX) (80/400 mg/day), tacrolimus (4 mg/day), azathioprine (100 mg/day), and morphine (240 mg/day). Information on drugs, dosage and time is summarized in Table 1.\n\nThe patient was immediately prescribed non-alcohol chlorhexidine mouthwash to control oral biofilm, and an incisional biopsy was performed on the retrocomissural lesion under local anesthesia. The microscopic analysis revealed a well differentiated SCC, and the patient was promptly referred to a head and neck surgery referral center.\n\nDiscussion\nGVHD is a common and important complication after HSCT; its prevalence is seen in between 25% and 80% in long-term survivors. The 5-year survival rate after HSCT is reported as being approximately 40% of patients with multisystem cGVHD.2., 3., 4., 5. Cumulative evidence suggests that GVHD is an important risk factor for carcinogenesis, and this association has also been described for oral tissues.\n\nIn 1997, Curtis et al.,6 in a multi-institution database study of 19,229 patients, showed that cGVHD was associated to higher risk of SCC in the oral cavity after HSCT. All 16 cases of oral SCC registered were associated to GVHD, and 11 had received immunosuppressive drugs for two or more years. In that study, the most frequent site of SCC was the tongue, followed by the salivary glands, lips, and gingivae.\n\nIn a study with 2,129 patients who underwent HSCT, Bathia et al.7 found that the risk of solid cancers after transplant varies according to the primary diagnosis. Among hematologic malignancies, patients with a diagnosis of acute and chronic myeloid leukemia tended to have higher incidence of solid tumors than the general population, the risk being significantly higher for liver, oral cavity, and cervical cancers.\n\nOther authors also stated that this high risk for oral SCC is a result of long-term immunologic injury to the oral mucosa by T-cells, and of immunodeficiency after prolonged drug use to control cGVHD. There is some speculation that oral tissue infections by viruses, particularly HPV, may also lead to the proliferation of cancer cells.2., 4., 8., 9.\n\nIt is well accepted that tissue damage results from the reaction of donor T cells against host histocompatibility antigens (HLA); this is aggravated by other known risk factors for cGVHD, such as gender mismatch (female donor to a male recipient), severity of previous aGVHD, the donor age, and older recipient.2., 9.\n\nIn the case described in this paper, the donor was female, and the host and donor were 35 and 38 years old, respectively at the time of HSCT. Moreover, the patient had an aggressive aGVHD 35 days after the HSCT, followed by multisystemic cGVHD, refractory to treatment.\n\nClinically, oral cGVHD resembles autoimmune disorders like lichen planus, scleroderma, and Sjogren's syndrome, and manifests in oral tissues as inflammation and erythema, hyperkeratotic lesions, atrophy, fibrosis with restricted mouth opening, depapillation of the tongue, hyposalivation, and pain.5\n\nAlthough it is well recognized that patients have a higher risk of oral complications after HSCT, such as tooth decay, gingivitis, and periodontitis, the case presented herein showed a far more dramatic condition of poor oral health. The oral mucosa had multiple ulcerations, lichenoid lesions, severe atrophy, and intense pain, which contributed to the lack of compliance to oral health hygiene measures.\n\nAs part of the immunosuppression treatment for his multiorgan cGVHD, the patient was initially prescribed cyclosporine and prednisone. The worsening of lesions led to the use of mycophenolate mofetil (MMF), also with poor response. Azathioprine and tacrolimus led to some improvements in the symptoms and manifestations (Table 1).\n\nSome studies have shown that the combination of prolonged immunosuppressive treatment for cGVHD increases the risk for solid tumors, such as oral SCC. This finding is consistent with the case-control study (n = 24,000) by Curtis et al.,9 who identified increased risk for oral malignancy and other solid tumors in individuals who developed severe cGVHD, and were submitted to a long protocol of azathioprine (over 24 months). According to these authors, these are the main risk factors for the occurrence of skin and oral cavity SCC.3 These findings were also described in a large (n = 5,931) solid organ transplant study,10 reinforcing that treatment with azathioprine is strongly associated with the risk of cutaneous SCC after transplantation. The risk of malignancy increases with the dose and the duration of treatment. They also found that the triple treatment regimen of azathioprine + cyclosporine + corticosteroids increases the risk of cutaneous SCC in 5-fold, and a high accumulated dose of corticosteroids after prolonged treatment (three years) enhances the risk of cutaneous SCC in organ transplanted patients. This cumulative association, according to their findings, however, was not relevant for cyclosporine.\n\nImmunosuppressive drugs are believed to cause SCC by a carcinogenic effect or by increasing the carcinogenic effect of other agents combined with its immunosuppressive effect.10 Azathioprine has been reported as a mutagenic agent, and associated to the promotion of secondary malignancies when used in cGVHD treatment. On the other hand, cyclosporine is not directly associated to an increased risk of SCC, but is believed to induce phenotypic changes, and promote tumor growth, including invasiveness.8\n\nDue to the severity of his cGVHD and the limited availability of other therapeutic tools (extracorporeal photopheresis, sirolimus, etc.), our patient was on azathioprine for more than 34 months, cyclosporine for 26 months, and corticosteroids for 56 months, all of which are associated to an increased risk for SCC.\n\nIn this case, the presence of multiorgan cGVHD and prolonged immunosuppressive therapy are factors that could be related to the development of SCC. A periodic and thorough oral examination should be recommended for all long-term HSCT survivals, with special attention to individuals who manifest cGVHD, and those on long-term cumulative immunosuppressant therapy.\n\nConflicts of interest\nThe authors declare no conflicts of interest.\n\nFigure 1 Diffuse hypochromic and hyperchromic skin lesions characteristic of chronic cutaneous graft-versus-host disease.\n\nFigure 2 Indurate and asymptomatic retrocomissural lesion. Poor oral hygiene was evident with multiple acute carious lesions, the accumulation of gross biofilm, gingivitis and restricted mouth opening.\n\nFigure 3 Panoramic radiograph showing the poor dental status.\n\nTable 1 Immunosuppressant treatment for acute and chronic graft-versus-host disease.\n\nYear\tDrug\tDosage\tPrescription (days)\t\n2003-2005\tCyclosporinea\t200-800 mg\t458\t\n\tPrednisone\t> 5 mg/kg/day\t708\t\n2005\tMycophenolate mofetil\t1 g\t30\t\n2006\tCyclosporine\t300 mg\t270\t\n\tPrednisone\t> 5 mg/kg/day\t240\t\n\tAzathioprine\t100 mg\t285\t\n2007\tCyclosporine\t300 mg\t45\t\n\tPrednisone\t> 5 mg/kg/day\t345\t\n\tAzathioprine\t100 mg\t365\t\n\tTacrolimus\t2-4 g\t330\t\n2008-2009\tPrednisone\t> 5 mg/kg/day\t395\t\n\tAzathioprine\t100 g\t395\t\n\tTacrolimus\t2-4 g\t395\t\na Dosage used to keep serum level between 200-400 mg/kg.\n==== Refs\nREFERENCES\n1. Baccarani M. Dreyling M. ESMO Guidelines Working Group. Chronic myeloid leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol. 21 Suppl 5 2010 165 167 \n2. Kruse A.L. Gratz K.W. Oral carcinoma after hematopoietic stem cell transplantation - a new classification based on a literature review over 30 years Head Neck Oncol 2009 1 29 19284679 \n3. Demarosi F. Lodi G. Carrassi A. Soligo D. Sardella A. Oral malignancies following HSCT: graft versus host disease and other risk factors Oral Oncol. 41 9 2005 865 877 16084755 \n4. Noguchi K. Nakase M. Inui M. Nakamura S. Okumura K. Tagawa T. A case of tongue carcinoma associated with chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation Aust Dent J. 55 2 2010 200 202 20604764 \n5. Meier J.K. Wolff D. Pavletic S. Greinix H. Gosau M. Bertz H. Lee S.J. Lawitschka A. Elad S. International Consensus Conference on Clinical Practice in cGVHD. Oral chronic graft-versus-host disease: report from the International Consensus Conference on clinical practice in cGVHD Clin Oral Investig. 15 2 2011 127 139 \n6. Curtis R.E. Rowlings P.A. Deeg H.J. Shriner D.A. Socíe G. Travis L.B. Solid cancers after bone marrow transplantation N Engl J Med. 336 13 1997 897 904 Comment in: N Engl J Med. 1997;336(13):949-50; N Engl J Med. 1997;337(5):345-6 9070469 \n7. Bhatia S. Louie A.D. Bhatia R. O’Donnell M.R. Fung H. Kashyap A. Solid cancers after bone marrow transplantation J Clin Oncol 19 2 2001 464 471 11208840 \n8. Arora M. Klein J.P. Weisdorf D.J. Hassebroek A. Flowers M.E. Cutler C.S. Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis Blood 117 24 2011 6714 6720 Comment in: Blood. 2011;117(24):6408-9 21493797 \n9. Curtis R.E. Metayer C. Rizzo J.D. Socié G. Sobocinski K.A. Flowers M.E. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study Blood 105 10 2005 3802 3811 15687239 \n10. Ingvar A. Smedby K.E. Lindelof B. Fernberg P. Bellocco R. Tufveson G. Immunosuppressive treatment after solid organ transplantation and risk of post-transplant cutaneous squamous cell carcinoma Nephrol Dial Transplant 25 8 2010 2764 2771 19729465\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1516-8484",
"issue": "36(1)",
"journal": "Revista brasileira de hematologia e hemoterapia",
"keywords": "Bone marrow transplantation; Graft-versus-host disease; Leukemia; Mouth neoplasms; Myeloid",
"medline_ta": "Rev Bras Hematol Hemoter",
"mesh_terms": null,
"nlm_unique_id": "101220159",
"other_id": null,
"pages": "65-8",
"pmc": null,
"pmid": "24624039",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "15687239;19624855;21493797;9070469;11208840;20555071;19729465;20859645;16084755;20604764",
"title": "Oral cancer after prolonged immunosuppression for multiorgan chronic graft-versus-host disease.",
"title_normalized": "oral cancer after prolonged immunosuppression for multiorgan chronic graft versus host disease"
} | [
{
"companynumb": "PHHY2014BR092913",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "The risk of recurrence of Crohn's disease (CD) from 1 to 10 years after surgery despite initial endoscopic remission (late post-operative recurrence) is not clear.\n\n\n\nWe performed a retrospective study, at 3 inflammatory bowel disease (IBD) centers in France and Belgium, of all patients with CD (n = 86) undergoing an ileocecal resection with curative intent from 2006 through 2016 who did not have endoscopic evidence for recurrence (Rutgeerts score less than i2) at their baseline assessment. Postoperative recurrence after baseline endoscopy was defined as a composite endpoint of at least 1 of the following: clinical recurrence, IBD-related hospitalization, occurrence of bowel damage, need for endoscopic balloon dilatation of the anastomosis, and need to repeat the surgery. Risk of mucosal disease progression was studied as a secondary outcome.\n\n\n\nThe median time between surgery and baseline endoscopy was 7 months (IQR, 5.7-9.5 months); 40 patients (46.5%) received medical prophylaxis in this period. The median follow-up time was 3.5 years (IQR, 1.6-5.3 years). Thirty-five patients (40.7%) had a late post-operative recurrence of CD, with a median time to disease recurrence after baseline endoscopy of 14.2 months (IQR, 6.3-26.1 months). Recurrence status did not differ significantly between patients with Rutgeerts scores of i0 (20/55) or i1 (15/31) at baseline (P = .28) and was independent of medical prophylaxis (16/40 with prophylactic therapy vs 19/46 without prophylactic therapy; P = .90). Mucosal disease progressed in 29 of the 71 patients (40.8%) with available data. We did not identify risk factors for late post-operative recurrence of CD or mucosal disease progression.\n\n\n\nAmong patients with CD treated by ileocecal resection, 40% of patients had a late recurrence, despite initial endoscopic remission, after a median follow-up time of 3.5 years. Tight monitoring of these patients is recommended beyond 18 months.",
"affiliations": "Imelda GI Clinical Research Centre, Imeldaziekenhuis Bonheiden, Bonheiden, Belgium; Department of Hepato-Gastroenterology, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;Unit of Methodology, Data-management and Statistic (UMDS), Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;Department of Gastroenterology, Liège University Hospital, Liège, Belgium.;Department of Gastroenterology, Liège University Hospital, Liège, Belgium.;Imelda GI Clinical Research Centre, Imeldaziekenhuis Bonheiden, Bonheiden, Belgium; Department of Gastroenterology, Heilig Hart Ziekenhuis, Lier, Belgium.;Department of Gastroenterology, Liège University Hospital, Liège, Belgium.;Department of Surgery, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;Unit of Methodology, Data-management and Statistic (UMDS), Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;Imelda GI Clinical Research Centre, Imeldaziekenhuis Bonheiden, Bonheiden, Belgium.;Department of Hepato-Gastroenterology, Nancy University Hospital, Vandoeuvre-lès-Nancy, France; Institut National de la Santé et de la Recherche Médicale (INSERM) 1256 NGERE, Lorraine University, Vandoeuvre-lès-Nancy, France. Electronic address: peyrinbiroulet@gmail.com.",
"authors": "Pouillon|Lieven|L|;Remen|Thomas|T|;Amicone|Caroline|C|;Louis|Edouard|E|;Maes|Sielte|S|;Reenaers|Catherine|C|;Germain|Adeline|A|;Baumann|Cédric|C|;Bossuyt|Peter|P|;Peyrin-Biroulet|Laurent|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2020.05.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "19(6)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Complications; Hemicolectomy; Relapse; Surveillance",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000714:Anastomosis, Surgical; D003424:Crohn Disease; D004724:Endoscopy; D006801:Humans; D007082:Ileum; D009364:Neoplasm Recurrence, Local; D012008:Recurrence; D012189:Retrospective Studies",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1218-1225.e4",
"pmc": null,
"pmid": "32445951",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk of Late Postoperative Recurrence of Crohn's Disease in Patients in Endoscopic Remission After Ileocecal Resection, Over 10 Years at Multiple Centers.",
"title_normalized": "risk of late postoperative recurrence of crohn s disease in patients in endoscopic remission after ileocecal resection over 10 years at multiple centers"
} | [
{
"companynumb": "FR-AMGEN-FRASP2021155726",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Pembrolizumab, an immune-checkpoint inhibitor (ICI), is a humanized monoclonal antibody that binds to programmed cell death-1 receptor (PD-1) and thereby inhibits binding to its ligand, which inhibits the suppression of activated T cells by cancer cells, resulting in enhancing antitumour immunity. Although several cases of encephalitis have been reported as immune-related adverse effects of ICIs, epilepsy has not been reported following ICI treatment. We describe the case of an elderly woman with bladder carcinoma who experienced two episodes of generalized seizures after treatment with pembrolizumab. The episodes were atypical of encephalitis, because the seizures were completely responsive to AEDs and the CSF parameters normalized completely without immunotherapy. Since interictal EEG revealed persistent epileptic discharges after the seizures, pembrolizumab was considered to have induced a chronic state of epileptogenicity as the possible pathology, with a clinical picture similar to that of autoimmune epilepsy. The possibility that ICIs may cause an immune-related adverse effect, such as a chronic epileptic condition, should be considered, since ICIs are used widely.",
"affiliations": "Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan, Epilepsy Center, Hiroshima University Hospital, Hiroshima, Japan.;Department of Urology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan, Epilepsy Center, Hiroshima University Hospital, Hiroshima, Japan.;Epilepsy Center, Hiroshima University Hospital, Hiroshima, Japan, Department of Neurosurgery, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan, Epilepsy Center, Hiroshima University Hospital, Hiroshima, Japan.",
"authors": "Takebayashi|Yoshiko|Y|;Neshige|Shuichiro|S|;Hayashi|Tetsutaro|T|;Aoki|Shiro|S|;Ueno|Hiroki|H|;Iida|Koji|K|;Maruyama|Hirofumi|H|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/epd.2021.1319",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "23(5)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "autoimmune epilepsy; blood brain barrier; immune-checkpoint inhibitors; immune-related adverse effect; temporal intermittent rhythmic delta activity",
"medline_ta": "Epileptic Disord",
"mesh_terms": null,
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "733-738",
"pmc": null,
"pmid": "34519645",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case of repetitive seizures following immune checkpoint inhibitor therapy as a feature of autoimmune encephalitis.",
"title_normalized": "a case of repetitive seizures following immune checkpoint inhibitor therapy as a feature of autoimmune encephalitis"
} | [
{
"companynumb": "JP-MYLANLABS-2022M1002217",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "4",
... |
{
"abstract": "Fatal hepatitis B virus (HBV) reactivation in lymphoma patients with \"resolved\" HBV infection (hepatitis B surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) can occur, but the true incidence and severity remain unclear. From June 2009 to December 2011, 150 newly diagnosed lymphoma patients with resolved HBV infection who were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy were prospectively followed. HBV DNA was checked at baseline, at the start of each cycle of chemotherapy, and every 4 weeks for 1 year after completion of rituximab-CHOP chemotherapy. Patients with documented HBV reactivation were treated with entecavir at a dosage of 0.5 mg/day for 48 weeks. HBV reactivation was defined as a greater than 10-fold increase in HBV DNA, compared with previous nadir levels, and hepatitis flare was defined as a greater than 3-fold increase in alanine aminotransferase (ALT) that exceeded 100 IU/L. Incidence of HBV reactivation and HBV-related hepatitis flares was 10.4 and 6.4 per 100 person-year, respectively. Severe HBV-related hepatitis (ALT >10-fold of upper limit of normal) occurred in 4 patients, despite entecavir treatment. Patients with hepatitis flare exhibited significantly higher incidence of reappearance of HBsAg after HBV reactivation (100% vs. 28.5%; P=0.003).\n\n\nCONCLUSIONS\nIn lymphoma patients with resolved HBV infections, chemotherapy-induced HBV reactivation is not uncommon, but can be managed with regular monitoring of HBV DNA and prompt antiviral therapy. Serological breakthrough (i.e., reappearance of HBsAg) is the most important predictor of HBV-related hepatitis flare. (Hepatology 2014;59:2092-2100).",
"affiliations": "Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.",
"authors": "Hsu|Chiun|C|;Tsou|Hsiao-Hui|HH|;Lin|Shyh-Jer|SJ|;Wang|Ming-Chung|MC|;Yao|Ming|M|;Hwang|Wen-Li|WL|;Kao|Woei-Yau|WY|;Chiu|Chang-Fang|CF|;Lin|Sheng-Fung|SF|;Lin|Johnson|J|;Chang|Cheng-Shyong|CS|;Tien|Hwei-Fang|HF|;Liu|Tsang-Wu|TW|;Chen|Pei-Jer|PJ|;Cheng|Ann-Lii|AL|;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D006514:Hepatitis B Surface Antigens; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.26718",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "59(6)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006801:Humans; D008224:Lymphoma, Follicular; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011446:Prospective Studies; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "2092-100",
"pmc": null,
"pmid": "24002804",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study.",
"title_normalized": "chemotherapy induced hepatitis b reactivation in lymphoma patients with resolved hbv infection a prospective study"
} | [
{
"companynumb": "TW-BAXTER-2014BAX048534",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Methicillin-resistant Staphylococcus aureus (MRSA) has become an increasingly common cause of difficult-to-treat head and neck infections. We report a retrospective analysis of 3 cases of MRSA otorrhea treated in our clinic between 2007 and 2009. Culture analysis of otorrhea isolates revealed MRSA infections with identical drug sensitivities. Treatment success was achieved using combinations of linezolid with gentamicin ear drops for 3 to 4 weeks or trimethoprim/sulfamethoxazole (TMP/SMX) with gentamicin drops for 6 weeks. This study illustrates the importance of determining individual drug sensitivities for optimal treatment and maintaining current knowledge of the local MRSA strains. Empiric combination therapy of TMP/SMX with gentamicin is an effective first-line treatment for MRSA otorrhea. Regional differences in clindamycin sensitivities warrant clinical discretion. Fluoroquinolones should be avoided because of high rates of resistance unless culture sensitivity determines that they are appropriate. First-line agents for severe infections include combination therapy with vancomycin or linezolid.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA.",
"authors": "Baugher|Katherine M|KM|;Hemme|Troy Sommers|TS|;Hawkshaw|Mary|M|;Sataloff|Robert T|RT|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/014556131109000206",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-5613",
"issue": "90(2)",
"journal": "Ear, nose, & throat journal",
"keywords": null,
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D004427:Ear Diseases; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D013203:Staphylococcal Infections",
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "60-79",
"pmc": null,
"pmid": "21328227",
"pubdate": "2011-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "MRSA otorrhea: A case series and review of the literature.",
"title_normalized": "mrsa otorrhea a case series and review of the literature"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK019864",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"dru... |
{
"abstract": "In early breast cancer chemotherapy, it is important to maintain the relative dose intensity(RDI). We retrospectively ana- lyzed the incidence and risk factors of febrile neutropenia(FN)among women receiving FEC(5-fluorouracil 500mg/m2, epirubicin 100mg/m2, and cyclophosphamide 500 mg/m2)chemotherapy. Of 72 patients, 33 patients developed FN and 39 patients did not. Excluding patients in whom the nadir could not be confirmed, we classified a final total of 28 patients into the FN group and 24 into the non-FN group. The number of leukocytes was significantly lower in the FN group(1,500/mL versus 2,146/mL, p=0.05). The reduction rate of leukocytes was also significantly lower in the FN group(74.5%versus 65.0%, p=0.02). In adjuvant FEC chemotherapy, the considerable reduction of leukocytes at nadir is a risk factor of FN. To manage FN appropriately, G-CSF therapy may be considered for these patients.",
"affiliations": "Dept. of Surgery, Chiba Rosai Hospital.",
"authors": "Ishii|Natsumi|N|;Fujimori|Toshihiko|T|;Kasagawa|Takahiro|T|;Udagawa|Ikuo|I|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D015251:Epirubicin; D064147:Febrile Neutropenia; D005260:Female; D005472:Fluorouracil; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors",
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"title": "Analysis of the Risk Factors of Febrile Neutropenia Among 72 Women Receiving FEC in Early Breast Cancer Chemotherapy.",
"title_normalized": "analysis of the risk factors of febrile neutropenia among 72 women receiving fec in early breast cancer chemotherapy"
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"abstract": "BACKGROUND\nAt least nine therapeutic options are recommended or approved for pancreatic neuroendocrine tumour (pNET). The primary endpoint of this study was to determine the number of therapeutic lines given before death. Secondary endpoints were to determine toxic events as a function of number of therapeutic lines and of time.\n\n\nMETHODS\nPatients with pNET treated between 1998 and 2010 at our centre were characterised. All therapeutic lines were recorded as well as tumour- or toxic-related deaths. Persistent treatment-related toxicity (PTRT) was defined as: chronic kidney disease, anaemia, thrombocytopenia, neutropenia, severe liver failure, cardiac failure and recurrent sepsis, precluding at least one other therapeutic option or second cancers.\n\n\nRESULTS\nNinety-two patients were analysed. The median follow-up was 7 years. The 1-, 2- and 5-year overall survival rates were 90, 81 and 51%, respectively. After 3 and 5 therapeutic lines, 23 and 50% of patients had died, respectively. After 3 and 5 lines, the frequency of toxic events was 8 and 24%, respectively. Overall, 17 toxic events were observed including 6 treatment-related deaths and 11 PTRT. After 1, 2 and 5 years of treatment, the frequency of toxic events was 6, 9 and 16%, respectively.\n\n\nCONCLUSIONS\nTumour- and toxic-related deaths as well as PTRT may preclude access to all therapeutic options in patients with pNET. Optimised risk benefit sequence should be investigated.",
"affiliations": "Department of Nuclear Medicine and Endocrine Tumours, Gustave Roussy, Université Paris XI, Villejuif, France.",
"authors": "Berdelou|Amandine|A|;Boige|Valérie|V|;Arfi-Rouche|Julia|J|;Malka|David|D|;Ederhy|Stéphane|S|;Izzedine|Hassan|H|;Leboulleux|Sophie|S|;Chougnet|Cécile N|CN|;Burtin|Pascal|P|;De Baere|Thierry|T|;Laplanche|Agnès|A|;Elias|Dominique|D|;Schlumberger|Martin|M|;Scoazec|Jean-Yves|JY|;Ducreux|Michel|M|;Baudin|Eric|E|",
"chemical_list": "D000969:Antinematodal Agents; D007155:Immunologic Factors",
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"issue": "105(1)",
"journal": "Neuroendocrinology",
"keywords": "Neuroendocrine tumour; Pancreatic tumour; Safety; Therapeutic lines",
"medline_ta": "Neuroendocrinology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000969:Antinematodal Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Not All Patients with a Pancreatic Neuroendocrine Tumour Will Benefit from All Approved or Recommended Therapeutic Options: A Real-Life Retrospective Study.",
"title_normalized": "not all patients with a pancreatic neuroendocrine tumour will benefit from all approved or recommended therapeutic options a real life retrospective study"
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"abstract": "Vesiculobullous lesions in systemic lupus erythematosus (SLE) are a rare cutaneous manifestation of cutaneous and/or systemic LE with variable presentation. The diagnosis of SLE-associated vesiculobullous diseases remains challenging, due to the poorly defined similarities and nosology in immunohistopathological and clinical and features.",
"affiliations": "Department of Rheumatology Sudan Medical Specialization Board Khartoum Sudan.;Department of Rheumatology Sudan Medical Specialization Board Khartoum Sudan.;Department of Clinical Medicine Medical and Cancer Research Institute Khartoum Sudan.;Faculty of Medicine University Of Gezira wad Medani Sudan.;Department of Rheumatology Sudan Medical Specialization Board Khartoum Sudan.",
"authors": "Mohammed Niamat Alla|Wigdan|W|;Mohamed Ali Ahmed|Burhan|B|;Adam Essa|Mohammed Elmujtba|ME|https://orcid.org/0000-0002-1050-2771;Abdalla Babker|Atif Elhadi|AE|;Mohammed Elagib|Elnour|E|",
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"doi": "10.1002/ccr3.4967",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4967\nCCR34967\nCase Report\nCase Report\nVesiculobullous disease with Cutaneous Systemic Lupus Erythematosus Treated by Rituximab: A case report\nMOHAMMED NIAMAT ALLA et al.\nMohammed Niamat Alla Wigdan 1\nMohamed Ali Ahmed Burhan 1\nAdam Essa Mohammed Elmujtba https://orcid.org/0000-0002-1050-2771\n2 3 Awadali818@yahoo.com\n\nAbdalla Babker Atif Elhadi 4\nMohammed Elagib Elnour 1 5\n1 Department of Rheumatology Sudan Medical Specialization Board Khartoum Sudan\n2 Department of Clinical Medicine Medical and Cancer Research Institute Khartoum Sudan\n3 Faculty of Medicine Alfashir University Alfashir Sudan\n4 Faculty of Medicine University Of Gezira wad Medani Sudan\n5 Department of Internal Medicine and Rheumatology Omdurman Military hospital Khartoum Sudan\n* Correspondence\nMohammed Elmujtba Adam Essa, Department of Clinical Medicine, Medical and Cancer Research Institute, Nyala, Sudan.\nEmail: Awadali818@yahoo.com\n\n15 10 2021\n10 2021\n9 10 10.1002/ccr3.v9.10 e0496705 10 2021\n23 9 2021\n06 10 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ 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.\n\nAbstract\n\nVesiculobullous lesions in systemic lupus erythematosus (SLE) are a rare cutaneous manifestation of cutaneous and/or systemic LE with variable presentation. The diagnosis of SLE‐associated vesiculobullous diseases remains challenging, due to the poorly defined similarities and nosology in immunohistopathological and clinical and features.\n\nVesiculobullous lesions in systemic lupus erythematosus (SLE) are a rare cutaneous manifestation of cutaneous and/or systemic LE with variable presentation. The diagnosis of SLE‐associated vesiculobullous diseases remains challenging, due to the poorly defined similarities and nosology in immunohistopathological and clinical and features.\n\noral ulceration\nrituximab\nsystemic lupus erythematosus\nvesiculobullous\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:15.10.2021\nMohammed Niamat Alla W , Mohamed Ali Ahmed B , Adam Essa ME , Abdalla Babker AE , Mohammed Elagib E . Vesiculobullous disease with Cutaneous Systemic Lupus Erythematosus Treated by Rituximab: A case report. Clin Case Rep. 2021;9 :e04967. 10.1002/ccr3.4967\n\nFunding information\n\nNo fund has been received\n==== Body\npmc1 INTRODUCTION\n\nSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation, vesiculobullous (VB) is different groups of oral disorders characterized by the formation of bullae. The aim of this report is to describe a case of a VB in SLE. A 43‐year‐old Sudanese housewife presented to our unit with recurrent painless oral ulceration associated with joints pain, morning stiffness, and generalized fatigue. She was diagnosed with SLE a year ago, and for which she is taking prednisolone, hydroxychloroquine (HCQ), and azathioprine. She also developed left side weakness of sudden onset. Immunological and radiological investigations showed a diagnosis of VB. The patient received hydrocortisone, pantoprazole, paracetamol, mebo cream, fusiderm cream, B.protien powder, metronidazole, ceftriaxone, flucloxacillin and Tonics, and IV Immunoglobulin (IVIM). Although her condition was not well improved. A week later rituximab has been administrated and the patient showed a dramatic response to it. Now she is on regular follow‐up. In conclusion, a middle age female diagnosed with SLE presented with joint pain and features suggested a diagnosis of VB, she received the regiment treatment but her condition was refractory hence treated with rituximab.\n\nSLE is an autoimmune condition with a variable range of clinical features from skin disease to systemic involvement. 1 , 2 VB diseases are a distinct group of oral disorders characterized by the formation of vesicles or bullae. 3 Bullous systemic lupus erythematosus (BSLE) is a rare blistering condition that mainly happens in females, 4 the incidence of SLE is about 1 to 10/100,000 annually, and its prevalence is around 6–130/100,000. 5 Approximately 60%–85% of SLE patients have cutaneous involvement; however, near 5% may develop vesiculobullous lesions, which occur in the form of bullae, vesicles, erosions, and sometimes crusts. 6\n\nBSLE is marked by the rapid and widespread progress of tense bullae and vesicles over erythematous macules or plaques. Preferential sites are as follows: proximal superior limbs, superior trunk, and the face. Mucosal involvement is common in the laryngeal, pharyngeal, perioral, and genital areas. The lesions usually develop with no scarring, but hyper or hypochromia can occur. 7 Here, we believed that this case report will receive the most attention from Sudanese clinicians and rekindle knowledge and awareness in regard to vesiculobullous disease in a patient who is known to be suffering from SLE.\n\n2 CASE REPORT\n\nA 43‐year‐old Sudanese housewife, presented on June 2021 at Omdurman military hospital, Khartoum, Sudan. With recurrent painless oral ulceration (Figure 1) for the last 2 years associated with joints pain affecting the metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), wrist joint of both hands, morning stiffness lasting for more than an hour, and generalized fatigue. Although she has no skin rash, genital ulcers, muscle pain, dry eye, or mouth. In September 2020, she was diagnosed with SLE based on her clinical presentation and the positive finding of ANA profile which was strongly positive for Ribonucleoproteins Abs (RNP), anti‐Smith Abs(Sm), anti‐Ribosomal Proteins Abs, (Ribp) and microalbuminuria. For which, Prednisolone 20 mg, hydroxychloroquine (HCQ) 200 mg, and azathioprine 50 mg were prescribed. Two months later, after the oral ulceration minimally improved new lesions in form of macular rash with vesicle and blister start to appear in her mouth, face, trunks, upper and lower limbs (Figure 2). When the blister is ruptured they lifted a hyper and hypopigmentation mark without scarring. During this period, she lost considerable weight and has a fever, hair loss, and headache. The patient has been referred to the dermatology department, in which a blood test for vitamin b12 level and desmoglein 1 and 3 were ordered, and their result was normal; therefore, topical treatments were prescribed without a clear diagnosis. After 5 months, the patient developed left side weakness of sudden onset. Although her cardiovascular, respiratory, gastrointestinal, and genitourinary systems were unremarkable. She has no history of any neurological disease, diabetes, or hypertension. She has a family history of SLE related to her sister. Her clinical examination upon admission showed generalized thin‐walled bullae, some of them are hemorrhagic with erythematous macule and area of hyper and hypopigmentation; however, no evidence of active synovitis was detected. Central nervous system examination showed no sign of meningism or cranial nerve involvement, she was conscious, oriented with Glasgow Coma Scale (GCS) 15/15. The left side of her body revealed an increased tone and reflex, power grade three with an upgoing plantar reflex, and a normal right side. Full workup was done showed low hemoglobin, high erythrocyte sedimentation rate (ESR), and C reactive protein 13, Normal urine analysis without active sediment, renal profile, liver profile, Vitamin B12 level, Antiphospholipid antibodies, chest X‐ray, echocardiography, electrocardiograph, viral screening, and lipid profile were all normal. Antinuclear antibody (ANA) profile showed strong positive (RNP/Sm ab, Sm ab, anti‐ RibP ab), urine for albumin/creatinine ratio was 9.6 mg/mmol (microalbuminuria), Complement 3 (C3) and Complement 4 (C4) were low. Desmoglien1 Abs is 16, desmoglein 3 Abs is 18. Based on the clinical and laboratory investigation, a diagnosis of vesiculobullous disease with SLE was established. The patient received Hydrocortisone intravenously (IV) 100 mg, Pantoprazole 40 mg IV, Paracetamol 1 g iv along with Mebo cream, fusiderm cream and B.protien powder, Metronidazole 500 mg iv, Ceftriaxone 1 gm, flucloxacillin and Tonics, and IVIM 4 mg/KG/day for 3 days. Her condition was improved partially However, bullous formation still continues to appear, hence, rituximab 500 mg/weekly for 4 weeks has been administrated followed by mycophenolate mofetil 500 mg BD. A few days later, the patient discharge with marked response to the treatment (Figure 3). Now she is on regular follow‐up.\n\nFIGURE 1 Showed the oral ulcer\n\nFIGURE 2 Showed tense bullae over erythematous macules\n\nFIGURE 3 Showed linear tense bullae of varying sizes over erythematous macules and plaques, A: showed the bullae before treatment, B: during treatment, C: after rituximab administration\n\n3 DISCUSSION\n\nA vesiculobullous disease is a rare autoimmune blistering disease that commonly occurs as tense bullae with or without vesicles in patients with SLE. 8 Due to the rarity of the condition, his epidemiology data are restricted, however, some reports showed an incidence of 3.4/million/year. The incidence of this disease with SLE is about 1%. As the knowledge about it is mainly based on case series or reports. 7 , 9 Patients with the vesiculobullous disease usually present with clinical features of SLE, the blisters mainly occur on the oral mucosa, neck, face, and upper extremities. 10 All the reported cases indicated these bullae were mostly triggered by sun exposure, they were also tense and heal with no scarring. 8 This is a classical presentation of our reported case as it is already diagnosed with SLE, the bullae occurred on the mouth, face, neck, and extremities. It was tense and was healed without any scars behind.\n\nThe pathophysiology of VB is mostly multifactorial, which includes environmental triggers, genetic predisposition, and ultraviolet aggravation leading to adaptive and innate immune response. 11 Activation of the immune system leads to the activation of self‐antigen‐specific T cells, autoreactive cytotoxic T lymphocytes from dermal autoantibody deposition cause hydropic degeneration of the basal‐cell layer of the epidermis and apoptotic keratinocytes. 12 The diagnosis of VB diseases should be done according to immunological, histopathological, and clinical grounds. Mucosal disorder and bullae can be diagnosed from clinical examination and brief history. The histopathology commonly shows sub‐epidermal bullae with neutrophil‐predominant inflammatory infiltrate below the bullae formation. Also, microabscesses can be present in the dermal papillae is also frequent. 13 Immunological assay for VB mainly can be done by detecting high desmoglein antibodies (DSG), DSG2 was found in all desmosome‐possessing tissues, such as nonepithelial myocardium; however, the expression of DSG1 and DSG3 was mainly limited to the epidermis and mucosa. 14 DSG delivered insight into the pathophysiology of a more common disease, bullous as well as the associated disease. 15 In our patient, both DSG1 and DSG2 were significant to the diagnosis. The erosions and blisters are formed by circulating immunoglobulin (IgG) autoantibodies against DSG1 and DSG3, adhesion molecules in desmosomes that have an essential role in the cohesion between keratinocytes. 16 The first treatment of autoimmune bullous diseases is systemic corticosteroids in combination with other immunosuppressants drugs to decrease autoantibody production. 17 In most patients, this course of treatment is effective; however, in refectory cases, more targeted drugs against autoantibody production such as rituximab are used. 18\n\nLimitation of the study: In this report, the patient refused to undergo though the tissue biopsy procedure, so the diagnosis was mainly based on immunological assay and clinical ground.\n\nIn conclusion, a middle‐aged Sudanese woman with SLE, presented with painless oral ulcer and joint pain for the last 2 years during the treatment she developed vesicles and blisters in most of her body part, clinical and immunological investigation revealed a diagnosis of VB associated with SLE, the patient received regiment treatment of steroids but her condition not improved, then rituximab has been used, which showed good response. Rituximab is a monoclonal antibody against CD 20, has been reported to be effective in refractory VD, is act through deplete antibody‐producing B cells a standard dose of it has been shown to offer long‐term efficacy in patients with refractory VD. 6 At present, there is no officially approved indication for rituximab in dermatologic conditions, although the drug is included as a treatment option for certain dermatological diseases when conventional treatment has not been effective. 16\n\nCONFLICT OF INTEREST\n\nNone.\n\nAUTHOR CONTRIBUTION\n\nAll authors contributed equally.\n\nETHICS APPROVAL AND CONSENT TO PUBLISH\n\nObtained.\n\nCONSENT\n\nObtained.\n\nACKNOWLEDGEMENT\n\nThe case was diagnosed and treated in Dr Elnour Mohammed Elagib rheumatologies unite at Omdurman Military hospital, Khartoum, Sudan.\n\nDATA AVAILABILITY STATEMENT\n\nAll the data used in the study are available from the first and corresponding author on reasonable request.\n==== Refs\nREFERENCES\n\n1 Manson JJ , Rahman A . Systemic lupus erythematosus. Orphanet J Rare Dis. 2006;1 :6. PubMed PMID: 16722594. Pubmed Central PMCID: PMC1459118.16722594\n2 Cojocaru M , Cojocaru IM , Silosi I , Vrabie CD . Manifestations of systemic lupus erythematosus. Maedica (Bucur). 2011;6 (4 ):330‐336. PubMed PMID: 22879850. Pubmed Central PMCID: PMC3391953.22879850\n3 Jayasri krupaa R , Balachander N , Janani S , Leena sankari S . Diagnosis of vesicullo bullous lesions‐simplified. Biomed Pharmacol J. 2016;9 (3 ):1063‐1066.\n4 Nico MM , Lourenço S . Multiple blisters along the lip vermilion are a clue to bullous lupus erythematosus. Acta Derm Venereol. 2012;92 (4 ):404‐405. PubMed PMID: 22293956.22293956\n5 Pons‐Estel GJ , Salerni GE , Serrano RM , et al. Therapeutic plasma exchange for the management of refractory systemic autoimmune diseases: report of 31 cases and review of the literature. Autoimmun Rev. 2011;10 (11 ):679‐684. PubMed PMID: 21569864.21569864\n6 Contestable JJ , Edhegard KD , Meyerle JH . Bullous systemic lupus erythematosus: a review and update to diagnosis and treatment. Am J Clin Dermatol. 2014;15 (6 ):517‐524. PubMed PMID: 25358414.25358414\n7 Padrao EMH , Teixeira LF , Maruta CW , et al. Bullous systemic lupus erythematosus ‐ a case report. Autopsy Case Rep. 2019;9 (1 ):e2018069. PubMed PMID: 30863736. Pubmed Central PMCID: 6394362.\n8 Torres Saavedra FA , Campo LR , Mendez MV , et al. Bullous lupus as the first manifestation of systemic lupus erythematosus in the pediatric population: a diagnostic challenge in daily practice. Lupus. 2020;29 (14 ):1937‐1942. PubMed PMID: 32842868.32842868\n9 Elqatni M , Qacif H , Zyani M , Amezyane T , Ghafir D . Bullous systemic lupus erythematosus. Presse Medicale. 2018;47 (2 ):190‐191. PubMed PMID: 29478791.\n10 Lourenço DMR , Cunha Gomes R , Aikawa NE , Campos LMA , Romiti R , Silva CA . Childhood‐onset bullous systemic lupus erythematosus. Lupus. 2014;23 (13 ):1422‐1425. PubMed PMID: 25074872.25074872\n11 Hejazi EZ , Werth VP . Cutaneous lupus erythematosus: an update on pathogenesis, diagnosis and treatment. Am J Clin Dermatol. 2016;17 (2 ):135‐146. PubMed PMID: 26872954.26872954\n12 Achtman JC , Werth VP . Pathophysiology of cutaneous lupus erythematosus. Arthritis Res Ther. 2015;17 :182. PubMed PMID: 26257198. Pubmed Central PMCID: 4530484.26257198\n13 Lewis D , Logas DB , Wojciechowski J , Friberg C . Bullous eruption in a patient with systemic lupus erythematosus. J Am Acad Dermatol. 1998;38 (6 Pt 1 ):1013‐1014. PubMed PMID: 9632025.\n14 Schäfer S , Koch PJ , Franke WW . Identification of the ubiquitous human desmoglein, Dsg2, and the expression catalogue of the desmoglein subfamily of desmosomal cadherins. Exp Cell Res. 1994;211 (2 ):391‐399. PubMed PMID: 8143788.8143788\n15 Stanley JR , Amagai M . Pemphigus, bullous impetigo, and the staphylococcal scalded‐skin syndrome. N Engl J Med. 2006;355 (17 ):1800‐1810. PubMed PMID: 17065642.17065642\n16 Kurihara Y , Yamagami J , Funakoshi T , et al. Rituximab therapy for refractory autoimmune bullous diseases: a multicenter, open‐label, single‐arm, phase 1/2 study on 10 Japanese patients. J Dermatol. 2019;46 (2 ):124‐130. PubMed PMID: 30585649.30585649\n17 Fardet L , Flahault A , Kettaneh A , et al. Corticosteroid‐induced clinical adverse events: frequency, risk factors and patient's opinion. Br J Dermatol. 2007;157 (1 ):142‐148. PubMed PMID: 17501951.17501951\n18 Eisenberg R , Looney RJ . The therapeutic potential of anti‐CD20 \"what do B‐cells do?\". Clin Immunol. 2005;117 (3 ):207‐213. PubMed PMID: 16169773.16169773\n\n",
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"title": "Vesiculobullous disease with Cutaneous Systemic Lupus Erythematosus Treated by Rituximab: A case report.",
"title_normalized": "vesiculobullous disease with cutaneous systemic lupus erythematosus treated by rituximab a case report"
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"abstract": "Membranous glomerulonephritis is the most common glomerular disease in adults. Its primary form has been characterized with formation of phospholipase A2 receptor antibodies. Malignancy, infections, and autoimmune disorders are the most common causes of secondary membranous glomerulonephritis. We present a case of a 55-year-old African American female who presented with nephrotic range proteinuria and diagnosed with secondary membranous glomerulonephritis based on distinct pathological features on kidney biopsy and absence of serum phospholipase A2 receptor antibodies. She initially underwent extensive workup for malignancies, infections, and common autoimmune disorders which were all negative. Her proteinuria remained resistant to steroid treatment and she was treated with subcutaneous adrenocorticotropic hormone injections. Meanwhile, she was also diagnosed with the anti-muscle specific kinase antibody variant of myasthenia gravis. In literature, there are few case reports of myasthenia gravis as a cause of secondary membranous glomerulonephritis. In our case, the lack of other inciting factors also suggested this association.",
"affiliations": "Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.",
"authors": "Hanna|Ramy M|RM|https://orcid.org/0000-0003-1807-8909;Arman|Farid|F|;Selamet|Umut|U|;Wallace|William D|WD|;Barsoum|Marina|M|;Rastogi|Anjay|A|;Nobakht|Niloofar|N|;Shieh|Perry|P|",
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"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1986976410.1177_2050313X19869764Case ReportSecondary membranous nephropathy in a patient with myasthenia gravis without thymic disease, and partial remission induced by adrenocorticotropic hormone therapy https://orcid.org/0000-0003-1807-8909Hanna Ramy M 12Arman Farid 1Selamet Umut 1Wallace William D 3Barsoum Marina 1Rastogi Anjay 1Nobakht Niloofar 1Shieh Perry 41 Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA2 Division of Nephrology, Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA, USA3 Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA4 Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USARamy M Hanna, Division of Nephrology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 700 Tiverton Avenue, Los Angeles, CA 90095, USA. Email: Rhannamd81@yahoo.com08 8 2019 2019 7 2050313X198697648 2 2019 23 7 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Membranous glomerulonephritis is the most common glomerular disease in adults. Its primary form has been characterized with formation of phospholipase A2 receptor antibodies. Malignancy, infections, and autoimmune disorders are the most common causes of secondary membranous glomerulonephritis. We present a case of a 55-year-old African American female who presented with nephrotic range proteinuria and diagnosed with secondary membranous glomerulonephritis based on distinct pathological features on kidney biopsy and absence of serum phospholipase A2 receptor antibodies. She initially underwent extensive workup for malignancies, infections, and common autoimmune disorders which were all negative. Her proteinuria remained resistant to steroid treatment and she was treated with subcutaneous adrenocorticotropic hormone injections. Meanwhile, she was also diagnosed with the anti-muscle specific kinase antibody variant of myasthenia gravis. In literature, there are few case reports of myasthenia gravis as a cause of secondary membranous glomerulonephritis. In our case, the lack of other inciting factors also suggested this association.\n\nNephrologyneurologyproteinuriamyasthenia gravissecondary membranous glomerulonephritisadrenocorticotropic hormonerituximabcover-dateJanuary-December 2019\n==== Body\nIntroduction\nMembranous glomerulonephritis (MGN) can be a primary condition or secondary to various exposures with each type having distinct pathological features. Secondary MGN can be associated with malignancy as well as other autoimmune, infectious, and drug-related exposures (such as non-steroidal anti-inflammatory drugs (NSAIDs) and interferon).1–4 Clinically, both primary and secondary MGN are typified by high-grade proteinuria and a nephrotic presentation though hematuria may rarely be seen along with severe proteinuria. Severe hypoalbuminemia and increased risk of venous thromboembolism are hallmarks of MGN due to loss of small proteins and peptides that regulate the clotting cascade.5\n\nPrimary MGN is associated with anti-phospholipase A2 receptor (PLA2R) antibodies and IgG4 antibody deposition, while secondary disease presents mesangial deposits and IgG1 subtype of immunoglobulins (Ig) in malignancy and other Ig subtypes in non-malignant secondary MGN.6 Thyroiditis, colitis, syphilis infection, and many types of drug exposures as stated above can be associated with development of secondary MGN. Pathologically, the disease appears similar with spike and ball pattern of antibody deposition along epithelial cells on electron microscopy, granular IgG immunofluorescence, and thickened glomerular basement membrane (GBM) on light microscopy.1–4 Anti-PLA2R can usually be detected on renal biopsy and serologically in 70% of primary MGN cases, and anti-thrombospondin domain type 1–containing 7a (Anti-THSD7A) is present in 10% of cases without anti-PLA2R. Primary MGN cases do not usually include mesangial deposits, which is a feature of secondary presentations of MGN.7\n\nMyasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that can be associated with various immunological disorders. Recent evidence supports the association between nephropathy and thymic diseases (thymoma, thymic hyperplasia, and MG). Minimal change disease (MCD) has been reported most often with a few reported cases of secondary MGN seen in association with MG.8 Here, we report a rare case of combination of MG with secondary membranous nephropathy.\n\nCase report\nOur case is 56-year-old female with a past medical history significant for squamous cell carcinoma of the cervix for which she had partial hysterectomy in 2000, and vaginal cancer in 2006 treated with radiation, presented with a new-onset high-grade proteinuria (13 g/day on 24-h urine) and up to 11.8 g urine protein/g creatinine on urine protein to creatinine ratio. She also clinically manifested with anasarca, hypoalbuminemia (albumin: 2.1 g/dL) and hyperlipidemia (low-density lipoprotein (LDL): 379 mg/dL) since September 2016, all consistent with nephrotic syndrome.\n\nClinically, the patient reported diplopia, weakness, and a decrease in exercise tolerance about at about the time of presentation (September 2016). She had been an avid marathon runner prior to presentation in 2016, and now she reported hardly being able to run a mile or walk briskly. She had intact renal function at the time of the presentation with serum creatinine of 70.72 µmol/L (0.8 mg/dL) and blood urea nitrogen (BUN) of 4.64 µmol/L (13 mg/dL) but significant proteinuria warranted a renal biopsy while initial serology workup was pending. Patient had renal biopsy on October 2016 with a pathology report that showed secondary membranous nephropathy. The specimen was sent for PLA2R immunofluorescence testing. Initial serology workup showed positive a low-titer positive ANA (antinuclear antibody) of 1:80, a low-titer positive anti-dsDNA at 1:282 IU(international units)/mL, with normal 171 mg/dL C3 and 36 mg/dL C4, high erythrocyte sedimentation rate (ESR) (121 mm/h), normal thyroid-stimulating hormone (TSH), negative HIV abs and negative Hepatitis B surface Abs and Antigens, and negative rheumatoid factor (RF). Serological testing for Anti-PLA2R and Anti-THSD7A both returned as negative as well.\n\nThe patient was started on Furosemide 40 mg twice daily, Pravastatin, Ergocalciferol 50,000 units orally weekly (for low vitamin D level), Losartan 25 mg daily, Aspirin 325 mg (after she has done the renal biopsy) because of the risk of hypercoagulation, and was instructed to be on low salt diet.\n\nThe patient obtained a PET-CT (positron emission tomography–computed tomography) scan from the skull base to the mid-thighs that revealed enlarged left axillary lymph node (24 × 16 mm) that is amenable to US-guided percutaneous biopsy, enlarged left subpectoral lymph node, multiple retroperitoneal/left para-aortic nodes, left common iliac lymph nodes/left internal iliac lymph nodes. The lymph node biopsy was negative for lymphoma and only showed the rest of the serology workup such as anti-neutrophil cytoplasmic antibody (ANCA), anti-phospholipid antibody (APLS), anti-cardiolipin (anti-CL) antibody, scleroderma antibodies (SSA/SSB), and anti-GBM antibodies were all negative.\n\nThe immunofluorescence staining of the renal biopsy specimen for PLA2R revealed no glomeruli are present on the section stained for PLA2R (inconclusive result); however, the presence of mesangial deposits in the biopsy suggested secondary MGN which was due to relapsing malignancy or an associated autoimmune condition. The immunofluorescence showed IgG and C3, but did not show the “full house” pattern of C3, C1q, IgM, IgG, IgA, excluding a diagnosis of membranous lupus nephritis. See Figure 1 for summary of slides and findings suggesting secondary MGN.\n\nFigure 1. Renal biopsy slides showing secondary glomerulonephritis: (a) light microscopy showed glomerulus with normal size and cellularity. Basement membrane spikes are not observed, consistent with early stage membranous nephropathy (Jones methenamine silver stain; original magnification 600×). (b) Immunofluorescence showed granular capillary wall staining for IgG at 2+ intensity (IgG direct immunofluorescence stain; original magnification 400×). (c) Electron microscopy demonstrated glomerular capillary with numerous small subepithelial electron-dense immune complex deposits (arrows) adjacent to occasional, very small, spikes of basement membrane material (Electron microscopy study; original magnification 5000×). (d) Electron microscopy demonstrating mesangial deposits (white arrow) (Electron microscopy study; original magnification 5000×).\n\nSince symptoms and serologies for systemic lupus were negative, and given the lymphadenopathy on PET-CT scan, concerns of relapsing malignancy were raised. Cancer surveillance testing was needed which included biopsy of the FDG-avid L.N, mammography, colonoscopy and bone marrow aspiration.\n\nOn 9 January 2017, CT-guided biopsy was done; bone marrow aspiration was done on 24 March 2017; and beside mammography and colonoscopy, all revealed no signs of malignant relapse. Meanwhile, the dose of Losartan was increased and she was switched from furosemide to bumetanide as the latter had longer half-life.\n\nSince May 2017, the patient started to feel more and more fatigued with complaints of weak nasal voice, and on June 2017, the patient started to note episodes of diplopia. According to the patient, she had the first episode of vertical diplopia in 2000 that lasted for few weeks and disappeared with few flares over the last 17 years but the most recent one was on June 2017.\n\nShe was referred to a neurologist for full neurological evaluation and was started on prednisone 60 mg with plans to switch to ACTHAR® (repository corticotropin injection). The steroid was tapered off, and on August 2017, the patient started ACTHAR® with plans of 6–12 months treatment course with slow titration once proteinuria is controlled. On September 2017, the neurological assessment revealed MG with negative anti-acetylcholinesterase receptor antibodies but positive anti-muscle specific kinase (anti-MuSK) antibody and positive repetitive nerve stimulation (RNS) testing. While a RNS test was reported as positive in charting, the tracings were not immediately available to us. Anti-titin antibody was not specifically tested in this workup, but anti-LDL receptor-related protein 4 (LRP4) is negative. JC virus testing to look for an alternate diagnosis, like progressive multifocal leukoencephalopathy (PML), importantly, was negative. MG grading clinically fluctuated between class IIa and IIb by the Myasthenia Gravis Foundation of America (MGFA) classification.\n\nShe had no bulbar symptoms, no trouble with speech or respiratory distress, and no extremity weakness in the past either. ACTHAR® was tapered off gradually with a switch to rituximab for anti-MuSK MG. B cell depletion has resulted in marked remission of her neurological symptoms due to MG as well as of her proteinuria.\n\nWith this regimen of treatment, the patient has showed a remarkable remission clinically and with the level of proteinuria (from 13 g/day at the time of presentation to 0.59 g/day). While albumin rose to 2.9 g/L on adrenocorticotropic hormone (ACTH), after rituximab, it nearly normalized to 3.7 g/L. After stopping ACTH, urine protein to creatinine level increased to 5.4 g protein/g creatinine (UPC) only to enter complete remission after treatment with rituximab. See Figure 2 for graph of urine protein to creatinine ratio and onset of symptoms, start and stop of corticosteroid treatment, trend of proteinuria in response to ACTH treatment, and start date of rituximab (4 April 2018).\n\nFigure 2. Graph of urine protein to creatinine ratio trend (g protein/g creatinine): black arrow shows start of symptoms of weakness and diplopia in September 2016 near initial diagnosis of nephrotic syndrome. Red arrow and line represent the initiation and duration of corticosteroid therapy (high dose 1 g/kg), and therapy end is denoted by end of red line. Green arrow and line indicate the start of adrenocorticotropic hormone therapy (ACTHAR©), 80 units twice a week dose, and therapy end is denoted by end of green line. Blue arrow and line indicate start of 0.375 g/m2 of body surface area (BSA) rituximab infusions weekly for a total of four infusions.\n\nDiscussion\nMGN is a common cause of nephrotic syndrome in non-diabetic adults.9 It usually occurs as idiopathic disease (primary MGN) due to kidney-limited autoimmune disorder.10 It is characterized by GBM thickening without prominent hypercellularity, and the presence of subepithelial electron-dense deposits.11\n\nA large percentage of membranous nephropathy cases are, however, secondary to systemic autoimmune diseases such as systemic lupus erythematosus (SLE), infections, and the use of certain drugs (NSAIDs).10 The mechanism by which the subepithelial deposits form in secondary MGN is not very clear, and can be explained by the deposition of circulating immune complexes in the subepithelial space.10\n\nMG is rarely associated with nephropathy.12 In some cases of nephrotic syndrome, the mechanism is an imbalance between T helper cells class 1 and 2.13 In MG, T cell dysfunction leads to the production of lymphokine, which increases the permeability of GBM.14 Evidence supporting the association between nephropathy and thymic disease (thymoma, thymic hyperplasia, and MG) is growing, in which MCD is being the most common among other nephropathies.15–25\n\nClinically, distinguishing between primary and secondary MGN is of absolute importance, since therapy in the secondary MGN must be directed at the underlying cause, and some of the treatments for idiopathic MGN, like calcineurins (CNIs), are potentially toxic to the kidney.9\n\nDifferentiating idiopathic MGN from secondary MGN, especially in elderly patients in whom malignancies tend to occur, necessitates the need for an accurate biomarker to use for differentiation.15,17 Studies have showed that the M-type PLA2R, a 185-kDa type I transmembrane glycoprotein expressed on glomerular podocytes, is the main target of autoantibodies in idiopathic MGN.16 Subepithelial deposits form as antibodies bind to a membrane-based antigen and complement.9,10\n\nThe finding of mesangial deposits in our case raised the possibility of a secondary form of MGN. The specimen obtained from the renal biopsy was sent for PLA2R immunofluorescence testing to differentiate primary from secondary MGN which was non-conclusive, but subsequent serological testing for serum-anti-PLA2R was negative, supporting the diagnosis of a secondary membranous nephropathy. It is not impossible that the patient had an atypical form of primary MGN with a non-PLA2R IgG4 type antibody, but the findings of mesangial deposits in primary glomerulonephritis are rare, and the concomitant diagnosis of an autoimmune anti-MuSK MG is highly unusual. A unifying diagnosis of secondary MGN with appropriate mesangial deposition associated with a clinically concomitant diagnosis of anti-MuSK MG is more likely and more elegant.\n\nSince the patient had no systemic manifestations of active SLE like joint pain, rash, oral ulcers and fever and the repeat ANA and anti-dsDNA were negative, the probability of lupus nephritis grade V was eliminated. Given her lymphadenopathy on PET-CT scan, concerns of relapsing malignancy were raised and cancer surveillance testing was needed which included biopsy of the FDG-avid L.N, mammography, colonoscopy and bone marrow aspiration.\n\nIn our case, the patient was started on prednisone and then switched to ACTHAR® (with a plan of 6–12 months of treatment) since steroids alone are not affective and ACTHAR® has been studied and was considered a safer alternative to CNI inhibitors and alkylating agents with reasonable efficacy in the treatment of membranous nephropathy.\n\nLonger treatment course of ACTHAR® is hoped to induce remission with less risk than CNIs and steroids, rituximab, and certainly alkylating agents, unless renal function deteriorates acutely or proteinuria worsens steadily, then rituximab would be considered. The benefit of therapy using steroids and immunosuppressants suggests that membranous nephropathy is related to the disordered immune system.12 Thymectomy, which is a standard therapy for MG, is still considered as an option for treatment. Thymectomy can be followed by numerous changes in lymphocyte functions which may require several years to be revealed,24 suggesting that careful long-term follow-up for is necessary. Secondary membranous nephropathy can be, rarely, associated with thymic disorders. Therefore, clinicians should keep in mind that association; however, in our case, the symptoms of nephropathy have preceded the diagnosis of MG.\n\nSee Table 1 for previously reported cases of MG with or without thymic disease and glomerular disease.1,8,18,19,22,23,26–39 A newer case report by Bolz et al.40 was added where the MGN could be classified as primary in setting of anti-PLA2R antibody positivity. There are 11 other cases with similar presentation to our currently presented case (total of 12 with current case): nine cases with MG and concomitant MGN and three cases with thymus disease (benign or malignant), MGN, but no active MG. A variety of other nephropathies that present with MG and both benign and malignant thymomas are also listed and totaled 70 cases.\n\nTable 1. Reported cases of thymic disease with or without myasthenia gravis and glomerular disease.\n\nAge\tGender\tMG\tn#\tProteinuria (g)\tThymic disease\tRenal biopsy result\tRef\t\n58\tF\tY\t1\t7.54\tBT\tMCD\t\n22\n\t\n44\tF\tY\t1\tneph\tMT\tMCD\t\n23\n\t\n82\tM\tY\t1\t9.54\tNo\tMCD\t\n3\n\t\n26\tF\tY\t1\tneph\tMT\tMGN\t\n24\n\t\n28\tM\tY\t1\tneph\tNo\tPGN\t\n25\n\t\n30–77\t9M, 12F\tY in 9/21\t21\tavg 12.8\t17 MT, 2 BT, 2 No\t5 MGN, 10 MCD, 3 LGN, 1 ECPGN, 3 FSGS\t\n14\n\t\n49\tF\tY\t1\tneph\tMT\tFSGS\t\n26\n\t\n43\tM\tY\t1\tneph\tBT\tMCD\t\n27\n\t\n47,62\t2F\tN\t2\t12.8, 8.1\t1 MT, 1 BT\tFSGS, MCD\t\n28\n\t\nAvg age: 55.6\t2M, 1F\tY\t3\tneph\t2 MT, 1 BT\t3 MCD\t\n29\n\t\n60,65\t1M, 1F\tN\t2\t10, 13\t2 MT\tMCD, MGN\t\n30\n\t\n37–82\t8F, 9M\tN\t17\tneph\t17 MT\t2 PGN, 1 MGN, 10 MCD, 2 FSGS, 1 no biopsy\t\n30\n\t\n43\tF\tY\t1\t3.6\tNo\tMGN\t\n31\n\t\n30–80\t2M, 1F\tY\t3\t1.5–3.8\t2 BT, 1 No\t2 MGN, ECPGN\t\n7\n\t\n36\tM\tY\t1\t13\tNo\tMPGN\t\n32\n\t\n25\tM\tY\t1\t0.2\tNo\tHSP\t\n33\n\t\n37, 57\t2F\tY\t2\t7, 27\t2 BT\t2 MCD\t\n34\n\t\n30–58\t2M, 1F\tY\t3\t0.5–1.5\t1 BT, 1 No\t3 IgA Neph\t\n35\n\t\n48–64\t2F, 1M\tY\t3\t10.5–23.7\t3 BT\tFPGN, FSGS, MCD\t\n36\n\t\n56\tM\tN\t1\tneph\tMT\tMCD\t\n37\n\t\n35\tM\tY\t1\tneph\tMT\tMCD\t\n38\n\t\n42\tM\tY\t1\t22.3\tNo\tMGN\t\n40\n\t\n55\tF\tY\t1\t13\tNo\tMGN\tCC\t\nAvg: average; BT: benign thymoma; CC: current case; F: female; ECPGN: extra-capillary proliferative glomerulonephritis; FPGN: focal proliferative glomerulonephritis; FSGS: focal segmental glomerulosclerosis; g: gram; HSP: Henoch–Schonlein Purpura; IgA Neph: IgA nephropathy; LGN: lupus glomerulonephritis; M: male; MCD: minimal change disease; MG: myasthenia gravis; MGN: membranous glomerulonephritis; MPGN: membrano-proliferative glomerulonephritis, MT: malignant thymoma; N: no; n#: number of patients; neph: nephrotic range proteinuria (no amount specified); PGN: proliferative glomerulonephritis; Ref: reference; Y: yes.\n\nConclusions\nWe report a rare coexistence of autoimmune anti-MuSK MG and secondary MGN as defined by negative serologies and mesangial deposits on biopsy.\n\nThere have been cases reported with a primary MGN and MG as defined by the presence of anti-PLA2R and -THSD7 antibodies as well.40\n\nTreatment of anti MuSK MG resulted in concomitant resolution of proteinuria.\n\nSecondary MGN can be due to autoimmune disease, not just malignancy, and treating concomitant autoimmune disease can result in a complete remission of proteinuria.\n\nAuthors’ Note: Authors confirm that this work contains no human research material. Patient agreed to publication of this report and provided documented written consent under condition of anonymity, with no publication of identifiable patient information. Ramy M Hanna is also affiliated with Division of Nephrology, Department of Medicine, UCI school of Medicine, Irvine, California.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Ramy M Hanna \nhttps://orcid.org/0000-0003-1807-8909\n==== Refs\nReferences\n1 \nIllies F Wingen AM Bald M et al \nAutoimmune thyroiditis in association with membranous nephropathy . 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"journal": "SAGE open medical case reports",
"keywords": "Nephrology; adrenocorticotropic hormone; myasthenia gravis; neurology; proteinuria; rituximab; secondary membranous glomerulonephritis",
"medline_ta": "SAGE Open Med Case Rep",
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"pages": "2050313X19869764",
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"pmid": "31448123",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10213666;10361423;10998921;11725628;14960028;15788438;16529002;19571279;19878810;21146128;21629349;22076873;23196599;2325804;2333543;23364518;23580814;25740009;25984023;26092827;26847174;27684864;28072685;29068987;2918953;30107838;3276418;4602050;6444865;6611840;7189201;7351020;7573199;8159312;9430883;9469510;9481441;9563224",
"title": "Secondary membranous nephropathy in a patient with myasthenia gravis without thymic disease, and partial remission induced by adrenocorticotropic hormone therapy.",
"title_normalized": "secondary membranous nephropathy in a patient with myasthenia gravis without thymic disease and partial remission induced by adrenocorticotropic hormone therapy"
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"drugadditional": "3",
... |
{
"abstract": "The emergence of herpes simplex virus (HSV) resistance to aciclovir (ACV) has increasingly been reported among hematopoietic stem cell transplant (HSCT) recipients and often associated with extended ACV prophylaxis.\n\n\n\nBetween June 2011 and June 2019, medical records of 532 HSCT recipients with suspected HSV infection were retrospectively analyzed. HSV-1 and HSV-2 positive samples were identified in 47 and 16 patients respectively. Analysis of HSV resistance to antivirals was performed at the Public Health England reference laboratory in London using phenotypic and/or genotypic resistance assays.\n\n\n\nThe prevalence of ACV-resistant HSV accounted for 17% (8/48) of infected HSV-1 cases. All 8 patients received T-cell depleted allogeneic HSCT for hematological malignancies. Half of these patients were male with a median age was 57.5 years (range; 26-63). Chronic Graft versus Host disease (cGVHD) affected 7 patients before HSV-1 diagnosis. HSV-1 infection developed while receiving either intravenous ACV (n = 2) or oral ACV (n = 6 patients) prophylaxis at a median of 373 [range,18-2183] days post-HSCT. ACV resistance was clinically suspected at a median of 25 [range,16-109] days after initial HSV diagnosis and subsequently laboratory confirmed at a median of 25 (range,10-59) days. All patients presented with hemorrhagic oral mucositis refractory to treatment dose ACV. Foscarnet (FOS) treatment was initiated in all 8 patients (pending laboratory confirmation of ACV resistance) with some effect but associated with significant toxicity burden. Four patients presented again with recurrent HSV infection or no resolution. Three with recurrent HSV died from other causes while suffering from persistent oral HSV lesions.\n\n\n\nA prolonged immunosuppressed state following T-deplete HSCTs alongside extended use of ACV, early onset systemic HSV infection, presence of cGVHD, and treatment toxicities pose a significant challenge to the management of ACV resistant HSV infections and alternative effective antiviral options remains an unmet need in this clinical setting.",
"affiliations": "South London Specialist Virology Centre, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Electronic address: v.anton-vazquez@nhs.net.;Department of Haematology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom.;Virus Reference Department, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom.;Virus Reference Department, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom.;Department of Dermatology, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.;Department of Dermatology, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.;Department of Haematology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom.;Department of Haematology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom.;Department of Haematology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom.;South London Specialist Virology Centre, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; Virus Reference Department, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom.",
"authors": "Anton-Vazquez|Vanesa|V|;Mehra|Varun|V|;Mbisa|Jean L|JL|;Bradshaw|Dan|D|;Basu|Tanya N|TN|;Daly|Marie-Louise|ML|;Mufti|Ghulam J|GJ|;Pagliuca|Antonio|A|;Potter|Victoria|V|;Zuckerman|Mark|M|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcv.2020.104421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "128()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Aciclovir-resistant; Allogeneic; Bone marrow transplant; HSV",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D000998:Antiviral Agents; D016026:Bone Marrow Transplantation; D024882:Drug Resistance, Viral; D005260:Female; D006561:Herpes Simplex; D006801:Humans; D016867:Immunocompromised Host; D008131:London; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014184:Transplantation, Homologous",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "104421",
"pmc": null,
"pmid": "32417677",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Challenges of aciclovir-resistant HSV infection in allogeneic bone marrow transplant recipients.",
"title_normalized": "challenges of aciclovir resistant hsv infection in allogeneic bone marrow transplant recipients"
} | [
{
"companynumb": "GB-OTSUKA-2020_014255",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "There is no consensus on optimal treatment for a chronic subdural hematoma (cSDH). In patients with only moderate symptoms treatment with tranexamic acid (TXA) has been suggested. We report off-label use of TXA in seven patients.\nBetween August 2016 and May 2018 we identified seven patients for primary conservative treatment with TXA until satisfactory clinical and radiological status was achieved. Primary outcome was surgery for cSDH evacuation. Radiological follow-up was performed at regular intervals for hematoma volume measurements.\nFive patients experienced complete resolution of symptoms, one patient had a burr-hole craniostomy five days after initiation of TXA treatment due to an increase of left-sided weakness and dysarthria and in one patient symptoms did not improve. Median follow-up was 15 weeks (range 6-25, without the operated patient). The median total volume before start of treatment was 83 mL (range 11-137) for all patients. At the last follow-up, the median total volume in the non-operated patients decreased by 73% to 33 mL (range 0-77).\nTXA could be considered as primary medical treatment in patients with a cSDH and mild symptoms. The results of current randomized clinical trials must be awaited.",
"affiliations": "Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.;Department of Radiology, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.;Neurosurgical Center Amsterdam, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands.",
"authors": "Lodewijkx|Roger|R|;Immenga|Steven|S|;van den Berg|René|R|;Post|René|R|;Westerink|Lucas G|LG|;Nabuurs|Rob J A|RJA|;Can|Anil|A|;Vandertop|William Peter|WP|;Verbaan|Dagmar|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02688697.2021.1918328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-8697",
"issue": null,
"journal": "British journal of neurosurgery",
"keywords": "Chronic subdural hematoma; neurosurgery; tranexamic acid",
"medline_ta": "Br J Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "8800054",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "34334070",
"pubdate": "2021-08-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tranexamic acid for chronic subdural hematoma.",
"title_normalized": "tranexamic acid for chronic subdural hematoma"
} | [
{
"companynumb": "NL-SA-2021SA268978",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "We report the case of a patient highly susceptible to invasive aspergillosis who received treatment with voriconazole (VRC). As part of therapeutic drug monitoring, VRC plasma trough concentrations were measured, showing undetectable levels (<0.16 µg/ml). Genotyping showed a heterozygous profile CYP2C19*1/*17, known to be associated with an ultrarapid-metabolism phenotype, contributing to the very low systemic exposure observed. Therefore, in this situation, the use of VRC treatment could be associated with therapeutic failure.",
"affiliations": "Infectious Diseases Division, CHU Sainte-Justine - University of Montreal, Montreal, QC, Canada.",
"authors": "Autmizguine|Julie|J|;Krajinovic|Maja|M|;Rousseau|Julie|J|;Théorêt|Yves|Y|;Litalien|Catherine|C|;Marquis|Christopher|C|;Tapiéro|Bruce|B|;Ovetchkine|Philippe|P|",
"chemical_list": "D011743:Pyrimidines; D014230:Triazoles; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.2217/pgs.12.175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "13(16)",
"journal": "Pharmacogenomics",
"keywords": null,
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001228:Aspergillosis; D065731:Cytochrome P-450 CYP2C19; D056726:Genetic Association Studies; D006105:Granulomatous Disease, Chronic; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "1961-5",
"pmc": null,
"pmid": "23215888",
"pubdate": "2012-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pharmacogenetics and beyond: variability of voriconazole plasma levels in a patient with primary immunodeficiency.",
"title_normalized": "pharmacogenetics and beyond variability of voriconazole plasma levels in a patient with primary immunodeficiency"
} | [
{
"companynumb": "CA-AUROBINDO-AUR-APL-2019-019750",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional"... |
{
"abstract": "The aim of the present study was to report an unusual case of multiple lower cranial nerve palsies in a patient with Wegener's granulomatosis (WG) during radiotherapy for glottic cancer. WG is an autoimmune disease characterized by necrotizing granulomas mainly in the upper and lower respiratory tract or kidneys; however, the involvement of cranial nerves is not uncommon. Prior to the use of cyclophosphamide (CYC) the 1-year mortality rate was ~82%; the introduction of rituximab (RTX) has revolutionized the course of the WG, with remission rates comparable to those of CYC and superior effectiveness in relapsing patients. Hypogammaglobulinemia and B-cell depletion are the best known monitored side effects affecting survival due to secondary infections. Immunodepression and relapse with lower cranial nerve palsy have a negative impact on prognosis. We herein present the case of a heavily pre-treated GPA patient with secondary immunosuppression, who underwent radiotherapy for glottic cancer and developed multiple low cranial nerve palsies during treatment, which was interrupted at 60 Gy. The possible related causes and the association between previous immunosuppressive treatments and radiotherapy were also analyzed to elucidate the cause of this complication.",
"affiliations": "Department of Radiation Oncology, S. Giuseppe Moscati Hospital, I-74100 Taranto, Italy.;Department of Radiology, S. Giuseppe Moscati Hospital, I-74100 Taranto, Italy.;Department of Otorhinolaryngology, S. Giuseppe Moscati Hospital, I-74100 Taranto, Italy.;Department of Infectious Diseases, S. Giuseppe Moscati Hospital, I-74100 Taranto, Italy.;Department of Radiation Oncology, S. Giuseppe Moscati Hospital, I-74100 Taranto, Italy.",
"authors": "Lazzari|Grazia|G|;Briatico Vangosa|Alessandra|A|;Assunta De Cillis|Maria|M|;Buccoliero|Giovanni|G|;Silvano|Giovanni|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2018.1748",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "10(1)",
"journal": "Molecular and clinical oncology",
"keywords": "antineutrophil cytoplasmic antibodies; glottic cancer; granulomatosis; rituximab; vasculitis",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "147-152",
"pmc": null,
"pmid": "30680194",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": "11405874;11817605;11870354;15316126;15673799;15851522;16134730;16269425;17299018;17602941;17658554;17937462;18098310;18506734;19446902;19565480;19727846;19797309;20647198;20647199;21083398;21484770;21798892;22569190;22629432;22892236;23045170;23182993;23788974;24265538;24831059;2660645;27733943;28521808;29493730;4748591;8388187;8774975",
"title": "Lower cranial nerve palsy during radiotherapy for glottic cancer in a patient with Wegener's granulomatosis: An interesting case report.",
"title_normalized": "lower cranial nerve palsy during radiotherapy for glottic cancer in a patient with wegener s granulomatosis an interesting case report"
} | [
{
"companynumb": "IT-TEVA-2018-IT-991711",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Carbapenemase-producing Klebsiella pneumoniae is an emerging threat worldwide. The appropriate therapy for infections due to these multidrug-resistant pathogens is not well defined and depends upon the susceptibilities of individual isolates, and the choices are often severely limited. We report a case of a 8-year-old male child with ARDS with left-sided tubercular pleural effusion who developed ventilator-associated pneumonia due to multidrug-resistant Klebsiella pneumoniae treated successfully with a regimen comprising a combination of colistin and double carbapenem.",
"affiliations": "Pulmonary Medicine, Amandeep Medicity Hospital, Amritsar, India. mandeepsingh27@gmail.com.;Pulmonary Medicine, Amandeep Medicity Hospital, Amritsar, India.;Amandeep Medicity Hospital, Amritsar, India.;Amandeep Medicity Hospital, Amritsar, India.",
"authors": "Singh|Mandeep|M|;Kaur|Lakhvir|L|;Bajaj|Renuka|R|;Arodhia|Sumeet|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015780:Carbapenems",
"country": "Poland",
"delete": false,
"doi": "10.5603/ARM.a2020.0195",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2451-4934",
"issue": "89(2)",
"journal": "Advances in respiratory medicine",
"keywords": "Klebsiella pneumoniae; double carbapenem; ventilator associated pneumonia",
"medline_ta": "Adv Respir Med",
"mesh_terms": "D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002648:Child; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007711:Klebsiella pneumoniae; D008297:Male; D053717:Pneumonia, Ventilator-Associated; D016879:Salvage Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101697329",
"other_id": null,
"pages": "203-206",
"pmc": null,
"pmid": "33559119",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Double carbapenem regimen used as salvage therapy to treat multidrug-resistant Klebsiella pneumoniae causing ventilator-associated pneumonia.",
"title_normalized": "double carbapenem regimen used as salvage therapy to treat multidrug resistant klebsiella pneumoniae causing ventilator associated pneumonia"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2021-24866",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional":... |
{
"abstract": "Objective: The study was conducted to summarize the treatment outcomes of newly diagnosed epilepsy (NDE) and analyse the risk factors for refractory epilepsy (RE) in Northeast China. Methods: A total of 466 adult patients with NDE were consecutively enrolled in this programme. Clinical data were collected at baseline and each follow-up. Several scales concerning recognition and mood were also completed at the first visit. Results: Seizure-free status was achieved by 52% (n = 244) of the patients; however, 15% (n = 68) manifested RE. A total of 286 (61%) patients continued with the first ASM as monotherapy, among which 186 (40%) patients became seizure-free. Fifteen (22%) patients with RE became seizure-free following ASM adjustment and 34 patients (14%) had breakthrough seizures after being classified as seizure-free. One patient developed RE after attaining seizure-free status. Breakthrough seizures during the first expected interictal interval [Odds ratio (OR) = 5.81, 95% CI: 2.70-12.50], high seizure frequency at baseline (OR = 1.24, 95% CI: 1.04-1.49), younger age of onset (OR = 1.42, 95% CI: 1.12-1.79), and male sex (OR = 2.64, 95% CI: 1.26-5.53) were risk factors for RE. Significance: Treatment outcomes of the majority of NDE cases are good. New risk factors could help physicians more promptly and accurately identify patients who are likely to develop RE. Seizure-free state is not long enough to commence the withdrawal of ASMs. RE is not permanent and seizure-free may be achieved subsequently by appropriate drug adjustment.",
"affiliations": "DDepartment of Neurology, The First Hospital of Jilin University, Changchun, China.;DDepartment of Neurology, The First Hospital of Jilin University, Changchun, China.;DDepartment of Neurology, The First Hospital of Jilin University, Changchun, China.;DDepartment of Neurology, The First Hospital of Jilin University, Changchun, China.;DDepartment of Neurology, The First Hospital of Jilin University, Changchun, China.",
"authors": "Li|Nan|N|;Li|Jing|J|;Chen|Yanyan|Y|;Chu|Chaojia|C|;Lin|Weihong|W|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2021.747958",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295\nFrontiers Media S.A.\n\n10.3389/fneur.2021.747958\nNeurology\nOriginal Research\nTreatment Outcome and Risk Factors of Adult Newly Diagnosed Epilepsy: A Prospective Hospital-Based Study in Northeast China\nLi Nan 1\n\nLi Jing 1\n\nChen Yanyan 1 2\n\nChu Chaojia 1\n\nLin Weihong 1 *\n\n1DDepartment of Neurology, The First Hospital of Jilin University, Changchun, China\n2Department of Neuroelectrophysiology, Changchun Six Hospital, Changchun, China\nEdited by: Emma Losito, Hôpital Necker-Enfants Malades, APHP, France\n\nReviewed by: Yam Nath Paudel, Monash University Malaysia, Malaysia; Daichi Sone, University College London, United Kingdom\n\n*Correspondence: Weihong Lin linwh@jlu.edu.cn\nThis article was submitted to Epilepsy, a section of the journal Frontiers in Neurology\n\n28 10 2021\n2021\n12 74795827 7 2021\n06 10 2021\nCopyright © 2021 Li, Li, Chen, Chu and Lin.\n2021\nLi, Li, Chen, Chu and Lin\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: The study was conducted to summarize the treatment outcomes of newly diagnosed epilepsy (NDE) and analyse the risk factors for refractory epilepsy (RE) in Northeast China.\n\nMethods: A total of 466 adult patients with NDE were consecutively enrolled in this programme. Clinical data were collected at baseline and each follow-up. Several scales concerning recognition and mood were also completed at the first visit.\n\nResults: Seizure-free status was achieved by 52% (n = 244) of the patients; however, 15% (n = 68) manifested RE. A total of 286 (61%) patients continued with the first ASM as monotherapy, among which 186 (40%) patients became seizure-free. Fifteen (22%) patients with RE became seizure-free following ASM adjustment and 34 patients (14%) had breakthrough seizures after being classified as seizure-free. One patient developed RE after attaining seizure-free status. Breakthrough seizures during the first expected interictal interval [Odds ratio (OR) = 5.81, 95% CI: 2.70–12.50], high seizure frequency at baseline (OR = 1.24, 95% CI: 1.04–1.49), younger age of onset (OR = 1.42, 95% CI: 1.12–1.79), and male sex (OR = 2.64, 95% CI: 1.26–5.53) were risk factors for RE.\n\nSignificance: Treatment outcomes of the majority of NDE cases are good. New risk factors could help physicians more promptly and accurately identify patients who are likely to develop RE. Seizure-free state is not long enough to commence the withdrawal of ASMs. RE is not permanent and seizure-free may be achieved subsequently by appropriate drug adjustment.\n\ndrug resistant epilepsy\nantiseizure medication\nrisk factors\nadult\nnewly diagnosed epilepsy\n==== Body\npmcIntroduction\n\nEpilepsy is a serious neurological disorder that affects more than 70 million people worldwide, ranging from neonates to older adults (1). In China, the number of patients with epilepsy was ~10 million in 2015 (2). Pharmacotherapy is the first choice for controlling epileptic seizures, and the majority of them could be controlled by currently available antiseizure medication (ASM). Refractory epilepsy (RE) is one of the most serious conditions, which affects 30–40% of people with epilepsy (3, 4). After years of multi-drug treatment with limited efficacy, patients with RE face great financial burden and mental pressure that seriously affect their quality of life. In this situation, making a precise diagnosis of RE is critical and would give a chance for appropriate subsequent treatments, such as neurostimulation and surgery. In previous studies (5–7), the diagnostic criteria for RE were inconsistent; thus, it is difficult to compare the conclusions across them. To set up explicit and practical criteria, the International League Against Epilepsy (ILAE) published a new definition of RE (8). That is, the minimum criteria for defining RE, ensuring that less time was wasted in inappropriate pharmacological therapy, thereby improving patient care. However, the definition has not been widely applied to the epidemiologic studies. Finding risk factors according to the new definition could help the physicians more promptly and accurately identify patients who are likely to develop RE.\n\nThis study consecutively enrolled patients with newly diagnosed epilepsy (NDE) at the Epilepsy Diagnosis and Treatment Center of the First Hospital of Jilin University, which is one of the biggest general hospitals in Jilin province, China. We summarized the treatment outcomes of NDE and analyzed the risk factors of RE in Northeast China.\n\nMaterials and Methods\n\nPatient Recruitment\n\nPatients visiting the Epilepsy Diagnosis and Treatment Center of the First Hospital of Jilin University were screened, and the adult patients who were newly diagnosed with epilepsy were consecutively enrolled in this programme between June 2015 and November 2019, and followed up until December 2020.\n\nThe definitions of epilepsy, the classification of seizure, and epileptic syndrome conformed to the diagnostic criteria published by ILAE (9–11). RE is defined as the failure of two tolerated and appropriate ASMs (whether monotherapy or in combination) to achieve sustained seizure-free state (8). The 50% defined daily dose (50% DDD) is considered as the “adequate dose” of each ASM (12). When patients are free from all seizures, including aura, for three times the interictal interval or 1 year (whichever is longer), they can be classified as seizure-free (8, 13). If the two abovementioned definitions cannot be satisfied, the outcome is designated as undetermined. The definition of a patient with NDE used in this study is a person with confirmed epilepsy who had not been diagnosed specifically with epilepsy or treated with ASMs previously.\n\nStudy Procedure\n\nAt their first visit, all the participants underwent a thorough clinical and laboratory investigation, including a 24-h video electroencephalogram (EEG) and 3.0-T high-resolution brain magnetic resonance imaging (MRI). The patients were administered an ASM following the 2012 guidelines of the National Institute for Health and Clinical Excellence (14), starting at a low dose. If the patients with NDE agreed to participate in the programme and signed an informed consent form, a baseline file was completed, which contained demographic, symptomatic and etiologic data, as well as the results of a systematic physical examination, an EEG, and an MRI. The symptomatic data were collected by interviews with the patients or the witnesses to seizure. Participants were then asked to complete a series of scales, including the Montreal cognitive assessment (MOCA), the Generalized Anxiety Disorder 7-item Scale (GAD-7), and the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (c-NDDI-E), to estimate their cognitive function and mood.\n\nThe patients enrolled in the programme were called back for a follow-up visit for treatment adjustments at 1, 3, and 6 months following the treatment and every 6 months thereafter. In cases of seizure recurrence between scheduled appointments, the patient could visit the specialist epilepsy clinics. The second ASM was considered when the first one was ineffective or the patient had intolerable side effects. At every scheduled visit, a follow-up file was completed for all patients, which recorded the patients' seizure types and frequency, the doses of the ASMs administered, and any adverse effects. If a face-to-face visit was inconvenient, the follow-up file would be completed by physicians based on the interviews with patients or caregivers by telephone. Instances of patients withdrawing the ASMs without medical advice were defined as poor compliance. Patients were excluded if the follow-up periods were <12 months. The ASMs were gradually reduced and stopped if the patients had no breakthrough seizure for at least 3 years and the repeated EEG was normal.\n\nStatistical Analyses\n\nStudent's t-test, analysis of variance (ANOVA), Pearson's chi-squared test, the rank-sum test, and Fisher's exact test were used to compare continuous and categorical variables. A survival (Kaplan-Meier) analysis was often used to visually summarize time-to-event data and Log-rank was used to estimate the difference between the groups. Cox regression model analysis was applied to identify the risk factors for retention of the first ASM. Logistic regression was used to analyse the risk factors of RE.\n\nValues for continuous variables are expressed as mean ± standard deviation (SD), and values for categorical variables are expressed as frequencies (%). All p-values were from two-tailed tests. P < 0.05 was considered to indicate statistical significance. The data were inputted by EpiData software (The EpiData Association, Odense, Denmark) and were subsequently analyzed using SPSS for Windows, Version 24.0 (SPSS Inc., Chicago, IL, USA).\n\nEthical Approval\n\nThe protocol for this study was approved by the Ethics Committee of the First Hospital of Jilin University [the approval number: 2017-326] and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Each enrolled patient provided a signed informed consent form before the study began.\n\nResult\n\nDemographic Information\n\nA total of 6,636 people with epilepsy (PWE) who visited the Epilepsy Diagnosis and Treatment Center of the First Hospital of Jilin University were screened, and 466 patients were diagnosed as NDE and enrolled in the programme. The demographic information is shown in Table 1. The median follow-up time was 24 (range, 12–48) months. After treatment adjustments based on the responses to ASMs, 52% (n = 244) of the patients achieved seizure-free status; however, 15% (n = 68) were diagnosed as RE. The others (33%, n = 154) were undetermined (Figure 1). The median duration of treatment before arriving at RE and seizure-free status were 12 (range, 3–36) months and 12 (range, 12–36) months, respectively. About 74% (n = 50) of the patients required at least 12 months before being diagnosed with RE.\n\nTable 1 Demographic data of the patients with newly diagnosed epilepsy, N (%) or mean ± standard deviation.\n\nVariable\tTotal at start\tRefractory epilepsy\tSeizure free\tP-valued\t\n\t(n = 466)\t(n = 68)\t(n = 244)\t\t\nGender\t\t\t\t0.142\t\n Male\t283 (61)\t46 (68)\t141 (58)\t\t\n Female\t183 (39)\t22 (32)\t103 (42)\t\t\nAge of onset, y\t31.2 ± 18.5\t27.4 ± 16.7\t31.4 ± 18.3\t0.093\t\nDuration of disease, y\t3.91 ± 7.69\t4.75 ± 8.75\t3.42 ± 7.10\t0.280\t\nBaseline frequency of seizure per month, median (interquartile range)\t1.00 (2.52)\t2.75 (14.0)\t1.00 (1.50)\t<0.001\t\nLower average income (<160 USD/month)\t61 (13)\t14 (21)\t27 (11)\t0.040\t\nTypes of seizure\t\t\t\t0.089\t\n Focal\t418 (90)\t66 (97)\t215 (88)\t\t\n Generalized\t43 (9.2)\t2 (2.9)\t26 (11)\t\t\n Unknown\t5 (1.1)\t0 (0.0)\t3 (1.2)\t\t\nHistory of status epilepticus\t21 (4.5)\t5 (7.4)\t8 (3.3)\t0.137\t\nEtiology\t\t\t\t0.212\t\n Structural\t96 (21)\t19 (28)\t41 (17)\t\t\n Genetic\t1 (0.2)\t0 (0.0)\t1 (0.4)\t\t\n Infectious\t9 (1.9)\t1 (1.5)\t5 (2.0)\t\t\n Immune\t1 (0.2)\t0 (0.0)\t0 (0.0)\t\t\n Unknown\t359 (77)\t48 (71)\t197 (80)\t\t\nFamily history of epilepsy\t49 (11)\t11 (16)\t24 (9.8)\t0.143\t\nHistory of febrile seizure\t44 (9.4)\t7 (10.3)\t23 (9.4)\t0.671\t\nMOCAa+, score\t24.1 ± 4.62\t24.1 ± 4.58\t24.6 ± 4.24\t0.482\t\nGAD-7b, score\t4.62 ± 4.38\t5.35 ± 4.76\t4.58 ± 4.05\t0.428\t\nc-NDDI-Ec, score\t8.09 ± 3.19\t8.34 ± 3.34\t7.90 ± 3.02\t0.444\t\na MOCA, Montreal cognitive assessment.\n\nb GAD-7, Generalized Anxiety Disorder 7-item Scale.\n\nc c-NDDI-E, Chinese version of the Neurological Disorders Depression Inventory for Epilepsy.\n\nd The p-value between the refractory group and seizure-free group.\n\nFigure 1 Flow diagram of the study.\n\nComparing the demographic data between the RE group and the seizure-free group, patients with RE were inclined to having a lower average income (Z = −1.764, p = 0.078) and younger age of onset (Z = −1.679, p = 0.093). The baseline seizure frequency in the RE group was more than that in the seizure-free group (Z = −3.911, p < 0.001).\n\nResponse to the First ASM\n\nThe first ASMs administrated to the patients are shown in Table 2. The focal seizure was the most common type of seizure and oxcarbazepine was the most commonly used ASM. A total of 370 (79%) patients remained on the first ASM at the last follow-up and 286 (61%) patients remained on the first ASM as monotherapy, among which 186 (40%) patients achieved seizure-free status. Among those who did not reach seizure-free status with the first ASM, 174 patients were treated with monotherapy (100 remaining on the first ASM with increased dosage and 74 switching to another monotherapy) and 102 patients with multiple therapy at the last visit; among these patients, 24% (n = 68) developed RE and 21% (n = 58) were seizure-free. For those who reached seizure-free status with the first ASM, the maintenance doses are shown in Table 2. The median maintenance doses were no more than 50% DDD except for oxcarbazepine. At the 12- and 24-month follow-up, lamotrigine (88 and 82%), levetiracetam (82 and 82%), and oxcarbazepine (84 and 83%) had a higher probability of retention, and topiramate had the lowest probability of retention (56 and 56%, respectively). Carbamazepine, phenobarbital, and other ASM (pregabalin and gabapentin) were excluded from the comparison due to the limited number of patients. The probability of retention of the first ASM is shown in Figure 2. There was a significant difference between the probability of the different types of ASMs (χ2= 17.807, p = 0.001). A total of 183 (39%) patients reduced the dose of the first ASM due to adverse effects, among whom 96 patients withdrew the first ASM. The causes of withdrawal or dose-reduction are shown in Table 3. The objective adverse effects were drowsiness, ataxia, dizziness, headache, memory decline, irritability, weight gain or loss, palpitation, and gastrointestinal complaints, among others.\n\nTable 2 Doses of the first antiseizure medication (ASM) for patients who reached seizure-free status with the first ASM.\n\n\tAt baseline,\tAs the only\tSeizure-free,\tMedian,\tMaximum,\tMinimum,\t\n\tn (%)\tmonotherapy, n (%)\tn (%)\tmg/d\tmg/d\tmg/d\t\nValproic acid\t52 (11)\t20 (7.0)\t14 (70)\t500.0\t750\t400\t\nCarbamazepine\t8 (1.7)\t4 (1.4)\t2 (50)\t500.0\t800\t200\t\nOxcarbazepine\t279 (60)\t186 (65)\t122 (66)\t600.0\t1,200\t240\t\nTopiramate\t19 (4.1)\t5 (1.7)\t2 (40)\t100.0\t125\t50\t\nLevetiracetam\t78 (16.7)\t52 (18)\t37 (71)\t750.0\t1,250\t375\t\nPhenobarbital\t4 (0.9)\t3 (1.0)\t1 (33)\t–\t–\t–\t\nLamotrigine\t24 (5.2)\t17 (6.0)\t8 (47)\t112.5\t150\t100\t\nOthersa\t2 (0.4)\t1 (0.3)\t0 (0.0)\t–\t–\t–\t\na “Others” refers to pregabalin and gabapentin.\n\nFigure 2 Probability of retention of the first antiseizure medication.\n\nTable 3 Causes of withdrawal or dose-reduction of the first antiseizure medication, n (%).\n\n\tAllergy\tIneffective\tLiver damage\tOther objective adverse effects\tPoor compliance\tSeizure-free for 3 y\t\nValproic acid\t3 (9.4)\t9 (28)\t4 (13)\t9 (28)\t8 (19)\t1 (3.1)\t\nCarbamazepine\t0 (0.0)\t0 (0.0)\t1 (25)\t1 (25)\t2 (50)\t0 (0.0)\t\nOxcarbazepine\t19 (19)\t16 (16)\t24 (25)\t28 (29)\t10 (10)\t1 (1.0)\t\nTopiramate\t3 (21)\t2 (14)\t0 (0.0)\t6 (43)\t3 (21)\t0 (0.0)\t\nLevetiracetam\t1 (3.8)\t7 (26)\t7 (26)\t9 (33)\t2 (7.4)\t1 (3.7)\t\nPhenobarbital\t0 (0.0)\t1 (50)\t1 (50)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nLamotrigine\t1 (17)\t3 (50)\t1 (17)\t0 (0.0)\t1 (17)\t0 (0.0)\t\nOthersa\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1 (100)\t0 (0.0)\t0 (0.0)\t\na “Others” refers to pregabalin and gabapentin.\n\nCox regression was used to analyse the influencing factors of the retention of the first ASM. Considering the types of the first ASM, gender, age of onset, average income, disease duration, seizure frequency, and types of seizure at baseline as independent variables in the Cox regression model analysis of the first ASM retention, the hazard ratio (HR) of withdrawal of valproic acid and topiramate were 2.31 [95% confidence intervals (CI): 1.35–3.93] and 2.93 (95% CI: 1.38–6.20), respectively, compared to that of oxcarbazepine.\n\nRisk Factors of Refractory Epilepsy\n\nAt the last visit, 4 (0.9%) patients were receiving no ASM, and 360 (77%), 81 (17%), 18 (4%), and 3 (0.6%) patients were receiving one, two, three, and four ASMs, respectively. The ratio of seizure-free patients was 0.4% (no ASM, n = 1), 91% (one ASM, n = 223), 7.4% (two ASMs, n = 18), and 0.8% (three ASMs, n = 2), respectively. During the treatment, 83 (18%) patients had ever withdrawn the ASMs without medical advice but the ASMs were re-administered at the nearest follow-up. Approximately 24% (n = 16) of the patients in the RE group and 16% (n = 38) in the seizure-free group had poor compliance, and no significant difference was found (χ2 = 2.352, p > 0.05). Breakthrough seizures during the first expected interictal interval following ASM treatment were compared between the RE (77%, n = 52) and seizure-free group (26%, n = 63), and there was a significant difference (χ2 = 58.622, p < 0.01).\n\nFifteen (22%) patients who had been diagnosed with RE reached seizure-free status following ASM adjustment (they were still classified to RE in the statistics described above). Among them, six, eight, and one patient(s) were treated with one, two, and three ASM(s), respectively. No significant difference in the demographic data was found between the patients with RE who achieved seizure-free status and patients who had not (p > 0.05). Finding alternative effective ASMs and increasing doses of the ASM in use were methods to achieve seizure-free status. Thirty-four patients (14%) had breakthrough seizures after being classified as seizure-free. The time of relapse was 6 to 36 months (median 6 months) (Figure 3). No significant difference in the demographic data or poor compliance was found between patients with seizure relapse and those without (p > 0.05). One patient developed RE after identifying as seizure-free.\n\nFigure 3 The distribution of patients with seizure relapse.\n\nLogistic regression was applied to analyse the risk factors of RE, and gender, age of onset, average income, disease duration, seizure frequency and types of seizure at baseline, history of status epilepticus, etiology, compliance, and breakthrough seizures during the first expected interictal interval were set as independent variables (Table 4). Breakthrough seizures during the first expected interictal interval (OR = 5.66, 95% CI: 3.05–10.51) and higher seizure frequency (increased every 5 times/month) (OR = 1.20, 95% CI: 1.02–1.41) were risk factors. When the scores of MOCA, GAD-7, and c-NDDI-E were adjusted in the analysis, men were more likely to develop RE than women [Odds ratio (OR) = 2.66, 95% CI: 1.26–5.62], and a younger age of onset (decrease of every 10 years) (OR = 1.42, 95% CI: 1.12–1.79) was also a risk factor of RE. Meanwhile, the ORs of breakthrough seizure during the first expected interictal interval and higher seizure frequency were 5.53 (95% CI: 2.57–11.92) and 1.22 (95% CI: 1.02–1.46), respectively (Table 4).\n\nTable 4 The logistic regression analysis for risk factors of refractory epilepsy in newly diagnosed epilepsy.\n\n\tVariables\tp-value\tOR\t95% CI\t\n\t\t\t\tLower\tUpper\t\nBefore adjusted by scales\tBreakthrough seizures during the first expected interictal interval\t<0.001\t5.66\t3.05\t10.51\t\n\tHigher seizure frequency (increased every 5 times/month)\t0.033\t1.20\t1.02\t1.41\t\nAfter adjusted by scales\tBreakthrough seizures during the first expected interictal interval\t<0.001\t5.53\t2.57\t11.92\t\n\tHigher seizure frequency (increased every 5 times/month)\t0.033\t1.22\t1.02\t1.46\t\n\tMale gender\t0.010\t2.66\t1.26\t5.62\t\n\tYounger age of onset (decrease of every 10 years)\t0.003\t1.42\t1.12\t1.79\t\n\nDiscussion\n\nILAE published a new definition of RE in 2010 to set up explicit and practical criteria. Based on this definition, we conducted the first prospective study on treatment outcome of NDE in Northeast China, and we identified the risk factors of RE according to the new definition, which can help physicians more quickly and accurately identify patients that are likely to develop RE.\n\nNearly half of the adult patients with NDE became seizure-free in our study and 91% of them were treated with monotherapy. This proportion is lower than that in previous studies (15, 16), but the criteria in these studies were relatively lenient compared to the ILAE criteria (no seizures for at least the previous year). Forty percent of the patients achieved seizure-free status with the first monotherapy and the median maintenance doses were no more than 50% DDD except for oxcarbazepine. This is consistent with the conclusion of previous studies that responsiveness may be identified with exposure to low ASM doses (12, 17). Most of the seizure-free statuses were obtained by monotherapy. Although Chi et al. found that combination therapy could increase the ratio of seizure-free patients compared to monotherapy (18), the latter is more acceptable for PWE in our clinic for fear of adverse effects. Dash et al. also found that reduction of the numbers of ASM may not aggravate seizures but decrease the side effects (19). Hence, combination therapy was always applied during the period of switching to another ASM or when the monotherapy did not work in our experience.\n\nThe probability of retention and the efficacy of levetiracetam and oxcarbazepine were satisfactory as the monotherapy, and liver damage and other objective adverse effects were the main causes of withdrawal. As a traditional ASM, valproic acid had relatively lower retention but it was also very efficient. Lamotrigine had a high likelihood of retention but did not perform as well as the other drugs. Neither the retention nor the efficacy of topiramate were satisfactory, and objective adverse effects were the main cause of withdrawal. In some studies with children, lamotrigine had better retention than oxcarbazepine (20) and topiramate (21). For older adults, carbamazepine is more likely to cause withdrawal symptoms than lamotrigine, levetiracetam, and valproic acid (22). Levetiracetam, on the other hand, has better efficacy than that of lamotrigine (23). Levetiracetam and oxcarbazepine were the more favorable drugs in terms of better tolerance and efficacy in our study. Unfortunately, we could not analyse their retention in older adults due to the limited number of patients.\n\nThe incidence of RE in adult NDE in our study was 15%, which is similar to the result of the systematic review on NDE (17%) (24). Although the ILAE definition is the minimum criteria, it could take more than 1 year for the majority of the patients to identify as RE. Moreover, patients with RE were inclined to have lower income, which means that the pharmacotherapy with the possibility of poor effect would put a huge burden on this population. Timely diagnosis helps physicians and patients to consider other optimal treatments, such as resective or palliative surgery, neurostimulation (25, 26), and ketogenic diet (27).\n\nBreakthrough seizures during the first expected interictal interval, high seizure frequency at baseline, younger age of onset, and the male sex were risk factors of RE in our study. Younger age at seizure onset and high initial seizure frequency were discussed as predictors of RE in previous studies (28–30). The breakthrough seizures during the first expected interictal interval reflect responses to the first ASM and the longitudinal data could be a more accurate predictor. Jiang et al. posited that more than two seizures in the first year after ASM initiation predicted less likelihood of achieving 2-year remission. Making the interictal interval as the observing time may be more suitable for each PWE with different seizure periods. Hughes et al. (31) found both the presence and number of post-breakthrough seizures indicated poor outcomes. Only one patient developed RE after achieving seizure-free status in our study, and others were undetermined for limited post-seizure follow-up; therefore we cannot reach the same conclusion. Previous research found that men were more susceptible to temporal lobe epilepsy-like seizures and seizure-related damage (32). Therefore, the severity of epilepsy and the degree of hemicranial volume loss were worse in men than that in women. The finding supports our conclusion that male sex was a risk factor of RE.\n\nNearly 14% of the patients with seizure-free status had seizure relapse and 88% of them had a relapse within 12 months. Hence, prolonging the period of ASM treatment and careful withdrawal should be emphasized, and the minimum period of ASM treatment should be 2 years of seizure-free status (33). Although diagnosing as RE, 22% of the patients achieved seizure-free status after changing to the alternative ASM regimen or increasing the doses of the ASMs in use, which is supported by a previous study (34). A patient with identified seizure-free status developed RE later in the course of her epilepsy. This is consistent with the patterns of previous research, and excessive expression of transporters for ASM removal and reduced drug-target sensitivity are the major probable theories (35). A new approach in anti-epilepsy rather than antiseizure treatment is necessary to reverse the unsatisfactory treatment scenario.\n\nIn conclusion, treatment outcomes of the majority of the NDE are good, and monotherapy could be efficient at a low dose. Levetiracetam and oxcarbazepine performed best in tolerance and efficacy. Breakthrough seizures during the first expected interictal interval, high seizure frequency at baseline, younger age of onset, and male sex predicted RE. Achieving seizure-free status is not enough to start the withdrawal of ASMs. RE is not permanent and seizure-free may be achieved subsequently by appropriate drug adjustment.\n\nLimitation\n\nThis was a single-center study and the findings might be difficult to extrapolate in the global settings. The follow-up period was not sufficient to determine RE for a part of patients. However, as our program is still going on, the follow-up time would be extended and the “undetermined” patients may achieve their outcome at the subsequent visits.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Ethics Committee of The First Hospital of Jilin University [the approval number: 2017-326]. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\n\nNL, JL, CC, and YC are responsible for including participants, data entry, and following up. WL is the designer of this project. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThe work was supported by fund from the Clinical Research Development Fund of The First Hospital of Jilin University [fund number: lcpyjj2017006].\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nWe thank Xin Zhang, Rui Zhong, Mengmeng Li, Yingxue Lu, and Qian Zhao for their help in including participants, data entry, and following up.\n==== Refs\nReferences\n\n1. 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"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "12()",
"journal": "Frontiers in neurology",
"keywords": "adult; antiseizure medication; drug resistant epilepsy; newly diagnosed epilepsy; risk factors",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "747958",
"pmc": null,
"pmid": "34777218",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "24099051;22573629;29279892;21414810;25128686;20557350;23880113;19889013;31185130;23106423;31085988;10660394;27878559;15946327;25891923;31244761;21163437;30223294;31734466;28235655;29302325;31608438;30246334;23583115;28276062;30900756;29789444;2502382;28474565;31244753;24730690;30686584;29957441;30426482",
"title": "Treatment Outcome and Risk Factors of Adult Newly Diagnosed Epilepsy: A Prospective Hospital-Based Study in Northeast China.",
"title_normalized": "treatment outcome and risk factors of adult newly diagnosed epilepsy a prospective hospital based study in northeast china"
} | [
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"companynumb": "CN-UCBSA-2021060043",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"activesubstancename": "LEVETIRACETAM"
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"abstract": "BACKGROUND\nFamilial Mediterranean Fever is a heritable illness typically characterized by recurrent fevers and serositis. Triggers of this illness include many things, such as cold or stress.\n\n\nMETHODS\nThis case describes a teenager who initially presented to the gynecologist office because of recurrent fevers with menses. Because she only had symptoms with menses, was healthy between attacks, and met the Livneh criteria, treatment with colchicine and combined oral contraceptive pills was initiated, with improvement of her symptoms.\n\n\nCONCLUSIONS\nThere are multiple etiologies for febrile illness during menses, and one should consider familial Mediterranean fever as a possible cause of cyclic fevers.",
"affiliations": "Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, New York.;Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, New York. Electronic address: katrina_nicandri@urmc.rochester.edu.",
"authors": "Soora|Raksha|R|;Nicandri|Katrina|K|",
"chemical_list": "D003277:Contraceptives, Oral, Combined; D003078:Colchicine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "28(6)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Familial Mediterranean fever; Menses; Periodic fever syndrome; Serositis",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000293:Adolescent; D003078:Colchicine; D003277:Contraceptives, Oral, Combined; D010505:Familial Mediterranean Fever; D005260:Female; D005334:Fever; D006801:Humans; D008297:Male; D008598:Menstruation",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "e193-5",
"pmc": null,
"pmid": "26324575",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Familial Mediterranean Fever: An Unusual Case Presentation.",
"title_normalized": "familial mediterranean fever an unusual case presentation"
} | [
{
"companynumb": "US-JNJFOC-20151116960",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "COLCHICINE"
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"drugadditional": null,
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"abstract": "Personalized therapy is becoming increasingly popular in oncological scenarios, not only based on molecular pharmacological targets, but also preventing any drug-drug-gene interaction (DDGI), which could lead to severe toxicities. Single nucleotide polymorphisms (SNPs), the individual germline sequence variations in genes involved in drug metabolism, are correlated to interindividual response to drugs and explain both efficacy and toxicity profiles reported by patients.\n\n\n\nWe present the case of a woman suffering from triple-positive breast cancer; she had early-stage disease at the onset and after four years developed metastatic disease. During her history, she presented different toxicities due to antineoplastic treatments. Particularly, hypertransaminasemia was found during every line of treatment. Nevertheless, we were able to guarantee the patient an excellent therapeutic adhesion thanks to the supportive treatments and the reduction of drug dosage. Moreover, we conducted a simultaneous analysis of the patient's biochemical and genomic data thanks to Drug-PIN software, and we found several significant SNPs of the main enzymes and transporters involved in drug metabolism.\n\n\n\nOur case report demonstrated the relevance of DDGI in clinical practice management of a patient treated for advanced breast cancer, suggesting the role of Drug-PIN software as an easy-to-use tool to prevent adverse events during cancer treatment and to help physicians in therapeutic algorithms. However, further studies are needed to confirm these results.",
"affiliations": "Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea Hospital, University \"La Sapienza\", 00167 Rome, Italy.;Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea Hospital, University \"La Sapienza\", 00167 Rome, Italy.;Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea Hospital, University \"La Sapienza\", 00167 Rome, Italy.;Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea Hospital, University \"La Sapienza\", 00167 Rome, Italy.",
"authors": "Panebianco|Martina|M|;Taurelli Salimbeni|Beatrice|B|;Roberto|Michela|M|0000-0001-5339-8348;Marchetti|Paolo|P|0000-0002-9064-8761",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/curroncol28030184",
"fulltext": "\n==== Front\nCurr Oncol\nCurr Oncol\ncurroncol\nCurrent Oncology\n1198-0052\n1718-7729\nMDPI\n\n10.3390/curroncol28030184\ncurroncol-28-00184\nCase Report\nAn Example of Personalized Treatment in HR+ HER2+ Long Survivor Breast Cancer Patient (Case Report)\nPanebianco Martina 1\nTaurelli Salimbeni Beatrice 1\nhttps://orcid.org/0000-0001-5339-8348\nRoberto Michela 12*\nhttps://orcid.org/0000-0002-9064-8761\nMarchetti Paolo 13\n1 Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea Hospital, University “La Sapienza”, 00167 Rome, Italy; martina.panebianco@uniroma1.it (M.P.); beatrice.taurellisalimbeni@uniroma1.it (B.T.S.); paolo.marchetti@uniroma1.it (P.M.)\n2 Department of Medical-Surgical Sciences and Translation Medicine, Sant’ Andrea Hospital, University “La Sapienza”, 00167 Rome, Italy\n3 Oncology Unit, Istituto Dermopatico Dell’Immacolata—Istituti di Ricovero e Cura a Carattere Scientifico of Rome, 00167 Rome, Italy\n* Correspondence: michela.roberto@uniroma1.it\n25 5 2021\n6 2021\n28 3 19801987\n17 3 2021\n16 5 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground. Personalized therapy is becoming increasingly popular in oncological scenarios, not only based on molecular pharmacological targets, but also preventing any drug–drug–gene interaction (DDGI), which could lead to severe toxicities. Single nucleotide polymorphisms (SNPs), the individual germline sequence variations in genes involved in drug metabolism, are correlated to interindividual response to drugs and explain both efficacy and toxicity profiles reported by patients. Case presentation. We present the case of a woman suffering from triple-positive breast cancer; she had early-stage disease at the onset and after four years developed metastatic disease. During her history, she presented different toxicities due to antineoplastic treatments. Particularly, hypertransaminasemia was found during every line of treatment. Nevertheless, we were able to guarantee the patient an excellent therapeutic adhesion thanks to the supportive treatments and the reduction of drug dosage. Moreover, we conducted a simultaneous analysis of the patient’s biochemical and genomic data thanks to Drug-PIN software, and we found several significant SNPs of the main enzymes and transporters involved in drug metabolism. Conclusion. Our case report demonstrated the relevance of DDGI in clinical practice management of a patient treated for advanced breast cancer, suggesting the role of Drug-PIN software as an easy-to-use tool to prevent adverse events during cancer treatment and to help physicians in therapeutic algorithms. However, further studies are needed to confirm these results.\n\nhormone receptor positive (HR+)\nHER2+ breast cancer\ndrug-drug-gene interaction (DDGI)\nsingle nucleotide polymorphisms (SNPs)\n==== Body\n1. Introduction\n\nThe idea of personalized therapy is becoming increasingly popular, not only on the basis of molecular targeted therapy, but also by considering any potential drug–drug–gene interaction (DDGI) to prevent adverse events during cancer treatment, in order to improve patients outcome [1]. Based on this consideration, the pharmacogenomics profile to define the DDGI and the use of smart software to easily understand the risk of toxicity during treatment could be very useful in personalized cancer management.\n\nWe present the case of a woman suffering from hormone receptor-positive (HR+) and HER2+ breast cancer, with metastatic disease after four years from cancer diagnosis. During her history, she presented different toxicities due to antineoplastic treatments. Particularly, severe hypertransaminasemia was found during every line of treatment. Thus, we retrospectively analyzed the SNPs of main enzymes and transporters involved in drug metabolism and showed the utility of Drug-PIN software in the management and prevention of adverse events during chemotherapy treatment.\n\n2. Case Presentation\n\nA 36-year-old woman presented at our hospital with a palpable mass at the external left breast quadrants in December 2011. The patient underwent breast ultrasound and breast magnetic resonance imaging (MRI) that confirmed the presence of a nodular formation of about 5 cm. In addition, at least three lymphadenopathies with eccentric hilum were identified in the left axillary cable, and remote staging tests were negative. In January 2012, breast biopsy diagnosed an infiltrating ductal carcinoma of the breast, grade 3, estrogen receptor (ER)-positive (90%), progesterone receptor (PR)-positive (36%), HER2-positive (3+ by IHC), and MIB-1 36%. The pathological nature of lymphadenopathies was confirmed by fine-needle aspiration.\n\nFrom January 2012 to April 2012, the patient received neoadjuvant chemotherapy with docetaxel (100 mg/m2) and trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) every three weeks for four cycles followed by cyclophosphamide (600 mg/m2) and doxorubicin (60 mg/m2) every three weeks for four cycles. The second cycle of chemotherapy was delayed due to hypertransaminasemia grade 2 (according to common terminology criteria for adverse events (CTCAE) version 5.0), treated with glutathione and prednisone 25 mg/die for five days. Treatment with docetaxel was resumed at 25% reduced dose, reporting only grade 1 hypertransaminasemia during subsequent cycles. In August 2012, the patient underwent bilateral mastectomy and axillary node resection with a partial response to neoadjuvant chemotherapy (ypT1c ypN1 Mx).\n\nFrom October 2012 to April 2013, the patient continued adjuvant therapy with trastuzumab administered subcutaneously (600 mg) every three weeks to complete one year of treatment and hormone therapy with tamoxifene plus luteinizing hormone-releasing hormone (LHRH) inhibitor since September 2012.\n\nIn January 2014, after the finding of thickening of the subcutaneous areola, the patient underwent surgical radical removal of the nipple and left areola. The diagnosis was intraductal carcinoma of cribriform type in galactophore ducts of high-grade sec. WHO 2012 and Paget’s disease, ER 90% PgR negative.\n\nShe continued regular clinico-radiological follow-up, negative for locoregional and distance recurrence, until January 2016 when a total body contrast-enhanced computed tomography (CECT) scan and an 18-fluor-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) confirmed the presence of bilateral pulmonary, mediastinal pathological lymph nodes and bone metastases. According to the disease stage, biomolecular tumor characteristics, and clinical conditions (PS 0 sec. ECOG), in January 2016, the patient started first-line therapy with pertuzumab plus trastuzumab and docetaxel every three weeks at standard doses. She reassumed the same regimen up to four courses and then she continued with dual HER2-blockage for a further three cycles. The CECT scan after three courses of treatment showed a partial response, but after the second cycle the patient showed grade 2 mucositis and grade 3 hypertransaminasemia, treated with glutathione and prednisone 25 mg/die for five days, and the third cycle was delayed. Antigens of hepatitis were tested and resulted negative.\n\nIn August 2016, an 18F-FDG PET/CT revealed lymph node and bone progression disease. Thus, she started second-line therapy with T-DM1 at 3.6 mg/kg every three weeks with concurrent denosumab every four weeks. From August 2016 to April 2018, she received 28 cycles. After the ninth cycle, due to the occurrence of grade 2 hypertransaminasemia, glutathione was introduced in chemotherapy regimens with the resolution of toxicity.\n\nIn April 2018, due to a lymph node and lung disease progression, the patient was enrolled in the phase III clinical trial SOPHIA (NCT02492711) and randomized to the control arm. The screening laboratory findings showed a grade 3 hypertransaminasemia that was treated with glutathione infusion. At the resolution of toxicity, since the patient had been randomized into the control arm, she began treatment with trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and navelbine (25 mg/mq d1–8 every three weeks). The treatment was poorly tolerated with grade 4 neutropenia and grade 2 anemia after the first cycle and grade 4 neutropenia after the second cycle with 50% dose reduction and secondary prophylaxis with granulocyte colony-stimulating factor (G-CSF). Due to hematological toxicities, she continued treatment without navelbine, and she received four courses with trastuzumab.\n\nIn October 2018, a further lymph node and lung disease progression was detected, and then she started fourth line with capecitabine (1000 mg/mq bid d1–14) plus lapatinib (1250 mg once daily) every three weeks. The patient received IX cycle from November 2018 to June 2019. After the first cycle, she presented grade 1 hypertransaminasemia, which was resolved with glutathione infusion.\n\nAfter a further lymph node and lung disease progression, she received fifth-line therapy with nab-paclitaxel 260 mg/m2 and trastuzumab every three weeks with primary prophylaxis with G-CSF. She received nine courses from July 2019 to December 2019, and she presented only grade 1 hypertransaminasemia.\n\nDue to the evidence of complete response and the patient’s preference to discontinue alopecitizing chemotherapy, she continued treatment with trastuzumab alone until March 2020, when an 18F-FDG PET/CT revealed lymph node and lung relapse. Then, in April 2020, she started sixth-line therapy with gemcitabine 1000 mg/m2·d1, d8 plus trastuzumab 6 mg/kg every three weeks. After the first cycle, she presented grade 2 hypertransaminasemia and grade 2 thrombocytopenia, so she stopped the treatment; due to the occurrence of pain in the left arm (VAS 8), we prescribed oxycodone plus naloxone. At the fourth cycle, she showed grade 3 hypertransaminasemia, and we decided to reduce gemcitabine dose, but the toxicity persisted. Therefore, liver virology was tested again. Moreover, at this time point (Figure 1), since the new technology for DDGI had become available at our center, we evaluated her genomic polymorphisms, including genes encoding for the main drug metabolism enzymes, and simultaneously analyzed all her clinical, biochemical, and genomic data by using the new Drug-PIN system comprehensive approach (https://aousa.drug-pin.com/app/ (accessed on 31 March 2020)) In particular, for the SNP analysis, the patient’s DNA was extracted from samples of 5 mL of peripheral blood, using the automatic QIAsymphony system for the extraction of nucleic acid (Qiagen, Hilden, Germany), and then the latter was processed using a next-generation sequencing platform Ion Chef/Ion S5 system (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions.\n\nDue to the results of the analysis (Table S1), we decided to maintain the reduced dose of gemcitabine and to introduce glutathione as part of cancer treatment from the sixth cycle of chemotherapy.\n\nFrom August to December 2020, the patient received 25% reduced dose gemcitabine with four vials of glutathione, and she showed maximum grade 2 liver toxicity.\n\nIn December 2020, an 18F-FDG PET/CT evaluation revealed oligometastatic lymph node and bone progression; therefore, we decided to treat with local radiotherapy on sternal dumbbell and left later-cervical, supraclavicular, and retro-pectoral lymph nodes, maintaining the same chemotherapy regimen. Today, the treatment with gemcitabine and trastuzumab is still ongoing, and the patient has reported an overall survival (OS) of 111 months from first diagnosis and of 50 months from recurrence.\n\n3. Discussion\n\nThe idea of personalized therapy is becoming increasingly popular, not only based on molecular targets, but also preventing any drug–drug–gene interactions (DDGIs), which could lead to serious adverse reactions, especially in patients who receive polypharmacotherapy due to comorbidities [1].\n\nThe pharmacogenomics profiling, including all cytochromes P450 (CYPs) enzyme superfamily, P-glycoprotein, ATP-binding cassette transporters, and detoxifying and DNA-repairing enzymes [2,3], is of fundamental importance to define DDGIs, which result from the combination between drug–drug interaction (DDI) and individual genetic polymorphisms [4]. In fact, single nucleotide polymorphisms (SNPs), the individual germline sequence variations in these genes, are involved in interindividual response to drugs and explain both efficacy and toxicity profiles reported by patients [5]. Not all the SNPs are “functional”, because only 1% of them are located in the coding portions of the DNA. To date, approximately 50,000–250,000 functional SNPs conferring a potential biological effect have been identified [6].\n\nTwo major examples in order to reflect the importance of SNPs in clinical practice concern those point mutations affecting dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene), methylene tetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS) implicated in fluoropyrimidine metabolism, as well as the SNPs of uridine diphosphate glucuronosyltransferases (UGTs) and CYP3A4*1B and CYP3A5*3 enzymes, implicated in irinotecan metabolism. In particular, based on UGT1A1 and DPYD polymorphisms, drug dose modification was recommended in clinical practice. Moreover, excision repair 1 endonuclease noncatalytic subunit (ERCC1), X-ray repair cross-complementing protein 1 (XRCC1), and glutathione S-transferase P1 (GSTP1) gene variants potentially impact the outcome of platinum derivative therapies, whereas ATP-binding cassette subfamily B member 1 (ABCB1) and CYP3A4*1B and CYP3A5*3 variants were correlated to the enzyme activity and outcome of taxanes [7,8].\n\nSeveral studies have evaluated correlations between toxicities and therapeutic outcomes in patients with breast cancer in the context of hormone therapy, chemotherapy, and radiotherapy [9,10,11,12,13,14,15].\n\nWe presented the case of a patient suffering from high-grade HR+ HER2+ cancer who received six treatment lines for the metastatic disease. As reported in Figure 2, during the different treatment lines, a series of toxicities were found, particularly grade 3 hypertransaminasemia and grade 2 mucositis in the course of first-line treatment with pertuzumab-trastuzumab plus docetaxel and grade 2 hypertransaminasemia under neoadjuvant treatment with docetaxel–trastuzumab, second-line treatment with trastuzumab–emtansine, and sixth-line treatment with gemcitabine–trastuzumab. Moreover, the patient presented hematological toxicity with grade 4 neutropenia and grade 2 anemia in the course of third-line treatment with vinorelbine–trastuzumab and grade 2 thrombocytopenia under sixth-line treatment with gemcitabine–trastuzumab.\n\nConsidering the adverse events reported and the availability of DDGI analysis at our center, we conducted the analysis of 132 SNPs (Table S1), including the main SNPs involved in drug transporters and metabolism, oxidation–reduction, DNA repair, and lipid metabolism and coagulation, as well as different receptors.\n\nCirculating taxanes are transported to the hepatocytes by solute carrier organic anion transporter family member 1B3 (SLCO1B3) and are converted into their metabolites by CYP450 enzymes. Finally, ATP-binding cassette transporters ABCB1 and ABCC2 eliminate the metabolites through bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to the development of toxicity in patients [16]. In particular, as reported in Table S1, three heterozygous polymorphisms of ABCB1 (ABCB1-C1236T, ABCB1-C3435T, and Intron Variant rs4148738) and a homozygous SNP of ABCC2-C24T were identified in our case. It was evidenced that patients with the “CT/TT” genotype of ABCB1 (C1236T) gene showed better tumor response to docetaxel therapy than those with “CC” in course of neoadjuvant chemotherapy for locally advanced breast cancer [17], but it was associated with higher neurotoxicity in non-small-cell lung cancer (NSCLC) treated with taxane-based regime. In fact, the area under the concentration–time curve (AUC) of patients treated with docetaxel increased for ABCB1 mutation subgroups [18]. In our case report, a grade 2 liver toxicity was evidenced under all taxane-based therapy, and we obtained a partial response to neoadjuvant chemotherapy as well metastatic setting taxanes.\n\nIn addition, the patient also presented a reduced activity of oxidation–reduction enzymes, involved in the prevention of cell damage by free radicals. In fact, the presence of heterozygous SNP of glutathione S-transferase protein 1 (GSTP1) A313G and GSTM1 deletion lead to decreased activity enzyme of GSTP1 and absent function of GSTM1, respectively (Table S1). However, the effect that GST polymorphisms might have on toxicity to taxanes is not well understood, but some studies have linked GSTP1 polymorphisms and hematological and neurological toxicity to taxanes [19,20,21,22,23]. In our case, the prevalent toxicity evidenced in course of taxane therapy was hepatological.\n\nAs regards the reported liver toxicity, it is also necessary to evaluate the concomitant therapy consisting of morphine derivatives (oxycodone predominantly) that the patient took for antalgic purposes. In fact, oxycodone is extensively metabolized in the liver via CYP3A4/5 to noroxycodone (45%) and via CYP2D6 to oxymorphone (19%) [24]. Allelic variants altering CYP2D6-mediated metabolism could be associated with reduced efficacy of hydrocodone and increased toxicity of codeine, each of which relies entirely on the CYP2D6 enzyme for phase 1 metabolism. In one study, such alterations were not accompanied by increased adverse events [25]. However, individual cases of reduced oxycodone efficacy [26] or increased toxicity [27] in CYP2D6 poor metabolizers have been reported [28]. As reported in Table S1, our patient was a carrier of CYP2D6 poor metabolizer.\n\nThe severe hematological toxicity (neutropenia grade 4 and anemia grade 2) that the patient developed during treatment with vinorelbine is also interesting, but there was no evidence of association between vinorelbine clearance and CYP3A5*1/*3 genotype or the ABCB1 SNPs tested for [29,30].\n\nMoreover, we conducted an analysis through Drug-PIN software that integrates the information derived from patient SNPs with concomitant drugs and chemotherapy assumed. The Drug-PIN technology can be defined as a “Functional Biochemistry based on Genomic Profile” (http://www.drug-pin.com/index.html (accessed on 31 March 2020)). The result of the DDGI analysis carried out by the Drug-PIN software is represented by a numerical score to be understood in a penalizing sense: the greater the associated number, the more dangerous the drug cocktail will be. In particular, we calculated two metabolizer scores: (i) DrugPin1 included chemotherapy (taxanes) and concomitant medications (pregabalin, oxycodone, and naloxone hydrochloride); (ii) DrugPin2 was the global score, including the DrugPin1 and SNP profile in the software analysis. As regards our patient, DrugPin1 and DrugPin2 were 22.71 and 92.73. These findings show that it is now essential for the oncology community to evaluate patients globally, also taking into account the genomic aspect. In fact, in this case, although the DrugPin1 score showed a moderate risk of developing toxicity derived from the interaction between concomitant drugs and chemotherapy, the DrugPin2 score showed a high risk of developing adverse events when information from the genomic profile was integrated with the therapy assumed.\n\n4. Conclusions\n\nWe presented the case of a patient with advanced breast cancer and a peculiar genomic profile that resulted in reduced activity of both enzymes and transporters involved in the metabolism of chemotherapeutics commonly used in clinical practice. In the course of her clinical history, the patient developed a series of toxicities, especially liver toxicities, which we tried to associate with the SNPs identified by genomic analysis. Thanks to the supportive treatments, especially in favor of hepatic detoxification, and the reduction of the dosage of drugs, we were able to guarantee the patient an excellent therapeutic adhesion. However, the possibility to use an easy-to-use pharmacogenomics tool such as Drug-PIN software [1] to prevent toxicities during cancer treatment through the evaluation of both clinical and genomic factors, as well as by taking into account the use of concomitant drugs, could ensure the application of personalized medicine and better compliance with treatments. Further studies are necessary for the identification of predictive factors of toxicity of treatments used in order to ensure maximum benefit to patients and minimum toxicity of proposed therapies.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/curroncol28030184/s1, Table S1: Panel of SNPs investigated.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, M.P., B.T.S. and M.R.; methodology, M.P. and B.T.S.; software, M.R.; validation, M.R. and P.M.; formal analysis, M.P.; investigation, M.P. and B.T.S.; resources, M.R and P.M.; data curation, M.R.; writing—original draft preparation, M.P. and B.T.S.; writing—review and editing, M.P., B.T.S. and M.R; visualization, M.R.; supervision, M.R.; project administration, M.R.; funding acquisition, M.P. and B.T.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nNo new data were created or analyzed in this study. Data sharing is not applicable to this article.\n\nConflicts of Interest\n\nThe authors have no conflict of interest to declare.\n\nFigure 1 Personalized medicine thanks to new Drug-PIN system comprehensive approach. PS, Performance Status; ECOG, Eastern Cooperative Oncology Group; OS, Overal Survival; SNP, Single Nucleotide polymorphism.\n\nFigure 2 Timeline of patient’s clinical history and toxicity reported in treatment lines. Legend: ER, estrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; LHRH, luteinizing hormone-releasing hormone; PD, progression disease; CR, complete response; RT, radiotherapy; SNPs, single nucleotide polymorphisms.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Roberto M. Rossi A. Panebianco M. Pomes L. Arrivi G. Ierinò D. Simmaco M. Marchetti P. Mazzuca F. Drug–Drug Interactions and Pharmacogenomic Evaluation in Colorectal Cancer Patients: The New Drug-PIN® System Comprehensive Approach Pharmaceuticals 2021 14 67 10.3390/ph14010067 33467633\n2. Tannenbaum C. Sheehan N.L. Understanding and preventing drug–drug and drug–gene interactions Expert Rev. Clin. Pharmacol. 2014 7 533 544 10.1586/17512433.2014.910111 24745854\n3. Lee Y.M. Danahey K. Knoebel R.W. Ratain M.J. Meltzer D.O. O’Donnell P.H. 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Strigari L. Gentile G. Cerbelli B. Pellegrini P. Pharmacogenetic Approach to Toxicity in Breast Cancer Patients Treated with Taxanes Anticancer Res. 2017 37 2633 2639 10.21873/anticanres.11610 28476838\n9. Chaturvedi P. Tulsyan S. Agarwal G. Lal P. Mittal R. Mittal B. Influence of ABCB1 genetic variants in breast cancer treatment outcomes Cancer Epidemiol. 2013 37 754 761 10.1016/j.canep.2013.04.012 23707158\n10. Córdoba E.E. Abba M.C. Lacunza E. Fernandez E.E. Güerci A.M. Polymorphic Variants in Oxidative Stress Genes and Acute Toxicity in Breast Cancer Patients Receiving Radiotherapy Cancer Res. Treat. 2016 48 948 954 10.4143/crt.2015.360 26790968\n11. Etienne-Grimaldi M.-C. Boyer J.-C. Beroud C. Mbatchi L. Van Kuilenburg A. Bobin-Dubigeon C. Thomas F. Chatelut E. Merlin J.-L. Pinguet F. New advances in DPYD genotype and risk of severe toxicity under capecitabine PLoS ONE 2017 12 e0175998 10.1371/journal.pone.0175998 28481884\n12. Pascual T. Apellániz-Ruiz M. Pernaut C. Cueto-Felgueroso C. Villalba P. Álvarez C. Manso L. Inglada-Pérez L. Robledo M. Rodriguez-Antona C. Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer PLoS ONE 2017 12 e0180192 10.1371/journal.pone.0180192 28727815\n13. Boso V. Herrero M.J. Santaballa A. Palomar L. Megias J.E. De La Cueva H. Rojas L. Marqués M.R. Poveda J.L. Montalar J. SNPs and taxane toxicity in breast cancer patients Pharmacogenomics 2014 15 1845 1858 10.2217/pgs.14.127 25495407\n14. Sini V. Botticelli A. Lunardi G. Gori S. Marchetti P. Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients Pharmacogenomics 2017 18 821 830 10.2217/pgs-2017-0006 28592202\n15. O’Donnell P.H. Trubetskoy V. Nurhussein-Patterson A. Hall J.P. Nath A. Huo D. Fleming G.F. Ingle J.N. Abramson V.G. Morrow P.K. Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015 Breast Cancer Res. Treat. 2020 181 623 633 10.1007/s10549-020-05603-8 32378051\n16. Jabir R.S. Naidu R. Annuar M.A.B.A. Ho G.F. Munisamy M. Stanslas J. Pharmacogenetics of taxanes: Impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity Pharmacogenomics 2012 13 1979 1988 10.2217/pgs.12.165 23215890\n17. Priyadarshini R. Raj G.M. Kayal S. Ramesh A. Shewade D.G. Influence of ABCB1 C3435T and C1236T gene polymorphisms on tumour response to docetaxel-based neo-adjuvant chemotherapy in locally advanced breast cancer patients of South India J. Clin. Pharm. Ther. 2019 44 188 196 10.1111/jcpt.12797 30637776\n18. Zhong J. Guo Z. Fan L. Zhao X. Zhao B. Cao Z. Cheng L. Shi Y. Li X. Zhang Y. ABCB1 polymorphism predicts the toxicity and clinical outcome of lung cancer patients with taxane-based chemotherapy Thorac. Cancer 2019 10 2088 2095 10.1111/1759-7714.13184 31571407\n19. Mir O. Alexandre J. Tran A. Durand J.-P. Pons G. Treluyer J.-M. Goldwasser F. Relationship between GSTP1 Ile105Val polymorphism and docetaxel-induced peripheral neuropathy: Clinical evidence of a role of oxidative stress in taxane toxicity Ann. Oncol. 2009 20 736 740 10.1093/annonc/mdn698 19223573\n20. Tran A. Jullien V. Alexandre J. Rabillon F. Girre V. Pons G. Goldwasser F. Rey E. Diéras V. Treluyer J. Pharmacokinetics and toxicity of docetaxel: Role of CYP3A, MDR1, and GST polymorphisms Clin. Pharmacol. Ther. 2006 79 570 580 10.1016/j.clpt.2006.02.003 16765145\n21. Sugishita M. Imai T. Kikumori T. Mitsuma A. Shimokata T. Shibata T. Morita S. Inada-Inoue M. Sawaki M. Hasegawa Y. Pharmacogenetic association between GSTP1 genetic polymorphism and febrile neutropenia in Japanese patients with early breast cancer Breast Cancer 2014 23 195 201 10.1007/s12282-014-0547-x 25008867\n22. Zhang B.L. Tong S.U. Zhang B.N. Zheng S. Ning L.Ü. Xu B.H. Xiang W.A. Chen G.J. Yu D.K. Lin D.X. Polymorphisms of GSTP1 is associated with differences of chemotherapy response and toxicity in breast cancer Chin. Med. J. 2011 124 199 204 21362365\n23. Yoshihama T. Fukunaga K. Hirasawa A. Nomura H. Akahane T. Kataoka F. Yamagami W. Aoki D. Mushiroda T. GSTP1 rs1695 is associated with both hematological toxicity and prognosis of ovarian cancer treated with paclitaxel plus carboplatin combination chemotherapy: A comprehensive analysis using targeted resequencing of 100 pharmacogenes Oncotarget 2018 9 29789 29800 10.18632/oncotarget.25712 30038720\n24. Kinnunen M. Piirainen P. Kokki H. Lammi P. Kokki M. Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone Clin. Pharmacokinet. 2019 58 705 725 10.1007/s40262-018-00731-3 30652261\n25. Heiskanen T. Olkkola K.T. Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone* Clin. Pharmacol. Ther. 1998 64 603 611 10.1016/S0009-9236(98)90051-0 9871425\n26. Susce M.T. Murray-Carmichael E. De Leon J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2006 30 1356 1358 10.1016/j.pnpbp.2006.03.018\n27. Foster A. Mobley E. Wang Z. Complicated Pain Management in a CYP450 2D6 Poor Metabolizer Pain Pract. 2007 7 352 356 10.1111/j.1533-2500.2007.00153.x 17986163\n28. Smith H.S. Opioid Metabolism Mayo Clin. Proc. 2009 84 613 624 10.1016/S0025-6196(11)60750-7 19567715\n29. Wong M. Balleine R.L. Blair E.Y. McLachlan A.J. Ackland S.P. Garg M.B. Evans S. Farlow D. Collins M. Rivory L.P. Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer J. Clin. Oncol. 2006 24 2448 2455 10.1200/JCO.2005.02.1295 16651648\n30. Gusella M. Pasini F. Caruso D. Barile C. Modena Y. Fraccon A.P. Bertolaso L. Menon D. Crepaldi G. Bononi A. Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: Correlations with pharmacokinetics and MDR1 polymorphisms Cancer Chemother. Pharmacol. 2019 83 493 500 10.1007/s00280-018-3751-0 30542768\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1198-0052",
"issue": "28(3)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "HER2+ breast cancer; drug-drug-gene interaction (DDGI); hormone receptor positive (HR+); single nucleotide polymorphisms (SNPs)",
"medline_ta": "Curr Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D057285:Precision Medicine; D017741:Survivors",
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "1980-1987",
"pmc": null,
"pmid": "34070464",
"pubdate": "2021-05-25",
"publication_types": "D002363:Case Reports",
"references": "16765145;21362365;28481884;16651648;14970847;24745854;19567715;33467633;28476838;30542768;12571262;29861877;25495407;28727815;30652261;30637776;31571407;16631290;25008867;23215890;17986163;30038720;24798722;32378051;9871425;26790968;23707158;19223573;28592202;30531378",
"title": "An Example of Personalized Treatment in HR+ HER2+ Long Survivor Breast Cancer Patient (Case Report).",
"title_normalized": "an example of personalized treatment in hr her2 long survivor breast cancer patient case report"
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"abstract": "A fixed drug eruption consists of erythematous patches that appear on the skin and/or mucous membranes following administration of a drug which, once healed, leaves residual hyperpigmentation. We report a 76-year-old male who presented to the Thriasio General Hospital, Athens, Greece, in 2016 with erythema, oedema and blistering of the lower lip and glans penis following the administration of silodosin for benign prostatic hyperplasia. The eruption regressed two weeks after silodosin was discontinued.",
"affiliations": "Department of Dermatology, Thriasio General Hospital, Athens, Greece.",
"authors": "Klimi|Eleni|E|",
"chemical_list": "D000317:Adrenergic alpha-Antagonists; D007211:Indoles; C095285:silodosin",
"country": "Oman",
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"journal": "Sultan Qaboos University medical journal",
"keywords": "Blister; Case Report; Drug Eruption; Erythema; Greece; Mucous Membranes; Silodosin",
"medline_ta": "Sultan Qaboos Univ Med J",
"mesh_terms": "D000317:Adrenergic alpha-Antagonists; D000368:Aged; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D004890:Erythema; D006115:Greece; D006801:Humans; D007211:Indoles; D008297:Male; D009061:Mouth Mucosa; D010413:Penis; D011470:Prostatic Hyperplasia",
"nlm_unique_id": "101519915",
"other_id": null,
"pages": "e402-e404",
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"pmid": "30607288",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": "17478380;19474709;21422354;21569741;22613857;24446836;25365443;25575983;26553194;26806055;27080836;29469697;29525693",
"title": "A Probable Case of Mucosal Fixed Drug Eruption Following Treatment with Silodosin.",
"title_normalized": "a probable case of mucosal fixed drug eruption following treatment with silodosin"
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"companynumb": "GR-LUPIN PHARMACEUTICALS INC.-2019-00361",
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"abstract": "Squamous cell carcinoma (SCC) of the colon, both primary and metastatic, are extremely rare malignancies. We present a case of a 60-year-old man with metastatic SCC of the tongue status after radiation and chemotherapy who presented with fatigue and melena. Colonoscopy revealed a 5 cm mass in the transverse colon. Pathology established the diagnosis of poorly differentiated SCC with p16 immunostaining, similar to biopsies from his initially diagnosed lingual cancer. To the best of our knowledge, there are no previously reported cases of primary SCC of the tongue metastasizing to the colon.",
"affiliations": "Department of Internal Medicine, Cleveland Clinic Florida, Weston, FL.;Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL.;Department of Internal Medicine, Cleveland Clinic Florida, Weston, FL.;Department of Internal Medicine, Cleveland Clinic Florida, Weston, FL.;Department of Internal Medicine, Cleveland Clinic Florida, Weston, FL.;Department of Pathology, Cleveland Clinic Florida, Weston, FL.;Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL.",
"authors": "Khan|Sikandar|S|;Ur Rahman|Asad|A|;Castillo|Michael|M|;Riaz|Amir|A|;Miret|Rafael|R|;Bejarano|Pablo|P|;Castro-Pavia|Fernando|F|",
"chemical_list": null,
"country": "United States",
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"doi": "10.14309/crj.0000000000000529",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\n33457440\nACGCR-20-0312\n10.14309/crj.0000000000000529\n00010\nCase Report\nColon\nA Rare Case of Metastatic Colon Cancer in a Patient With Squamous Cell Carcinoma of the Tongue\nKhan Sikandar MD 1\nUr Rahman Asad MD 2Rahmanf3@ccf.org\n\nCastillo Michael MD 1castilm3@ccf.org\n\nRiaz Amir MD 1riaza@ccf.org\n\nMiret Rafael DO 1miretr@ccf.org\n\nBejarano Pablo MD 3bejarap@ccf.org\n\nCastro-Pavia Fernando MD 2castrof@ccf.org\n\n1 Department of Internal Medicine, Cleveland Clinic Florida, Weston, FL\n2 Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL\n3 Department of Pathology, Cleveland Clinic Florida, Weston, FL\nCorrespondence: Sikandar Khan, MD (khans14@ccf.org).\n1 2021\n13 1 2021\n8 1 e0052904 4 2020\n04 9 2020\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nABSTRACT\n\nSquamous cell carcinoma (SCC) of the colon, both primary and metastatic, are extremely rare malignancies. We present a case of a 60-year-old man with metastatic SCC of the tongue status after radiation and chemotherapy who presented with fatigue and melena. Colonoscopy revealed a 5 cm mass in the transverse colon. Pathology established the diagnosis of poorly differentiated SCC with p16 immunostaining, similar to biopsies from his initially diagnosed lingual cancer. To the best of our knowledge, there are no previously reported cases of primary SCC of the tongue metastasizing to the colon.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nSquamous cell cancer (SCC) of the colon is a rare entity and has an incidence of 0.1–0.27 per 1,000 of all colorectal malignancies.1 Colonic metastases from primary SCC of the lung, cervix, and esophagus have previously been reported in the literature.2 These large bowel metastases can occur hematogenously or via transperitoneal seeding from adjacent organs.3 SCC of the head and neck usually metastasizes to the lung, bone, and liver via hematogenous spread.4 Although metastasis of SCC of the head and neck has been reported in the small bowel,5 there have been very few reported cases in the literature recognizing spread to the large intestines. We present a rare case of colonic metastasis in the transverse colon from a lingual SCC. Treatment options are poorly defined, and disease progression despite chemoradiation carries a worse prognosis.6\n\nCASE REPORT\n\nA 60-year-old man was admitted to the hospital with worsening fatigue and melena for 2 weeks. His medical history was significant for stage IV SCC of the tongue (p16+, human papillomavirus [HPV]+), diagnosed 3 years earlier, with metastasis to the lungs and brain. He had undergone surgical resection of the tumor with adjuvant radiation therapy and was receiving pembrolizumab. The patient endorsed intermittent black tarry stools and fatigue for the past few months. Notably, he was admitted 2 months before for persistent dysphagia and odynophagia. At the time, speech-language pathology evaluation found persistent airway invasion during swallowing, for which he underwent upper endoscopy with the placement of percutaneous endoscopic gastrostomy (PEG) tube for supplemental enteral nutrition. Apart from mild candida esophagitis, no other abnormalities were noted on upper endoscopy. Abdominal and pelvic computed tomography performed at that time showed mesenteric lymphadenopathy and jejunal wall thickening that was relatively unchanged from previous imaging. He denied hematemesis, hematochezia, or bleeding through the PEG tube. He endorsed using daily meloxicam for back pain but denied use of any other nonsteroidal anti-inflammatory drug use. He reported a colonoscopy 6 years ago, which was unremarkable. Family history was negative for any gastrointestinal cancer, and he had a previous 35 pack-year smoking history.\n\nOn admission, he was hemodynamically stable but cachectic appearing on physical examination. Laboratory testing showed a hemoglobin of 4.3 g/dL. His baseline was 7–8 g/dL. He was appropriately transfused, and the decision was made to proceed with colonoscopy because his upper endoscopic examination 2 months ago was unremarkable. Colonoscopy demonstrated an exophytic ulcerated nonobstructing 5 cm mass suspicious for malignant neoplasm in the transverse colon (Figure 1). Biopsy of the results showed poorly differentiated SCC with ulceration (Figure 2). Stains were positive for p40 and p16, similar to the original pathology report from the resected lingual cancer specimen (Figure 3). Because of the disease progression on pembrolizumab, the patient opted for hospice and comfort care and died 5 weeks later.\n\nFigure 1. A 5 cm exophytic ulcerated mass in the transverse colon.\n\nFigure 2. Poorly differentiated squamous cell carcinoma with ulceration.\n\nFigure 3. Immunostaining positive for P16.\n\nDISCUSSION\n\nAmong oropharyngeal squamous cell cancers, cancer from the tongue is the second most common primary site associated with distant spread. In a previous study, the rate of distant metastasis from the lingual SCC was found to be around 4.1%.7 In an analysis of literature from 1937 to 2015 by Irani, involving 67 men and 36 women with distant metastasis from oral SCC, the most common secondary sites of spread were found to be the lungs, heart, and skin.8 Our patient had an unusual site of metastasis from his primary SCC of the tongue. There are 2 cases since 2016 that report metastatic spread to the colon from a head and neck primary SCC, and 1 case of a synchronous metastatic SCC of the colon and cervical lymph nodes with an unknown primary.2,3,9 Our patient had a new colonic mass in the setting of a known primary SCC of the tongue. Our review of literature found this to be the fourth documented case of metastatic SCC of the colon from a head and neck primary and the first such case with the tongue as the primary site of malignancy.\n\nRisk factors for SCC of the head and neck include tobacco use and HPV infection,6 whereas risk factors for distant metastasis include disease extension and achievement of locoregional control.5 In a retrospective study by Hauswald et al looking at 127 patients between 1992 with advanced stage IV SCC of the head and neck, distant metastasis despite chemoradiation had worse long-term outcomes.4 Our patient was a former smoker with endoscopic biopsies of the colonic lesion positive for p16 stain. This is a marker for HPV infection. Furthermore, he continued to have extranodal and regional extension of his disease, despite surgery and chemoradiation, portending a worse prognosis. Although iatrogenic spread of head and neck cancers through PEG tube insertion has been reported in the past,10 our patient did not have risk factors, such as a gastrocolic fistula during insertion or subsequent imaging, which would explain spread to the large bowel from his PEG insertion site.11 More studies are needed to establish, further delineate, and standardize goals of care for such patients.\n\nIn patients with known SCC of the head and neck presenting with melena in the setting of a negative esophagogastroduodenoscopy, metastatic disease of the colon should be considered, and a colonoscopy should be included as part the differential workup. Owing to the rarity of the disease, no standardized treatment guidelines currently exist for patients with metastatic SCC of the colon. Prompt surgical evaluation and palliative care consultation are often the mainstays of treatment.\n\nDISCLOSURES\n\nAuthor contributions: All authors contributed equally to this manuscript. A. Ur Rahman is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Abdelqader A Jabaji R Albugeaey M Palese C Squamous cell carcinoma of the ascending colon: Two cases. J Commun Hosp Intern Med Perspect 2017;7 (1 ):53–5.\n2. Ito H Miyakura Y Tsukui H Synchronous metastatic squamous cell carcinoma to the colon and cervical lymph nodes from a carcinoma of unknown primary site: A case report. J Surg Case Rep 2016;2016 (5 ):rjw084.27173884\n3. Tariq H Kamal MU Mehershahi S A rare case of colonic metastases from tonsillar carcinoma: Case report and review of literature. World J Oncol 2018;9 (1 ):35–7.29581814\n4. Garavello W Ciardo A Spreafico R Gaini RM Risk factors for distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132 (7 ):762–6.16847186\n5. Dwivedi RC Kazi R Agrawal N Comprehensive review of small bowel metastasis from head and neck squamous cell carcinoma. Oral Oncol 2010;46 (5 ):330–5.20189444\n6. Hauswald H Simon C Hecht S Debus J Lindel K Long-term outcome and patterns of failure in patients with advanced head and neck cancer. Radiat Oncol 2011;6 :70.21663634\n7. Osaki T Yoneda K Yamamoto T Clinical investigation on pulmonary metastasis of head and neck carcinomas. Oncology 2000;59 :196–203.11053986\n8. Irani S Distant metastasis from oral cancer: A review and molecular biologic aspects. J Int Soc Prev Community Dent 2016;6 (4 ):265–71.27583211\n9. Greenberg S Inman JC Esther Y Choo EB Colon mass: A rare site of metastasis for squamous cell cancer of the head and neck. J Surg Case Rep 2020;2020 :rjz391.32064074\n10. Huang AT Georgolios A Espino S Kaplan B Neifeld J Reiter ER Percutaneous endoscopic gastrostomy site metastasis from head and neck squamous cell carcinoma: Case series and literature review. J Otolaryngol Head Neck Surg 2013;42 (1 ):20.23672761\n11. Stamatakos M Karaiskos I Pateras I Alexiou I Stefanaki C Kontzoglou K Gastrocolic fistulae; from Haller till nowadays. Int J Surg 2012;10 (3 ):129–33.22361308\n\n",
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"issn_linking": "2326-3253",
"issue": "8(1)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00529",
"pmc": null,
"pmid": "33457440",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "28634528;29581814;22361308;20189444;16847186;32064074;21663634;27583211;27173884;23672761;11053986",
"title": "A Rare Case of Metastatic Colon Cancer in a Patient With Squamous Cell Carcinoma of the Tongue.",
"title_normalized": "a rare case of metastatic colon cancer in a patient with squamous cell carcinoma of the tongue"
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"companynumb": "US-009507513-2205USA007566",
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"activesubstancename": "PEMBROLIZUMAB"
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{
"abstract": "Although glucocorticoids are the mainstay of treatment in Takayasu arteritis (TA), anti-tumor necrosis factor agents are other treatment options in refractory disease. The onset of TA is generally observed in females of reproductive age. Certolizumab pegol (CZP) lacks a fragment crystallizable region and this gives advantage of minimal transfer through the placenta, which makes CZP a safer option in pregnancy. Although there are case reports and trials about use of infliximab, etanercept, and adalimumab in TA, there are scarce data about use of CZP. In this article, we present three TA cases treated with CZP. While two patients benefited from CZP, one patient was refractory to CZP.",
"affiliations": "Department of Internal Medicine, Division of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.",
"authors": "Ataş|Nuh|N|;Varan|Özkan|Ö|;Babaoğlu|Hakan|H|;Satiş|Hasan|H|;Bilici Salman|Reyhan|R|;Tufan|Abdurrahman|A|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5606/ArchRheumatol.2019.7177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2148-5046",
"issue": "34(3)",
"journal": "Archives of rheumatology",
"keywords": "Anti-tumor necrosis factor; Takayasu arteritis; certolizumab pegol; pregnancy",
"medline_ta": "Arch Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101639000",
"other_id": null,
"pages": "357-362",
"pmc": null,
"pmid": "31598605",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "17636564;26472566;22999907;30114347;21221688;29030361;16762772;22230484;7909656;23200982;19542212;19646348;26354797;22155781;25422327;29623679;28405087;1975175;23045170;28977672;23830517;23995735;20075700;12052713;21152919;9546941;22328491;30010945",
"title": "Certolizumab Pegol Treatment in Three Patients With Takayasu Arteritis.",
"title_normalized": "certolizumab pegol treatment in three patients with takayasu arteritis"
} | [
{
"companynumb": "TR-ACCORD-160424",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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{
"actiondrug": "1",
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"activesubstancename": "METHOTREXATE"
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"dr... |
{
"abstract": "OBJECTIVE\nTo report a case of presumed gemcitabine-induced retinopathy and nephropathy.\n\n\nMETHODS\nCase Report. Retrospective chart review.\n\n\nRESULTS\nA 64-year-old woman with a recent diagnosis of metastatic cholangiocarcinoma presented with progressive visual loss and renal failure shortly after the initiation of a chemotherapy regimen which included gemcitabine. Clinical examination and fluorescein angiography showed findings of severe retinal ischemia.\n\n\nCONCLUSIONS\nAlthough gemcitabine chemotherapy has been reported to cause a Purtscher-like retinopathy, we propose in our patient a gemcitabine-induced vasculopathy that lead to significant retinal and renal ischemia.",
"affiliations": "*Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York; †Department of Ophthalmology, NYU School of Medicine, New York, New York; and ‡Vitreous Retina Macula Consultants of New York, New York, New York.",
"authors": "Sheyman|Alan T|AT|;Wald|Kenneth J|KJ|;Pahk|Patricia J|PJ|;Freund|K Bailey|KB|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "8(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008875:Middle Aged; D012164:Retinal Diseases; D012189:Retrospective Studies; D014786:Vision Disorders",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "107-9",
"pmc": null,
"pmid": "25372321",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine associated retinopathy and nephropathy.",
"title_normalized": "gemcitabine associated retinopathy and nephropathy"
} | [
{
"companynumb": "US-ACCORD-027127",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nExudative age-related macular degeneration is commonly treated with intravitreal injection of medications containing antibodies against vascular endothelial growth factors, including ranibizumab (Lucentis, Genentech, South San Francisco, CA) and bevacizumab (Avastin, Genentech). To the best of our knowledge, hyphema has not previously been reported as a complication of intravitreal injection of ranibizumab or bevacizumab.\n\n\nMETHODS\nRetrospective case series.\n\n\nRESULTS\nThree patients developed hyphema after intravitreal injection of anti-vascular endothelial growth factor medications: one after ranibizumab and two after bevacizumab. Two patients were pseudophakic and taking warfarin in combination with low-dose aspirin, and one was phakic and not taking any coagulation-altering medications. A total of 26,184 intravitreal injections of ranibizumab or bevacizumab were given during the study period, for an estimated incidence of hyphema after intravitreal injection of approximately 1 in 10,000.\n\n\nCONCLUSIONS\nThe authors describe hyphema, either gross or microscopic, as a complication of intravitreal injection of anti-vascular endothelial growth factor medications. In all three patients, best-corrected vision returned to baseline after resolution of the hyphema and subsequent injections occurred without complication.",
"affiliations": "From the Associated Retinal Consultants, Royal Oak, Michigan.",
"authors": "Ranchod|Tushar M|TM|;Walsh|Mark K|MK|;Capone|Antonio|A|;Hassan|Tarek S|TS|;Williams|George A|GA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0b013e3181e1802d",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "5(1)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "87-90",
"pmc": null,
"pmid": "25389692",
"pubdate": "2011",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hyphema after intravitreal injection of ranibizumab or bevacizumab.",
"title_normalized": "hyphema after intravitreal injection of ranibizumab or bevacizumab"
} | [
{
"companynumb": "US-BAYER-2014-177151",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
"drugadditional": null,
... |
{
"abstract": "A patient with autoimmune Addison's disease treated with hydrocortisone and fludrocortisone became mineralocorticoid-deficient whilst taking lithium carbonate for a bipolar illness. During an in-patient metabolic balance study she required 1.0 mg fludrocortisone daily and dietary sodium supplementation to make plasma renin activity and serum potassium normal, and to abolish postural hypotension. We present data to suggest that lithium carbonate inhibits the action of fludrocortisone on the distal renal tubule.",
"affiliations": "Department of Medicine, Western General Hospital, Edinburgh, UK.",
"authors": "Stewart|P M|PM|;Grieve|J|J|;Nairn|I M|IM|;Padfield|P L|PL|;Edwards|C R|CR|",
"chemical_list": "D016651:Lithium Carbonate; D008094:Lithium; D012964:Sodium; D012083:Renin; D005438:Fludrocortisone",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2265.1987.tb00839.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0664",
"issue": "27(1)",
"journal": "Clinical endocrinology",
"keywords": null,
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000224:Addison Disease; D000328:Adult; D001714:Bipolar Disorder; D005260:Female; D005438:Fludrocortisone; D006801:Humans; D007684:Kidney Tubules; D007686:Kidney Tubules, Distal; D008094:Lithium; D016651:Lithium Carbonate; D012083:Renin; D012964:Sodium",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "63-8",
"pmc": null,
"pmid": "3115635",
"pubdate": "1987-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Lithium inhibits the action of fludrocortisone on the kidney.",
"title_normalized": "lithium inhibits the action of fludrocortisone on the kidney"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1024201",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDROCORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe challenge in renal transplantation is to improve long-term patient and graft survival without increasing early acute rejection by minimizing immunosuppression.\n\n\nMETHODS\nThis multicenter, observational study investigated the effects of withdrawal of steroids or mycophenolate mofetil (MMF) from a tacrolimus-based triple regimen (tac/MMF/steroids) 3 months posttransplant at 3 years; no additional interventions or assessments were undertaken. Adult patients, included in the intent-to-treat population of the THOMAS study, participated. Patient and graft survival, adverse events, rejection episodes, and immunosuppressive and concomitant medications were assessed.\n\n\nRESULTS\nData at Year 3 was available for 718 patients (triple therapy, n=237; steroid stop, n=235; MMF stop, n=246). The original randomized regimen was maintained in 45.6% of patients in the triple, 62.6% in the steroid stop, and 53.9% in the MMF stop groups. Graft survival rates were 88.1% (triple), 86.4% (steroid stop), and 85.8% (MMF stop); patient survival was 96.1%, 95.9%, and 95.7%, respectively. The incidence of biopsy-proven acute rejection was similar in all groups between Month 7 and Year 3: 1.2% (triple), 2.0% (steroid stop) and 2.0% (MMF stop). Patients in the steroid stop group had less hypertension and significantly lower mean total cholesterol and LDL-cholesterol at Year 3 compared with Month 3 (P=0.02). Median serum creatinine levels remained stable throughout the follow-up and were comparable between groups.\n\n\nCONCLUSIONS\nImmunosuppression minimization initiated at Month 3 was maintained at Year 3 in over half of the patients. Steroid withdrawal was advantageous in reducing the cardiovascular risk factors hyperlipidemia, hypertension and diabetes mellitus. Renal function was stable in all groups.",
"affiliations": "Servicio Nefrologia, Hospital Ramon y Cajal, Madrid, Spain. jpascual.hrc@salud.madrid.org",
"authors": "Pascual|Julio|J|;van Hooff|Johannes P|JP|;Salmela|Kaija|K|;Lang|Philippe|P|;Rigotti|Paolo|P|;Budde|Klemens|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D013256:Steroids; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/01.tp.0000225806.80890.5e",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "82(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D002318:Cardiovascular Diseases; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid; D013256:Steroids; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "55-61",
"pmc": null,
"pmid": "16861942",
"pubdate": "2006-07-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Three-year observational follow-up of a multicenter, randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplant.",
"title_normalized": "three year observational follow up of a multicenter randomized trial on tacrolimus based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplant"
} | [
{
"companynumb": "NVSC2020ES057951",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "A 4-year-old boy presented with fatigue and was found to have severe kidney injury requiring haemodialysis. A renal ultrasound demonstrated bilateral nephromegaly with mild loss of corticomedullary differentiation but preserved echogenicity. He had a persistent isolated monocytosis. Renal biopsy revealed extensive infiltration by primary renal diffuse large B-cell lymphoma. He required haemodialysis for 18 days and received chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab and intrathecal methotrexate. He achieved remission with an estimated glomerular filtration rate of 50 mL/min/1.73 m2, and his kidneys returned to normal size. Nephromegaly due to renal-limited haematolymphoid disease is extremely rare, especially in children.",
"affiliations": "Department of Pediatrics, Section of Nephrology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.",
"authors": "South|Andrew Michael|AM|http://orcid.org/0000-0002-3204-4142",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "acute renal failure; dialysis; haematology (incl blood transfusion); paediatric oncology; paediatrics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D006801:Humans; D007680:Kidney Neoplasms; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009361:Neoplasm Invasiveness; D006435:Renal Dialysis; D014463:Ultrasonography",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30257873",
"pubdate": "2018-09-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18235140;12649096;15388825;21552148;17954302;3594375;22714941;16844565;22015620;8338926;27903857;16020119;12671156;22975997;27040111;2511102;9121151",
"title": "Primary renal diffuse large B-Cell lymphoma causing haemodialysis-dependent nephromegaly in a child.",
"title_normalized": "primary renal diffuse large b cell lymphoma causing haemodialysis dependent nephromegaly in a child"
} | [
{
"companynumb": "US-ACCORD-088938",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening hypersensitivity reaction to medication. While a relatively rare phenomenon, early identification and discontinuation of the offending agent is pivotal to patient management. To our knowledge this is the first reported case of probable atorvastatin induced DRESS syndrome without rash.\n\n\nMETHODS\nAn adult female presented with 4 days of persistent fevers, abdominal and flank pain, malaise, and generalized muscle weakness without any cutaneous reaction following 20 days of therapy with atorvastatin. She was febrile (38.5 °C), at presentation with a heart rate of 72, and blood pressure of 93/51 mmHg. Her laboratory investigations at their peak demonstrated an Alkaline Phosphatase (ALP) of 792 U/L, Alanine aminotransferase (ALT) of 265 U/L, gamma glutamyl transferase (GGT) of 236 U/L, total bilirubin at 21 mg/dL, eosinophils 3100 cells/µL, leukocytes 20.2 K/µL, hemoglobin of 12.5 gm/dL. During her admission she had normal creatinine and troponin. Her serology for Hepatitis A, B and C were negative. Cytomegalovirus, Epstein-Barr viral serologies were negative. Antinuclear Antibody (ANA), rheumatoid factor, anti-neutrophil cytoplasmic antibody (ANCA), mitochondrial antibody, and smooth muscle antibody were negative. The patient was initially diagnosed as having pyelonephritis due to nonspecific bilateral flank pain but given ongoing fevers and lack of clinical and laboratory improvement with antibiotics, a diagnosis of atorvastatin induced DRESS syndrome was considered probable, and atorvastatin was discontinued. The patients' clinical status improved gradually without any further therapy and her liver enzymes and eosinophils normalized over the course of a month.\n\n\nCONCLUSIONS\nIn patients who present with systemic organ involvement and eosinophilia, even without cutaneous manifestations, clinicians should apply the RegiSCAR criteria for DRESS syndrome. This can then help guide treatment with discontinuation of offending agent, or treatment with systemic corticosteroids.",
"affiliations": "McMaster University, Hamilton, ON, Canada. arman.zereshkian@medportal.ca.;McMaster University, Hamilton, ON, Canada.",
"authors": "Zereshkian|Arman|A|;Waserman|Susan|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13223-021-00581-y",
"fulltext": "\n==== Front\nAllergy Asthma Clin Immunol\nAllergy Asthma Clin Immunol\nAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology\n1710-1484\n1710-1492\nBioMed Central London\n\n581\n10.1186/s13223-021-00581-y\nCase Report\nLiver enzyme elevation and eosinophilia with atorvastatin: a case of probable DRESS without cutaneous symptoms\nZereshkian Arman arman.zereshkian@medportal.ca\n\nWaserman Susan\ngrid.25073.33 0000 0004 1936 8227 McMaster University, Hamilton, ON Canada\n30 7 2021\n30 7 2021\n2021\n17 8124 5 2021\n18 7 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\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening hypersensitivity reaction to medication. While a relatively rare phenomenon, early identification and discontinuation of the offending agent is pivotal to patient management. To our knowledge this is the first reported case of probable atorvastatin induced DRESS syndrome without rash.\n\nCase presentation\n\nAn adult female presented with 4 days of persistent fevers, abdominal and flank pain, malaise, and generalized muscle weakness without any cutaneous reaction following 20 days of therapy with atorvastatin. She was febrile (38.5 °C), at presentation with a heart rate of 72, and blood pressure of 93/51 mmHg. Her laboratory investigations at their peak demonstrated an Alkaline Phosphatase (ALP) of 792 U/L, Alanine aminotransferase (ALT) of 265 U/L, gamma glutamyl transferase (GGT) of 236 U/L, total bilirubin at 21 mg/dL, eosinophils 3100 cells/µL, leukocytes 20.2 K/µL, hemoglobin of 12.5 gm/dL. During her admission she had normal creatinine and troponin. Her serology for Hepatitis A, B and C were negative. Cytomegalovirus, Epstein-Barr viral serologies were negative. Antinuclear Antibody (ANA), rheumatoid factor, anti-neutrophil cytoplasmic antibody (ANCA), mitochondrial antibody, and smooth muscle antibody were negative. The patient was initially diagnosed as having pyelonephritis due to nonspecific bilateral flank pain but given ongoing fevers and lack of clinical and laboratory improvement with antibiotics, a diagnosis of atorvastatin induced DRESS syndrome was considered probable, and atorvastatin was discontinued. The patients’ clinical status improved gradually without any further therapy and her liver enzymes and eosinophils normalized over the course of a month.\n\nConclusion\n\nIn patients who present with systemic organ involvement and eosinophilia, even without cutaneous manifestations, clinicians should apply the RegiSCAR criteria for DRESS syndrome. This can then help guide treatment with discontinuation of offending agent, or treatment with systemic corticosteroids.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is a serious, potentially life threatening condition that typically presents with generalized skin rash, fevers, enlarged lymph nodes, hematological abnormalities in addition to eosinophilia and multi-organ dysfunction [1]. The diagnosis of DRESS is often challenging, with heterogeneity in clinical presentation, often initially misdiagnosed as infection [2]. Given this diagnostic dilemma, The Register of Severe Cutaneous Adverse Reactions (RegiSCAR) created a diagnostic validation score which is now widely used for the diagnosis of DRESS syndrome. The criteria are scored from − 4 to 9, with a scores of less than 2 excluding the diagnosis of DRESS, 2–3 being possible, 4–5 probable, and a score above 6 being definite [3].\n\nMany different medications are implicated in DRESS, however the most common causes are typically seen with anticonvulsants and antibiotics [1, 4]. Statin class medications are not typically implicated or associated with DRESS [1]. In our review of the literature, there are 4 case reports of statin associated DRESS syndrome. Given that statins are one of the most commonly used treatments for cholesterol lowering and prevention of cardiovascular disease, further classification of DRESS-like reactions are especially warranted. To our knowledge, we report the first case report of statin associated DRESS syndrome in a patient who did not develop any cutaneous findings during the clinical course.\n\nCase presentation\n\nA 50-year-old female with a past medical history remarkable for generalized anxiety disorder initially presented to the emergency department with a one-day history of retrosternal chest pain. Her other medications included ASA, Ramipril, and Citalopram. In the emergency department her electrocardiogram (ECG) demonstrated ST segment changes suggestive of a non-ST elevation myocardial infarction (NSTEMI) which prompted urgent coronary artery catheterization. Her coronary angiogram demonstrated Type 3 spontaneous coronary artery dissection (SCAD) with diffuse coronary ectasia and preserved left ventricular ejection fraction. She was treated conservatively with Acetylsalicylic acid 81 mg daily, Ramipril 2.5 mg daily, and Atorvastatin 80 mg daily and discharged two days later.\n\nShe presented to the emergency department 20 days later with a 4-day history of fevers (> 38.5 °C) and bilateral flank pain that were non-responsive to non-steroidal anti-inflammatory drugs (NSAIDs). Laboratory investigations in the emergency department were remarkable for leukocytosis (16.6 K/µL), normal eosinophils (300 cells/µL), ALP 365 U/L, ALT 265 U/L, GGT 185 U/L and total bilirubin of 10 mg/dL. Her lipase was normal. Urinalysis in the emergency department demonstrated pyuria and trace ketones without nitrites. She had an unremarkable chest x-ray and computed tomography of the abdomen/pelvis. She was treated with a single dose of Ceftriaxone for presumptive pyelonephritis due to vague complaints of bilateral flank pain and discharged with follow up to her family physician.\n\nDespite this, she continued to have persistent fevers, myalgias, malaise, lower limb weakness, and abdominal pain prompting a return to the emergency department two days later where she was admitted to the hospital with a diagnosis of fever of unknown origin (FUO).\n\nOn admission her eosinophils were 500 cell/µL, leukocytes 20.2 K/ µL, ALP 666 U/L, ALT 236 U/L, GGT 236 U/L. Her lipase and urinalysis were normal. Abdominal ultrasound demonstrated borderline gallbladder thickening but no evidence of infection. Blood cultures from two days prior were normal. She had a negative nasopharyngeal swab for Sars-Cov-2 virus. Her vital signs on admission were as follows: Temperature 38.5 °C, heart rate of 72, blood pressure of 93/51, and oxygen saturation of 100 percent on room air. Her physical examination demonstrated a low jugular venous pressure but otherwise normal cardiorespiratory examination. Abdominal examination was normal with a soft, non-tender abdomen and no hepatosplenomegaly. Skin and joint examination were also unremarkable, as were her conjunctivae, and oral mucosa. There was no cervical lymphadenopathy.\n\nOn admission she was given a single dose of metronidazole and Ceftriaxone, with her antibiotic regimen subsequently broadened to Piperacillin-Tazobactam. Her serology for Hepatitis A, B and C were negative. Cytomegalovirus, Epstein-Barr virus serologies were negative. Antinuclear Antibody (ANA), rheumatoid factor, anti-neutrophil cytoplasmic antibody (ANCA) as well mitochondrial antibody, smooth muscle antibody were also negative. Gastroenterology was consulted for her elevated liver enzyme tests and abdominal pain. Eosinophils were elevated at 1900 cells/µL, raising the question of a drug reaction causing her hepatitis as opposed to sepsis. Infectious Disease (ID) physician felt that this was drug induced liver injury with eosinophilia and “probable” DRESS syndrome secondary to Atorvastatin as the culprit, given her lack of response to antibiotics and increasing eosinophils.\n\nCeftriaxone, metronidazole and Atorvastatin were held. Her liver enzymes started to trend downwards, and her symptoms improved. She was discharged in stable condition 2 days later. Eosinophils peaked at 3100 cells/µL prior to discharge. Three weeks into her follow up, eosinophils and liver function test abnormalities had completely normalized. She was asymptomatic one month post discharge and remained off Atorvastatin.\n\nDiscussion\n\nDRESS syndrome is typically a dermatological condition, with a diffuse maculopapular eruptions that progresses to erythematous rash with edema [4]. A retrospective review in one institution in the UK found that nearly all patients diagnosed with DRESS syndrome had cutaneous findings [2]. Our review of the literature revealed four published cases of suspected DRESS syndrome attributed to statin medications, however, all these reported rash as a cardinal finding, unlike our patient. Herein we report the first case of probable DRESS syndrome attributed to a statin without any cutaneous findings.\n\nThe diagnosis of DRESS syndrome in this case was made using RegiSCAR diagnostic criteria Table 1 [5]. Our patient scored a 4 indicating “probable” DRESS syndrome. The delay in diagnosis in patients with DRESS syndrome is noted to be on average 1.7 days, with 50% of cases initially being misdiagnosed as infection [2]. In this case, the patient’s diagnosis was reached after 4 days given the lack of classic erythematous rash, possibility of Urinary Tract Infection and later elevation of eosinophils. An important learning point from this case is to consider a diagnosis of DRESS syndrome even in the absence of cutaneous symptoms. Another learning point is the spectrum of hypersensitivity reaction that can occur due to drug therapy. Well described with statins, albeit rare, is drug-induced liver injury [6]. The spectrum of statin hepatotoxicity can be quite variable including ALT elevation and cholestatic liver enzyme elevation, and in a subset of patients, fever and rash [6]. Given the similarity of these findings to DRESS syndrome, this raises the question of whether statin induced hepatotoxicity may be part of the spectrum of DRESS related drug reactions, which requires further study.Table 1 RegiSCAR Criteria for DRESS Syndrome with our patient’s score calculated in the right most column with a total score of 4 (probable)\n\nScoring Criteria\tScore modifier if present\tScore modifier if absence\tSpecial score considerations\tScoring for our patient\t\nFever (≥ 38.5 °C)\t0\t− 1\t–\tPresent (0)\t\nLymphadenopathy (> 1 cm in two sites)\t1\t0\t–\tAbsent (0)\t\nEosinophilia\t1 (If > 700 cells/µL)\t0\t2 (if > 1500 cells/µL)\tHighly present (2)\t\nAtypical lymphocytosis (on blood film)\t1\t0\tN/A\tNot assessed (0)\t\nSkin rash (> 50% body surface area)\t1\t0\t–\tAbsent (0)\t\nSkin Biopsy (if applicable)\t1 (if + for DRESS)\t− 1 (if negative for DRESS)\t–\tNot assessed (0)\t\nOrgan involvement\t1\t0\tIf more than one organ involvement + 1 score for a total of 2\tOne organ involvement (1)\t\nResolution > 15 days\t0\t− 1\t–\tPresent (0)\t\nOther causes excluded (3 or more of below negative)\n\nAntinuclear antibody\n\nBlood culture\n\nSerology for viral hepatitis\n\nChlamydia/mycoplasma\n\n\t1\t0\t–\t3 causes ruled out (1)\t\n\nManagement of DRESS syndrome is dependent on severity, with mild disease treated with supportive care. Severe disease (such as those with lung or kidney involvement) requires oral glucocorticoids with a slow taper over 6 to 8 weeks. In those who fail to improve with steroids, second line immunosuppressive medications, such as cyclosporine or Intravenous immunoglobulin (IVIG) can be added, although evidence is limited [7].\n\nConclusions\n\nDRESS syndrome is associated with significant morbidity and has a 10% mortality rate, hence timely diagnosis is critical [4]. This diagnosis should be considered when patients present with extensive rash with eosinophilia and organ involvement. However, clinicians should remember that rash is not required for a diagnosis of DRESS syndrome and that it should be considered in their differential diagnosis of hypersensitivity drug reactions. While certain medications are more often associated with DRESS syndrome, drug reaction could potentially occur with any medication, and as such, a review of recently started drug therapies is critical.\n\nStatins are a rarely described potential cause of DRESS syndrome, and here we report a case that presented without the typical rash. In patients that present with liver injury after the start of any new medication, diagnostic clarity for DRESS syndrome may be achieved using the RegiSCAR criteria to prevent morbidity and potentially mortality.\n\nAcknowledgements\n\nNo acknowledgement to declare.\n\nAuthors' contributions\n\nAZ research and drafted the manuscript in conjunction with feedback, edits and restructuring with SW. Both authors read and approved the final manuscript.\n\nFunding\n\nThis project received no funding.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe need for ethics approval was waived as per our institutional practice (Hamilton Integrated Research Ethics Board). Consent was obtained from the patient.\n\nConsent for publication\n\nConsent has been provided.\n\nCompeting interests\n\nNo competing interest to declare.\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. Mustafa SF Zafar MR Miller TW Rosuvastatin use implicated in the drug reaction with eosinophilia and systemic symptoms Cureus 2020 12 2 1 6 10.7759/cureus.7098\n2. Lee H, Walsh S, Creamer D. Initial presentation of DRESS: often misdiagnosed as infections. 2012;148(9):1085–1087. https://jamanetwork.com/journals/jamadermatology/fullarticle/1359491.\n3. Kardaun SH Sekula P Valeyrie-Allanore L Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study Br J Dermatol. 2013 169 5 1071 1080 10.1111/bjd.12501 23855313\n4. De A Rajagopalan M Sarda A Das S Biswas P Drug Reaction with Eosinophilia and Systemic Symptoms: An Update and Review of Recent Literature Indian J Dermatol 2018 63 2 125 130 10.4103/ijd.IJD 29692453\n5. Kardaun SH Sidoroff A Valeyrie-Allanore L Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? [20] Br J Dermatol 2007 156 3 609 611 10.1111/j.1365-2133.2006.07704.x 17300272\n6. Russo MW Hoofnagle JH Gu J The spectrum of statin hepatotoxicity: experience of the drug induced liver injury network Hepatology 2014 60 2 679 686 10.1002/hep.27157.The 24700436\n7. Shiohara T Mizukawa Y Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): An update in 2019 Allergol Int 2019 68 3 301 308 10.1016/j.alit.2019.03.006 31000444\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1710-1484",
"issue": "17(1)",
"journal": "Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology",
"keywords": null,
"medline_ta": "Allergy Asthma Clin Immunol",
"mesh_terms": null,
"nlm_unique_id": "101244313",
"other_id": null,
"pages": "81",
"pmc": null,
"pmid": "34330325",
"pubdate": "2021-07-30",
"publication_types": "D016428:Journal Article",
"references": "24700436;23855313;29527023;32231894;31000444;17300272;22986875",
"title": "Liver enzyme elevation and eosinophilia with atorvastatin: a case of probable DRESS without cutaneous symptoms.",
"title_normalized": "liver enzyme elevation and eosinophilia with atorvastatin a case of probable dress without cutaneous symptoms"
} | [
{
"companynumb": "CA-APOTEX-2021AP039452",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Concomitant administration of chemotherapy and radiotherapy is currently recognized as the standard of treatment in locally advanced inoperable non-small cell lung cancer (NSCLC). Our study aimed to compare the efficacy and toxicities of three different chemotherapy regimens delivered concurrently with radiotherapy. We retrospectively reviewed the clinical records of patients who received the PE (cisplatin, 50 mg/m(2), on days 1, 8, 29, and 36 plus etoposide, 50 mg/m(2), on days 1 to 5 and 29 to 33), PD (docetaxel, 20 mg/m(2), on day 1 plus cisplatin, 20 mg/m(2), on day 1, every week), and PC (carboplatin, AUC 2 plus paclitaxel, 45 mg/m(2), on day 1, every week) regimens concurrently with radiotherapy. A total of 227 patients were evaluated in the study. Median follow-up time was 13 months (2-101). There were 27 females (11.9 %) and 200 males (88.1 %) with a median age of 61 (38-82) years. The PD group had higher rates of esophagitis, mucositis, and anemia (p < 0.05). The PC group had higher rates of neuropathy (p = 0.000). The progression-free survival (PFS) time was 10 months for patients in the PC group, 15 months for patients in the PD group, and 21 months for the PE group (p = 0.010). Patients in the PC group had a median overall survival time of 23 months, those in the PD group 27 months, and those in the PE group 36 months (p = 0.098). Combination of cisplatin-etoposide with radiotherapy led to a more favorable outcome compared with the other two regimens. It shows generally manageable toxicity profile and compliance to treatment is noticeable.",
"affiliations": "Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey. drmelike.ozcelik@gmail.com.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Radiation Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.;Department of Medical Oncology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Kartal Dr. Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.",
"authors": "Ozcelik|Melike|M|;Korkmaz|Taner|T|;Odabas|Hatice|H|;Gemici|Cengiz|C|;Ercelep|Ozlem|O|;Yuksel|Sinemis|S|;Mert|Aslihan Guven|AG|;Surmeli|Heves|H|;Isik|Deniz|D|;Aydin|Dincer|D|;Seker|Mesut|M|;Mayadagli|Alparslan|A|;Ozdemir|Pınar|P|;Aliustaoglu|Mehmet|M|;Gumus|Mahmut|M|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D005047:Etoposide; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s13277-015-4776-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-4283",
"issue": "37(7)",
"journal": "Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine",
"keywords": "Concurrent chemoradiation; Non-small cell lung cancer; Stage III",
"medline_ta": "Tumour Biol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D000077143:Docetaxel; D005047:Etoposide; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D043823:Taxoids",
"nlm_unique_id": "8409922",
"other_id": null,
"pages": "8901-7",
"pmc": null,
"pmid": "26753955",
"pubdate": "2016-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "22418243;17404369;16087941;26214630;12743155;24403265;19443340;21903745;12177106;26480859;7165009;10669675;21056507;19097774;22237781;26691657;20530281;20351327;18378568;17084621;12226051;20625120;19001323;15005280;11777624",
"title": "Comparison of efficacy and safety of three different chemotherapy regimens delivered with concomitant radiotherapy in inoperable stage III non-small cell lung cancer patients.",
"title_normalized": "comparison of efficacy and safety of three different chemotherapy regimens delivered with concomitant radiotherapy in inoperable stage iii non small cell lung cancer patients"
} | [
{
"companynumb": "TR-PFIZER INC-2016400261",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nNo standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor.\n\n\nMETHODS\nBetween May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov, number NCT01621568.\n\n\nRESULTS\n41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14.0-18.4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12.1-45.3, 95% CI 10.2-48.4) had partial responses, 15 (65%, 95% CI 42.7-83.6) achieved stable disease, and two (9%, 1.1-28.0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0.2-30.2) had a partial response, 12 (75%, 47.6-92.7) had stable disease, and three (19%, 4.1-45.7) had progressive disease. The most common grade 3 and 4 treatment-related adverse events were lymphocytopenia (eight [20%] of 40 patients), fatigue (eight [20%]), and oral mucositis (eight [20%]). Five (13%) patients had decreases in left-ventricular ejection fraction, of which three (8%) were grade 3 events. Three (8%) patients died during treatment, including one individual who died of cardiac arrest that was possibly treatment-related.\n\n\nCONCLUSIONS\nSunitinib is active in previously treated patients with thymic carcinoma. Further studies are needed to identify potential biomarkers of activity.\n\n\nBACKGROUND\nNational Cancer Institute (Cancer Therapy Evaluation Program).",
"affiliations": "Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Department of Hematology and Oncology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Division of Hematology/Oncology, Indiana University Medical Center, Indianapolis, IN, USA.;Department of Hematology and Oncology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.;Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Division of Hematology/Oncology, Indiana University Medical Center, Indianapolis, IN, USA.;Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA. Electronic address: gg496@georgetown.edu.",
"authors": "Thomas|Anish|A|;Rajan|Arun|A|;Berman|Arlene|A|;Tomita|Yusuke|Y|;Brzezniak|Christina|C|;Lee|Min-Jung|MJ|;Lee|Sunmin|S|;Ling|Alexander|A|;Spittler|Aaron J|AJ|;Carter|Corey A|CA|;Guha|Udayan|U|;Wang|Yisong|Y|;Szabo|Eva|E|;Meltzer|Paul|P|;Steinberg|Seth M|SM|;Trepel|Jane B|JB|;Loehrer|Patrick J|PJ|;Giaccone|Giuseppe|G|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "16(2)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors; D011379:Prognosis; D011758:Pyrroles; D000077210:Sunitinib; D015996:Survival Rate; D013945:Thymoma; D013953:Thymus Neoplasms",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "177-86",
"pmc": null,
"pmid": "25592632",
"pubdate": "2015-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "12202865;14991904;20103246;19276342;18083403;20859122;12712448;24391639;19461405;23313005;20525992;24974848;10880395;18187653;20571495;18927310;25146529;18356031;11090072;25482724;12531805;23328550;20651610;21645144;22434312;8201378;11766079;4074823;24439931;24801577;22658128",
"title": "Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial.",
"title_normalized": "sunitinib in patients with chemotherapy refractory thymoma and thymic carcinoma an open label phase 2 trial"
} | [
{
"companynumb": "US-PFIZER INC-2015058674",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": null,
... |
{
"abstract": "This article reports the case of a 22-year-old male patient presented with electrocardiographic ST elevation and elevated cardiac biomarkers. The clinical cascade set into events within an hour of administration of a single-dose of amoxicillin on being diagnosed with acute tonsillitis. The case was preliminarily diagnosed and treated according to the acute coronary syndrome protocol, but on performing coronary angiography no abnormalities in the coronary artery were found. Acute myocarditis was excluded in cardiac MRI. Considering possible hypersensitive reaction of amoxicillin in the absence of major cardiovascular risk in the young patient, diagnosis of Kounis syndrome (KS) was inferred. A thorough clinical observation of the patient after stopping the administration of amoxicillin revealed that there was a resolution of ST-elevation towards baseline. It coincided with falling cardiac biomarkers concomitant with subsided pain. The asymptomatic patient was discharged after 5 days of hospital stay. Telephonic follow-up one week after discharge from the hospital confirmed his pain-free and overall normal clinical status. Aim of the present report is to emphasize the need for increased awareness of KS induced by amoxicillin.",
"affiliations": "Department of Cardiology and Angiology, Marien Hospital, Herne, University of Bochum, Herne, Germany.;Department of Cardiology and Angiology, Marien Hospital, Herne, University of Bochum, Herne, Germany.;Department of Cardiology and Angiology, Marien Hospital, Herne, University of Bochum, Herne, Germany.",
"authors": "Pradhan|Snehasis|S|;Christ|Martin|M|;Trappe|Hans-Joachim|HJ|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.21037/cdt.2018.03.07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2223-3652",
"issue": "8(2)",
"journal": "Cardiovascular diagnosis and therapy",
"keywords": "Kounis syndrome (KS); ST-elevation; amoxicillin; coronary vasospasm; vasospastic angina",
"medline_ta": "Cardiovasc Diagn Ther",
"mesh_terms": null,
"nlm_unique_id": "101601613",
"other_id": null,
"pages": "180-185",
"pmc": null,
"pmid": "29850410",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports",
"references": "27684599;23623347;16626819;1793697;21569746;23490289;17091059;24801079;18632172;26512841;19277706;28153536;16249041;23907697",
"title": "Kounis syndrome induced by amoxicillin following vasospastic coronary event in a 22-year-old patient: a case report.",
"title_normalized": "kounis syndrome induced by amoxicillin following vasospastic coronary event in a 22 year old patient a case report"
} | [
{
"companynumb": "DE-DRREDDYS-USA/GER/18/0102369",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "1",
... |
{
"abstract": "Novel induction agents markedly improved remission rates in multiple myeloma (MM), and the continued use of chemotherapy for CD34+ stem cell mobilization (SCM) has been questioned. We examined the additional effect of chemotherapy in SCM regarding remission status/morbidity. We reviewed 236 consecutive MM patients (aged 36 to 75 years) with first autologous stem cell transplantation from January 2009 to March 2016 after chemotherapy-based SCM. Responses were measured by changes in intact Ig and free light chain levels before and after chemomobilization (International Myeloma Working Group [IMWG] criteria). Most patients (225/236, 95.3%) received novel induction regimens, which were bortezomib-based (n = 223) and/or lenalidomide-based (n = 19). Most patients (170/190, 89.5%) achieved at least partial remission postinduction and pre-SCM. Stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide-based (212/227, 93.4%) or etoposide-based (15/227, 6.6%) regimens. There were insignificant changes in serum Ig and free light chain levels before and after chemomobilization either in the whole cohort or subgroups. Significant improvements of the IMWG remission status were documented in only 7 of 236 patients (3.0%). Sixty-seven patients (28.4%) developed chemotherapy-related complications (neutropenic fever, sepsis, and others), resulting in 9 hospitalizations (3.8%). Our study suggests that although causing significant morbidity, chemotherapy-based mobilization fails to improve remission status. The value of incorporating additional chemotherapy for SCM is thus not evident.",
"affiliations": "Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany; Department of Internal Medicine, University of Botswana, Botswana.;Department of Hematology and Medical Oncology, Medical Center University of Göttingen, Germany.;Department of Hematology and Oncology, University Hospital Giessen and Marburg, Germany.;Department of Hematology and Oncology, University Hospital Giessen and Marburg, Germany.;Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, Germany.;Department of Internal Medicine V, University of Heidelberg, Germany; Institute of Transfusion Medicine, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany.;Department of Hematology and Medical Oncology, Medical Center University of Göttingen, Germany.;Department of Hematology, Inselspital Bern, Bern, Switzerland.;Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: nkroeger@uke.uni-hamburg.de.",
"authors": "Oyekunle|Anthony|A|;Shumilov|Evgenii|E|;Kostrewa|Philippe|P|;Burchert|Andreas|A|;Trümper|Lorenz|L|;Wuchter|Patrick|P|;Wulf|Gerald|G|;Bacher|Ulrike|U|;Kröger|Nicolaus|N|",
"chemical_list": "D010266:Paraproteins",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2017.10.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(2)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Autologous stem cell transplantation (ASCT); Multiple myeloma (MM); Novel induction regimens; Remission status; Stem cell mobilization",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010266:Paraproteins; D012074:Remission Induction; D012189:Retrospective Studies; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "276-281",
"pmc": null,
"pmid": "29037891",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens.",
"title_normalized": "chemotherapy based stem cell mobilization does not result in significant paraprotein reduction in myeloma patients in the era of novel induction regimens"
} | [
{
"companynumb": "DE-TAKEDA-2018MPI016976",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Kara A, Devrim İ, Çağlar İ, Bayram N, Kundak S, Apa H, Altan EV. Stevens-Johnson syndrome and toxic epidermal necrolysis: a report of six cases. Turk J Pediatr 2019; 61: 538-543. Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous adverse reactions commonly caused by exposure to drugs and can end up with significant morbidity and mortality. We reported our experience with six patients who were diagnosed with Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis with a different clinical presentation. In patients, drugs and Mycoplasma pneumoniae infection were implicated as a trigger. Intravenous Immunoglobulin treatment was given to all patients, and intensive treatment was applied for skin and mucosal lesions. The median period of stay in hospital was 13.5 days. The most common long-term complication was ocular involvement. Among six patients, corneal epithelial defects occurred in one patient. Consequently, ophthalmological evaluation should be performed both at the time of diagnosis and before hospital discharge.",
"affiliations": "Departments of Pediatric Infectious Diseases, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.;Departments of Pediatric Infectious Diseases, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.;Departments of Pediatric Infectious Diseases, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.;Departments of Pediatric Infectious Diseases, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.;Departments of Dermatology, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.;Departments of Pediatrics, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.;Ophthalmology, Dr. Behçet Uz Children's Hospital, İzmir, Turkey.",
"authors": "Kara|Ahu|A|;Devrim|İlker|İ|;Çağlar|İlknur|İ|;Bayram|Nuri|N|;Kundak|Selcen|S|;Apa|Hurşit|H|;Altan|Emir Volkan|EV|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "61(4)",
"journal": "The Turkish journal of pediatrics",
"keywords": "Stevens-Johnson syndrome; drug reaction; mycoplasma",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008297:Male; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "538-543",
"pmc": null,
"pmid": "31990471",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stevens-Johnson syndrome and toxic epidermal necrolysis: a report of six cases.",
"title_normalized": "stevens johnson syndrome and toxic epidermal necrolysis a report of six cases"
} | [
{
"companynumb": "NVSC2020TR033848",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "1",
"dr... |
{
"abstract": "BACKGROUND\nWe previously reported 57% 12-month event free survival (EFS) in Malawian children with stage I to III Burkitt lymphoma (BL) with an intermediate dose chemotherapy protocol lasting 77 days. This protocol was shortened to 42 days and evaluated in children with stage I to IV disease for EFS and toxicity.\n\n\nMETHODS\nAll Malawian children admitted to Queen Elizabeth Central Hospital, from 03/08/2000 to 12/03/2002 with confirmed BL were eligible. A fine needle aspirate, bone marrow aspirate, cerebrospinal fluid cytology, haemoglobin (Hb), white cell count (WCC), malaria smear, ELISA for HIV, and abdominal ultrasound were performed routinely. Murphy staging was used. The first dose of chemotherapy (COP1) consisted of 300 mg cyclophosphamide (CPM), 1 mg vincristine, and 60 mg prednisone given on day 1 and followed by COP2 on day 8 (only for patients with larger tumour volumes, stage III or IV disease). The vincristine dose in COP2 was 2 mg. COMP1 and 2 given on days 22 and 36 consisted of 500 mg CPM, 2 mg vincristine, 60 mg prednisone, and 2 g methotrexate. All doses were calculated per body surface area. Intrathecal methotrexate and hydrocortisone were given with COP1 and 2.\n\n\nRESULTS\nForty-two patients, 30 boys and 12 girls median ages 6 and 7.5 years, respectively, had Murphy stage I(n5), II(n8), III(n21), and IV(n8) disease. The face was involved in 74%, abdomen in 55%, bone marrow in 14%, kidneys in 24%, and 12% had paraplegia. Fourteen children died during or shortly after completion of chemotherapy. Three of these were disease related. Twelve patients suffered a local relapse after 57-328 days, and one a CNS relapse at 76 days. The projected EFS at 12 months is 50% in stage I, 50% in stage II, 24% in stage III, 25% in stage IV, and 33% for all patients. The cumulative mean dose of CPM was 62 mg/kg in survivors and 64 mg/kg in children who relapsed. One third of patients experienced significant marrow suppression, and infections after COMP1.\n\n\nCONCLUSIONS\nThirty-three percent of children are in first remission at 12 months. The morbidity and mortality of treatment was high. The high relapse rate in all stages may be due to the low cumulative dose of CPM.",
"affiliations": "Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa. pbh@sun.ac.za",
"authors": "Hesseling|Peter|P|;Broadhead|Robin|R|;Mansvelt|Erna|E|;Louw|Mercia|M|;Wessels|Glynn|G|;Borgstein|Eric|E|;Schneider|Johann|J|;Molyneux|Elizabeth|E|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.20254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "44(3)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D008295:Malawi; D008297:Male; D008727:Methotrexate; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011241:Prednisone; D014750:Vincristine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "245-50",
"pmc": null,
"pmid": "15547922",
"pubdate": "2005-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The 2000 Burkitt lymphoma trial in Malawi.",
"title_normalized": "the 2000 burkitt lymphoma trial in malawi"
} | [
{
"companynumb": "ZA-PFIZER INC-HQWYE880308MAR05",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
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"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
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{
"abstract": "Enteroviruses-associated acute necrotizing encephalopathy (ANE) of childhood is rarely reported in the literature. Clinico-radiological features of ANE are well-recognized and bilateral thalamic nuclei are frequently affected by ANE. Neuropsychiatric symptoms are rarely seen. Thalamic damage can cause psychosis.\n\n\n\nHerein, we present a pediatric case of enterovirus-associated ANE presenting with psychosis related to thalamus damage in whom a favorable response to treatment was achieved.\n\n\n\nThalamic damage occurs during the Enteroviruses-associated acute necrotizing encephalopathy and it can be related psychiatric sympthoms. Clinicians should be aware of uncommon presentations of ANE, and patients with thalamic damage should be followed for neuropsychiatric manifestations. Early recognition and appropriate treatment of ANE is important to obtain favorable outcomes.",
"affiliations": "Departments of Pediatric Neurology, Gazi University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Neurology, Gazi University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Neurology, Gazi University Faculty of Medicine, Ankara, Turkey.;Departments of Child and Adolescent Psychiatry, Gazi University Faculty of Medicine, Ankara, Turkey.;Departments of Child and Adolescent Psychiatry, Gazi University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Neurology, Gazi University Faculty of Medicine, Ankara, Turkey.",
"authors": "Orgun|Leman Tekin|LT|;Arhan|Ebru|E|;Aydın|Kürşad|K|;Torun|Yasemin Taş|YT|;Güney|Esra|E|;Serdaroğlu|Ayşe|A|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "62(2)",
"journal": "The Turkish journal of pediatrics",
"keywords": "childhood; encephalopathy; enterovirus; psychosis; thalamus damage",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D001927:Brain Diseases; D002648:Child; D006801:Humans; D004684:Leukoencephalitis, Acute Hemorrhagic; D008279:Magnetic Resonance Imaging; D011618:Psychotic Disorders",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "320-325",
"pmc": null,
"pmid": "32419427",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute necrotizing encephalopathy with organic psychosis: a pediatric case report.",
"title_normalized": "acute necrotizing encephalopathy with organic psychosis a pediatric case report"
} | [
{
"companynumb": "NVSC2020TR147553",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"drugadditional": "3",
"dr... |
{
"abstract": "Ozurdex® 0.7 mg (dexamethasone 0.7 mg implant, Allergan, Dublin, Ireland), an intravitreal biodegradable implant, is indicated for cystoid macular edema due to various causes. One of its known and uncommon complications is implant migration to the anterior chamber, causing corneal edema that, in some cases, is irreversible. Reported risk factors for device migration are open or defective lens capsule and prior history of vitrectomy. We present a case of dexamethasone implant migration through a congenital iris coloboma in a pseudophakic patient with an intact lens capsule. The patient is a 56-year-old pseudophakic man with a history of congenital iris coloboma, myopia, retinal tears, and a branch retinal vein occlusion with subsequent cystoid macular edema resistant to anti-VEGF medications but responsive to corticosteroids. He presented with sudden painless decreased vision in his left eye, 8 weeks following dexamethasone implant (Ozurdex) injection to the same eye. Upon presentation, he was diagnosed with corneal edema caused by anterior chamber migration of the implant. He was referred for immediate surgical intervention to extract the implant, with a resolution of the corneal edema within 2 weeks postoperatively. To conclude, this is the first case that reports Ozurdex implant migration through an iris coloboma in the setting of an intact posterior capsule. In addition, we describe a novel surgical approach for implant removal from the anterior chamber that is simple and efficient.",
"affiliations": "Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv, Israel.;Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv, Israel.;Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv, Israel.",
"authors": "Glidai|Yoav|Y|;Schwartz|Shulamit|S|;Cohen|Eyal|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000505638",
"fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699 S. 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.com \n\n10.1159/000505638\ncop-0011-0073\nCase Report\nDexamethasone Implant Migration through an Iris Coloboma\nGlidai Yoav ab* Schwartz Shulamit ab Cohen Eyal ab aDepartment of Ophthalmology, Tel Aviv Medical Center, Tel Aviv, Israel\nbSackler School of Medicine, Tel Aviv University, Tel Aviv, Israel\n*Yoav Glidai, MD, Department of Ophthalmology, Tel Aviv Medical Center, Weizmann Street 6, Tel Aviv 6423906 (Israel), yoavglidai@gmail.com\nJan-Apr 2020 \n5 2 2020 \n5 2 2020 \n11 1 73 78\n29 10 2019 30 12 2019 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Ozurdex® 0.7 mg (dexamethasone 0.7 mg implant, Allergan, Dublin, Ireland), an intravitreal biodegradable implant, is indicated for cystoid macular edema due to various causes. One of its known and uncommon complications is implant migration to the anterior chamber, causing corneal edema that, in some cases, is irreversible. Reported risk factors for device migration are open or defective lens capsule and prior history of vitrectomy. We present a case of dexamethasone implant migration through a congenital iris coloboma in a pseudophakic patient with an intact lens capsule. The patient is a 56-year-old pseudophakic man with a history of congenital iris coloboma, myopia, retinal tears, and a branch retinal vein occlusion with subsequent cystoid macular edema resistant to anti-VEGF medications but responsive to corticosteroids. He presented with sudden painless decreased vision in his left eye, 8 weeks following dexamethasone implant (Ozurdex) injection to the same eye. Upon presentation, he was diagnosed with corneal edema caused by anterior chamber migration of the implant. He was referred for immediate surgical intervention to extract the implant, with a resolution of the corneal edema within 2 weeks postoperatively. To conclude, this is the first case that reports Ozurdex implant migration through an iris coloboma in the setting of an intact posterior capsule. In addition, we describe a novel surgical approach for implant removal from the anterior chamber that is simple and efficient.\n\nKeywords\nOzurdexImplantMigrationIris colobomaSurgical technique\n==== Body\nBackground\nOzurdex® 0.7 mg (dexamethasone 0.7 mg implant, Allergan, Dublin, Ireland) is a 0.46 by 6 mm biodegradable implant, injected into the vitreous cavity for the treatment of macular edema due to several conditions, among them cystoid macular edema (CME) due to vein occlusion [1]. In recent years, clinical indications for this treatment have been expanded, and episodes of implant migration to the anterior chamber (AC) have been reported. The main risk factors for device migration are open or defective lens capsule and prior history of vitrectomy [2, 3]. Recently, Stepanov et al. [4] and Stelton et al. [5] reported of implant migration in patients with an iris defect, suggesting it could serve as the migration route. Of note, all the reported cases had, in addition to an iris defect, a defective lens capsule. To the best of our knowledge, there has been only one report of migration in the setting of an intact posterior capsule, in which migration was speculated to occur through weak or ruptured zonules [6].\n\nWhen an Ozurdex device migrates to the AC, it can cause rapid development of corneal edema and as a consequence, corneal decompensation [2, 3], therefore it is crucial to remove the implant promptly. We present a case of dexamethasone implant migration through a congenital iris coloboma in a pseudophakic patient with an intact lens capsule.\n\nCase Presentation\nA 56-year-old pseudophakic man presented with a sudden painless decrease in vision in his left eye (LE), 8 weeks following dexamethasone implant (Ozurdex) injection to the same eye. He was treated with Ozurdex implant for macular edema resulting from branch retinal vein occlusion (BRVO) that occurred 4 years prior to his current presentation; this was his second Ozurdex implantation. His other past ocular history included congenital inferior iris coloboma in his LE, axial myopia in both eyes, right 11 dpt, and left 2 dpt. His myopia was corrected at a young age with glasses, and amblyopia was not documented at any stage. The patient underwent laser refractive surgery correction in his right eye (RE) when reaching adulthood. Additionally, he had posterior vitreous detachment (PVD) in both eyes and a history of several retinal tears in both eyes treated with laser retinopexy and cryotherapy. Three years prior to his presentation, the patient had uneventful cataract surgery to his LE with posterior chamber intraocular lens (PCIOL) implantation.\n\nThe patient had experienced BRVO in his LE with subsequent macular edema 4 years before his presentation. When he began retinal clinic follow-up and treatment at our center, his best-corrected visual acuity (BCVA) was 6/6 and 1/24 in his RE and LE, respectively. A macular optical coherence tomography (OCT) of his LE demonstrated CME with an elevated central macular thickness (CMT) of 465 µm. During his retinal clinic follow-up, he was treated with intravitreal anti-VEGF agents, including bevacizumab, ranibizumab, and aflibercept injections, showing no improvement of the macular edema and even worsening, with LE VA decreasing to 1/36. As second-line therapy, triamcinolone was injected intravitreally, resulting in partial improvement of the macular edema with a fair amount of fluid absorption. Macular OCT under triamcinolone treatment demonstrated a decrease in CMT from 507 to 440 µm. As this improvement suggested a good response to corticosteroid treatment, he qualified for Ozurdex implant injection. The first implant was inserted with no complications. One month following the insertion, we witnessed a significant improvement in his LE macular edema, with an OCT scan showing a decrease in measured CMT from 405 to 311 µm and BCVA improving from 1/36 to 6/60. Eight weeks before his presentation, he underwent a second Ozurdex injection with a similar response.\n\nThe patient presented with sudden decreased “hazy” vision in his LE; visual acuity was 1/36 in his LE. Slit-lamp examination revealed central and inferior stromal corneal edema in his LE. The AC was deep, with the dexamethasone implant lying in the inferior angle touching the inferior cornea (Fig. 1). Iris coloboma was open, and PCIOL was correctly situated in the bag with an intact posterior capsule, LE intraocular pressure measured 18 mm Hg.\n\nAfter ruling out other causes for corneal edema, we estimated that the etiology was implant migration. A literature review on such cases was conducted, concluding that prompt extraction of the implant is required to avoid persistent corneal decompensation. The patient was referred for surgical intervention within 24 h from his presentation.\n\nThe surgery was initiated by making two 1.0-mm corneal incisions 180 degrees apart, introducing an AC maintainer with a basic salt solution through one incision and a spatula gently opening the second incision directly across. Due to the pressure gradient and stream created by the maintainer, the dexamethasone implant was navigated toward the second incision and easily ejected from the AC. Following implant extraction, intracameral cefuroxime was injected, and incision hydration was made (online suppl. Video; for all online suppl. material, see www.karger.com/doi/10.1159/000505638).\n\nOne day postoperatively on eye examination, the corneal edema was still evident, AC was deep and quiet, intraocular pressure was 15 mm Hg. On examination 2 weeks postoperatively, the patients' LE BCVA was 6/120, and corneal edema had resolved entirely. Corneal endothelial cell density measured 903 cells/mm2 in his LE and 2,474 cells/mm2 in his RE, macular OCT showed increased macular edema with CMT rising from 342 to 477 µm. Following careful deliberation (elaborated in “Discussion”), we found that the best course of action would be a repeated injection of Ozurdex, and the patient underwent a third implant injection to his LE. In follow-up visits, there has not been a recurrence of implant migration.\n\nDiscussion\nAnterior chamber Ozurdex implant migration is a rare complication that can lead to permanent corneal decompensation. In a retrospective study, Khurana et al. [3] showed that early removal of the implant is essential for corneal recovery. The “classic” risk factors for implant migration identified in that study were a history of pars plana vitrectomy and open or defective lens capsule. In a recent review article by Rahimy and Khurana [2], two additional risk factors were described: iris defect (patent laser iridotomy or surgical iridectomy) and zonular dehiscence (from previous trauma or cataract surgery). Kocak et al. [6] were the first to describe implant migration in the setting of an intact posterior capsule, assuming the culprits were weak zonules. Two cases have been reported about iris defects being the route of passage. First was Stelton et al. [5], who described a patient with PCIOL and a disrupted posterior capsule that also had a large peripheral inferior iridectomy. Later, Stepanov et al. [4] described a patient that underwent inferior iridectomy due to silicone oil insertion during pars plana vitrectomy for treating retinal detachment, which was later on implanted with iris-claw ACIOL (Artisan). Although it is fairly likely that in both cases the implant migrated through the iris defects, both patients also had the “classic” risk factors (prior pars plana vitrectomy and disrupted lens capsule). In the presented case, the patient had an intact posterior capsule. As discussed by Stepanov et al. [4], an iris defect that is situated in the inferior iris (as in our case) is more susceptible to be a route of passage for an implant, as it usually sinks to the bottom of the vitreous cavity.\n\nCongenital iris colobomas arise from incomplete closure of the embryonic fissure during fetal development. A “typical” congenital iris coloboma is located at the inferonasal quadrant and, therefore, must be considered a risk factor for an AC implant migration. This case is the first report of Ozurdex implant migration through an iris coloboma in the absence of capsular defects. It is reasonable to assume that the migration occurred through weak, absent or defective zonules, perhaps as a result of his previous cataract surgery or a congenital defect that is associated with the iris coloboma. The presence of PVD in this scenario is also likely to have facilitated the dislocation and mobility of the implant. Therefore, it is essential to inform these patients of having an increased risk for implant migration and the importance of seeking an immediate medical consultation with any sudden change of vision as early removal of the implant increases corneal recovery rates [3].\n\nFollowing the migrating implant removal, the patient had an exacerbation of the CME. Our team of experts came together for a convergent thinking process, with several alternatives weighed. The first option considered was to reinitiate injections of anti-VEGF agents. However, our patient was unresponsive to all anti-VEGF treatments; therefore, a repeated trial would probably be infertile. The second alternative considered was implanting a different intraocular steroidal implant. Fluocinolone acetonide 0.59 mg (Retisert®, Bausch and Lomb, Rochester, NY, USA) and fluocinolone acetonide 0.19 mg (Iluvien®, Alimera Sciences, Alpharetta, GA, USA) are two steroidal implants available for intraocular use. Although Iluvien is designed to provide sustained therapy for a more extended period, it is also free-floating, but smaller in size than Ozurdex, making it even more susceptible to migrate. Only two cases of Iluvien migration have been reported, with both patients suffering from consequent corneal edema [7, 8]. Despite being anchored to the sclera, Retisert has also been reported to dislocate to the AC, inducing corneal edema, possibly as a result of medication reservoir dissociation from its sutured strut [9, 10, 11].\n\nAnother possibility considered was iris coloboma repair, pupilloplasty. Despite being an appealing alternative, pupilloplasty is an additional anterior segment surgery, which involves a risk to a cornea that has already gone through a considerable amount of procedures, thus jeopardizing it again. A corneal endothelial cell density of 903/µm2 in his LE further reinforced the impression that additional surgery should be avoided. Moreover, the patients' extensive ocular history was taken into consideration. The patient LE BCVA was only slightly improved from 1/36 to 20/200 during Ozurdex treatment, despite the absorption of the macular edema. We estimated that the visual potential in the LE is limited due to the extended presence of subretinal fluid and photoreceptor compromise. Since Ozurdex treatment had a substantial effect on the patients' CME and improved his VA, repeating the procedure was positively considered. After thorough deliberation on the above alternatives, we decided to repeat Ozurdex insertion, concluding that any other option would carry either the same or a higher risk to the patients' eye. The patient accepted our recommendation and underwent a third Ozurdex implantation. The patient was instructed to return at any sudden change of vision. As mentioned, in a follow-up of 12 months and repeated Ozurdex injections, implant migration did not recur.\n\nConclusion\nWe have presented a case of dexamethasone implant migration to the AC through a congenital coloboma, resulting in corneal edema. This report is the first description of implant migration through a congenital iris coloboma in the setting of an intact posterior capsule. We also described our surgical approach for implant removal that is simple, efficient, and cost-effective. Physicians should inform patients with iris defects of the risk of implant migration. It is eminent to emphasize that at any decrease or change in vision, the patient should seek urgent medical attention.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient for publication of this article and any accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo financial support was received for this submission.\n\nAuthors Contribution\nY.G. contributed to the manuscript conception, design, and acquisition. E.C. and S.S. contributed to the acquisition, analysis, and interpretation of data. All authors have been involved in drafting the manuscript or revising it critically and have given final approval of this version to be published and agreed to be accountable for all aspects of the work.\n\nAcknowledgement\nNo organization has contributed to this or the manuscript.\n\nFig. 1 Slit-lamp biomicroscopy capturing dexamethasone implant dislocated through inferior iris coloboma to the anterior chamber with corneal edema and Descemet folds.\n==== Refs\nReferences\n1 Haller JA Bandello F Belfort R Jr Blumenkranz MS Gillies M Heier J OZURDEX GENEVA Study Group Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion Ophthalmology 2010 6 117 (6) 1134 1146.e3 20417567 \n2 Rahimy E Khurana RN Anterior segment migration of dexamethasone implant: risk factors, complications, and management Curr Opin Ophthalmol 2017 5 28 (3) 246 51 28376511 \n3 Khurana RN Appa SN McCannel CA Elman MJ Wittenberg SE Parks DJ Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies Ophthalmology 2014 1 121 (1) 67 71 23890421 \n4 Stepanov A Codenotti M Ramoni A Prati M Jiraskova N Rozsival P Anterior chamber migration of dexamethasone intravitreal implant (Ozurdex®) through basal iridectomy (Ando) in a pseudophakic patient Eur J Ophthalmol 2016 4 26 (3) e52 4 26615950 \n5 Stelton CR Townsend J Peterson LT Khurana RN Yeh S Surgical Management of Anterior Chamber Migration of a Dexamethasone Intravitreal Implant Ophthalmic Surg Lasers Imaging Retina 2015 Jul-Aug 46 (7) 756 9 26247457 \n6 Kocak N Ozturk T Karahan E Kaynak S Anterior migration of dexamethasone implant in a pseudophakic patient with intact posterior capsule Indian J Ophthalmol 2014 11 62 (11) 1086 8 25494252 \n7 Papastavrou VT Zambarakji H Dooley I Eleftheriadis H Jackson TL OBSERVATION: FLUOCINOLONE ACETONIDE (ILUVIEN) IMPLANT MIGRATION INTO THE ANTERIOR CHAMBER Retin Cases Brief Rep 2017 11 (1) 44 6 26909535 \n8 El-Ghrably IA Saad A Dinah C A Novel Technique for Repositioning of a Migrated ILUVIEN(®) (Fluocinolone Acetonide) Implant into the Anterior Chamber Ophthalmol Ther 2015 12 4 (2) 129 33 26199036 \n9 Almeida DR Chin EK Mears K Russell SR Mahajan VB Spontaneous dislocation of a fluocinolone acetonide implant (Retisert) into the anterior chamber and its successful extraction in sympathetic ophthalmia Retin Cases Brief Rep 2015 9 (2) 142 4 25411930 \n10 Chang PY Kresch Z Samson CM Gentile RC Spontaneous Dissociation of Fluocinolone Acetonide Sustained Release Implant (Retisert) with Dislocation into the Anterior Chamber Ocul Immunol Inflamm 2015 23 (6) 454 7 24724735 \n11 Akduman L Cetin EN Levy J Becker MD Mackensen F Lim LL Spontaneous dissociation and dislocation of Retisert pellet Ocul Immunol Inflamm 2013 21 (1) 87 9 23590151\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "11(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Implant; Iris coloboma; Migration; Ozurdex; Surgical technique",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "73-78",
"pmc": null,
"pmid": "32110233",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "23590151;25494252;20417567;26909535;24724735;26615950;23890421;28376511;25411930;26247457;26199036",
"title": "Dexamethasone Implant Migration through an Iris Coloboma.",
"title_normalized": "dexamethasone implant migration through an iris coloboma"
} | [
{
"companynumb": "IL-REGENERON PHARMACEUTICALS, INC.-2020-24035",
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"activesubstancename": "BEVACIZUMAB"
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{
"abstract": "Introduction: Limited data exist regarding paracetamol metabolism after overdose in the neonate. We report a case of repeated supratherapeutic overdose in a neonate with paracetamol metabolite concentrations.Case report: A 10-day-old male neonate presented to hospital after repeated supratherapeutic dosing of paracetamol. Paracetamol concentration 19.5 h post-last dose was 381 μmol/L and 236 μmol/L, 9 h later. Initial alanine aminotransferase (ALT) was normal (18 IU/L) and total bilirubin was 262 μmol/L (N < 300). Acetylcysteine infusion was commenced and ceased 27 h later, when serum paracetamol was undetectable and alanine aminotransferase remained normal.Initial paracetamol elimination half-life was 14.5 h. Analysis of serum paracetamol metabolites showed paracetamol-glucuronide was the major metabolite on presentation (64%). After acetylcysteine was commenced, paracetamol concentration fell, serum bilirubin increased, and paracetamol-sulfate represented a larger proportion of total metabolites (72%). Notably, paracetamol cytochrome (CYP450), cysteine- and mercapturate-conjugates, represented 21% of total measured metabolites on presentation.Conclusion: Repeated supratherapeutic ingestion of paracetamol in the neonate was associated with prolonged elimination half-life. Of note, this was in the presence of unconjugated hyperbilirubinaemia. CYP450 metabolism of paracetamol did not appear to be reduced in this neonate when compared to paracetamol metabolite ratios in older age groups.",
"affiliations": "Monash Toxicology Unit and Emergency Medicine Service, Monash Health, Victoria, Australia.;Monash Toxicology Unit and Emergency Medicine Service, Monash Health, Victoria, Australia.;SEALS Laboratory, Prince of Wales Hospital, Sydney, Australia.;Department of Paediatrics, Dandenong Hospital, Monash Health, Victoria, Australia.;Department of Paediatrics, Dandenong Hospital, Monash Health, Victoria, Australia.;Monash Toxicology Unit and Emergency Medicine Service, Monash Health, Victoria, Australia.",
"authors": "Abadier|Monica|M|;Wong|Anselm|A|;Stathakis|Paul|P|;Singsit|John|J|;Pillay|Melanie|M|;Graudins|Andis|A|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000082:Acetaminophen; C037386:acetaminophen glucuronide; C045667:acetaminophen sulfate ester; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2019.1587450",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "57(12)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Gut and hepatotoxicity; acetaminophen; metabolic",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D062787:Drug Overdose; D006207:Half-Life; D006801:Humans; D006932:Hyperbilirubinemia; D007231:Infant, Newborn; D008297:Male",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "1154-1156",
"pmc": null,
"pmid": "30856016",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of accidental neonatal paracetamol overdose with prolonged half-life and measured metabolites.",
"title_normalized": "a case of accidental neonatal paracetamol overdose with prolonged half life and measured metabolites"
} | [
{
"companynumb": "AU-APOTEX-2019AP016961",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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... |
{
"abstract": "BACKGROUND\nPneumocystis pneumonia (PcP) is an opportunistic fungal infection. Although T-cell immunity is classically related to Pneumocystis defense, recent data support roles for B lymphocytes in the development of PcP in animals, and we have observed several cases of PcP in patients receiving rituximab. These observations prompted a systematic review of our experience to define the spectrum of clinical presentations in which PcP has occurred in the setting of rituximab therapy.\n\n\nMETHODS\nUsing a computer-based search, we reviewed the records of patients who received rituximab and developed PcP at Mayo Clinic Rochester over the years 1998 to 2011 to establish the underlying conditions, clinical course, possible risk factors, and potential association between this drug and the development of PcP.\n\n\nRESULTS\nOver this period, 30 patients developed PcP during treatment with rituximab. The underlying diseases included hematologic malignancies in 90% of cases. Glucocorticoids were used in 73% of these patients, under different chemotherapeutic regimens. Three patients (10%) developed PcP in the setting of rituximab without concomitant chemotherapy or significant glucocorticoid exposure. Of these 30 patients, 88% developed acute hypoxemic respiratory failure and 53% required ICU admission. The clinical course was fatal in 30%.\n\n\nCONCLUSIONS\nPcP can occur in association with rituximab, with the majority of cases having also received cytotoxic chemotherapy or significant doses of glucocorticoids. The clinical course of cases of PcP in patients treated with rituximab can be quite fulminant, with significant mortality. Primary prophylaxis should be considered in patients at risk, and secondary prophylaxis provided unless immune reconstitution is well assured.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN; Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Seville, Spain.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN. Electronic address: limper.andrew@mayo.edu.",
"authors": "Martin-Garrido|Isabel|I|;Carmona|Eva M|EM|;Specks|Ulrich|U|;Limper|Andrew H|AH|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1378/chest.12-0477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "144(1)",
"journal": "Chest",
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"title": "Pneumocystis pneumonia in patients treated with rituximab.",
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"abstract": "Syncope is a sudden but reversible brief loss of consciousness secondary to an acute reduction of cerebral perfusion. Reflex syncope denotes neurologically mediated syncope, which includes vasovagal, carotid sinus syndrome, and other situational syncope. The most frequent form of syncope is vasovagal, which is triggered by emotional stress or prolonged standing, and may be diagnosed with the tilt table test. A thorough investigation of syncope is necessary as serious cardiovascular disorders may also be a cause. A tilt table test is a widely used tool utilized by clinicians to diagnose vasovagal syncope and is sometimes augmented with isoproterenol, a β-sympathomimetic that acts on the heart. This report seeks to explain a case of a 48-year-old previously healthy woman who experienced inferior wall ST elevations during tilt table test supplemented with isoproterenol. There is reason to believe that the results of this patient's tilt table test were due to vasovagal syncope in conjunction with right coronary artery vasospasm.",
"affiliations": "Ross University, Miramar, FL, USA.;Ross University, Miramar, FL, USA.;Ross University, Miramar, FL, USA.;Kern Medical Center-UCLA, Bakersfield, CA, USA.;Kern Medical Center-UCLA, Bakersfield, CA, USA.",
"authors": "Duong|Hanh|H|0000-0003-0638-2030;Masarweh|Omar Maher|OM|;Campbell|Grant|G|;Win|Theingi Tiffany|TT|;Joolhar|Fowrooz|F|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620966862\n10.1177_2324709620966862\nCase Report\nIsoproterenol Causing Coronary Vasospasm and ST Elevations During Tilt Table\nTesting\nhttps://orcid.org/0000-0003-0638-2030Duong Hanh MS12 Masarweh Omar Maher MS12 Campbell Grant MS12 Win Theingi Tiffany MD2 Joolhar Fowrooz MD2 1 Ross University, Miramar, FL, USA\n2 Kern Medical Center—UCLA, Bakersfield, CA,\nUSA\nHanh Duong, MS, Kern Medical Center, 1700 Mount\nVernon Avenue, Bakersfield, CA 93306, USA. Email:\nhanhduong7@gmail.com\n20 10 2020 \nJan-Dec 2020 \n8 232470962096686227 7 2020 5 9 2020 10 9 2020 © 2020 American Federation for Medical Research2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Syncope is a sudden but reversible brief loss of consciousness secondary to an acute\nreduction of cerebral perfusion. Reflex syncope denotes neurologically mediated syncope,\nwhich includes vasovagal, carotid sinus syndrome, and other situational syncope. The most\nfrequent form of syncope is vasovagal, which is triggered by emotional stress or prolonged\nstanding, and may be diagnosed with the tilt table test. A thorough investigation of\nsyncope is necessary as serious cardiovascular disorders may also be a cause. A tilt table\ntest is a widely used tool utilized by clinicians to diagnose vasovagal syncope and is\nsometimes augmented with isoproterenol, a β-sympathomimetic that acts on the heart. This\nreport seeks to explain a case of a 48-year-old previously healthy woman who experienced\ninferior wall ST elevations during tilt table test supplemented with isoproterenol. There\nis reason to believe that the results of this patient’s tilt table test were due to\nvasovagal syncope in conjunction with right coronary artery vasospasm.\n\ncoronary vasospasmstilt table testingisoproterenolST elevationsyncopecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nSyncope can be defined as a temporary loss of consciousness that may be related to\ninsufficient blood flow to the brain. Although there are many different causes it is usually\nbroken down into neurologically mediated, cardiac syncope, orthostatic, and the most common,\nvasovagal syncope (VVS). VVS is usually accompanied by a prodrome, an inciting or trigger\nevent, but is often not reported, whereas cardiac syncope is usually sudden in onset with a\nquick recovery.1 The diagnosis is aided by the use of multiple tests including 24-hour Holter monitors\nas well as provocative testing such as the tilt table test (TTT). TTT is a widely used\nnoninvasive tool in assessing patients with unexplained syncope. It has been reported that\nthe TTT has a 30% to 90% positive rate and above 90% specificity in detecting VVS.2 This relatively safe and effective method is sometimes augmented with medications,\nsuch as isoproterenol (ISO) to provoke a stronger response. ISO is a nonselective β agonist\nthat is commonly used in TTT since it is more effective and efficient in inducing positive\nvasovagal response compared with the standard passive TTT.3 Its mechanism as a β-agonist is vital in producing coronary vasospasm when used in\ncombination with the TTT. There have been reports of rare yet life-threatening complications\nwith this test including myocardial infarction, ventricular tachycardia, as well as cardiac\narrest.4-6 In 50% to 60% of cases, the use of ISO\ncaused coronary vasospasm leading to ST elevation (STE).7,8 In those cases, patients would exhibit a rapid decrease in heart rate\nprior to complaints of angina and presyncope. Although the mechanism is unclear, it is\nproposed that the sympathetic stimulation and parasympathetic activation plays a critical\nrole in inducing coronary vasospasm. We present a similar case of a 48-year-old female who\nunderwent TTT and subsequently had coronary vasospasms leading to STEs after infusion of ISO\nwith resolution of her chest pain after administration of nitroglycerin.\n\nCase Presentation\nA 48-year-old female presents to clinic for syncopal episodes with associated severe\nburning sensation in her throat radiating to her chest. Patient underwent tilt table testing\nfor further evaluation. Findings were unremarkable during her initial and exercise phase\n(Figures 1 and 2). During the second stage, ISO was\nstarted at 1 µg/min with increasing dosages between 3 and 5 µg/min. At 3 µg/min, the patient\nreported blurry vision that quickly self-resolved. ISO was increased to 5 µg/min for 5\nminutes and discontinued once the patient reported feeling tired. The patient was brought to\na supine position and within minutes reported 10/10 chest pain. Electrocardiogram showed ST\nsegment elevations in leads II, III, and aVF (Figure 3) with bradycardia from 57 to 41 beats per\nminute and blood pressure of 77/57 mm Hg. Nitroglycerin 0.4 mg, normal saline bolus 250 mL,\nand supplemental oxygen was immediately administered. Approximately 25 minutes after, the\npatient reported her chest pain had resolved. She was admitted after to hospital for\ncontinued monitoring. During her hospital course, patient underwent coronary angiogram that\nshowed patent coronary arteries without stenosis. Her echocardiogram was also normal with\nejection fraction of 60%. The patient had reproducible symptoms. She is currently being\ntreated with calcium channel blockers and long-acting nitrate without recurrence of\nsymptoms.\n\nFigure 1. ECG stage 1 at 0 seconds. Heart rate 57 beats per minute and blood pressure 110/61 mm\nHg.\n\nFigure 2. ECG stage 6 at 4:57 seconds. Heart rate 105 beats per minute and blood pressure 97/77\nmm Hg.\n\nFigure 3. ECG at recovery stage 1 at 13 seconds. ST elevations in leads II, III, aVF, and V3.\nHeart rate 57 beats per minute and blood pressure 77/57 mm Hg.\n\nDiscussion\nVasovagal syncope is a common and dangerous event many patients often face. It is an\nautonomic syncope invoked by parasympathetic hyperactivity (bradycardia), and/or sympathetic\nhypoactivity (vasodilatation).7 As a result of this response the patient experiences reduced blood pressure and\ncerebral perfusion. The findings of the patient tested were unremarkable during initial TTT\nand also initially during exercise mimicking TTT, when the patient was intravenously given\nISO. It was shortly after the patient became tired and ISO was stopped that the patient was\nplaced back into supine position and STE were noticed and 10/10 chest pain was reported.\nAlthough the patient was supine at the time, this was clearly a positive TTT due to\nbradycardia and hypotension. The interest drawn from this study is the concomitant inferior\nwall STE and severe chest pain responsive to nitroglycerin. This finding indicates vasospasm\nof the right coronary artery, which was later validated by a normal coronary angiogram and\nechocardiogram.\n\nThe exact pathogenesis of coronary vasospasm is still unclear. Studies have shown that\ninvolvement of endothelial dysfunction, oxidative stress, chronic low-grade inflammation,\nand deficient aldehyde dehydrogenase 2 activity may contribute to it.9 Regarding the use of ISO causing vasospasm, arguments of autonomic nervous system\nimbalance have been proposed. With regard to changes in heart rate during TTT, studies found\nincrease in parasympathetic activity initially followed by increase in sympathetic activity.4 While another study proposed that it is a withdrawal of parasympathetic activity that\ninduces coronary vasospasms.5,10 Although\nconflicting ideas, from these studies we can conclude that the autonomic system does play an\nimportant role in coronary vasospasms.\n\nAs seen in previous case reports, ISO causes coronary vasospasms leading to STE causing\nangina. Even though most cases have been reported when it is used during tilt table testing,\nit can be seen with electrophysiology studies as well,11 suggesting that ISO may have the potential to cause vasospasm by itself. A study done\nfrom 1997 to 2000 on 16 patients ranging from 42 to 75 years of age who underwent tilt table\ntesting with ISO showed that patients who had coronary vasospasms, the right coronary was\nmost frequently affected in 75% of the cases.7 Similarly, our patient also showed STE in inferior leads correlating with right\ncoronary artery vasospasm. Our patient also showed bradycardia with complaints of chest pain\nimmediately when changed to supine position. This agrees with the explanation of autonomic\ndysfunction due to repositioning the patient, triggering the coronary vasospasm. With change\nfrom upright to supine, this activates parasympathetic response causing bradycardia and\nhypotension. The contrasting sympathomimetic action of ISO infusion in combination with the\nparasympathetic hyperactivity induces the coronary vasospasm. This finding is supported by a\n15-patient study, which concluded that the TTT test with ISO infusion provoked coronary\nspasm with syncope or presyncope in 60% of patients with vasospastic angina. In the test\npositive group a significant reduction in heart rate preceded the vasospastic angina and\nsyncope. The finding suggests that autonomic parasympathetic activation plays an important\nrole in the provocation of coronary spasm in a subgroup of patients with vasospastic\nangina.3,10\n\nOther studies have proposed that coronary artery vasospasm in the setting of ISO and TTT\nmay suggest that this subgroup of patients have a more severe form of disease as compared\nwith patients who do not develop STE.2 Additionally, it appears that patients who develop more prominent bradycardia with\npositive test results indicate higher sensitivity of autonomic dysregulation.2\n\nConclusion\nAlthough it is rare, ISO has the potential to cause coronary vasospasms in healthy patients\nwithout coronary artery stenosis. It is important to consider this possibility when\nconducting TTT and to be prepared with nitroglycerin as coronary vasospasm can be fatal.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Ethical approval to report this case was obtained from the institutional review board\n(IRB #20044).\n\nInformed Consent: Informed consent for patient information to be published in this article was not obtained\nbecause patient was lost to follow-up.\n\nORCID iD: Hanh Duong \nhttps://orcid.org/0000-0003-0638-2030\n==== Refs\nReferences\n1 \nColman N Wieling W Wilde AAM \nA patient with recurrent syncope and ST-elevation on the\nelectrocardiogram\n. Europace .\n2004 ;6 :296 -300\n. doi:10.1016/j.eupc.2004.03.003 15172653 \n2 \nWang CH Hung MJ Kuo LT Cherng WJ. \nCardiopulmonary resuscitation during coronary vasospasm induced by tilt\ntable testing\n. Pacing Clin Electrophysiol .\n2000 ;23 :2138 -2140\n.11202262 \n3 \nShen WK Jahangir A Beinborn D , et al\nUtility of a single-stage\nisoproterenol tilt table test in adults\n. J Am Coll\nCardiol .\n1999 ;33 :985 -990\n.10091825 \n4 \nYoshio H Shimizu M Sugihara N , et al\nAssessment of autonomic nervous\nactivity by heart rate spectral analysis in patients with variant\nangina\n. Am Heart J .\n1993 ;125 (2 \npt 1):324 -329\n.8427123 \n5 \nLanza GA Pedrotti P Pasceri V Lucente M Crea F Maseri A. \nAutonomic changes associated with spontaneous coronary spasm in patients\nwith variant angina\n. J Am Coll Cardiol .\n1996 ;28 :1249 -1256\n.8890823 \n6 \nGoolamali SI Loh VH Sopher M. \nThe head-up tilt test—a cause of myocardial infarction\n.\nEuropace .\n2004 ;6 :548 -551\n.15519258 \n7 \nHung MJ Wang CH Cherng WJ. \nProvocation of coronary vasospastic angina using an isoproterenol head-up\ntilt test\n. Angiology .\n2004 ;55 :271 -280\n. doi:10.1177/000331970405500306 15156260 \n8 \nMiyata S Inoue HK Horimoto M , et al\nHead-up tilt test combined with\nisoproterenol infusion provokes coronary vasospastic angina\n. Jpn\nCirc J .\n1998 ;62 :670 -674\n.9766705 \n9 \nYasue H Mizuno Y Harada E. \nCoronary artery spasm—clinical features, pathogenesis and\ntreatment\n. Proc Jpn Acad Ser B Phys Biol Sci .\n2019 ;95 :53 -66\n. doi:10.2183/pjab.95.005 \n10 \nRen ZW Wu N Chen MY , et al\nSuggestion of tilt table test for\ndiagnosis of vasovagal syncope [in Chinese]\n. Chin J\nCardio .\n1998 ;26 :325 -327\n.\n11 \nKumar N Aksoy I Phan K Vainer J Timmermans C. \nCoronary spasm during cardiac electrophysiological study following\nisoproterenol infusion\n. Interv Med Appl Sci .\n2014 ;6 :183 -186\n. doi:10.1556/IMAS.6.2014.4.7 25598993\n\n",
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"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "ST elevation; coronary vasospasms; isoproterenol; syncope; tilt table testing",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000318:Adrenergic beta-Agonists; D001794:Blood Pressure; D003329:Coronary Vasospasm; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate; D006801:Humans; D007545:Isoproterenol; D008875:Middle Aged; D000072657:ST Elevation Myocardial Infarction; D019462:Syncope, Vasovagal; D018667:Tilt-Table Test",
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"title": "Isoproterenol Causing Coronary Vasospasm and ST Elevations During Tilt Table Testing.",
"title_normalized": "isoproterenol causing coronary vasospasm and st elevations during tilt table testing"
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"abstract": "Calcium channel blockers (CCBs) are a mainstay for the treatment of hypertension. Here we report a case of a male who after intentionally ingesting amlodipine presented with overdose symptomology. His QTc (corrected QT) was 525 ms (millisecond) on admission, he was treated with calcium intravenous infusion and subsequently his QTc narrowed to 393 ms, but he also developed iatrogenic pancreatitis. His serum calcium levels were not checked during the infusion. He was treated with supportive care, which led to the normalization of serum calcium levels and a favorable outcome. Further studies are required regarding how frequently calcium levels should be checked during infusions.",
"affiliations": "Internal Medicine, Guthrie Clinic/Robert Packer Hospital, Sayre, USA.;Internal Medicine - Critical Care, Guthrie Clinic/Robert Packer Hospital, Sayre, USA.;Internal Medicine, North Shore University Hospital, Hempstead, USA.;Internal Medicine - Critical Care, Guthrie Clinic/Robert Packer Hospital, Sayre, USA.;Internal Medicine - Critical Care, Guthrie Clinic/Robert Packer Hospital, Sayre, USA.",
"authors": "Khan|Salman|S|;Norville|Kim J|KJ|;Khan|Imran|I|;Siddiqui|Faraz|F|;Karki|Apurwa|A|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4493Internal MedicineCalcium Channel Blocker Overdose Treated with Calcium Resulting in Pancreatitis: A Case Report Muacevic Alexander Adler John R Khan Salman 1Norville Kim J 2Khan Imran 3Siddiqui Faraz 2Karki Apurwa 2\n1 \nInternal Medicine, Guthrie Clinic/Robert Packer Hospital, Sayre, USA \n2 \nInternal Medicine - Critical Care, Guthrie Clinic/Robert Packer Hospital, Sayre, USA \n3 \nInternal Medicine, North Shore University Hospital, Hempstead, USA \nSalman Khan salmankhan6994@gmail.com18 4 2019 4 2019 11 4 e449326 2 2019 13 3 2019 Copyright © 2019, Khan et al.2019Khan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/17984-calcium-channel-blocker-overdose-treated-with-calcium-resulting-in-pancreatitis-a-case-reportCalcium channel blockers (CCBs) are a mainstay for the treatment of hypertension. Here we report a case of a male who after intentionally ingesting amlodipine presented with overdose symptomology. His QTc (corrected QT) was 525 ms (millisecond) on admission, he was treated with calcium intravenous infusion and subsequently his QTc narrowed to 393 ms, but he also developed iatrogenic pancreatitis. His serum calcium levels were not checked during the infusion. He was treated with supportive care, which led to the normalization of serum calcium levels and a favorable outcome. Further studies are required regarding how frequently calcium levels should be checked during infusions.\n\npancreatitishypercalcemiacalcium channel blockeroverdoseThe 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\nHypercalcemia is a relatively rare condition with up to 80% of cases considered to be from primary hyperparathyroidism and malignancy, and limited literature is found on hypercalcemia as a complication of intravenous calcium infusion [1]. This case discusses hypercalcemia-induced pancreatitis after infusion of calcium for calcium channel blocker overdose. Supportive care and aggressive hydration corrected the metabolic abnormalities and the patient survived.\n\nCase presentation\nA 57-year-old male was evaluated in the emergency department for lightheadedness. Approximately 12 hours prior to presentation, he intentionally ingested 30 tablets of amlodipine 10 mg with suicidal intent, and afterwards he took a nap. When he woke up, he was unable to move his legs and felt lightheaded. He had been on amlodipine for three years as a treatment for hypertension. His past medical history was significant for chronic alcoholism and human immunodeficiency virus (HIV) apart from hypertension. On arrival, the patient was alert but reported feeling weakness all throughout his body and lightheadedness. On examination, he was found to be bradycardic with a heart rate of 50 beats per minute and he had hypotension with a systolic blood pressure of 70 mm Hg. He was administered 2 liters of intravenous 0.9% saline. His laboratory investigation was remarkable for potassium of 3.2 mmol/L (reference range 3.5-5.1), bicarbonate of 19 mmol/L (reference range 22-30), creatinine of 5.3 mg/DL (reference range 0.82-1.5), and calcium of 8.2 mg/DL (reference range 8.3 to 10.1).\n\nThe patient was administered two more liters of 0.9% normal saline as a bolus, and after consultation with the regional Poison Control Center, a recommendation to administer 20 grams of calcium gluconate in dextrose solution was made. The initial QTC on electrocardiogram (EKG) was 525 (Figure 1). The initial EKG showed normal sinus rhythm with prolonged QT interval with U waves. The patient was admitted to the medical intensive care unit (ICU) for further treatment.\n\nFigure 1 Electrocardiogram (EKG) with QTC of 525 ms\nIntravenous infusion of calcium chloride 20 grams in dextrose 5% was administered at the rate of 100 ml/hour. Basic metabolic profile (BMP) drawn prior to the calcium chloride infusion showed potassium 2.7 mmol/L, bicarbonate 17 mmol/L, creatinine 4.7 mg/DL, and calcium 9.3 mg/DL. Approximately six hours after the infusion of calcium chloride was started, the BMP was checked and showed potassium of 3.6 mmol/L as it was supplemented, bicarbonate of 18 mmol/L, creatinine of 2.7 mg/DL, and calcium of 22.7 mg/DL. At that point, the calcium chloride infusion was stopped. EKG at that time showed QTC 393 ms (Figure 2). The serum calcium level was checked five hours later and showed calcium of 19.4 mg/DL. His urine output over the last five hours was 400 to 425 ml an hour. Three hours later, the patient started complaining of severe central abdominal pain. A computer tomography (CT) scan of the abdomen without contrast was obtained and showed significant peripancreatic stranding extending within the anterior pararenal space and tracking down along the right psoas muscle and left psoas muscle into the pelvis. These signs were consistent with acute pancreatitis (Figure 3). Treatment was started with intravenous isotonic solution, and this improved his blood pressure and pain management was achieved with as-needed opiate. Twenty-four hours after arrival into the hospital, his potassium was 4.0 mmol/L, creatinine was 1.3 mg/DL, and calcium was 11.3 mg/DL.\n\nFigure 2 Electrocardiogram (EKG) with QTC 393 ms\nFigure 3 Computed tomography of the abdomen with arrows pointing towards the inflammation seen in pancreatitis\nThe patient's clinical course gradually improved and he no longer required ICU monitoring and was transferred to the floor. Inpatient psychiatry consultation was placed and he was recommended for admission to the Behavioral Science unit. On the day of discharge, his potassium level was 4.0 mmol/L, creatinine was 1.0 mg/DL, and calcium was 9.5 mg/DL.\n\nDiscussion\nCalcium channel blockers (CCBs) are often prescribed for essential hypertension. The overuse of CCBs can lead to arterial vasodilation resulting in hypotension and bradycardia [2]. Patients may also present with altered sensorium and hyperglycemia due to reduced insulin secretion [3].\n\nThe management of CCB overdose is to optimize intravascular volume and restore cardiac output. If the patient develops hypotension, the addition of inotropes may be warranted. Intravenous calcium, insulin or glucagon can be utilized as well [4]. Another modality is sodium bicarbonate, which can be especially useful in the presence of metabolic acidosis and, if used, may improve the hemodynamic status [5].\n\nIn an observational study conducted over one year, 139 patients were studied with calcium channel blocker overdose. Calcium was administered to 23 patients and it demonstrated improvements in hemodynamics but no specific dose was established [6]. Another study investigated dosage of calcium administration. The authors utilized a loading dose of 0.6 ml kg-1 of 10% calcium gluconate and infusion of 0.6-1.6 ml/kg/hour titrated to hemodynamic parameters and a serum ionized calcium up to two times the upper limit of the reference range [7]. In our case, after consultation with the regional poison control, we opted to use 20 grams of calcium gluconate.\n\nAs mentioned above, infusion of calcium via intravenous therapy is beneficial for hemodynamic stability in CCB overdose. However, no specific dose has been established. High normal ranges to twice the normal range of calcium are advised [3]. One case report demonstrated a calcium level of 32.3 mg/DL that induced iatrogenic pancreatitis leading to anuric kidney injury, which required continuous renal replacement therapy but the patient ultimately succumbed to his injuries [8]. In our case, our highest level of calcium was 22.7 g/dl, which induced pancreatitis. If calcium levels had been measured more frequently, the calcium dose might have been adjusted earlier, possibly reducing the risk of an onset of pancreatitis in our patient. The first calcium level was not checked until six hours after transfusion was initiated. We suggest frequent measurements of serum calcium and goal‐directed tapering of the infusion rate as do the authors Van Veggel et al. [9]. There are no guidelines available for the management of CCB overdose with intravenous calcium or monitoring for hypercalcemia; however, utilizing clinical judgement and the patient’s condition can be the driving factor.\n\nConclusions\nThe treatment of calcium channel blocker overdose can be challenging and unique. Overdose of calcium channel blockers can result in myocardial depression along with arterial vasodilation. Vasodilatory shock can play a part in their toxicity and the use of vasopressors might be needed. Intravenous calcium administration can have an effect on contractility, and careful monitoring is suggested. In our case the use of intravenous calcium therapy was utilized as suggested by poison control, but given the large dose, frequent monitoring during the infusion was needed to prevent pancreatitis. This was treated with aggressive intravenous normal saline therapy.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Differential diagnosis of hypercalcemia J Bone Miner Lafferty FW 51 59 6 1991 \n2 Pharmacology, pathophysiology and management of calcium channel blocker and beta blocker toxicity Toxicol Rev DeWitt CR Waksman JC 223 238 23 2004 https://www.ncbi.nlm.nih.gov/pubmed/15898828 15898828 \n3 Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies Br J Clin Pharmacol Graudins A Lee HM Druda D 453 461 81 2016 26344579 \n4 Management of calcium channel antagonist overdose Drug Saf Salhanick SD Shannon MW 65 79 26 2003 12534324 \n5 Unresponsive shock due to amlodipine overdose: an unexpected cause J Cardiovasc Thorac Res Kumar S Thakur D Gupta RK Sharma A 246 247 10 2018 30680086 \n6 A one‐year evaluation of calcium channel blocker overdoses: toxicity and treatment Ann Emerg Med Ramoska EA Spiller HA Winter M Borys D 196 200 22 1993 8427431 \n7 Management of beta‐adrenergic blocker and calcium channel antagonist toxicity Emerg Med Clin North Am Kerns W II 309 331 25 2007 17482022 \n8 A fatal case of iatrogenic hypercalcemia after calcium channel blocker overdose J Med Toxicol Sim MT Stevenson FT 25 29 4 2008 18338308 \n9 A critical note on treatment of a severe diltiazem intoxication: high‐dose calcium and glucagon infusions Basic Clin Pharmacol Toxicol Van Veggel M Van der Veen G Jansen T Westerman E 447 449 121 2017 28503840\n\n",
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"issue": "11(4)",
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"keywords": "calcium channel blocker; hypercalcemia; overdose; pancreatitis",
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"title": "Calcium Channel Blocker Overdose Treated with Calcium Resulting in Pancreatitis: A Case Report.",
"title_normalized": "calcium channel blocker overdose treated with calcium resulting in pancreatitis a case report"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP006387",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"druga... |
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