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"abstract": "BACKGROUND\nRecombinant granulocyte colony-stimulating factors (G-CSFs) such as Filgrastim are used to treat chemotherapy-induced neutropenia. We investigated a new G-CSF, XM02, and compared it to Neupogen after myelotoxic chemotherapy in breast cancer (BC) patients.\n\n\nMETHODS\nA total of 348 patients with BC receiving docetaxel/doxorubicin chemotherapy were randomised to treatment with daily injections (subcutaneous 5 microg/kg/day) for at least 5 days and a maximum of 14 days in each cycle of XM02 (n = 140), Neupogen (n = 136) or placebo (n = 72). The primary endpoint was the duration of severe neutropenia (DSN) in cycle 1.\n\n\nRESULTS\nThe mean DSN in cycle 1 was 1.1, 1.1, and 3.9 days in the XM02, Neupogen, and placebo group, respectively. Superiority of XM02 over placebo and equivalence of XM02 with Neupogen could be demonstrated. Toxicities were similar between XM02 and Neupogen.\n\n\nCONCLUSIONS\nXM02 was superior to placebo and equivalent to Neupogen in reducing DSN after myelotoxic chemotherapy.",
"affiliations": "Faculdade de Medicina do ABC, Sao Paulo, Brazil. sandrabr@netpoint.com.br",
"authors": "del Giglio|A|A|;Eniu|A|A|;Ganea-Motan|D|D|;Topuzov|E|E|;Lubenau|H|H|",
"chemical_list": "D011994:Recombinant Proteins; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D004317:Doxorubicin; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2407-8-332",
"fulltext": "\n==== Front\nBMC CancerBMC Cancer1471-2407BioMed Central 1471-2407-8-3321901449410.1186/1471-2407-8-332Research ArticleXM02 is superior to placebo and equivalent to Neupogen™ in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy del Giglio A 1sandrabr@netpoint.com.brEniu A 2aleniu@iocn.roGanea-Motan D 3motan_doina@yahoo.comTopuzov E 4egtopuzov38@mail.ruLubenau H 5heinz.lubenau@t-online.de1 Auro del Giglio, Faculdade de Medicina do ABC, Santo André, Sao Paulo, Brazil and Hospital Israelita Albert Einstein Sao Paulo, Brazil2 Alexandru Eniu, Institutul Oncologic Ion Chiricuţă, Cluj-Napoca, Romania3 Doina Ganea-Motan, Spitalul Judetean de Urgenta, Suceava, Romania4 Eskender Topuzov, Mechnikov State Medical Academy, Saint-Petersburg, Russia5 Heinz Lubenau, BioGeneriX AG, Mannheim, Germany2008 12 11 2008 8 332 332 28 4 2008 12 11 2008 Copyright © 2008 del Giglio et al; licensee BioMed Central Ltd.2008del Giglio et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground\nRecombinant granulocyte colony-stimulating factors (G-CSFs) such as Filgrastim are used to treat chemotherapy-induced neutropenia. We investigated a new G-CSF, XM02, and compared it to Neupogen™ after myelotoxic chemotherapy in breast cancer (BC) patients.\n\nMethods\nA total of 348 patients with BC receiving docetaxel/doxorubicin chemotherapy were randomised to treatment with daily injections (subcutaneous 5 μg/kg/day) for at least 5 days and a maximum of 14 days in each cycle of XM02 (n = 140), Neupogen™ (n = 136) or placebo (n = 72). The primary endpoint was the duration of severe neutropenia (DSN) in cycle 1.\n\nResults\nThe mean DSN in cycle 1 was 1.1, 1.1, and 3.9 days in the XM02, Neupogen™, and placebo group, respectively. Superiority of XM02 over placebo and equivalence of XM02 with Neupogen™ could be demonstrated. Toxicities were similar between XM02 and Neupogen™.\n\nConclusion\nXM02 was superior to placebo and equivalent to Neupogen™ in reducing DSN after myelotoxic chemotherapy.\n\nTrial Registration\nCurrent Controlled Trials ISRCTN02270769\n==== Body\nIntroduction\nMyelotoxic chemotherapy frequently leads to neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are effective pharmaceutical substances and are successfully applied in the prevention of chemotherapy-induced neutropenia and the associated risk of infection. [1-3]\n\nNatural human G-CSF is a glycoprotein composed of a single polypeptide chain of 174 or 177 amino acids.[4,5] The first bacterially synthesised non-glycosylated recombinant methionyl form of human G-CSF (r-metHuG -CSF) was approved by the Food and Drug Administration (FDA) in 1991 under the generic name Filgrastim. Alternatively, a second glycosylated recombinant human G-CSF is available on the market under the generic name Lenograstim which is produced by Chinese hamster ovary (CHO) cells.\n\nMore recently, a biosimilar non-glycosylated r-metHuG-CSF expressed in Escherichia coli for intravenous (i.v.) and subcutaneous (s.c.) administration was clinically developed by BioGeneriX AG for the treatment of chemotherapy-induced neutropenia. The manufacturing process was developed by Sicor Biotech. XM02 will be named with the international non-proprietary name filgrastim. Filgrastim marketed under the trade name Neupogen™ was used as reference product in this study.\n\nThe primary aim of the study was to demonstrate the activity of XM02 compared to Neupogen™ and placebo. We show that XM02 is safe and well tolerated in breast cancer patients undergoing chemotherapy and is very similar to Neupogen™ in effectively stimulating neutrophil recovery.\n\nMethods\nPatients\nBetween December 2004 and September 2005, patients with breast cancer requiring chemotherapy participated in this multinational, multicentre, randomised and controlled phase III study at 52 study centres in 10 countries. The study was approved by all local institutional review boards and ethics committees concerned. The first ethics committee approval was given by the National Ethics Committee of Medicamentului Student Clinic, Bucharest, subsequently followed by the approvals for all 52 centres involved. Male and female patients ≥ 18 years of age with breast cancer high risk stage II, III or IV (classification according to American Joint Committee on Cancer) were eligible to participate if they signed written informed consent, were planned/eligible to receive treatment with docetaxel/doxorubicin as routine chemotherapy for their breast cancer, were chemotherapy-naïve, had Eastern Cooperative Oncology Group performance status ≤ 2, an absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, adequate cardiac function (including left ventricular ejection fraction ≥ 50% as assessed by echocardiography within 4 weeks prior to randomisation), adequate hepatic function, i.e., alanine and aspartate aminotransferases <2.5 × upper limit of normal (ULN), alkaline phosphatase <5 × ULN, bilirubin <ULN, and adequate renal function, i.e., creatinine <1.5 × ULN.\n\nMethods\nA total of 348 patients were randomised in a 2:2:1 ratio to treatment with either XM02 (n = 140), Neupogen™ (n = 136) or placebo (n = 72). Patients in the placebo group switched to treatment with XM02 after completion of cycle 1. Patients underwent a maximum of 4 chemotherapy cycles (3 weeks per cycle), consisting of doxorubicin 60 mg/m2 (i.v. bolus injection) and docetaxel 75 mg/m2 (at least 1 hour infusion). Starting one day after chemotherapy, patients received daily injections of either XM02 or Neupogen™ (both s.c. 5 μg/kg/day based on actual body weight) or s.c. placebo (in the first cycle only) for at least 5 days and a maximum of 14 days. The dose of XM02 was chosen based on bioequivalence between XM02 and Neupogen™ previously demonstrated in healthy volunteers [6]. Both used G-CSF had to be stopped when an ANC of ≥ 10 × 109/L after nadir was reached. Blood samples for the determination of the ANC were taken within 24 hours before chemotherapy and then daily from Day 2 until Day 15, or longer until ANC reached ≥ 2.0 × 109/L. Body temperature (axillary) was measured with a standardised device daily until Day 15, or longer until ANC reached ≥ 2.0 × 109/L.\n\nA true double-blind design was not feasible because XM02 and Neupogen™ were formulated in different volumes. For this reason, the study drug was administered by qualified unblinded study personnel and the investigator was kept blinded and performed all assessments of the patient without knowledge of treatment. Moreover, it was considered that the efficacy endpoints of this study (based on ANC) were very unlikely to be influenced by the investigator's or patient's knowledge of the treatment. During cycle 1, safety was closely monitored by an independent, unblinded Safety Monitoring Board in order to ensure that patients in the placebo arm were not exposed to an unjustifiable risk.\n\nEndpoints and definitions\nThe primary endpoint was the duration of severe neutropenia (DSN) in cycle 1, defined as the number of days with grade 4 neutropenia with an ANC <0.5 × 109/L. Secondary endpoints included incidence of observed febrile neutropenia (FN) (observed FN defined as body temperature of >38.5°C for more than 1 hour and ANC <0.5 × 109/L, both measured on the same day) and of protocol defined FN (administration of systemic antibiotics) by cycle and across all cycles, DSN in cycles 2 to 4, depth of ANC nadir in cycles 1 to 4, and time to ANC recovery in cycles 1 to 4. Safety assessments were based on adverse events (AEs), safety laboratory at the beginning of each cycle and at the end of study, immunogenicity samples before treatment, after the end of each cycle and 180 days after the start of treatment, physical examinations, and vital signs. In a subgroup of patients per treatment group pharmacokinetic samples were taken in cycle 1 and cycle 4 on day 1 and after repeated dosing on the day after the ANC had reached 2 × 109/L. Serum concentrations were determined with the enzyme-linked immunosorbent assay test (ELISA) kit (Quantikine®, R&D Systems, USA) by Cirion Biopharma Research Inc., Canada.\n\nStatistical methods\nFirst, assay sensitivity with respect to DSN in cycle 1 was confirmed by comparing XM02 versus placebo. If this difference was significant (analysis of covariance [ANCOVA], two sided p ≤ 0.05 with shorter DSN for XM02), equivalence between XM02 and Neupogen™ was assessed. To show equivalence between XM02 and Neupogen™, the 2-sided 95% confidence interval (CI) for the difference in DSN in cycle 1 had to lie entirely within the equivalence range of [-1 day, +1 day]. A difference of 1 day was considered to be the maximum clinically acceptable difference. Safety endpoints were summarised using descriptive statistics and the incidence of AEs was compared for XM02 versus Neupogen™ using Fisher's exact test.\n\nResults\nThe treatment groups were similar with regard to demographic and baseline characteristics. There were no relevant differences between treatment groups for incidence of prior or concomitant medications. Demographic and baseline characteristics are summarised in Table 1.\n\nTable 1 Patient Characteristics\n\n\tXM02\n(n = 140)\tNeupogen™\n(n = 136)\tPlacebo/XM02*\n(n = 72)\t\nGender [N (%)]\t\t\t\t\n\t\nMale\t1 (0.7%)\t1 (0.7%)\t-\t\nFemale\t139 (99.3%)\t135 (99.3%)\t72 (100.0%)\t\n\t\nAge [years]\t\t\t\t\n\t\nMean\t51.0\t51.4\t49.5\t\nSD\t9.7\t10.7\t10.3\t\nMedian\t51.0\t51.0\t48.0\t\nRange\t25–75\t28–74\t28–74\t\n\t\nRace [N (%)]\t\t\t\t\n\t\nCaucasian\t120 (85.7%)\t118 (86.8%)\t62 (86.1%)\t\nBlack\t1 (0.7%)\t5 (3.7%)\t2 (2.8%)\t\nHispanic\t10 (7.1%)\t10 (7.4%)\t6 (8.3%)\t\nOther\t9 (6.4%)\t3 (2.2%)\t2 (2.8%)\t\n\t\nBody Mass Index [kg/m2]\t\t\t\t\n\t\nMean\t27.77\t28.20\t27.42\t\nSD\t6.11\t5.70\t6.02\t\nMedian\t27.55\t26.90\t27.30\t\nRange\t16.2–56.2\t15.9–45.4\t17.0–41.3\t\n\t\nCancer stage [N (%)]\t\t\t\t\n\t\nHigh risk stage II\t23 (16.4%)\t36 (26.5%)\t15 (20.8%)\t\nStage III\t79 (56.4%)\t69 (50.7%)\t38 (52.8%)\t\nStage IV\t38 (27.1%)\t31 (22.8%)\t19 (26.4%)\t\n\t\nTherapy [N (%)]\t\t\t\t\n\t\nAdjuvant\t96 (68.6%)\t96 (70.6%)\t47 (65.3%)\t\nMetastatic\t44 (31.4%)\t40 (29.4%)\t25 (34.7%)\t\n\t\nPrior radiation therapy [N (%)]\t\t\t\t\n\t\nNo\t125 (89.3%)\t127 (93.4%)\t63 (87.5%)\t\nYes\t15 (10.7%)\t9 (6.6%)\t9 (12.5%)\t\nAbbreviations: SD = Standard deviation,\n\nBody Mass Index calculated as body weight/(height)2\n\n*Patients in this group received placebo in cycle 1 and XM02 afterwards\n\nEfficacy\nThe patients were exposed to the study drug for a median of 38 days (range: 1 to 55 days). Median duration within a cycle was 9 or 10 days (range 1 to 16 days). The patients were exposed to a mean of 15,739.6 μg (range: 540 to 29,280 μg) of active study drug (XM02 or Neupogen™). There were no differences between the XM02 and Neupogen™ groups with regard to amount of active study drug and the duration of exposure.\n\nResults are summarised in Table 2 for the full analysis (FA) set.\n\nTable 2 Results of Efficacy Endpoints\n\nTreatment group\tXM02\tNeupogen™\tPlacebo/XM02*\t\nFull analysis set [n]\t(n = 140)\t(n = 136)\t72\t\nMean DSN [days]\t\t\t\t\n Cycle 1\t1.1\t1.1\t3.8\t\n ANCOVA [CI]#\t0.028 [-0.261, 0.316]\t\t\t\n Cycle 4\t0.7\t0.7\t0.6\t\n\t\nMean ANC nadir [109/L]\t\t\t\t\n Cycle 1\t0.7\t0.7\t0.2\t\n ANCOVA [CI]#\t-0.001 [-0.190, 0.189]\t\t\t\n Cycle 4\t1.0\t1.0\t1.1\t\n\t\nMean time to ANC recovery [days]\t\t\t\t\n Cycle 1\t8.0\t7.8\t14.0\t\n ANCOVA [CI]#\t0.207 [-0.425, 0.838]\t\t\t\n Cycle 4\t7.6\t7.1\t7.2\t\n\t\nIncidence of FN [%]+\t\t\t\t\n Cycle 1\t12.1\t12.5\t36.1\t\n Across all cycles\t20.7\t22.1\t41.7\t\nAbbreviations: DSN: duration of severe neutropenia; ANC: absolute neutrophil count; FN: febrile neutropenia; ANCOVA: analysis of covariance, CI: confidence interval.\n\n* Patients in this group received placebo in cycle 1 and XM02 afterwards (including in cycle 4).\n\n# ANCOVA estimate and 2-sided 95% confidence interval for difference XM02 – Filgrastim in cycle 1.\n\n+ Observed or protocol defined FN.\n\nDuration of Severe Neutropenia\nIn the per protocol (PP) set, mean DSN in cycle 1 was 1.1, 1.1, and 3.9 days in the XM02, Neupogen™, and placebo group, respectively. DSN ranged from 0 to 5 days in the XM02 and Neupogen™ groups, and from 0 to 9 days in the placebo group. Results were similar in the FA set, i.e., mean DSN in cycle 1 was 1.1, 1.1, and 3.8 days in the XM02, Neupogen™, and placebo group, respectively.\n\nSuperiority versus placebo and assay sensitivity were evaluated by comparing XM02 with placebo for the FA set. The least square mean of DSN was significantly shorter in the XM02 group (1.141 days) than in the placebo group (3.823 days). Thus, assay sensitivity was demonstrated. Results for the PP set were similar and confirmed superiority of XM02 over placebo and assay sensitivity.\n\nEquivalence of XM02 and Neupogen™ was assessed based on the PP set, using the ANCOVA model to calculate a 2-sided 95% CI for \"XM02 minus Neupogen™\". The least square mean of DSN in cycle 1 was 1.119 and 1.087 days in the XM02 and Neupogen™ group, respectively. The 95% CI for \"XM02 versus Neupogen™\" was [-0.262 days, 0.325 days], which was entirely included in the pre-specified equivalence range [-1, 1], thus, equivalence was concluded. Results for the FA set were similar and confirmed equivalence of XM02 and Neupogen™.\n\nThe mean DSN in cycles 2 to 4 was similar in all treatment groups. Mean DSN was 0.7, 0.7, and 0.5 days in cycle 2, 0.6, 0.7, and 0.6 days in cycle 3, and 0.7, 0.7, and 0.6 days in cycle 4 in the XM02, Neupogen™, and placebo/XM02 group (treated with XM02 in cycles 2 to 4), respectively.\n\nFebrile Neutropenia\nIn cycle 1, the incidence of observed or protocol defined FN was distinctly lower in the XM02 and Neupogen™ groups (12.1% and 12.5%, respectively) compared to the placebo group (36.1%). There were no significant differences with regard to FN incidence between the XM02 and Neupogen™ groups neither in cycle 1 nor across all cycles.\n\nAbsolute Neutrophil Count\nIn cycle 1 in the placebo group, mean ANC values decreased after Day 2 and reached a nadir on Day 11, whereas in the XM02 and Neupogen™ groups, mean values distinctly increased, reaching a maximum on Day 3, and then decreased to a nadir on Day 7. Thereafter, mean values in the active treatment groups distinctly increased again, reaching a maximum on Day 11. On Day 21, mean values returned to values as observed on Day 1 in all treatment groups. In the subsequent cycles, all treatment groups demonstrated the same trends as for XM02 and Neupogen™ in cycle 1 (see Figure 1).\n\nFigure 1 Mean (± SD) of Absolute Neutrophil Counts in Cycle 1 – FA Set.\n\nIn cycle 1, the mean ANC nadir was deeper in the placebo group (0.2 × 109/L) compared to the XM02 and Neupogen™ groups (0.7 × 109/L). In cycles 2, 3, and 4, the mean ANC nadir was not as deep as in cycle 1 and was similar across treatment groups with a mean value of approximately 1.0 × 109/L.\n\nIn cycle 1, the median time to ANC recovery was shorter in the XM02 and Neupogen™ groups (8.0 and 8.0 days) compared to the placebo group (15.0 days). In cycles 2, 3, and 4, the time to ANC recovery was similar in all treatment groups with a median of 8.0 days.\n\nAdverse events\nDuring the course of the study, 329 (94.5%) patients experienced a total of 3,268 AEs. Of these, 177 were considered as severe in 104 (29.9%) patients. There were 72 serious adverse events (SAEs) in 49 (14.1%) patients. Nine patients (2.6%) discontinued the study due to an AE, i.e., 2 (1.4%) patients in the XM02 group, 3 (2.2%) in the Neupogen™ group, and 4 (5.6%) in the placebo/XM02 group. The AEs leading to discontinuation in these nine patients were: sepsis, cardio-respiratory arrest, ischaemic stroke, syncope, pulmonary infarction, ALT increased, hyperglycaemia and myalgia, ALT and AST increased, thrombocytopenia. There were 3 deaths during the study treatment period (sepsis in the placebo group/cycle 1, cardiorespiratory arrest in the placebo group/cycle 1, and ischaemic stroke in the XM02 group/cycle 1), and 1 death after the end of study visit (metastasis in brain). All deaths were considered not related to the study drug.\n\nThe most commonly reported AEs were nausea (in 49.4% of patients), alopecia (48.0%), and asthenia (36.5%). Most commonly reported drug-related AEs included bone pain (10.3%), asthenia (7.8%), myalgia (6.3%), and diarrhoea (5.2%). In general, drug-related AEs occurred early in the study, i.e., they were reported within 15 days after study start and within the first 4 days of a cycle.\n\nThe AE profile was similar between the XM02 and Neupogen™ groups with exception of the incidence of drug-related AEs across all cycles, which were seen more frequently in the Neupogen™ group (in 39.7% of patients) than in the XM02 group (25.7%) (p = 0.0149).\n\nPatients in the placebo group in cycle 1 had a higher incidence of AEs, SAEs, and severe SAEs compared to the XM02 and Neupogen™ groups. The Safety Monitoring Board decided to continue with the placebo group after 200 of a total of 350 planned patients had completed cycle 1.\n\nImmunogenicity was low in all treatment groups. Few patients developed binding anti-G-CSF antibodies in all treatment groups whereas no confirmed plausible neutralising antibodies were detected.\n\nPharmacokinetics\nThe pharmacokinetic profiles of XM02 and Neupogen™ were similar and t1/2 values correspond to published data on Neupogen™. In cycle 1 and cycle 4 in both profiles, mean serum concentrations of XM02 and Neupogen™ increased, reaching a maximum at 4 to 6 hours after dosing, and returned to pre-dose values by 24 hours. The median of t1/2 was similar in the XM02 and Filgrastim groups, i.e., 3.040 and 3.225 hours, respectively, in cycle 1 first profile, and 3.390 and 3.085 hours, respectively, in the second profile. In cycle 4, in both profiles, the median of t1/2 was similar in all treatment groups, ranging from 3.395 to 3.865 hours.\n\nDiscussion\nThe primary aim of this study was to compare XM02 with placebo and Neupogen™ in terms of efficacy and safety in the treatment of chemotherapy-induced neutropenia. By testing of superiority of XM02 versus placebo, assay sensitivity with respect to the primary endpoint, DSN in cycle 1, was confirmed.\n\nIn this study, mean DSN in cycle 1 was 1.1 days for patients treated with Neupogen™ or XM02, and 3.9 days for patients receiving placebo. In the subsequent cycles, where all patients received XM02 or Neupogen™, mean DSN ranged from 0.5 to 0.7 days. These are similar results as observed in a study conducted by Holmes et al. [1], comparing filgrastim with pegfilgrastim in breast cancer patients, where mean DSN in the filgrastim group was 1.8 days in cycle 1, and ranged between 1.1 and 1.3 days in the subsequent cycles. The shorter DSN observed in the present study may be explained by the fact that only chemotherapy-naïve patients were included.\n\nThe incidence of observed or protocol defined FN in cycle 1 in the XM02 and Neupogen™ groups (12.1% and 12.5%, respectively) was about one third (33.5% and 34.6% respectively) compared to the placebo group (36.1%). In a study conducted by Timmer-Bonte et al. [7], the incidence of FN in cycle 1 during chemotherapy for lung cancer was 10% in patients treated with antibiotics plus G-CSF. The incidence of observed or protocol defined FN across all cycles in our study was 20.7% and 22.1% in the XM02 and Neupogen™ groups, respectively. Similar results were seen in the Holmes study [1], where 18% of patients in the Neupogen™ group developed FN across all cycles. This comparison has to be interpreted with caution as in the Holmes study [1] a different definition of FN was used. Brain et al. [8] reported an incidence for FN of 40.8% in a breast cancer study using doxorubicin 50 mg/m2/docetaxel 75 mg/m2 and suggested to use primary G-CSF prophylaxis for this regimen. Vogel et al. [9] showed that pegfilgrastim markedly reduced the incidence of FN in breast cancer patients under moderate myelosuppressive chemotherapy with incidences of 1% with pegfilgrastim compared to 17% with placebo.\n\nFor patients receiving XM02 or Neupogen™, the ANC values distinctly increased after start of treatment, reaching a maximum on Day 3, and then decreased to a nadir on Day 7. Thereafter, ANC values increased again, reaching a maximum on Day 11. On Day 21, mean values returned to values as observed on Day 1. In a study conducted by Crawford et al. in patients with lung cancer under chemotherapy [10], in the filgrastim group, ANC values reached a maximum around Day 5, decreased to a nadir around Day 10 and reached a second maximum on Day 15. Holmes et al. [1] reported the same biphasic ANC profile under treatment with filgrastim in breast cancer patients treated with doxorubicin/docetaxel chemotherapy. In their study, the mean time to ANC recovery was 9.7 days for filgrastim, in our study the median time was 8.0 days for both XM02 and Neupogen™.\n\nIn general, the safety profile of XM02 and Neupogen™ was similar, whereas patients receiving placebo had distinctly more AEs and SAEs. Most commonly reported drug-related AEs were bone pain, asthenia, and myalgia, AEs that were expected from previous studies and experience with Neupogen™. In this study, drug-related AEs were seen significantly more frequently in the Neupogen™ than in the XM02 group.\n\nIn our study both G-CSF treatments were started one day after chemotherapy according to the Summary of Product Characteristics of Neupogen™ in order to properly compare both treatments. In clinical practice, G-CSF can also be administered starting from day 5 to 6 of each cycle [11]. This remains to be investigated in future studies with XM02 as well. More recently, pegfilgrastim, a pegylated form of filgrastim with a longer half life and duration of action was introduced into the market allowing a once per cycle administration [1].\n\nIn summary, XM02 treatment of breast cancer patients under docetaxel/doxorubicin resulted in a significant reduction of the DSN and the incidence of FN in cycle 1 to one third when compared to placebo. The reduction was similar in the XM02 and Neupogen™ group.\n\nConclusion\nIn conclusion, treatment with XM02 is beneficial in ameliorating severe neutropenia and FN in breast cancer patients receiving myelosuppressive chemotherapy. XM02 is safe and well tolerated in the doses applied in this study.\n\nConflicts of interests\nThis study was sponsored and funded by BioGeneriX AG.\n\nA. del Giglio has a consultancy agreement with BioGeneriX AG. H. Lubenau is an employee of BioGeneriX AG.\n\nAuthors' contributions\nAG was coordinating investigator of the trial and participated in the design, conduct and evaluation of the study as well as in the manuscript writing. AE, DG, ET were involved in the conduct of the study and in the writing and review of the manuscript. HL was involved in the design, implementation, coordination and evaluation of the trial and in the drafting of the manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\n\n\nAcknowledgements\nThanks to the Medical Writer, Dr. Kristian Kunde, PAREXEL International GmbH, Berlin.\n\nWe thank the participating investigators:\n\nEdvard Zavrid, Leanid Putyrski, Minsk, Belarus; Zigmund Gedrevich, Minsk, Belarus; Vasili Beliakouski, Gomel, Belarus; Iztoc Takac, Maribor, Slovenia; Jeremia Daniel Edward Cronje, Bloemfontein, South Africa; Artur Malzyner, São Paulo, Brazil; Gilson Luchezi Delgado, Sorocaba, Brazil; Geraldo Silva Queiroz, Goiânia, Brazil; José Luiz Pedrini, Porto Alegre, Brazil; Célia Tosello de Oliveira, São Paulo, Brazil; Eduardo Patricio Yanez Ruiz, Temuco, Chile; Jose Miguel Reyes Vidal, Santiago, Chile; Luis Soto Diaz, Santiago, Chile; Miguel Juan Fodor Becsky, Santiago, Chile; Marta Palma, Puerto Montt, Chile; Vladimir Semiglazov, Saint-Petersburg, Russia; Georgy Manikhas, Saint-Petersburg, Russia; David Korman, Moscow, Russia; Natalia Dobrovolskaya, Moscow, Russia; Andrey Zaritskey, Saint-Petersburg, Russia; Vladimir Moiseyenko, Saint-Petersburg, Russia; Maria Konstantinova, Saint-Petersburg, Russia; Irina Zbarskaya, Saint Petersburg, Russia; Boris Afanasyev, Saint-Petersburg, Russia; Vera Gorbunova, Moscow, Russia; Vasiliy Borisov, Moscow, Russia; Anatoly Makhson, Moscow, Russia; Marina Matrosova, Nizhny Novgorod, Russia; Eduard Voznyi, Moscow, Russia; Lydia Neluybina, Moscow, Russia; Mikhail Biakhov, Moscow, Russia; Leonid Bisenkov, Saint-Petersburg, Russia; Foat Akhmetzyanov, Kazan, Russia; Sufia Safina, Kazan, Russia; Agnes Ruzsa, Zalaegerszeg, Hungary; Elona Juozaiyte, Kaunas, Lithuania; Valerijus Ostapenko, Vilnius, Lithuania; Gediminas Kunigelis, Klaipeda, Lithuania; Zilvinas Saladzinskas, Kaunas, Lithuania; Stefan Curescu, Timisoara, Romania; Monica Patran, Sibiu, Romania; Lucia Milian, Oradea, Romania; Lucian Vata, Hunedoara, Romania; Lucian Miron, Iasi, Romania; Marcel Ionescu, Craiova, Romania; Maria Blasinska-Morawiec, Lodz, Poland; Agnieszka Jagiello-Gruszfeld, Olsztyn, Poland; Piotr Koralewski, Kraków, Poland; Cezary Szczylik, Warszawa, Poland.\n==== Refs\nHolmes FA O'Shaughnessy JA Vukelja S Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer J Clin Oncol 2002 20 727 31 11821454 10.1200/JCO.20.3.727 \nSmith TJ Khatcheressian J Lyman GH American Society of Clinical Oncology. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based, clinical practice guideline J Clin Oncol 2006 24 3187 205 16682719 10.1200/JCO.2006.06.4451 \nAapro MS Cameron DA Pettengell R EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours Eur J Cancer 2006 42 2433 53 16750358 10.1016/j.ejca.2006.05.002 \nDale DC Colony-stimulating factors for the management of neutropenia in cancer patients Drugs 2002 62 1 15 12479591 10.2165/00003495-200262001-00001 \nMartin-Christin F Granulocyte colony stimulating factors: How different are they? How to make a decision? Anti-cancer Drugs 2001 12 185 91 11290864 10.1097/00001813-200103000-00002 \nLubenau H Bias P Maly AK Pharmacokinetic and Pharmacodynamic Profile of New Biosimilar Filgrastim XM02 Equivalent to Marketed Filgrastim Neupogen®: Single-blind, Randomised, Cross-over Trial BioDrugs \nTimmer-Bonte JN de Boo TM Smit HJ Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: A Dutch randomized Phase III study J Clin Oncol 2005 23 7974 84 16258098 10.1200/JCO.2004.00.7955 \nBrain EGC Bachelot T Serin D Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer JAMA 2005 293 2367 71 15900007 10.1001/jama.293.19.2367 \nVogel CL Wojtukiewicz MZ Carroll RR First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study J Clin Oncol 2005 23 1178 84 15718314 10.1200/JCO.2005.09.102 \nCrawford J Ozer H Stoller R Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer N Engl J Med 1991 325 164 70 1711156 \nLilienfeld-Toal M Hahn-Ast C Kirchner H A randomized comparison of immediate versus delayed application of G-CSF in induction therapy for patients with acute myeloid leukemia unfit for intensive chemotherapy Haematologica 2007 92 1719 1720 18056004 10.3324/haematol.11516\n\n",
"fulltext_license": "CC BY",
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"references": "11290864;16682719;1711156;15718314;15900007;19344191;18056004;11821454;16750358;12479591;16258098",
"title": "XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy.",
"title_normalized": "xm02 is superior to placebo and equivalent to neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel doxorubicin chemotherapy"
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"abstract": "We report a 37-year-old man with a history of cirrhosis and methicillin-sensitive staphylococcus aureus (MSSA) bacteremia who presented from a nursing home with 1 week of progressive confusion followed by acute onset of aphasia, forced left eye deviation and right sided weakness. While clinical presentation was concerning for a left middle cerebral artery stroke, MRI was consistent with leukoencephalopathy. The man had been on metronidazole for 2 months for treatment of Clostridium difficile infection. This case exemplifies a stroke mimic to be considered when a patient presents with an acute focal neurological deficit.",
"affiliations": "Department of Neurology, University of Pittsburgh Medical Center, Kaufmann Medical Building Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.;Department of Neurology, University of Pittsburgh Medical Center, Kaufmann Medical Building Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.;Department of Neurology, University of Pittsburgh Medical Center, Kaufmann Medical Building Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA. Electronic address: jadhavap@upmc.edu.",
"authors": "Demel|Stacie L|SL|;Jovin|Tudor G|TG|;Jadhav|Ashutosh P|AP|",
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"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Flagyl; Hemiparesis; Leukoencephalopathy; Stroke mimic",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001037:Aphasia; D016470:Bacteremia; D016360:Clostridioides difficile; D004761:Enterocolitis, Pseudomembranous; D006801:Humans; D056784:Leukoencephalopathies; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008795:Metronidazole; D018908:Muscle Weakness; D016896:Treatment Outcome",
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"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metronidazole toxicity presenting with acute onset of aphasia and right sided weakness.",
"title_normalized": "metronidazole toxicity presenting with acute onset of aphasia and right sided weakness"
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"abstract": "We herein report the first case of purulent pericarditis associated with aortic stent-graft infection in an 80-year-old Japanese man that was caused by methicillin-susceptible Staphylococcus aureus, which appropriate antibiotics failed to treat. The detailed clinical course and autopsy images revealed that purulent pericarditis associated with aortic stent-graft infection caused cardiac tamponade and eventually led to mortality. We therefore suggest that surgical procedures, including drainage, should be introduced for such cases.",
"affiliations": "Department of Cardiology, Kanazawa University Graduate School of Medicine, Japan.;Department of Cardiology, Kanazawa University Graduate School of Medicine, Japan.;Department of Cardiology, Kanazawa University Graduate School of Medicine, Japan.;Division of Rheumatology, Kanazawa University Graduate School of Medicine, Japan.;Department of Cardiology, Kanazawa University Graduate School of Medicine, Japan.;Department of Cardiology, Kanazawa University Graduate School of Medicine, Japan.",
"authors": "Yamagami|Kan|K|;Tanaka|Yoshihiro|Y|;Tada|Hayato|H|;Fujii|Hiroshi|H|;Takamura|Masayuki|M|;Kawashiri|Masa-Aki|MA|",
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"doi": "10.2169/internalmedicine.2994-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3129239110.2169/internalmedicine.2994-19Case ReportThe First Report of Purulent Pericarditis Associated with Aortic Stent-graft Infection Caused by Methicillin-susceptible Staphylococcus aureus Yamagami Kan 1Tanaka Yoshihiro 12Tada Hayato 1Fujii Hiroshi 3Takamura Masayuki 1Kawashiri Masa-aki 1\n1 Department of Cardiology, Kanazawa University Graduate School of Medicine, Japan\n2 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, USA\n3 Division of Rheumatology, Kanazawa University Graduate School of Medicine, JapanCorrespondence to Dr. Yoshihiro Tanaka, y.tanaka@northwestern.edu\n\n10 7 2019 1 11 2019 58 21 3103 3106 8 3 2019 12 5 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein report the first case of purulent pericarditis associated with aortic stent-graft infection in an 80-year-old Japanese man that was caused by methicillin-susceptible Staphylococcus aureus, which appropriate antibiotics failed to treat. The detailed clinical course and autopsy images revealed that purulent pericarditis associated with aortic stent-graft infection caused cardiac tamponade and eventually led to mortality. We therefore suggest that surgical procedures, including drainage, should be introduced for such cases. \n\npurulent pericarditisautopsystent-graft infection\n==== Body\nIntroduction\nPurulent pericarditis is a rare condition that is associated with high morbidity and mortality (1). It can cause severe complications, such as cardiac tamponade, which can be fatal without acute pericardial drainage because it can cause sudden cardiac decompensation (2,3). Staphylococcus aureus is the most common pathogen causing purulent pericarditis (31%), followed by Streptococcus pneumoniae (22%) (3,4). Hematogenous spread, direct spread from adjacent organs, extension from subdiaphragmatic infections, and complication of trauma or surgery are the known causes (1,5). Treatment options include appropriate antibiotics and emergent pericardial drainage.\n\nAlthough the incidence of endograft infection ranges from 0.2% to 5%, its mortality rate is high (6). S. aureus is the most common causative pathogen, with a prevalence of 30-70% (7,8). Treatment options include the surgical removal of the endograft with adequate antibiotics. As mentioned above, purulent pericarditis and endograft infection share common pathogens and characteristics of requiring surgical intervention with an elevated mortality rate.\n\nWe herein report, to our knowledge, the first case of purulent pericarditis associated with aortic stent-graft infection caused by methicillin-susceptible S. aureus (MSSA), which appropriate antibiotics failed to treat.\n\nCase Report\nAn 80-year-old man with a history of aortic arch aneurysm treated with thoracic endovascular aortic repair (TEVAR) and end-stage renal cell carcinoma (RCC) was referred to our hospital due to gradually worsening dyspnea and a fever.\n\nTwo years prior to admission, he had been diagnosed with MSSA bacteremia after TEVAR and treated with meropenem and vancomycin for one month. Five days prior to admission, he experienced general malaise and shortness of breath on exertion. One day prior to admission, his body temperature increased to 38.0℃, and he was transferred to our hospital. He was alert and had nonacute distress on admission. He denied any upper respiratory, abdominal, or urinary symptoms. His vital signs included a body temperature of 38.6℃, blood pressure of 166/92 mmHg, heart rate of 100 beats/min, respiratory rate of 20/min, and O2 saturation of 96% in room air. On a physical examination, his oral hygiene was unremarkable. He had jugular vein distention, and his wheezes were audible bilaterally on auscultation. Neither cardiac murmur nor pericardial friction rub was audible. The results of abdominal examinations were benign. His lower extremities were cold with slight edema. On the surface of the skin, no decubitus, tinea unguium, or scratches were detected.\n\nChest X-ray revealed cardiomegaly and pulmonary congestion. Small pleural effusion was shown bilaterally. 12-lead electrocardiography (ECG) revealed sinus tachycardia and T-wave inversion in precordial leads from V2 to V5. Blood test results revealed a slight elevation in the white blood cell count (9,810 cells/μL) that was associated with an increase in C-reactive protein levels (up to 9.6 mg/dL). His serum creatinine level showed an increase compared with a previous test (from 1.86 to 2.09 mg/dL). Brain natriuretic peptide levels increased to 1,562 pg/dL. There was no evidence of pericardial effusion according to echocardiography performed at admission.\n\nHis body temperature decreased and pulmonary congestion disappeared soon after diuretics and broad-spectrum antibiotics (piperacillin-tazobactam 4.5 g/day) were administered as an initial treatment after two sets of blood cultures had been obtained. On day 3, his blood culture turned positive for MSSA; subsequently, antibiotics were de-escalated from piperacillin-tazobactam 4.5 g/day to cefazolin 4 g/day. Sputum and urinary cultures were negative, and echocardiography showed no valvular vegetation or deterioration of any valvular regurgitation other than the slight accumulation of fluid in the pericardial space, which was also observed on computed tomography (CT) (Fig. 1A, arrowheads). His vital signs were stable with no signs of cardiac tamponade. Therefore, pericardial fluid was considered nonspecific, and we decided to conduct follow-up using echocardiography.\n\nFigure 1. Pericardial effusion detected by computed tomography. A: Slight pericardial effusion was detected by nonenhanced computed tomography (CT) on day 3 (arrowheads). B: Follow-up CT was performed on day 9 because of deterioration of the patient’s general condition. The amount of pericardial effusion dramatically increased over six days (arrowheads). Bilateral pleural effusion became evident (asterisk).\n\nAt this time, an endograft infection was considered the most likely differential diagnosis despite the cause of the infection being unclear. On day 5, his dyspnea did not improve, and peripheral malperfusion was still observed, although the blood culture was negative. Echocardiography revealed the massive accumulation of pericardial effusion within two days after the last follow-up. It was challenging to perform therapeutic pericardiocentesis due to the small amount of pericardial effusion on the anterior surface (<10 mm) and his poor physical status. Surgical pericardiocentesis was thus considered as the treatment choice. However, taking his physical status and prognosis of end-stage RCC into consideration, we decided to avoid invasive therapy after a discussion with his family.\n\nHis blood urea nitrogen level increased considerably with a concomitant decrease in urine output, although his body temperature did not increase after the initiation of antibiotic therapy, and his blood culture remained negative. Acute exacerbation of renal failure due to a low cardiac output was considered as a cause of his low urine output. Subsequently, the administration of diuretics was ceased, and renal replacement therapy using hemodialysis was performed. However, his renal function did not improve after treatment. His consciousness suddenly deteriorated on day 9 without any overt findings from blood gas testing or 12-lead ECG, and he died. Written informed consent was obtained from his family for an autopsy and postmortem CT (PMCT).\n\nPMCT revealed the massive accumulation of fluid in the pericardial space (Fig. 1B, arrowheads), bilateral pulmonary congestion, and consolidation surrounding the descending aorta. No intratracheal foreign body or sputum was detected. Cardiac tamponade was clinically considered as a possible cause of death based on the PMCT findings. The autopsy was performed 4 hours after his death. Notable autopsy findings included a massive amount of pus (roughly 500 mL) in the pericardial space (Fig. 2A and B) and around the outer layer of the aortic endograft (Fig. 3A and B), significant mediastinal lymphadenopathy, and systemic metastasis of malignancy (pancreas, liver, lungs, abdominal aortic lymph nodes, and peritoneum). RCC was considered the origin of the metastases. MSSA was identified from cultures of both the pericardium and periaortic tissues. However, continuity of the pus from the ascending aorta to the pericardial space was not clearly identified. Severe neutrophil infiltration was observed in the pericardium and no microscopic bacterial infiltration was observed in aortic stent (Fig. 2C and D). The autopsy did not reveal apparent coronary thrombosis, valvular vegetation, pulmonary embolism, aortic dissection, intratracheal foreign body or sputum, or massive hemorrhaging in the pleural, pericardial, or abdominal spaces. These findings suggested that the cause of death was cardiac tamponade due to purulent pericarditis associated with aortic stent-graft infection by MSSA.\n\nFigure 2. Autopsy findings of the mediastinum. A: The mediastinum was observed from a ventral view. The asterisk indicates the heart. A massive amount of pus was observed in the pericardial space. B: Collection of the pus from the pericardial space. In total, approximately 500 mL of creamy pus was collected. C: Cytological findings of the pus. Papanicolaou staining was performed. Infiltration of numerous neutrophils was observed. These findings were compatible with purulent pericarditis.\n\nFigure 3. Autopsy and pathological findings of the aorta. A: Pus was observed around the outer layer of the aortic stent-graft from the ascending aorta to the descending aorta. B: Magnified view of the ascending aorta. Pus was observed around the outer layer of the aortic stent-graft (arrow). No penetration or tearing of the intima was observed. C: Histopathological findings of pus. Hematoxylin and Eosin staining was performed. Numerous neutrophils infiltrated the pericardial tissues. D: Magnified view of pus of the aorta. Neutrophil (not bacterial) infiltration was observed.\n\nDiscussion\nPurulent pericarditis is rare but can be fatal even if adequate treatment is provided, and its early detection and treatment are necessary in order to reduce the morbidity and mortality. However, the diagnosis of purulent pericarditis is challenging and difficult to establish until an autopsy is performed (5).\n\nIn the present case, the patient never complained of chest pain during the hospital course. Furthermore, ECG revealed no signs of pericarditis, except for T-wave inversion in precordial leads on admission, which was generally not compatible with pericarditis but was compatible with coronary artery disease. In addition, blood cultures were negative after antibiotic therapy, and echocardiography revealed no vegetation and only slight pericardial effusion. Finally, the decrease in body temperature after the initiation of antibiotics incorrectly suggested that the patient was under appropriate treatment and that the infection was responding to the treatment. Together, these conditions were considered to have delayed the purulent pericarditis diagnosis. This view is supported by two previous studies that reported that patients with purulent pericarditis were less likely to complain of chest pain than those with acute pericarditis associated with other causes (3,5).\n\nAlthough our patient appeared physically active before admission, he had chronic kidney disease and end-stage RCC, both of which were considered critical risk factors for purulent pericarditis in the present case (9). The recurrence of aortic stent-graft infection due to MSSA was a possible cause of this clinical course in this patient, as he had a history of MSSA bacteremia after TEVAR two years prior to admission that was treated via long-term antibiotic therapy. The recurrence rate of MSSA bacteremia after appropriate antibiotics therapy was 2.1% in a previous study, but the recurrence rate of aortic stent-graft infection by MSSA was not reported (10).\n\nIn the present case, the autopsy revealed a massive amount of pus around the outer layer of the aortic stent-graft at the TEVAR site in addition to the pericardial space. This finding raised a chicken-and-egg issue regarding the primary focus of infection. There were no findings suggesting a direct invasion of infection from the aorta to the pericardium. In addition, pericardial effusion was not observed on admission. Considering these findings, it is reasonable to conclude that the aortic stent-graft site is a primary focus of infection and that subsequent hematogenous spread to the pericardial space can occur. However, several case reports have demonstrated purulent pericarditis complicated with infected aneurysm, where the direct spread of infection from the aorta to the pericardial space was suspected (11,12). In the present case, the possibility of direct pathogen invasion from the ascending endograft to the pericardial space could not be completely ruled out because the proximal part of the endograft was located across the pericardial reflection on CT.\n\nAlthough enhanced CT may be useful for identifying the focus of infection, we refrained from using it due to the patient's worsening renal function. Another diagnostic option is positron emission tomography (PET)-CT. The diagnostic utility of PET-CT was reported in a case of graft infection of the aorta (13). If the patient had been in a good condition, first-line therapy would have been emergent surgical drainage followed by aortic replacement therapy with long-term antibiotics administration. However, the patient's general condition gradually deteriorated after admission, and no surgical treatment could have been performed, even if a precise diagnosis had been made in the present case.\n\nIn conclusion, we herein report, to our knowledge, the first case of purulent pericarditis associated with aortic stent-graft infection caused by MSSA, which appropriate antibiotics failed to treat successfully. We suggest that surgical procedures, including drainage, should be introduced in such cases.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nKeersmaekers T , Elshot SR , Sergeant PT \nPrimary bacterial pericarditis . Acta Cardiol \n57 : 387 -389 , 2002 .12405580 \n2. \nGabler M \nCardiac tamponade secondary to purulent pericarditis diagnosed with the aid of emergency department ultrasound . Am J Emerg Med \n35 : 1212.e1 -1212.e3 , 2017 .\n3. \nRubin RH , Moellering RC \nClinical, microbiologic and therapeutic aspects of purulent pericarditis . Am J Med \n59 : 68 -78 , 1975 .1138554 \n4. \nKlacsmann PG , Bulkley BH , Hutchins GM \nThe changed spectrum of purulent pericarditis: an 86 year autopsy experience in 200 patients . Am J Med \n63 : 666 -673 , 1977 .930941 \n5. \nSagristà-Sauleda J , Barrabés JA , Permanyer-Miralda G , Soler-Soler J \nPurulent pericarditis: review of a 20-year experience in a general hospital . J Am Coll Cardiol \n22 : 1661 -1665 , 1993 .8227835 \n6. \nSmeds MR , Duncan AA , Harlander-Locke MP , et al \nTreatment and outcomes of aortic endograft infection . J Vasc Surg \n63 : 332 -340 , 2016 .26804214 \n7. \nBrown SL , Busuttil RW , Baker JD , Machleder HI , Moore WS , Barker WF \nBacteriologic and surgical determinants of survival in patients with mycotic aneurysms . J Vasc Surg \n1 : 541 -547 , 1984 .6436514 \n8. \nJohnson JR , Ledgerwood AM , Lucas CE \nMycotic aneurysm. New concepts in therapy . Arch Surg \n118 : 577 -582 , 1983 .6687676 \n9. \nTam WC , Lee WS , Cheng CY \nPurulent pericarditis complicating cardiac tamponade in a uremic patient caused by Staphylococcus aureus . J Microbiol Immunol Infect \n51 : 695 -696 , 2018 .29108782 \n10. \nWalker TM , Bowler IC , Bejon P \nRisk factors for recurrence after Staphylococcus aureus bacteraemia. A retrospective matched case-control study . J Infect \n58 : 411 -416 , 2009 .19394703 \n11. \nNagano N , Yamamoto T , Amano A , Kikuchi K \nInfected aneurysm of the aortic arch with purulent pericarditis caused by Streptococcus pneumoniae . Interact Cardiovasc Thorac Surg \n10 : 459 -461 , 2010 .20007205 \n12. \nSaito S , Matsuura A , Miyahara K , Takemura H , Sawaki S , Ito H \nInfected aortic aneurysm, purulent pericarditis, and pulmonary trunk rupture caused by methicillin-resistant Staphylococcus aureus . Gen Thorac Cardiovasc Surg \n57 : 250 -252 , 2009 .19440821 \n13. \nBianco V , Kilic A , Gleason TG , Arnaoutakis GJ , Sultan I \nManagement of thoracic aortic graft infections . J Card Surg \n33 : 658 -665 , 2018 .30178475\n\n",
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"issue": "58(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "autopsy; purulent pericarditis; stent-graft infection",
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001011:Aorta; D002305:Cardiac Tamponade; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008712:Methicillin; D010490:Pericardial Effusion; D010493:Pericarditis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D015607:Stents; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3103-3106",
"pmc": null,
"pmid": "31292391",
"pubdate": "2019-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26804214;12405580;8227835;20007205;30178475;19394703;28473276;19440821;6687676;1138554;29108782;930941;6436514",
"title": "The First Report of Purulent Pericarditis Associated with Aortic Stent-graft Infection Caused by Methicillin-susceptible Staphylococcus aureus.",
"title_normalized": "the first report of purulent pericarditis associated with aortic stent graft infection caused by methicillin susceptible staphylococcus aureus"
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{
"abstract": "BACKGROUND\nEosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem necrotizing vasculitis associated with eosinophilia and extravascular granuloma and classically involving the upper and lower airways. There have only been a few reported cases of gynecologic involvement in EGPA.\n\n\nMETHODS\nWe present an 8-year-old girl diagnosed with EGPA with a vulvar granuloma in what is, to our knowledge, the first reported pediatric gynecologic manifestation of EGPA. Interestingly, the vulvar granuloma did not respond to initial immunosuppressant treatment with prednisone and methotrexate and required treatment regimen modification with mycophenolate mofetil resulting in granuloma resolution.\n\n\nCONCLUSIONS\nEGPA in the pediatric population has a relatively high mortality rate compared with in the adult population thus it is important that vulvar granulomas associated with EGPA should be included in the differential diagnosis of a vulvar mass allowing for the prompt diagnosis and treatment of this potentially fatal disease in children.",
"affiliations": "Department of Obstetrics and Gynecology, Kaiser Permanente, Roseville, California; Drexel University College of Medicine, Philadelphia, Pennsylvania.;Department of Obstetrics and Gynecology, Kaiser Permanente, Roseville, California; Drexel University College of Medicine, Philadelphia, Pennsylvania.;Department of Obstetrics and Gynecology, Kaiser Permanente, Roseville, California. Electronic address: Nichole.Tyson@kp.org.",
"authors": "Swain|Celeste A|CA|;Sherry|Timothy R|TR|;Tyson|Nichole|N|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2019.03.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "32(4)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Churg-Strauss; Eosinophilic granulomatosis; Granuloma; Vasculitis; Vulvar lesion; Vulvar mass",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000328:Adult; D002648:Child; D015267:Churg-Strauss Syndrome; D003937:Diagnosis, Differential; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D014844:Vulva",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "425-428",
"pmc": null,
"pmid": "30904627",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Childhood-Onset Eosinophilic Granulomatosis with Polyangiitis with a Vulvar Granuloma: A Case Report and Review of the Literature.",
"title_normalized": "childhood onset eosinophilic granulomatosis with polyangiitis with a vulvar granuloma a case report and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2019135790",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nDolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).\n\n\nMETHODS\nING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16.\n\n\nRESULTS\nThirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16.\n\n\nCONCLUSIONS\nThe DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199.",
"affiliations": "University of California, San Diego.;Anthony Mills, MD, Inc, Los Angeles, California.;The Miriam Hospital, Providence, Rhode Island.;GlaxoSmithKline, Durham, North Carolina.;GlaxoSmithKline, Durham, North Carolina.;GlaxoSmithKline, Durham, North Carolina.;GlaxoSmithKline, Durham, North Carolina.;GlaxoSmithKline, Durham, North Carolina.",
"authors": "Letendre|Scott L|SL|;Mills|Anthony M|AM|;Tashima|Karen T|KT|;Thomas|Deborah A|DA|;Min|Sherene S|SS|;Chen|Shuguang|S|;Song|Ivy H|IH|;Piscitelli|Stephen C|SC|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; C492871:abacavir, lamivudine drug combination; D019259:Lamivudine; C562325:dolutegravir",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu477",
"fulltext": "\n==== Front\nClin Infect DisClin. Infect. DiscidcidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University Press 10.1093/cid/ciu477ciu477HIV/AIDSING116070: A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in Cerebrospinal Fluid in HIV-1–Infected, Antiretroviral Therapy–Naive Subjects Letendre Scott L. 1Mills Anthony M. 2Tashima Karen T. 3Thomas Deborah A. 4Min Sherene S. 4Chen Shuguang 4Song Ivy H. 4Piscitelli Stephen C. 4on behalf of the extended ING116070 study team1 University of California, San Diego2 Anthony Mills, MD, Inc, Los Angeles, California3 The Miriam Hospital, Providence, Rhode Island4 GlaxoSmithKline, Durham, North CarolinaCorrespondence: Stephen C. Piscitelli, PharmD, GlaxoSmithKline, 5 Moore Dr, Durham, NC 27709 (stephen.c.piscitelli@gsk.com).01 10 2014 18 6 2014 18 6 2014 59 7 1032 1037 15 4 2014 6 6 2014 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2014This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com.Median dolutegravir concentrations in cerebrospinal fluid were similar to unbound concentrations in plasma and all subjects exceeded the in vitro 50% inhibitory concentration for wild-type viruses (0.2 ng/mL) by ≥66-fold, suggesting therapeutic concentrations are achieved in cerebrospinal fluid..\n\nBackground. Dolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).\n\nMethods. ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy–naive, HIV-1–infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16.\n\nResults. Thirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non–drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4–23 ng/mL) at week 2 and 13 ng/mL (4–18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were −3.42 and −3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16.\n\nConclusions. The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma.\n\nClinical Trials Registration. NCT01499199.\n\ncerebrospinal fluiddolutegravirHIV\n==== Body\nDespite the advent of modern, potent antiretroviral therapy (ART), human immunodeficiency virus (HIV)–associated neurocognitive impairment continues to be clinically significant [1–3]. In HIV-infected patients receiving therapy, HIV has been found in the cerebrospinal fluid (CSF) of individuals who have an undetectable plasma viral load, both for patients with neurologic symptoms [4] and for those who are neurologically asymptomatic [5]. Such discordant findings between plasma and CSF may be influenced by choice of therapy, because treatment with ART that has better estimated distribution into the central nervous system (CNS) has been associated with better viral suppression in CSF [6–8]. Thus, it has become increasingly important to understand to what degree components of ART can exert activity within the brain, a long-considered “sanctuary” site [6, 9–11].\n\nAlthough the CSF space is not equivalent to the brain extracellular or intracellular environment, drug distribution into the CSF is a practical way to gain some understanding of the potential for CNS tissue distribution. Therefore, CSF provides a valuable surrogate to estimate drug distribution and antiviral effects across the blood-brain barrier and blood-CSF barrier [12–14]. The CSF distribution of many antiretrovirals, including lopinavir, darunavir, efavirenz and raltegravir, has been assessed [15–18].\n\nDolutegravir (DTG; Tivicay, ViiV Healthcare, Research Triangle Park, North Carolina) is a novel HIV integrase inhibitor (INI) with a pharmacokinetic profile that allows once-daily administration in INI-naive subjects. The efficacy and safety of DTG in large, phase III trials have been reported elsewhere [19, 20]. Dolutegravir is approximately 99% bound to plasma proteins and is primarily metabolized via uridine 5′-diphospho-glucuronosyltransferase 1A1, with cytochrome P450 3A4 as a minor pathway. It is also a substrate of P-glycoprotein and breast cancer resistance protein. These attributes indicate that distribution across the blood-brain barrier and blood-CSF barrier will be limited. However, owing to the potency of DTG, even modest distribution into the CNS may result in concentrations that provide antiviral activity.\n\nStudy ING116070 was designed to assess the extent of DTG entry into the CSF compartment, and to evaluate virologic responses in CSF and plasma. Results from the planned week 16 primary analysis are presented.\n\nMETHODS\nDesign and Study Population\nING116070 is an ongoing, 96-week, phase IIIb, single-arm, open-label, multicenter (3 US sites) study in ART-naive (≤10 days of prior therapy), HIV-1–infected adults (≥18 years old). Eligible participants had a screening plasma HIV-1 RNA level ≥5000 copies/mL and a CD4+ cell count ≥200 cells/mm3 and were negative for the HLA-B*5701 allele. Exclusions included contraindication to lumbar puncture, moderate or severe cognitive impairment, evidence of primary viral resistance, active US Centers for Disease Control and Prevention category C disease (except Kaposi sarcoma), defined laboratory values, pregnancy, breastfeeding, moderate or severe hepatic impairment, hepatitis B virus infection, anticipated need for hepatitis C virus therapy during the study period, malignancy, or recent treatment with HIV-1 vaccines or immunomodulators. Ethics committee approval was obtained at all participating centers in accordance with the principles of the 2008 Declaration of Helsinki. Each patient provided written informed consent before undergoing study procedures. This study is registered at ClinicalTrials.gov (NCT01499199).\n\nEligible subjects received (DTG 50 mg) along with the dual nucleoside reverse-transcriptase inhibitor (NRTI) combination tablet abacavir/lamivudine (ABC/3TC [Kivexa/Epzicom, ViiV Healthcare]; 600/300 mg), all taken once daily. The intention-to-treat exposed and safety populations both comprised all randomized subjects who received ≥1 dose of study medication.\n\nStudy End Points\nThe primary study analyses occurred at week 16; additional analyses were preplanned for weeks 2 and 96. The primary end point was the DTG concentration in CSF at week 16. Secondary end points included DTG concentrations in plasma (total and unbound) and CSF (total), the relationship between DTG concentrations in plasma and CSF, the proportion of subjects with plasma HIV-1 RNA <50 or <400 copies/mL, change from baseline in plasma and CSF HIV-1 RNA, the relationship between DTG concentration in CSF and HIV-1 RNA in CSF, and the relationship between plasma and CSF HIV-1 RNA suppression and HIV disease progression and safety parameters (ie, adverse events [AEs] and laboratory abnormalities). Additionally, the incidence of treatment-emergent genotypic and phenotypic resistance to DTG and other on-study ART was assessed for any subject with protocol-defined virologic failure (PDVF).\n\nProcedures and Assessments\nStudy visits occurred at baseline and weeks 2, 4, 8, 12, and 16; additional visits for this ongoing study were scheduled for weeks 24, 36, and 48, and every 12 weeks thereafter until week 96. Plasma samples were collected at each visit to evaluate HIV-1 RNA levels (all visits) and plasma DTG concentrations (weeks 2 and 16; plasma pharmacokinetic samples were collected 2–6 hours after the dose). The CSF samples were obtained by lumbar puncture at baseline and weeks 2 and 16 for evaluation of HIV-1 RNA levels and at weeks 2 and 16 for evaluation of CSF DTG concentrations (collected 2–6 hours after the dose and within 1 hour of the plasma pharmacokinetic sample). The CD4+ cell counts were determined at each visit (except week 2).\n\nCentral laboratory facilities (Quest Diagnostics) provided hematologic, clinical chemistry, and HIV-1 RNA testing. The CSF HIV-1 RNA levels were determined using an HIV-1 RNA SuperLow assay (testing provided by bioMONTR Labs) with a lower limit of detection of 2 copies/mL. First, 2 mL of plasma was lysed and extracted on the EasyMAG platform (bioMérieux). Eluates containing HIV-1 RNA were aliquoted and amplified by 3 enzymes: T7 RNA polymerase, Avian myeloblastosis virus reverse transcriptase, and RNase H. Primers and molecular beacons targeting the pol/gag region of HIV-1 RNA were used for amplification and detection by isothermal reactions at 41°C. Quantitation of HIV-1 RNA was determined by a proprietary reduction algorithm in conjunction with the NucliSENS EasyQ HIV-1 v2.0 Director software (bioMérieux). Plasma HIV-1 RNA levels were determined using the RealTime HIV-1 PCR assay (Abbott Molecular); the plasma lower limit of detection was 40 copies/mL.\n\nMeasurements of DTG concentrations were performed using validated analytic methods based on protein precipitation, followed by high-performance liquid chromatography tandem mass spectrometry analysis [21]. The DTG concentrations in plasma were analyzed by GlaxoSmithKline, and the CSF samples were analyzed by QPS (Newark, Delaware). For total plasma concentration, the DTG lower limit of quantification was 20 ng/mL, and the upper limit was 20 000 ng/mL. Unbound plasma DTG concentration and total CSF DTG concentrations both had a lower limit of quantification of 1 ng/mL and an upper limit of 1000 ng/mL.\n\nSafety was assessed throughout the study period, with monitoring and recording of all AEs, serious AEs (SAEs), vital signs, and laboratory parameters (eg, hematologic, fasting lipid profile, and chemistry results). The AEs were assessed and graded according to the Division of AIDS toxicity scales [22]. Liver chemistry threshold stopping criteria were implemented to ensure subject safety and to evaluate causes of liver inflammation.\n\nProtocol-defined virologic failure was defined as 2 consecutive plasma HIV-1 RNA values >200 copies/mL on or after week 16, with cases triggering virologic resistance testing. Resistance testing was performed by Monogram Biosciences.\n\nStatistical Analyses\nING116070 was a single-arm study to assess the distribution of DTG into the CSF compartment. As such, it included no formal hypothesis test. Pearson correlations between DTG concentrations in plasma (total and unbound) and CSF at weeks 2 and 16 were calculated. Efficacy analyses were based on the intention-to-treat exposed population. Subjects' responses (eg, <50 copies/mL) for plasma HIV-1 RNA were calculated and summarized according to a missing, switch, or discontinuation equals failure (MSDF) algorithm, as codified by the US Food and Drug Administration Snapshot algorithm [23], wherein all subjects without plasma HIV-1 RNA data at the visit of interest (eg, owing to missing data or early discontinuation) or who changed their concomitant ART (except for switches to permitted NRTIs before week 2) were treated as nonresponders. Otherwise, virologic success or failure for the visit of interest was determined by the last available HIV-1 RNA assessment while the subject was receiving treatment. Descriptive summaries were provided for the following: absolute values and change from baseline in HIV-1 RNA (plasma and CSF) and CD4+ cell counts; the incidence and severity of all AEs, treatment-related AEs, AEs leading to withdrawal, SAEs, and graded laboratory abnormalities; plasma (total and unbound) and CSF (total) DTG concentrations; and the incidence of PDVF or treatment-emergent genotypic and phenotypic resistance to DTG and other on-study ART. The assessments of DTG concentrations in plasma and CSF, and of CSF HIV-1 RNA responses, were based on all available data.\n\nRESULTS\nOf 17 subjects screened, 13 subjects enrolled and received study medication. All subjects were white men, 3 (23%) were of Hispanic ethnicity, and their median age was 42 years (range, 28–52 years). Baseline characteristics are summarized in Table 1. At the week 16 analysis, 2 subjects had prematurely withdrawn (1 before week 2 owing to a non–drug-related SAE of pharyngitis and 1 owing to lack of treatment efficacy [ie, plasma HIV-1 RNA never suppressed to <200 copies/mL by week 16]). No subjects had switched background NRTI therapy.\nTable 1. Baseline Characteristics in the Intention-to-Treat Exposed Population (N = 13)\n\nCharacteristic\tResults\t\nBaseline plasma HIV-1 RNA\t\n ≤100 000 copies/mL, No. (%)\t8 (62)\t\n >100 000 copies/mL, No. (%)\t5 (38)\t\n Mean (SD), log10 copies/mL\t4.93 (0.86)\t\n Median (range), log10 copies/mL)\t4.73 (3.60, 6.57)\t\nBaseline CSF HIV-1 RNA\t\n Mean (SD), log10 copies/mL\t3.59 (1.21)\t\n Median (range), log10 copies/mL\t3.64 (1.46, 5.60)\n\t\nBaseline CD4+ cell count\t\n <350 cells/mm3, No. (%)\t6 (46)\t\n ≥350 cells/mm3, No. (%)\t7 (54)\t\n Mean (SD), cells/mm3\t409 (188)\t\n Median (range), cells/mm3\t360 (152, 863)\t\nNonreactive hepatitis B and C test results, No. (%)a\t13 (100)\t\nCDC category, No. (%)b\t\n A\t7 (54)\t\n B\t3 (23)\t\n C\t3 (23)\t\nAbbreviations: CDC, US Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; HIV-1, human immunodeficiency virus type 1; SD, standard deviation.\n\na Nonreactive results showed neither hepatitis B nor hepatitis C.\n\nb CDC category A is defined as asymptomatic, lymphadenopathy, or acute HIV infection; category B, symptomatic, not AIDS; and category C, AIDS.\n\n\n\nEvaluable, paired CSF and plasma pharmacokinetic samples were available from 12 subjects at week 16; 1 subject at week 2 had pharmacokinetic samples collected outside the required 2–6 hour postdose sampling window, resulting in 11 evaluable subjects at week 2. The DTG concentrations in CSF and plasma are shown in Table 2. The median DTG concentrations in CSF were 18 ng/mL (range, 4–23 ng/mL) at week 2 and 13 ng/mL (4–18 ng/mL) at week 16, both of which exceeded the in vitro 50% inhibitory concentration (IC50) of 0.2 ng/mL. Concentrations of DTG in CSF were low compared with plasma with median CSF-plasma ratios of 0.52% (range, 0.12%–0.66%) at week 2 and 0.41% (range, 0.30%–2.04%) at week 16. The DTG concentrations in CSF were similar to unbound plasma concentrations (Table 2). Ratios of DTG CSF total concentration to plasma total concentration were similar to the unbound fractions of DTG in plasma; these seemed to stay constant during the sampling window and were similar between weeks 2 and 16.\nTable 2. Dolutegravir Concentrations in Plasma and Cerebrospinal Fluid\n\nDolutegravir Concentration\tWeek 2 (n = 12)\tWeek 16 (n = 12)\t\nMean (SD)\tMedian (Range)\tMean (SD)\tMedian (Range)\t\nPlasma total, ng/mL\t3420 (831)\t3360 (2090–5280)\t3030 (1350)\t3210 (640–4920)\t\nPlasma unbound, ng/mL\t16.8 (4.10)\t17.1 (10.3–24.0)\t23.0 (8.24)\t23.9 (3.81–32.1)\t\nUnbound fraction in plasma, %\t0.495 (0.082)\t0.488 (0.333–0.655)\t0.995 (1.05)\t0.701 (0.488–4.30)\t\nCSF total, ng/mL\t16.2 (5.84)a\t18.2 (4.0–23.2)a\t12.6 (3.64)\t13.2 (3.7–18.3)\t\nCSF–total plasma ratio, %\t0.467 (0.178)a\t0.516 (0.115–0.658)a\t0.546 (0.480)\t0.412 (0.299–2.04)\t\nAbbreviations: CSF, cerebrospinal fluid; SD, standard deviation.\n\na n = 11 (excluding 1 subject with pharmacokinetic samples collected outside the 2–6-hour postdose window).\n\n\n\nAt week 16, there was a significant correlation between total DTG concentrations in CSF and plasma, as well as between total DTG concentrations in CSF and unbound DTG concentrations in plasma (Pearson correlation coefficient, 0.65 [P = .023] and 0.73 [P = .007], respectively).\n\nCSF HIV-1 RNA levels decreased rapidly, with a median change of −2.19 log10 copies/mL by week 2; 7 of 12 (58%) and 11 of 12 (92%) subjects had CSF HIV-1 RNA levels <50 or <400 copies/mL, respectively, at week 2. By week 16, the median change from baseline in CSF HIV-1 RNA was −3.42 log10 copies/mL, which was similar to that observed in plasma (−3.04 log10 copies/mL) at the same time point, although there was no statistically significant correlation between the two. In addition, DTG concentrations in CSF did not correlate with changes from baseline in CSF HIV-1 RNA at week 16.\n\nResults at week 16 showed that 10 (77%) and 12 (92%) of 13 subjects had plasma HIV-1 RNA levels <50 copies/mL or <400 copies/mL, respectively, using the US Food and Drug Administration Snapshot MSDF algorithm, and all 11 subjects (100%) had CSF HIV-1 RNA levels below 50 copies/mL, using all available data. Another subject had a late (day 141) assessment for week 16 CSF HIV-1 RNA, which was <50 copies/mL. Overall, at week 16, all subjects had CSF HIV RNA levels <2 copies/mL, except 1 subject with a value of 5 copies/mL. Eleven subjects had both plasma and CSF HIV-1 RNA data available at week 16. Nine (82%) of them had HIV-1 RNA levels <50 copies/mL in both plasma and CSF.\n\nOne subject met the definition of PDVF. This subject entered the study with a plasma HIV-1 RNA level of 6.57 log10 copies/mL, which rapidly declined to 743 copies/mL by week 2, but never decreased to <200 copies/mL through week 16 (viral load, 236 copies/mL at week 16). No INI or major NRTI, nonnucleoside reverse-transcriptase inhibitor or protease inhibitor mutations were detected at the time of PDVF. Additionally, phenotypic analyses showed susceptibility to all tested NRTIs, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitor and no fold change in susceptibility to either DTG or raltegravir (the first INI approved for HIV treatment); the fold change in response to both DTG and raltegravir was <1 at baseline.\n\nAt week 16, the median increase in CD4+ cell count was 226 cells/mm3 (interquartile range, 136–337 cells/mm3). Through the week 16 analysis, no subject reported a new or recurrent Centers for Disease Control and Prevention category B or C condition.\n\nIn general, DTG was well tolerated. Most AEs were grade 1 or 2 in intensity. Headache was the only AE reported by >2 subjects (7 of 13 [54%]), with 2 headaches reported as being related to the study drug. Headache is a known AE associated with lumbar punctures, with the majority of such headaches reported following the lumbar puncture.\n\nTable 3 summarizes drug-related AEs reported in >1 subject; all were considered grade 1 in intensity with the exception of a single grade 2 worsening of depression that the investigator thought might be related to the investigational product. The subject had an extensive personal and family history of depression and was maintained in the study. No deaths occurred. One subject prematurely withdrew from the study before week 2; this was because of a grade 4, non–drug-related SAE of pharyngitis and a grade 2 AE of syphilis. The only other SAE reported during the study, in a different subject, was a non–drug-related SAE of cholecystitis. No clinically significant trends in postdose laboratory abnormalities were observed.\nTable 3. Most Common Drug-Related Adverse Eventsa\n\nType of Event\tAdverse Events, No. (%)\t\nAny event\t8 (62)\t\nFatigue\t2 (15)\t\nHeadache\t2 (15)\t\nNausea\t2 (15)\t\na Adverse events reported for >1 subject in the safety population (N = 13).\n\n\n\nDISCUSSION\nMany consider that distribution of antiretroviral drugs into “sanctuary” sites in therapeutic concentrations favors suppression of HIV replication there. One such site, the CNS, may be especially important because drug-resistant viruses that are not present in blood have been found there (ie, the viruses can have a different fold change in IC50 compared with those found in the plasma [24]). In this study, DTG was measurable in all CSF samples collected 2–6 hours after dosing and exceeded the IC50 against wild-type virus (0.51 nmol/L = 0.2 ng/mL) [25]. Median DTG CSF concentrations were 90-fold and 66-fold above the IC50 at weeks 2 and 16, respectively, suggesting that DTG achieves therapeutic concentrations in the CSF. The planned narrow sampling window does not allow us to demonstrate persistence of drug in the CSF over the entire dosing interval, especially at the end of the interval when CSF concentrations might be lowest. However, DTG likely has slow clearance of drug and flat concentration-time profiles in the CSF, similar to what has been observed with other antiretrovirals [26–28]. In addition, ABC and 3TC both distribute well into the CNS [29, 30], indicating that a combination regimen of ABC/3TC with DTG might be effective in rapidly clearing HIV from the CSF. In parallel with these pharmacokinetic data, HIV-1 RNA rapidly declined in both plasma and CSF, and was undetectable (<50 copies/mL) at week 16 in the CSF in all evaluable subjects and in plasma in 10 of 12 evaluable subjects (83%), demonstrating the potent antiviral activity of this regimen in multiple compartments.\n\nDolutegravir is highly protein bound in plasma, and only total DTG was measured in the CSF owing to assay limits. However, the impact of protein binding for unbound DTG concentration in the CSF is probably small because the concentration of binding proteins (eg, albumin and α-1 acid glycoprotein) in CSF is much lower than in plasma (100- to 1000-fold lower) [31, 32]. This is supported by findings of other studies with other highly bound antiretrovirals demonstrating that nearly all the drug in the CSF was unbound [33]. The similarity of the concentration of DTG in CSF and the unbound concentration in plasma implies that the distribution of DTG into CSF is probably governed mainly by passive diffusion with a low possibility of active transporter involvement.\n\nThe more rapid decline in plasma HIV-1 RNA for an INI-based versus an efavirenz-based regimen [34] makes the INI class attractive for patients with high viral loads or with significant issues, such as neurocognitive impairment. The distribution of raltegravir into CSF was evaluated in HIV-infected patients [28]. Although raltegravir has a higher CSF-to-plasma ratio of approximately 6% versus 0.5% for DTG, the greater potency of DTG results in a much higher CSF inhibitory quotient (ratio of drug concentration to IC50). The raltegravir concentrations in CSF exceeded the IC50 for wild-type HIV (3.2 ng/mL) in all specimens by a median of 4.5-fold, whereas in this study DTG exceeded the IC50 by 66–90-fold. Although the clinical relevance of these values is unknown, they suggest the potential for a greater effect, especially if INI resistance is present. Furthermore, DTG has demonstrated wild-type activity against most INI single-mutant HIV-1 and thus provides a greater barrier to the development of resistance in the CNS [25].\n\nA previous phase IIa study (ING111521) has demonstrated good correlation between DTG plasma concentration and reduction in HIV-1 RNA in plasma after 10-day monotherapy [35]. In this current study, no correlation was identified between DTG concentration in CSF and HIV-1 RNA reduction in CSF, primarily because CSF concentrations were well in excess of the IC50 and most subjects in the study had good responses to therapy in both plasma and CSF. The uniformity of response did not allow for the description of a concentration-effect relationship.\n\nIn general, DTG was well tolerated in the ART-naive, HIV-1–infected subjects in this study. The most common AE was headache, which was often temporally related to lumbar puncture and not deemed related to study drug by the investigator in most cases. Overall, the safety profile of DTG plus ABC/3TC in this limited number of patients is consistent with findings of larger phase III studies administering the same regimen [19, 20].\n\nIn 1 subject with PDVF, integrase genotypic or phenotypic results did not show development of resistance to INIs or NRTIs. Other studies of DTG (50 mg once daily) in ART-naive patients have demonstrated a lack of NRTI or INI resistance in participants with PDVF for up to 96 weeks of study, despite the development of resistance in the comparator treatment arm [19, 20]. Given the pharmacokinetic and efficacy data in this study, the combination of DTG, ABC, and 3TC may be an effective regimen in subjects with neurocognitive complications of HIV disease.\n\nNotes\nAcknowledgments. Thanks to ING116070 study participants, their families and caregivers, the staff at each investigator site, and Katrina Oie Rodenberger and Gina Uhlenbrauck for editorial assistance during the development of the manuscript.\n\nDisclaimer. The contents are the responsibility of the authors and do not necessarily reflect the views of the funders.\n\nFinancial support. This work was supported by ViiV Healthcare.\n\nPotential conflicts of interest. S. L. L. and K. T. T. received grant support from ViiV Healthcare that supported their work on this study. S. L. L. has grant support pending through institutions, including the National Institutes of Health (grants K24 MH097673, HHSN271201000036C), AbbVie, Merck, and Gilead; has acted as a consultant for Merck; and has developed educational presentations for which he has received payment for ViiV Healthcare and AbbVie. K. T. T. has received grant support and has grant support pending through institutions including Merck, Bristol-Myers Squibb, and Gilead Sciences. A. M. M. has received grant support and honoraria from ViiV Healthcare; has grant support pending through institutions, including Gilead Sciences, Bristol-Myers Squibb, and AbbVie; and has received fees for lectures from Gilead Sciences, including service on speakers bureaus. D. A. T., S. S. M., S. C., I. H. S., and S. C. P. are employees of GlaxoSmithKline and own stock in the company.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1 Heaton RK Clifford DB Franklin DR Jr CHARTER Group HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study Neurology 2010 75 2087 96 21135382 \n2 Heaton RK Franklin DR Ellis RJ CHARTER and HNRC Groups HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors J Neurovirol 2011 17 3 16 21174240 \n3 Spudich S González-Scarano F HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment Cold Spring Harb Perspect Med 2012 2 a007120 22675662 \n4 Canestri A Lescure FX Jaureguiberry S Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy Clin Infect Dis 2010 50 773 8 20100092 \n5 Edén A Fuchs D Hagberg L HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment J Infect Dis 2010 202 1819 25 21050119 \n6 Letendre S Capparelli E Best B Better antiretroviral penetration into the central nervous system is associated with lower CSF viral load 2006 13th Conference on Retroviruses and Opportunistic Infections, Denver, 5–8 February Colorado \n7 Letendre S Marquie-Beck J Capparelli E CHARTER Group Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system Arch Neurol 2008 65 65 70 18195140 \n8 Cusini A Vernazza PL Yerly S the Swiss HIV Cohort Study Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid J Acquir Immune Defic Syndr 2013 62 28 35 23018371 \n9 Price RW Spudich S Antiretroviral therapy and central nervous system HIV type 1 infection J Infect Dis 2008 197 suppl 3 S294 306 18447615 \n10 Gisslen M Hagberg L Rosengren L Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers J Neuroimmune Pharmacol 2007 2 112 9 18040834 \n11 Sinclair E Ronquillo R Lollo N Antiretroviral treatment effect on immune activation reduces cerebrospinal fluid HIV-1 infection J Acquir Immune Defic Syndr 2008 47 544 52 18362693 \n12 Tibbling G Link H Ohman S Principles of albumin and IgG analyses in neurological disorders: I. Establishment of reference values Scand J Clin Lab Invest 1977 37 385 90 337459 \n13 Power C Kong PA Crawford TO Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier Ann Neurol 1993 34 339 50 7689819 \n14 Reichel A The role of blood-brain barrier studies in the pharmaceutical industry Curr Drug Metab 2006 7 183 203 16472107 \n15 Isaac A Taylor S Cane P Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen J Antimicrob Chemother 2004 54 498 502 15254024 \n16 Yilmaz A Izadkhashti A Price RW Darunavir concentrations in cerebrospinal fluid and blood in HIV-1–infected individuals AIDS Res Hum Retroviruses 2009 25 457 61 19320601 \n17 Best BM Koopmans PP Letendre SL CHARTER Group Efavirenz concentrations in CSF exceed IC50 for wild-type HIV J Antimicrob Chemother 2011 66 354 57 21098541 \n18 Yilmaz A Gisslén M Sudich S Raltegravir cerebrospinal fluid concentrations in HIV-1 infection PLoS One 2009 4 e6877 19721718 \n19 Raffi F Jaeger H Quiros-Roldan E extended SPRING-2 Study Group Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial Lancet Infect Dis 2013 13 927 35 24074642 \n20 Walmsley SL Antela AA Clumeck N SINGLE Investigators Dolutegravir plus abacavir–lamivudine for the treatment of HIV-1 infection N Engl J Med 2013 369 1807 18 24195548 \n21 Bennetto-Hood C Tabolt G Savina P Acosta EA A sensitive HPLC-MS/MS method for the determination of dolutegravir in human plasma J Chromatog B Analyt Technol Biomed Life Sci 2014 945–946 225 32 \n22 Division of AIDS, National Institute of Allergy and Infectious Diseases Division of AIDS table for grading the severity of adult and pediatric adverse events: version 1.0, December 2004; clarification August 2009 Available at: http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf Accessed 11 April 2014 \n23 Smith F Hammerstrom T Soon G A meta-analysis to assess the FDA DAVP's TLOVR algorithm in HIV submissions Drug Inf J 2011 45 291 300 \n24 Antinori A Perno CF Giancola ML Efficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma Clin Infect Dis 2005 41 1787 93 16288405 \n25 Kobayashi M Yoshinaga T Seki T In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor Antimicrob Agents Chemother 2011 55 813 21 21115794 \n26 Letendre SL Capparelli EV Ellis RJ McCutchan JA HIV Neurobehavioral Research Center Group Indinavir population pharmacokinetics in plasma and cerebrospinal fluid Antimicrob Agents Chemother 2000 44 2173 5 10898694 \n27 Croteau D Letendre S Best BM CHARTER Group Therapeutic amprenavir concentrations in cerebrospinal fluid Antimicrob Agents Chemother 2012 56 1985 9 22290964 \n28 Croteau D Letendre S Best BM CHARTER Group Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1 Antimicrob Agents Chemother 2010 54 5156 60 20876368 \n29 Capparelli EV Letendre SL Ellis RJ Patel P Holland D McCutchan JA Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid Antimicrob Agents Chemother 2005 49 2504 6 15917556 \n30 Foudraine NA Hoetelmans RMW Lange JMA Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine Lancet 1998 351 1547 51 10326538 \n31 Adam P Sobek O Táborský L Hildebrand T Tutterová O Zácek P CSF and serum orosomucoid (α-1-acid glycoprotein) in patients with multiple sclerosis: a comparison among particular subgroups of MS patients Clin Chim Acta 2003 334 107 10 12867280 \n32 Haas DW Johnson B Nicotera J Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma Antimicrob Agents Chemother 2003 47 2131 7 12821458 \n33 Croteau D Rossi SS Best BM CHARTER Group Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration J Antimicrob Chemother 2013 68 684 9 23143899 \n34 van Lunzen J Maggiolo F Arribas JR Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial Lancet Infect Dis 2012 12 111 8 22018760 \n35 Min S Sloan L DeJesus E Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults AIDS 2011 25 1737 45 21716073\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1058-4838",
"issue": "59(7)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV; cerebrospinal fluid; dolutegravir",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D002555:Cerebrospinal Fluid; D015224:Dideoxynucleosides; D004338:Drug Combinations; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D010949:Plasma; D011728:Pyridones; D012367:RNA, Viral; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1032-7",
"pmc": null,
"pmid": "24944232",
"pubdate": "2014-10",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "23143899;15254024;19320601;16288405;18362693;20876368;18040834;21716073;16472107;21135382;22290964;12821458;12867280;22018760;20100092;21174240;22675662;15917556;10326538;7689819;21098541;10898694;24074642;23018371;24361860;21050119;24195548;337459;21115794;18195140;19721718;18447615",
"title": "ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.",
"title_normalized": "ing116070 a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in hiv 1 infected antiretroviral therapy naive subjects"
} | [
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"activesubstancename": "ABACAVIR\\LAMIVUDINE"
},
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{
"abstract": ": Dabigatran is a direct thrombin inhibitor that was approved as an alternative to warfarin because it offers the benefit of predictable pharmacokinetic properties, favorable safety profile and ease of administration. Despite the improved safety profile, dabigatran use can lead to bleeding events. The bleeding risk associated with dabigatran is higher in the setting of renal impairment or drug-drug interactions resulting in supratherapeutic serum concentrations. Unfortunately, clinically significant interactions are not always identified by providers, especially in the case of infrequent drug-drug combinations. Dabigatran-related coagulopathy can be effectively reversed by idarucizumab. However, high dabigatran serum concentrations can lead to increased tissue distribution resulting in decreased idarucizumab efficacy and repeat idarucizumab doses may be warranted. This case describes a patient presenting with uncontrolled bleeding due to a significant drug-drug interaction between quinidine and dabigatran resulting in acute kidney injury and persistent coagulopathy despite multiple idarucizumab doses and transfusion measures.",
"affiliations": "Inpatient Pharmacy Department, Texas Health Harris Methodist Hospital, Fort Worth, Texas, USA.",
"authors": "George|Stephy|S|;Taburyanskaya|Margarita|M|;Lewis|Vicky|V|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000991:Antithrombins; C000594745:idarucizumab; D000069604:Dabigatran; D011802:Quinidine",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000782",
"fulltext": null,
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"issn_linking": "0957-5235",
"issue": "30(1)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D058186:Acute Kidney Injury; D061067:Antibodies, Monoclonal, Humanized; D000991:Antithrombins; D001777:Blood Coagulation; D000069604:Dabigatran; D004347:Drug Interactions; D006470:Hemorrhage; D006801:Humans; D011802:Quinidine; D013918:Thrombin Time",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "42-46",
"pmc": null,
"pmid": "30431448",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Probable drug-drug interaction between dabigatran and quinidine resulting in thrombin time rebound despite multiple idarucizumab doses.",
"title_normalized": "probable drug drug interaction between dabigatran and quinidine resulting in thrombin time rebound despite multiple idarucizumab doses"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-056532",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUCIZUMAB"
},
... |
{
"abstract": "Although reproductive-aged women use both menstrual cups and intrauterine devices (IUDs) simultaneously, it is unknown whether concomitant use reduces contraceptive effectiveness. We report seven cases wherein IUD expulsion occurred during concomitant menstrual cup use. Further research is needed to determine mechanisms of expulsion, predictors and strategies to avoid expulsions.",
"affiliations": "University of Colorado School of Medicine, Department of Obstetrics and Gynecology, Division of Family Planning, 12631 E. 17th Ave, MS B198-2, Aurora, CO 80045. Electronic address: Rebecca.Seale@ucdenver.edu.;University of Colorado School of Medicine, Department of Obstetrics and Gynecology, Division of Family Planning, 12631 E. 17th Ave, MS B198-2, Aurora, CO 80045. Electronic address: Lisa.Powers@ucdenver.edu.;University of Colorado School of Medicine, Department of Obstetrics and Gynecology, Division of Family Planning, 12631 E. 17th Ave, MS B198-2, Aurora, CO 80045. Electronic address: mguiahi@ucdenver.edu.;University of Colorado, College of Nursing, Mail Stop C288, 13120 East 19th Avenue, Aurora, CO 80045. Electronic address: Kate.Coleman-Minahan@ucdenver.edu.",
"authors": "Seale|Rebecca|R|;Powers|Lisa|L|;Guiahi|Maryam|M|;Coleman-Minahan|Kate|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.contraception.2019.03.047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-7824",
"issue": "100(1)",
"journal": "Contraception",
"keywords": "Expulsion; Intrauterine device; Long acting reversible contraception; Menstrual cup; Menstrual hygeine",
"medline_ta": "Contraception",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003120:Colorado; D005260:Female; D006801:Humans; D007433:Intrauterine Device Expulsion; D007434:Intrauterine Devices; D052576:Menstrual Hygiene Products; D055815:Young Adult",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "85-87",
"pmc": null,
"pmid": "30981842",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unintentional IUD expulsion with concomitant menstrual cup use: a case series.",
"title_normalized": "unintentional iud expulsion with concomitant menstrual cup use a case series"
} | [
{
"companynumb": "US-BAYER-2019-084807",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
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... |
{
"abstract": "Pseudoseptic arthritis is an increasingly recognised entity. It is an inflammatory arthritis that mimics septic arthritis; however, Gram stain and cultures are persistently negative. It is a diagnosis of exclusion. We present the first case, to date, in which pseudoseptic arthritis led to such severe joint degeneration that joint replacement surgery was required. A 54-year-old truck driver with rheumatoid arthritis, on immunosuppressive therapy, presented with acute onset severe left hip pain. He was given a clinical diagnosis of septic arthritis and treated with two prolonged courses of antibiotics despite persistently negative synovial fluid cultures. He experienced progressive joint destruction necessitating a two-stage total hip replacement. A retrospective diagnosis of pseudoseptic arthritis was made. This case demonstrates the difficulties inherent in differentiating between septic and pseudoseptic arthritis. This case also highlights the importance of accurate diagnosis and treatment for pseudoseptic arthritis to avoid accelerated joint destruction.",
"affiliations": "Department of Plastic Surgery, Queen Elizabeth Hospital, Birmingham, UK.;North West Deanery, Manchester, UK.;Department of Trauma and Orthopaedics, Good Hope Hospital, Birmingham, UK.",
"authors": "Page|Felicity|F|;Chadwick|Sarah|S|;Banerjee|Brian|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001170:Arthritis, Infectious; D001172:Arthritis, Rheumatoid; D019644:Arthroplasty, Replacement, Hip; D005500:Follow-Up Studies; D006621:Hip Joint; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25948848",
"pubdate": "2015-05-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17067443;1525630;22447330;15288866;4090478;3716411;21733734;18524807;17436053;8118071;17870515;1757931;17126056;3675014;22567482;18749907;8230039;22937184;20576228;1433023",
"title": "Pseudoseptic arthritis resulting in joint destruction.",
"title_normalized": "pseudoseptic arthritis resulting in joint destruction"
} | [
{
"companynumb": "PHHY2016GB160496",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A woman in her early 60s noticed bilateral breast masses and visited a different hospital. Core needle biopsy showed diffuse large B-cell lymphoma of the right breast and invasive ductal carcinoma of the left breast. After referral to our department, PET-CT was performed. Compared with mild fluorodeoxyglucose accumulation in left breast cancer(BC), highly accumulated lesions were found on the right breast, left anterior chest wall, nasopharynx, and tonsil. The right breast lesion was the largest with a diameter of 30mm and was considered the primary lesion of malignant lymphoma(ML). The ML was classified as stage Ⅳ, pathologically proven with erythema of the left breast and nasopharynx. Three courses of R-CHOP were performed. However, due to suspicion of heart failure, chemotherapy was changed to R-CEOP(non-anthracycline-containing regimen)and 3 courses were additionally performed. The therapeutic effect of R-Chemo for ML was CR. Left BC showed a tendency of shrinkage. After intrathecal administration of anticancer drugs to prevent infiltration of ML into the central nervous system and preoperative endocrine therapy with aromatase inhibitor, left lumpectomy and sentinel lymph node biopsy were performed. BC was classified as clinical stage ⅠA and had an estrogen receptor score of 3b. Postoperative whole breast radiotherapy was completed, and the planned internal use of exemestane was more than 5 years. With multidisciplinary therapy, 3.5 years had passed since the initial treatment without recurrence.",
"affiliations": "Dept. of Hematology, Kanto Rosai Hospital.",
"authors": "Fujii|Tomoki|T|;Ohno|Nobuhiro|N|;Matsui|Tomoharu|T|;Sahara|Naohi|N|;Yoneyama|Satomi|S|;Inoue|Hisako|H|;Matsunaga|Takashi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(11)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D001943:Breast Neoplasms; D044584:Carcinoma, Ductal; D018270:Carcinoma, Ductal, Breast; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D015412:Mastectomy, Segmental; D009364:Neoplasm Recurrence, Local; D009378:Neoplasms, Multiple Primary; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1775-1778",
"pmc": null,
"pmid": "31748491",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Synchronous Diffuse Large B-Cell Lymphoma of the Right Breast and Invasive Ductal Carcinoma of the Left Breast.",
"title_normalized": "a case of synchronous diffuse large b cell lymphoma of the right breast and invasive ductal carcinoma of the left breast"
} | [
{
"companynumb": "JP-PFIZER INC-2019544105",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Diamond-Blackfan anemia (DBA) is a rare congenital disease caused by mutations in ribosomal protein genes and is characterized by pure red cell aplasia. While the prognosis is relatively favorable, quality of life (QOL) among DBA patients is negatively impacted by the adverse effects of long-term prednisolone (PSL) therapy and blood transfusions. We describe a 43-year-old man who was diagnosed with DBA (Hb of 2.18 g/dl) at the age of two months. He was initially treated with PSL and blood transfusions, followed by cyclosporine and low-dose (6 mg/day) PSL, which resulted in a sustained hemoglobin level of 9 g/dl without severe adverse events or loss of QOL. High levels of eADA and GSH as well as a RPS19 gene mutation were confirmed. The only curative therapy is hematopoietic stem cell transplantation, which is associated with significant mortality. However, using low-dose PSL to maintain a stable hemoglobin level may improve QOL for patients who receive curative treatment.",
"affiliations": "Department of Medicine, Tokyo Women's Medical University Medical Center East.;Department of Medicine, Tokyo Women's Medical University Medical Center East.;Department of Medicine, Tokyo Women's Medical University Medical Center East.;Department of Medicine, Tokyo Women's Medical University Medical Center East.;Department of Pediatrics, Tokyo Women's Medical University Medical Center East.;Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University.;Department of Pediatrics, Hirosaki University Graduate School of Medicine.",
"authors": "Ogasawara|Toshie|T|;Kawauchi|Kiyotaka|K|;Mori|Naoki|N|;Sakura|Hiroshi|H|;Katoh|Fumiyo|F|;Kanno|Hitoshi|H|;Ito|Etsuro|E|",
"chemical_list": "D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.917",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(8)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Adult; Diamond-Blackfan anemia; Prednisolone; RPS19",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D029503:Anemia, Diamond-Blackfan; D006801:Humans; D008297:Male; D011239:Prednisolone; D013997:Time Factors",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "917-921",
"pmc": null,
"pmid": "28883274",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful long-term management with low-dose prednisolone in an adult patient with Diamond-Blackfan anemia.",
"title_normalized": "successful long term management with low dose prednisolone in an adult patient with diamond blackfan anemia"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000003",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
... |
{
"abstract": "BACKGROUND\nBisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient's quality of life in an extensive manner. Adalimumab (Humira®), a fully human recombinant antibody specific for tumor necrosis factor- α, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn's disease.\n\n\nMETHODS\nIn March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn's disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009.\n\n\nCONCLUSIONS\nThis patient with a medical history of Crohn's disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.",
"affiliations": "Department of Oral and Maxillofacial Surgery, University of Erlangen, Glückstraße 11, Erlangen 91054, Germany. raimund.preidl@uk-erlangen.de.",
"authors": "Preidl|Raimund H M|RH|;Ebker|Tobias|T|;Raithel|Martin|M|;Wehrhan|Falk|F|;Neukam|Friedrich W|FW|;Stockmann|Philipp|P|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1186/1471-230X-14-6",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central 1471-230X-14-62440072210.1186/1471-230X-14-6Case ReportOsteonecrosis of the jaw in a Crohn’s disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report Preidl Raimund HM 1raimund.preidl@uk-erlangen.deEbker Tobias 1tobias.ebker@uk-erlangen.deRaithel Martin 2martin.raithel@uk-erlangen.deWehrhan Falk 1falk.wehrhan@uk-erlangen.deNeukam Friedrich W 1friedrich.neukam@uk-erlangen.deStockmann Philipp 1philipp.stockmann@uk-erlangen.de1 Department of Oral and Maxillofacial Surgery, University of Erlangen, Glückstraße 11, Erlangen 91054, Germany2 Department of Gastroenterology, Pneumology and Endocrinology, University of Erlangen, Erlangen, Germany2014 8 1 2014 14 6 6 13 6 2013 3 1 2014 Copyright © 2014 Preidl et al.; licensee BioMed Central Ltd.2014Preidl et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nBisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient´s quality of life in an extensive manner. Adalimumab (Humira®), a fully human recombinant antibody specific for tumor necrosis factor- α, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn’s disease.\n\nCase presentation\nIn March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn’s disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009.\n\nConclusion\nThis patient with a medical history of Crohn’s disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.\n\nOsteonecrosis of the jawBisphosphonateAdalimumabCrohn’s disease\n==== Body\nBackground\nBisphosphonates are primarily applied in patients with skeletal complications associated with osteoporosis as well as malignancy [1,2]. Bisphosphonate–associated osteonecrosis of the jaw (BRONJ), first described in 2003, poses a serious complication in patients currently or previously treated with Bisphosphonates and is associated with exposed bone in the maxillofacial region for at least 8 weeks without any radiotherapy of the jaw in the past [3,4]. The occurrence of BRONJ not only depends on the duration of the BP therapy but also varies between oral and intravenous application with far more cases reported after intravenous infusions with a cumulative incidence of 0,8%- 12% [5,6]. Although the pathomechanism is not yet completely understood, there are local risk factors like extraction of teeth, placement of dental implants, periapical surgery or dental abscesses going along with an increased incidence of osteonecrosis [7]. Beyond this, genetic and drug- related factors influence the appearance of BRONJ [8]. Clinically BRONJ presents as non-vital, exposed bone that might go along with inflammatory reactions due to secondary infection and therefore the gingival or mucosal tissue is usually sensitive to palpation. This process can aggravate to bone sequestration going along with acute osteomyelitis resulting in spreading and increased mobility of additional teeth [9]. Presumably, BRONJ is associated with infection and therefore immune-modulating drugs, as applied in patients with Crohn’s disease or rheumatoid arthritis, might be an important risk factor in the development of necrotic lesions in the jaw [10,11]. We already know that not only Bisphosphonates but also Denosumab or other biologicals are under suspicion to promote or even cause necrotic lesions in the jaw [12,13]. To our knowledge there is currently no published case of BRONJ in a patient with Crohn’s disease also affecting the oral cavity and treated with Adalimumab.\n\nCase presentation\nA 36-year-old female presented in March 2013 with right-sided perimandibular swelling, cervical lymphadenopathy on the right side, dysphagia and pain on the lower face. In January 2013, tooth 47 was removed by the family dentist followed by episodes of recurrent pain during the following two months. On clinical investigation exposed bone surrounded by gingival inflammatory reaction was observed in the region of former tooth 47 (Figure 1). Panoramic radiograph revealed a persistent extraction socket of 47 (Figure 2a).\n\nFigure 1 Intraoperative situation with exposed necrotic bone lingual and crestal in the region of former tooth 47 (white arrow). Inflammatory reaction within the necrotic region is also leading to local sugillations and bleedings as mucosal integrity seems to be disturbed. Crowned tooth 46 was removed within the operation.\n\nFigure 2 Pre- and postoperative panoramic radiographs. Preoperative radiograph (a) is showing a persistent extraction socket and hypersclerosis of the mandibular bone in the region 46/47 after extraction of 47 in January 2013. Postoperative panoramic radiograph (b) revealing a reduction of the mandibular bone height after repeated osteotomy and adequate ossification of the former extraction sockets.\n\nHer medical history revealed Crohn’s disease diagnosed in March 2000 affecting the colon, small intestine and stomach as well as aphthous oral lesions in the vestibulum in the years 2000 and 2001, fistula disease and extraintestinal manifestation with arthralgia. The patient was treated with varying doses of steroids together with 5-aminosalicylic (5-ASA) between 2000 and 2008 (Figure 3). In 2004 steroid-induced osteoporosis was diagnosed and associated with sintering fractures in the lower lumbar spine. Since then Calcium 500 mg and Cholecalciferol 1000 I.E. with concomitant oral Risedronate (Actonel®) 35 mg/week was applied until 2007 followed by two single 4 mg infusions of Zoledronic acid (Alcasta®) in 2008 and 2009. In September 2008, prednisolon and 5-ASA therapy was replaced by Adalimumab (Humira®) 40 mg/ 2 weeks for 3 years and later on monthly (cumulative dose approximately 3,6 g) leading to a total gastrointestinal remission regarding Crohn’s symptoms at the end of 2009 confirmed by endoscopy, histology and clinical disease activity in 2012. Between 2008 and 2013 recurrent events of psoriatic-like lesions, lupus-like erythrodermia and conjunctivitis were observed and treated with topically applied medication. She reported to be allergic to metals (gold, silver, nickel) and had no family history of Crohn’s disease.\n\nFigure 3 Drug regime since Crohn’s disease was diagnosed in 2000.\n\nIn March 2013, the patient was treated after previous MR-imaging revealed increased signalling in the jaw in the area of teeth 44 until 48 and additionally confirmed prominent lymph nodes on both sides of the submandibular region (Figure 4). Due to the fact that the mandibular bone was already exposed more than 8 weeks with no medical history of radiotherapy, BRONJ was diagnosed according to the AAOMS guidelines [6]. Surgical treatment consisted of osteotomy until healthy bone with bleeding from the surfaces was visible. Biopsies of bone were sent for pathological examination. Additionally, sharp edges of bone that can potentially traumatise the surrounding were removed. A mucoperiosteal flap was raised and primary wound closure was carried out without tension on the mucoperiosteal flap after incision of the periosteum with resorbable suture material (Vicryl 5–0, Ethicon, Norderstedt, Germany) [14]. Furthermore tooth 46 had to be removed because the necrotic bone affected the roots. Antibiotic therapy consisting of ampicillin/sulbactam (Ampicillin + Sulbactam-ratiopharm®, Ratiopharm, Ulm, Germany) 3 g/day and metronidazol (Metronidazol B. Braun®, B. Braun, Meisingen, Germany) 1,5 g/day and was administered intravenously for 8 days. Oral food intake was not allowed for 10 days and antiseptic mouth rinses (Hexetidin, 5-Amino-1,3-bis(2- ethylhexal) hexahydro-5-methylpyrimidin, Pfizer Pharma GmbH, Karlsruhe, Germany) was performed three times a day.\n\nFigure 4 Magnetic Resonance Imaging (MRI), t2 weighted, showing increased signalling in the jaw within the region of teeth 44 until 47 as well as in the ipsi- and contralateral lymph nodes (left side with white arrow). Additionally, perimandibular soft tissue swelling is detectable on the affected side.\n\nHistological examination showed a granulomatous inflammatory reaction with necrotic, avital bone and actinomyces colonisation but no growth of mycobacteria or fungus and no multinucleated giant cells. Humira® therapy was stopped in March 2013 after consultation with the department of gastroenterology and due to the patient’s wish suffering from recurrent psoriatic-like lesions, lupus- like erythrodermia and conjunctivitis. 10 days after discharge the patient presented with adequate wound healing and mild clinical symptoms. During removal of the stitches bone got re-exposed again indicating a compromised mucosal healing. The patient was followed up weekly and received a second operative intervention at the beginning of April 2013 which improved the clinical situation (Figures 2b and 5).\n\nFigure 5 Postoperative situation in October 2013 showing recovery of the affected side after extraction of tooth 46 and repeated osteotomy.\n\nDiscussion\nAminobisphosphonates are well established in the therapy of osteoporosis and metastatic cancer disease. Although BRONJ is a serious adverse event especially after intravenous administration, Aminobisphosphonates improve cancer control and increase long-term survival. This case report presents an extraordinary course of osteonecrosis of the jaw after mainly oral Bisphosphonate therapy and application of Adalimumab in a Crohn’s disease patient affecting almost the whole gastrointestinal tract. Bisphosphonates can cause gastrointestinal mucosal injuries and reduce bone remodelling by predominantly inhibiting osteoclasts via RANKL. Furthermore these drugs seem to have anti-angiogenic effects contributing to impaired wound-healing for example after tooth extraction [15,16].\n\nAdalimumab, representing a fully humanised anti-TNF-α antibody, is an established biologic agent in the treatment of Crohn’s disease with proven clinical benefits [17]. Unfortunately there are already some reports about serious adverse effects like new-onset of multiple sclerosis, psoriasiform lesions, lupus like syndrome and infectious complications including sepsis in patients treated with the agent [18,19].\n\nCases of osteonecrosis in extracranial bones like the femur or the talus in patients with Inflammatory Bowel Disease and long lasting corticoid therapies have already been published [20,21]. Some even maintain that avascular osteonecrosis might be an extraintestinal manifestation of Inflammatory Bowel Disease although in some cases the interval between steroid treatment and avascular bone necrosis was quite extended [22,23]. However, in this report we present the first case of osteonecrosis in the jaw with the underlying history of Crohn’s disease being currently treated with Adalimumab (Humira®) which can be seen in a certain correlation to other cases demonstrating patients with osteonecrosis of the jaw and biological anti-TNF-α therapy with Infliximab [13].\n\nThe EXTEND trial revealed improved mucosal healing of gastrointestinal tissue under anti-TNF-α therapy [24], despite this it is still unclear whether anti-TNF-α treatment affects the oral mucosa and/or interferes with bone physiology, bone turnover, local immunity and wound repair on the long run. Pathomechanistically one could speculate at this stage that an inhibitory effect of Adalimumab on bone turnover might be mediated by a reduction of RANKL which could already be shown in patients with rheumatoid arthritis and anti-TNF-α therapy [25,26]. Interestingly osteonecrotic lesions in the jaw have also been reported within treatment regimes including Denosumab in cancer patients assuming that a blockade of receptor activator of nuclear factor-kappa-B (RANK) and receptor activator of nuclear factor-kappa-B- ligand (RANKL) interaction affects monocytic migration as well as osteoclast function comparable to Bisphosphonates [27]. We already know that Adalimumab induces apoptosis of activated human monocytes [28]. While apoptosis of disease-specific or reactive monocytes may be beneficial in idiopathic Inflammatory Bowel Disease, apoptosis of monocytes activated by infectious agents still present within the oral cavity may worsen wound healing, mucosal repair and bone repair of the jaw after necrosis. However, it still has to be investigated how bone metabolism and local infections surveillance in patients with Inflammatory Bowel Disease is influenced in the long run and how therapeutic strategies including biological substances lead to avascular bone necrosis in the jaw. Especially when considering already observed infectious complications due to immunosuppression associated with Adalimumab application it has to be investigated if osteonecrotic lesions might also occur because of spreading ongoing infections and/or have to be seen within the context of a certain innate immune dysfunction lacking defensin expression [29,30].\n\nRegarding this case, on-going oral Crohn’s disease might be a confounder in terms of mucosal healing. Although the patient had no gastrointestinal symptoms including aphthous lesions in the oral cavity during Adalimumab- therapy, general oral mucosal healing capacities might be compromised.\n\nConclusion\nPatients with Inflammatory Bowel Disease and planned treatment with biological drugs like Adalimumab and a history of Bisphosphonate therapy should be also clinically investigated by a dentist before prescription of biologicals. Furthermore they should be monitored carefully with regard to osteonecrotic lesions of the jaw especially after dental procedures or within periodontal disease.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAbbreviations\n5-ASA: 5-aminosalicylic; BONJ: Bisphosphonate-associated osteonecrosis of the jaw; RANK: Receptor activator of nuclear factor-kappa-B; RANKL: Receptor activator of nuclear factor-kappa-B- ligand.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nRP, TE, PS, FW examined and treated the patient and collected the data. RP, TE, MR, FWN discussed the case and data. RP, FW, MR, FWN and PS wrote the manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-230X/14/6/prepub\n\nAcknowledgement\nWe acknowledge support by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg within the funding programme Open Access Publishing.\n==== Refs\nKamel HK Update on osteoporosis management in long-term care: focus on bisphosphonates J Am Med Dir Assoc 2007 8 434 440 10.1016/j.jamda.2007.06.005 17845945 \nColeman RE Risks and benefits of bisphosphonates Br J Cancer 2008 98 1736 1740 10.1038/sj.bjc.6604382 18506174 \nRuggiero SL Dodson TB Assael LA Landesberg R Marx RE Mehrotra B American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws–2009 update J Oral Maxillofac Surg 2009 67 2 12 19371809 \nMarx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J Oral Maxillofac Surg 2003 61 1115 1117 10.1016/S0278-2391(03)00720-1 12966493 \nFleisher KE Jolly A Venkata UD Norman RG Saxena D Glickman RS Osteonecrosis of the jaw onset times are based on the route of bisphosphonate therapy J Oral Maxillofac Surg 2013 71 513 519 10.1016/j.joms.2012.07.049 22999296 \nRuggiero SL Dodson TB Assael LA Landesberg R Marx RE Mehrotra B American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw - 2009 update Aust Endod J 2009 35 119 130 10.1111/j.1747-4477.2009.00213.x 19961450 \nMarx RE Cillo JE JrUlloa JJ Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment J Oral Maxillofac Surg 2007 65 2397 2410 10.1016/j.joms.2007.08.003 18022461 \nStockmann P Nkenke E Englbrecht M Schlittenbauer T Wehrhan F Rauh C Beckmann MW Fasching PA Kreusch T Mackensen A Major histocompatibility complex class II polymorphisms are associated with the development of anti-resorptive agent-induced osteonecrosis of the jaw J Craniomaxillofac Surg 2013 41 71 75 10.1016/j.jcms.2012.10.018 23218978 \nMigliorati CA Siegel MA Elting LS Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment Lancet Oncol 2006 7 508 514 10.1016/S1470-2045(06)70726-4 16750501 \nStockmann P Wehrhan F Schwarz-Furlan S Stelzle F Trabert S Neukam FW Nkenke E Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: an immunohistological study J Transl Med 2011 9 135 10.1186/1479-5876-9-135 21843332 \nAllen MR Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench Cells Tissues Organs 2009 189 289 294 10.1159/000151371 18698128 \nKyrgidis A Toulis KA Denosumab-related osteonecrosis of the jaws Osteoporos Int 2011 22 369 370 10.1007/s00198-010-1177-6 20306021 \nEbker T Rech J von Wilmowsky C Neukam FW Stockmann P Fulminant course of osteonecrosis of the jaw in a rheumatoid arthritis patient following oral bisphosphonate intake and biologic therapy Rheumatology (Oxford) 2013 52 218 220 10.1093/rheumatology/kes351 23238981 \nStockmann P Vairaktaris E Wehrhan F Seiss M Schwarz S Spriewald B Neukam FW Nkenke E Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up Support Care Cancer 2010 18 449 460 10.1007/s00520-009-0688-1 19609572 \nRoelofs AJ Thompson K Gordon S Rogers MJ Molecular mechanisms of action of bisphosphonates: current status Clin Cancer Res 2006 12 6222s 6230s 10.1158/1078-0432.CCR-06-0843 17062705 \nNagano Y Matsui H Shimokawa O Hirayama A Nakamura Y Tamura M Rai K Kaneko T Hyodo I Bisphosphonate-induced gastrointestinal mucosal injury is mediated by mitochondrial superoxide production and lipid peroxidation J Clin Biochem Nutr 2012 51 196 203 23170047 \nDryden GW JrOverview of biologic therapy for Crohn's disease Expert Opin Biol Ther 2009 9 967 974 10.1517/14712590903048909 19591627 \nMatsumoto T Nakamura I Miura A Momoyama G Ito K New-onset multiple sclerosis associated with adalimumab treatment in rheumatoid arthritis: a case report and literature review Clin Rheumatol 2013 32 271 275 10.1007/s10067-012-2113-2 23149905 \nJoyau C Veyrac G Dixneuf V Jolliet P Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect? Clin Exp Rheumatol 2012 30 700 706 22935567 \nHauzeur JP Malaise M Gangji V Osteonecrosis in inflammatory bowel diseases: a review of the literature Acta Gastroenterol Belg 2009 72 327 334 19902866 \nFreeman HJ Osteomyelitis and osteonecrosis in inflammatory bowel disease Can J Gastroenterol 1997 11 601 606 9395761 \nLanyi B Dienes HP Kruis W Recurrent aseptic osteonecrosis in Crohn's disease - extraintestinal manifestation or steroid related complication? Dtsch Med Wochenschr 2005 130 1944 1947 10.1055/s-2005-872607 16123897 \nKlingenstein G Levy RN Kornbluth A Shah AK Present DH Inflammatory bowel disease related osteonecrosis: report of a large series with a review of the literature Aliment Pharmacol Ther 2005 21 243 249 10.1111/j.1365-2036.2005.02231.x 15691298 \nRutgeerts P Van Assche G Sandborn WJ Wolf DC Geboes K Colombel JF Reinisch W Kumar A Lazar A Camez A Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial Gastroenterology 2012 142 1102 1111 e1102 10.1053/j.gastro.2012.01.035 22326435 \nZiolkowska M Kurowska M Radzikowska A Luszczykiewicz G Wiland P Dziewczopolski W Filipowicz-Sosnowska A Pazdur J Szechinski J Kowalczewski J High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment Arthritis Rheum 2002 46 1744 1753 10.1002/art.10388 12124857 \nGonzalez-Alvaro I Ortiz AM Tomero EG Balsa A Orte J Laffon A Garcia-Vicuna R Baseline serum RANKL levels may serve to predict remission in rheumatoid arthritis patients treated with TNF antagonists Ann Rheum Dis 2007 66 1675 1678 10.1136/ard.2007.071910 17666448 \nAkhtar NH Afzal MZ Ahmed AA Osteonecrosis of jaw with the use of denosumab J Cancer Res Ther 2011 7 499 500 10.4103/0973-1482.92020 22269422 \nShen C Assche GV Colpaert S Maerten P Geboes K Rutgeerts P Ceuppens JL Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept Aliment Pharmacol Ther 2005 21 251 258 10.1111/j.1365-2036.2005.02309.x 15691299 \nLawrance IC Radford-Smith GL Bampton PA Andrews JM Tan PK Croft A Gearry RB Florin TH Serious infections in patients with inflammatory bowel disease receiving anti-tumor-necrosis-factor-alpha therapy: an Australian and New Zealand experience J Gastroenterol Hepatol 2010 25 1732 1738 10.1111/j.1440-1746.2010.06407.x 21039834 \nGersemann M Wehkamp J Stange EF Innate immune dysfunction in inflammatory bowel disease J Intern Med 2012 271 421 428 10.1111/j.1365-2796.2012.02515.x 22324936\n\n",
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"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D003424:Crohn Disease; D004164:Diphosphonates; D005260:Female; D006801:Humans; D010020:Osteonecrosis",
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"title": "Osteonecrosis of the jaw in a Crohn's disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report.",
"title_normalized": "osteonecrosis of the jaw in a crohn s disease patient following a course of bisphosphonate and adalimumab therapy a case report"
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"abstract": "Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is characterized by metachronously occurring tumors including pheochromocytoma, renal cell carcinoma (RCC), and hemangioblastoma. Although VHL disease leads to reduced life expectancy, its diagnosis is often missed and tumor screening guidelines are sparse. VHL protein acts as a tumor suppressor by targeting hypoxia-inducible factors (HIFs) for degradation through an oxygen-dependent mechanism. VHL mutants with more severely reduced HIF degrading function carry a high risk of RCC, while mutants with preserved HIF degrading capacity do not cause RCC but still lead to other tumors. VHL disease is classified into clinical types (1 and 2A-2C) based on this genotype-phenotype relationship. We report a case of bilateral pheochromocytomas and no other VHL-related tumors in a patient with Y175C VHL and show that this mutant preserves the ability to degrade HIF in normal oxygen conditions but, similar to the wild-type VHL protein, loses its ability to degrade HIF under hypoxic conditions. This study adds to the current understanding of the structure-function relationship of VHL mutations, which is important for risk stratification of future tumor development in the patients.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.;Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.;Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.;Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.;Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.",
"authors": "Astapova|Olga|O|0000-0002-7649-2211;Biswas|Anindita|A|;DiMauro|Alessandra|A|;Moalem|Jacob|J|;Hammes|Stephen R|SR|",
"chemical_list": null,
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"doi": "10.1155/2018/8967159",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2018/8967159Case ReportBilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation http://orcid.org/0000-0002-7649-2211Astapova Olga olga_astapova@urmc.rochester.eduBiswas Anindita DiMauro Alessandra Moalem Jacob Hammes Stephen R. Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USAAcademic Editor: Carlo Capella\n\n2018 10 7 2018 2018 896715927 4 2018 14 6 2018 Copyright © 2018 Olga Astapova 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.Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is characterized by metachronously occurring tumors including pheochromocytoma, renal cell carcinoma (RCC), and hemangioblastoma. Although VHL disease leads to reduced life expectancy, its diagnosis is often missed and tumor screening guidelines are sparse. VHL protein acts as a tumor suppressor by targeting hypoxia-inducible factors (HIFs) for degradation through an oxygen-dependent mechanism. VHL mutants with more severely reduced HIF degrading function carry a high risk of RCC, while mutants with preserved HIF degrading capacity do not cause RCC but still lead to other tumors. VHL disease is classified into clinical types (1 and 2A-2C) based on this genotype-phenotype relationship. We report a case of bilateral pheochromocytomas and no other VHL-related tumors in a patient with Y175C VHL and show that this mutant preserves the ability to degrade HIF in normal oxygen conditions but, similar to the wild-type VHL protein, loses its ability to degrade HIF under hypoxic conditions. This study adds to the current understanding of the structure-function relationship of VHL mutations, which is important for risk stratification of future tumor development in the patients.\n==== Body\n1. Introduction\nVon Hippel-Lindau (VHL) is a tumor suppressor gene associated with inhibition of angiogenesis, apoptosis, cell cycle exit, fibronectin matrix assembly, and proteolysis. Germline mutations in VHL occur with a frequency of 1:36,000 in Europe [1] and a 20% de novo rate. Mutations are passed down in an autosomal dominant pattern with almost complete penetrance by the age of 60 [2]. People with VHL mutations metachronously develop various benign and malignant tumors. More than half of the patients develop CNS and retinal hemangioblastomas (most commonly in the cerebellum or spinal cord). Other common life-threatening tumors are pheochromocytoma and clear cell renal cell carcinoma (RCC). An increased frequency of pancreatic neuroendocrine tumors, endolymphatic sac tumors, epididymal tumors, and benign cysts in the pancreas and the kidneys is also reported. Because of time lag between occurrences of different tumors, the diagnosis of VHL disease is often delayed, resulting in increased mortality [3].\n\nVHL regulates the cellular response to low oxygen conditions by interacting with hypoxia-inducible factors (HIFα: HIF1α and HIF2α). In normoxic conditions, HIFα is hydroxylated on conserved proline residues by prolyl hydroxylases, which require oxygen as a cofactor. Hydroxylated HIFα is recognized by VHL which acts in complex with its cofactors elongin B and elongin C to ultimately target HIFα for ubiquitination and proteasomal degradation [4]. In hypoxic conditions, prolyl hydroxylases become inactive, and unhydroxylated HIFα is not recognized by VHL. This leads to accumulation of HIFα, which forms heterodimers that translocate to the nucleus, bind to hypoxia-response elements, and induce the transcription of genes involved in adaptations to hypoxia, including angiogenesis. The same process occurs in the absence of functional VHL and leads to tumorigenesis in patients with VHL disease, most likely through the two-hit model [2, 5].\n\nStudies of over a dozen different VHL mutations have identified several phenotypic subtypes revealing a structure-function relationship in which the severity of the mutation predicts the likelihood of RCC [6]. VHL mutants that retain the ability to downregulate HIFα are less likely to be associated with RCC than those that lose that ability [4, 7, 8]. Patients with type 1 VHL have deletion or truncation mutations that completely abolish any functional protein expression. They have a high risk of RCC and also present with both retinal and CNS hemangioblastomas; however, pheochromocytomas are uncommon [9]. Type 2 VHL is characterized by pheochromocytomas and is caused by point mutations with variable degrees of limitation of VHL activity. It is further subdivided into 2A, 2B, and 2C based on the frequency of RCC and hemangioblastomas. RCC appears more frequently in patients with the more severely dysfunctional VHL resulting in higher expression of HIFα, such as types 1 and 2B. By contrast, type 2C mutations retain their ability to fully downregulate HIFα and present with only pheochromocytomas, indicating that HIFα-independent mechanisms are at play in the pathogenesis of VHL-related pheochromocytomas. Some in vitro studies suggest that type 2C VHL mutants cause defective fibronectin matrix assembly, while retaining the ability to suppress HIFα and stop the growth of RCC cells in culture [10, 11].\n\n2. Case Presentation\nA 53-year-old man of Puerto-Rican origin presented to the endocrinology clinic after undergoing bilateral adrenalectomy for multifocal pheochromocytomas. He had a prior history of morbid obesity, obstructive sleep apnea, diabetes, and hypertension. He was followed by his primary care physician for persistent hematuria ranging from 3 to 35 red blood cells per high power field on urinalysis, as well as urinary frequency, weak stream, and nocturia three times per night for the previous three years. He had been unable to tolerate an empiric trial of tamsulosin for benign prostate hypertrophy due to orthostatic dizziness. Negative symptoms pertinent to this case include flushing, headaches, sweating, palpitations, anxiety, blurry vision, or dizziness. His family history was notable for death from a myocardial infarction in his father at the age of 57 and an unknown genitourinary cancer in his sister. There was no family history of adrenal tumors, hyperparathyroidism, medullary thyroid cancer, renal cancer, or pituitary tumors. The patient was a smoker with several past attempts at quitting.\n\nDue to the persistent hematuria, smoking, and the family history of cancer, a CT urogram was performed to screen for bladder cancer. While no abnormalities were seen within the urogenital tract, bilateral, irregular, heterogeneous large adrenal masses (Figure 1) measuring 4.7 cm (R) and 1.6 cm (L) were noted. In addition, a prominent and suspicious lymph node was identified. Biochemical characterization of the adrenal masses revealed significantly elevated 24-hour urine normetanephrine (1090 micrograms/gram of creatinine; normal range, 0–400 micrograms/gram of creatinine), leading to the diagnosis of pheochromocytoma. Urine metanephrine level was within normal range. Cushing's syndrome was ruled out with an undetectable late-night salivary cortisol level. Electrolyte levels, kidney function, and complete blood count were within normal limits. In search for additional, extra-adrenal foci, a metaiodobenzylguanidine (MIBG) scan was performed but was nondiagnostic due to lack of cardiac activity. Nevertheless, given the available imaging and biochemical findings, there was concern for malignant pheochromocytoma, and the patient ultimately underwent an open bilateral adrenalectomy and paracaval lymph node excision. Intraoperatively, the patient required vasopressor support and a large amount of crystalloid resuscitation (13 liters) to maintain hemodynamic stability. Intraoperative ultrasound was used to identify one mesenteric lymph node of mildly suspicious appearance which was resected, in addition to a large retroperitoneal paracaval lymph node.\n\nSurgical pathology confirmed pheochromocytomas in the bilateral adrenal glands (right, 5.0 x 3.5 x 2.5 cm, and left, 1.5 x 1.3 x 1.0 cm) which were both confined to the adrenal glands. The paracaval lymph node was described as paraganglioma versus metastatic pheochromocytoma measuring 1.6 cm in the greatest dimension with no lymphoid tissue identified. The immediate postoperative course was unremarkable. The patient was started on life-long glucocorticoid and mineralocorticoid replacement. His diabetes and hypertension resolved.\n\nDue to the multifocal nature of the pheochromocytomas and the presence of first-degree relatives likely to be affected, the patient was offered genetic screening for familial paraganglioma syndromes. With the patient's informed written consent, genomic DNA was isolated from a peripheral blood sample and targeted gene sequencing was performed using PGLNext. Coding exons and adjacent intron nucleotides of the 12 targeted genes associated with hereditary pheochromocytoma syndromes were amplified and then sequenced using PCR and next-generation sequencing. Gross deletion and duplication analysis was also performed. The patient was found to have a heterozygous germline mutation, c.524A>G in the VHL gene, corresponding to the Y175C substitution in the protein. This was identified as a likely pathogenic variant and confirmed by Sanger sequencing. In one study, this alteration was described in a patient with a personal and family history of pheochromocytoma and no other VHL-associated tumors and segregated with disease in this family [12].\n\nIn order to better define the risk of RCC in this patient and others with this mutation, we assessed the ability of Y175C VHL to degrade HIFα in vitro. Stable wild-type (WT) or Y175C VHL-expressing cells lines were generated by transfection and clonal selection of VHL-null 786-O cells derived from a human RCC as previously described [10, 13]. Control cells were transfected with GFP. We detected HIF2α expression in the control VHL-null cell line, while stable overexpression of either WT or Y175C VHL resulted in the disappearance of HIF2ɑ (Figure 2, left panel). To further characterize the function of Y175C VHL under hypoxic conditions, the cells were placed into a hypoxia incubator at 1% O2 for 24 hours. As expected, the WT VHL lost the ability to induce HIF2α degradation in hypoxia (Figure 2, right panel). The Y175C VHL similarly did not reduce HIF2α abundance in hypoxia. HIF2α abundance was also similar in WT and Y175C VHL-expressing cells after 6 hours and 12 hours of hypoxia (data not shown). Thus, under both normoxic and hypoxic conditions, Y175C VHL functions similarly to the WT with regard to HIFα degradation.\n\n3. Discussion\nDifferential diagnoses of VHL include other hereditary syndromes such as multiple endocrine neoplasia type 2, polycystic kidney disease, type 1 neurofibromatosis, and hereditary pheochromocytoma-paraganglioma syndrome. Germline mutations in known susceptibility genes including SDHB (succinate dehydrogenase complex B) and others are identified in 11-13% of patients with sporadic pheochromocytomas [14]. While screening should not be offered to every patient with a pheochromocytoma, guidelines including those from the Massachusetts General Hospital [1] suggest consideration of genetic screening for syndromes of pheochromocytoma in patients with other factors such as certain other tumors, pancreatic cysts, and multiple pheochromocytomas or those under 40 years of age. In general, genetic screening is likely underutilized according to these guidelines. Genetic screening was recommended for this patient due to the presence of bilateral pheochromocytomas.\n\nAlthough Y175C VHL has been reported in another family with a similar phenotype, its molecular function has not been studied to date. We have shown that the Y175C mutation preserves the ability of VHL to degrade HIFα under normal oxygen conditions. The mutant also functions similarly to the wild-type protein in hypoxia, which abrogates VHL-mediated HIFα degradation. This is the first reported molecular study of Y175C VHL and it adds to the growing body of knowledge about various VHL mutants. Based on our findings, this patient has type 2C VHL, the subtype with preserved HIFα degradation ability and with pheochromocytomas as the sole presenting feature. Previously reported type 2C VHL mutants with pheochromocytoma as the only notable disease manifestation include L188V and V84L. These mutants also demonstrated preserved ability to ubiquitinate HIFα [10].\n\nOur case is similar to a previously described Spanish cohort with the same mutation [12] that presented with pheochromocytomas in mutation carriers and no other VHL-associated tumors. The authors of that study calculated the folding energy of Y175C VHL and found that it was only slightly higher than that of the wild-type, indicating that Y175C VHL is predicted to be fairly stable. In contrast, the folding energies of mutants with more severe disease phenotypes are dramatically higher than the wild-type, resulting in unstable proteins and predicted loss of function. Our in vitro findings are in line with this in silico prediction which supports a low risk of RCC in this patient.\n\nAlthough HIFα degradation is better characterized, many studies have shown that VHL is also important in extracellular matrix assembly and cell membrane structure through regulating fibronectin and integrins, and loss of this function leads to tumor development as well. Fibronectin is upregulated by VHL at the mRNA level and independently of hypoxia [15] or the HIFα pathway [16] and requires covalent modification of VHL by NEDD8, a ubiquitin-like molecule [16]. Mutants that escape this modification are involved in tumorigenesis despite adequate HIFα suppression. VHL also reduces the protein abundance of several subtypes of integrins in an oxygen-independent manner, via proteasomal degradation, suggesting that VHL is important in cell adhesion and maintenance of tight junctions [17]. Further, depletion of HIF-2α alone does not fully recapitulate the effects of VHL replacement in a VHL-null cell line [18], particularly the downregulation of integrins and resulting morphological changes. These mechanisms are likely involved in VHL-associated tumorigenesis, particularly in pheochromocytoma, where the HIFα pathway does not play a significant role.\n\nAcknowledgments\nThe authors thank Dr. Keith Nehrke and Dr. Teresa Sherman for providing the hypoxia chamber used in this experiment.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 CT scan of the abdomen showing the right adrenal tumor ((a), arrow) and the left adrenal tumor ((b), arrow) prior to adrenalectomy.\n\nFigure 2 Western blot of HIF2α, HA-VHL, and GAPDH expression in normal oxygen (left) and hypoxic (right) conditions. VHL-null 786-O cells were transfected and clonally selected for stable expression of either WT or Y175C VHL or GFP (null), as indicated.\n==== Refs\n1 Schmid S. Gillessen S. Binet I. Management of von Hippel-Lindau disease: An interdisciplinary review Oncology Research and Treatment 2014 37 12 761 771 10.1159/000369362 25531723 \n2 Cassol C. Mete O. Endocrine manifestations of von Hippel-Lindau disease Archives of Pathology & Laboratory Medicine 2015 139 2 263 268 2-s2.0-84921474603 10.5858/arpa.2013-0520-RS 25611110 \n3 Binderup M. L. M. Jensen A. M. Budtz-Jørgensen E. Bisgaard M. L. Survival and causes of death in patients with von Hippel-Lindau disease Journal of Medical Genetics 2017 54 1 11 18 2-s2.0-84983503756 10.1136/jmedgenet-2016-104058 27539272 \n4 Clifford S. C. Maher E. R. Von hippel-lindau disease: Clinical and molecular perspectives Advances in Cancer Research 2001 82 85 105 2-s2.0-0034963935 10.1016/S0065-230X(01)82003-0 11447766 \n5 Gossage L. Eisen T. Maher E. R. VHL, the story of a tumour suppressor gene Nature Reviews Cancer 2015 15 1 55 64 2-s2.0-84925546346 10.1038/nrc3844 25533676 \n6 Barontini M. Dahia P. L. M. VHL Disease Best Practice & Research Clinical Endocrinology & Metabolism 2010 24 3 401 413 2-s2.0-77956596804 10.1016/j.beem.2010.01.002 20833332 \n7 Li L. Zhang L. Zhang X. Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations Molecular and Cellular Biology 2007 27 15 5381 5392 2-s2.0-34547174217 10.1128/MCB.00282-07 17526729 \n8 Rechsteiner M. P. Von Teichman A. Nowicka A. Sulser T. Schraml P. Moch H. VHL gene mutations and their effects on hypoxia inducible factor HIFα : identification of potential driver and passenger mutations Cancer Research 2011 71 16 5500 5511 10.1158/0008-5472.CAN-11-0757 2-s2.0-80051697173 21715564 \n9 Lonser R. R. Glenn G. M. Walther M. Von Hippel-Lindau disease The Lancet 2003 361 9374 2059 2067 10.1016/s0140-6736(03)13643-4 2-s2.0-0037709883 \n10 Hoffman M. A. Ohh M. Yang H. Klco J. M. Ivan M. Kaelin W. G. Jr. Von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF Human Molecular Genetics 2001 10 10 1019 1027 2-s2.0-0035336706 10.1093/hmg/10.10.1019 11331612 \n11 Clifford S. C. Cockman M. E. Smallwood A. C. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease Human Molecular Genetics 2001 10 10 1029 1038 10.1093/hmg/10.10.1029 11331613 \n12 Ruiz-Llorente S. Bravo J. Cebrián A. Genetic characterization and structural analysis of VHL spanish families to define genotype-phenotype correlations Human Mutation 2004 23 2 160 169 10.1002/humu.10309 2-s2.0-10744222427 14722919 \n13 Ding Z. German P. Bai S. Genetic and pharmacological strategies to refunctionalize the von hippel lindau R167Q mutant protein Cancer Research 2014 74 11 3127 3136 2-s2.0-84902170698 10.1158/0008-5472.CAN-13-3213 24755468 \n14 Brito J. P. Asi N. Bancos I. Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: A systematic review Clinical Endocrinology 2015 82 3 338 345 2-s2.0-84923069909 10.1111/cen.12530 24954084 \n15 Bluyssen H. A. R. Lolkema M. P. J. K. Van Beest M. Fibronectin is a hypoxia-independent target of the tumor suppressor VHL FEBS Letters 2004 556 1-3 137 142 2-s2.0-9144232529 10.1016/S0014-5793(03)01392-9 14706840 \n16 Stickle N. H. Chung J. Klco J. M. Hill R. P. Kaelin Jr. W. G. Ohh M. pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development Molecular and Cellular Biology 2004 24 8 3251 3261 10.1128/MCB.24.8.3251-3261.2004 2-s2.0-1842557655 15060148 \n17 Ji Q. Burk R. D. Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation The International Journal of Biochemistry & Cell Biology 2008 86 3 227 234 2-s2.0-44949139859 10.1139/O08-035 18523483 \n18 Hughes M. D. Kapllani E. Alexander A. E. Burk R. D. Schoenfeld A. R. HIF-2alpha downregulation in the absence of functional VHL is not sufficient for renal cell differentiation Cancer Cell International 2007 7 p. 13\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2018()",
"journal": "Case reports in endocrinology",
"keywords": null,
"medline_ta": "Case Rep Endocrinol",
"mesh_terms": null,
"nlm_unique_id": "101576457",
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"pages": "8967159",
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"pmid": "30105105",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "12814730;15060148;25611110;24954084;14722919;25531723;17526729;11331612;20833332;11447766;24755468;14706840;25533676;18523483;27539272;17598890;11331613;21715564",
"title": "Bilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation.",
"title_normalized": "bilateral pheochromocytomas in a patient with y175c von hippel lindau mutation"
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-042563",
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"activesubstancename": "TAMSULOSIN HYDROCHLORIDE"
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"abstract": "Chemotherapy with G-CSF is used to mobilize peripheral stem cells in multiple myeloma (MM) patients, with plerixafor as a rescue strategy for poorly mobilizing patients. Preclinical studies suggested that the nonsteroidal anti-inflammatory drug meloxicam enhances the mobilization of CD34+ cells. In this single-center study, we evaluated whether adding meloxicam to chemotherapy/G-CSF mobilization increases peripheral hematopoietic CD34+ cell levels and reduces the need of using plerixafor. We prospectively compared two consecutive cohorts of MM patients in first remission mobilized with G-CSF and non-myelosuppressive chemotherapy with vinorelbine or gemcitabine. The second cohort additionally received oral meloxicam. The cohorts comprised 84 patients without meloxicam (-M) and 66 patients with meloxicam (+M). Meloxicam was well tolerated and associated with similar hematologic engraftment after transplantation and equal survival rates. However, the meloxicam group had higher CD34+ cell levels on day 8 of the mobilization procedure (53 200 versus 35 600 CD34+ cells/mL; P=0.007), and fewer patients needed >1 collection day (+M: 6 (9%) patients versus -M: 16 (19%) patients; P=0.04). This resulted in reduced plerixafor administrations (+M: 7 (11%) patients versus -M: 18 (21%) patients; P=0.03) and less costs. Our data suggest that meloxicam enhances the mobilization of hematopoietic CD34+ blood cells in MM patients.",
"affiliations": "Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Hematology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Hematology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Clinical Research, University of Bern, Bern, Switzerland.;Department of Clinical Research, University of Bern, Bern, Switzerland.;SAKK Coordinating Centre, Bern, Switzerland.;Department of Oncology, Kantonsspital, Fribourg, Switzerland.;Department of Oncology, Regionalspital, Thun, Switzerland.;Department of Oncology, Kantonsspital, Solothurn, Switzerland.;Department of Hematology, Kantonsspital, Lucerne, Switzerland.;Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.",
"authors": "Jeker|B|B|;Novak|U|U|;Mansouri Taleghani|B|B|;Baerlocher|G M|GM|;Seipel|K|K|;Mueller|B U|BU|;Bigler|M|M|;Betticher|D|D|;Luethi|J-M|JM|;Farese|S|S|;Ruefer|A|A|;Pabst|T|T|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000077239:Meloxicam",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2017.234",
"fulltext": null,
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"issn_linking": "0268-3369",
"issue": "53(2)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "175-179",
"pmc": null,
"pmid": "29058701",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "21410373;21537168;16439213;24497560;11732870;22281595;25278456;16863437;26294015;19324903;22802322;8807097;12621490;14574413;23584435;20703299;12519430;14574412;12736280;21447828;23485965;24884311;21360286;12162470;20305640;9552064;8649495;22248715;11264472;17581586;25891070;19363221",
"title": "NSAID treatment with meloxicam enhances peripheral stem cell mobilization in myeloma.",
"title_normalized": "nsaid treatment with meloxicam enhances peripheral stem cell mobilization in myeloma"
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"companynumb": "CH-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-010962",
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"activesubstancename": "MELOXICAM"
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"abstract": "Although acute hepatitis may be a side effect of many medications, most cases are reversible after treatment interruption, and fulminant hepatic failure (FHF) is rare. Venlafaxine and trazodone are 2 popular antidepressant agents. Alteration of liver enzyme levels has been reported as a side effect of these drugs at normal doses. Herein we have reported the case of a 48-year-old woman without any previous history of liver disease, who developed fulminant liver failure after 4 months of venlafaxine and trazodone therapy. She required liver transplantation, a procedure that was successful with full patient recovery. The first 5 years of follow-up were uneventful. This case documented that venlafaxine and trazodone at normal doses can produce severe liver toxicity. Liver tests should be monitored regularly in patients who receive this therapy.",
"affiliations": "Department of Abdominal Surgery and Transplantation, CHU de Liège, University of Liège, Sart Tilman B35, B4000 Liège, Belgium. oli.detry@chu.ulg.ac.be",
"authors": "Detry|O|O|;Delwaide|J|J|;De Roover|A|A|;Hans|M F|MF|;Delbouille|M H|MH|;Monard|J|J|;Honoré|P|P|",
"chemical_list": "D003511:Cyclohexanols; D017367:Serotonin Uptake Inhibitors; D000069470:Venlafaxine Hydrochloride; D005165:Factor V; D001219:Aspartate Aminotransferases; D001663:Bilirubin; D014196:Trazodone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2009.09.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "41(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D001219:Aspartate Aminotransferases; D001663:Bilirubin; D003511:Cyclohexanols; D003863:Depression; D005165:Factor V; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D007565:Jaundice; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008875:Middle Aged; D017367:Serotonin Uptake Inhibitors; D014196:Trazodone; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3435-6",
"pmc": null,
"pmid": "19857765",
"pubdate": "2009-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant hepatic failure induced by venlafaxine and trazodone therapy: a case report.",
"title_normalized": "fulminant hepatic failure induced by venlafaxine and trazodone therapy a case report"
} | [
{
"companynumb": "BE-MYLANLABS-2010S1001242",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nTo determine how often serious or life-threatening medication administration errors with the potential to cause harm (potential adverse drug events) result in actual harm (adverse drug events (ADEs)) in the hospital setting.\n\n\nMETHODS\nRetrospective chart review of clinical events following observed medication administration errors.\n\n\nBACKGROUND\nMedication errors are common at the medication administration stage for inpatients. While many errors can cause harm, it is unclear exactly how often.\n\n\nMETHODS\nIn a previous study where 14 041 medication administrations were directly observed, 1271 medication administration errors were discovered, of which 133 had the potential to cause serious or life-threatening harm and were considered serious or life-threatening potential adverse drug events. As a follow-up, clinical reviewers conducted detailed chart review of serious or life-threatening potential ADEs to determine if they caused an ADE. Reviewers assessed severity of the ADE and attribution to the error.\n\n\nRESULTS\nTen (7.5% (95% CI 6.98 to 8.01)) actual ADEs resulted from the 133 serious and life-threatening potential ADEs, of which 6 resulted in significant, three in serious, and one life threatening injury. Therefore 4 (3% (95% CI 2.12 to 3.6)) of serious or life threatening potential ADEs led to serious or life threatening ADEs. Half of the ADEs were caused by dosage or monitoring errors for anti-hypertensives.\n\n\nCONCLUSIONS\nUnintercepted potential ADEs at the medication administration stage can cause serious patient harm. At hospitals where 6 million doses are administered per year, about 4000 preventable ADEs would be attributable to medication administration errors annually.",
"affiliations": "Division of General Medicine and Primary Care, Brigham & Women's Hospital, 1620 Tremont St, Boston, MA 02120, USA.",
"authors": "Kale|Abhivyakti|A|;Keohane|Carol A|CA|;Maviglia|Saverio|S|;Gandhi|Tejal K|TK|;Poon|Eric G|EG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bmjqs-2012-000946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2044-5415",
"issue": "21(11)",
"journal": "BMJ quality & safety",
"keywords": null,
"medline_ta": "BMJ Qual Saf",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D004334:Drug Administration Schedule; D006801:Humans; D008508:Medication Errors; D012189:Retrospective Studies; D012308:Risk Management",
"nlm_unique_id": "101546984",
"other_id": null,
"pages": "933-8",
"pmc": null,
"pmid": "22791691",
"pubdate": "2012-11",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "15069223;7503827;11311101;9609500;8332330;1824793;20821969;9002493;21228071;10718351;9002492;7791255;7790981;20445181;12387650;7791256;21732130;17078408;17452541;15289635;12196090",
"title": "Adverse drug events caused by serious medication administration errors.",
"title_normalized": "adverse drug events caused by serious medication administration errors"
} | [
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"companynumb": "US-TEVA-568039USA",
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
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"drugadditio... |
{
"abstract": "OBJECTIVE\nTo illustrate the potential value of pharmacogenetic testing to identify patients at risk for nonsteroidal anti-inflammatory drug-induced gastropathy.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nWe report a case encountered in an outpatient setting for pain management.\n\n\nMETHODS\nWe present a case of a patient treated with celecoxib who developed severe nonsteroidal anti-inflammatory drug-induced gastropathy.\n\n\nMETHODS\nSuspecting a relation between this adverse event and altered drug metabolism, pharmacogenetic testing was performed to assess the role of the cytochrome P450 (CP450) enzyme profile.\n\n\nRESULTS\nPharmacogenetic testing revealed a relation between this adverse event and an allelic variant of cytochrome P450, CYP2C9, subsequently leading to discontinuation of the drug along with counseling to caution the patient to avoid the use of celecoxib and other drugs metabolized by the same enzyme.\n\n\nCONCLUSIONS\nAlthough pharmacogenetic testing is not routinely used in clinical decision making, pain physicians must be aware of the potential benefits of this testing for managing patients with pain, and to improve drug efficacy and safety profile.",
"affiliations": "University Pain Institute, Division of Pain Medicine & Regional Anesthesiology.;Clinical Research Group, Department of Anesthesiology and Perioperative Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.;Clinical Research Group, Department of Anesthesiology and Perioperative Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.;Clinical Research Group, Department of Anesthesiology and Perioperative Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.",
"authors": "Gupta|Anita|A|;Zheng|Lu|L|;Ramanujam|Vendhan|V|;Gallagher|John|J|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000068579:Celecoxib",
"country": "England",
"delete": false,
"doi": "10.1111/pme.12654",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-2375",
"issue": "16(5)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "CP450; CYP2C9; Efficacy; Gastropathy; NSAIDs; Outcomes; Pharmacogenetic Testing",
"medline_ta": "Pain Med",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000068579:Celecoxib; D018856:Cystitis, Interstitial; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005756:Gastritis; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult",
"nlm_unique_id": "100894201",
"other_id": null,
"pages": "866-9",
"pmc": null,
"pmid": "25585969",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Novel Use of Pharmacogenetic Testing in the Identification of CYP2C9 Polymorphisms Related to NSAID-Induced Gastropathy.",
"title_normalized": "novel use of pharmacogenetic testing in the identification of cyp2c9 polymorphisms related to nsaid induced gastropathy"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2015-01940",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CELECOXIB"
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"drugadditional"... |
{
"abstract": "Maple Syrup Urine Disease (MSUD) is a rare inherited disorder of branched chain amino acid metabolism characterized by cerebral edema and death in uncorrected metabolic crisis. It is conventionally treated with intensive nutritional therapy to prevent and correct metabolic crisis. This paper reports the use of growth hormone as a pharmacologic rescue agent in the case of an 11-year-old male with MSUD and metabolic crisis refractory to standard interventions. The initiation of short courses of growth hormone correlated with corrected mental status, resolution of metabolic acidosis, and improvement in plasma leucine levels on two occasions during an admission to the pediatric intensive care unit. This is the first known case report of the use of growth hormone in MSUD since contemporary dietary management became available. The discussion includes a literature review of the use of growth hormone in inherited diseases of amino acid metabolism and a brief discussion of protein anabolic pharmacotherapeutic agents shown to improve net protein balance in pediatric burn patients. We propose that growth hormone and other protein anabolic agents may be valuable adjuvants to standard therapy in children with inherited metabolic disease.",
"affiliations": "1501 Kennewick Rd, Baltimore, MD 21218, United States of America.;Prisma Health Systems, Greenville, SC 29605, United States of America.;Division of Pediatric Critical Care, Department of Pediatrics, University of Maryland Medical Center, Baltimore, MD 21201, United States of America.;Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD 21218, United States of America.;Department of Nutrition, University of Maryland Medical Center, Baltimore, MD 21201, United States of America.;Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland Medical Center, Baltimore, MD 21201, United States of America.;Division of Genetics, Department of Pediatrics, University of Maryland Medical Center, Baltimore, MD 21201, United States of America.",
"authors": "Kimbrell|Brooke E|BE|;Hicks|Faith|F|;Foster|Cortney B|CB|;Kishk|Omayma A|OA|;Quinteros-Fernandez|Sara A|SA|;Nikita|Maria Eleni|ME|;Greene|Carol L|CL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ymgmr.2020.100685",
"fulltext": "\n==== Front\nMol Genet Metab Rep\nMol Genet Metab Rep\nMolecular Genetics and Metabolism Reports\n2214-4269 Elsevier \n\nS2214-4269(20)30131-2\n10.1016/j.ymgmr.2020.100685\n100685\nCase Report\nGrowth hormone as a rescue treatment in maple syrup urine disease with lessons from pediatric burn literature, case report and brief literature review\nKimbrell Brooke E. bekimbrell@gmail.comkimbrell@kennedykrieger.orgai⁎ Hicks Faith Faith.hicks@prismahealth.orgb Foster Cortney B. Cfoster@som.umaryland.educ Kishk Omayma A. d Quinteros-Fernandez Sara A. saraquinteros@umm.edue Nikita Maria Eleni mnikita@som.umaryland.eduf Greene Carol L. carol.greene@som.umaryland.edugh a 1501 Kennewick Rd, Baltimore, MD 21218, United States of America\nb Prisma Health Systems, Greenville, SC 29605, United States of America\nc Division of Pediatric Critical Care, Department of Pediatrics, University of Maryland Medical Center, Baltimore, MD 21201, United States of America\nd Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD 21218, United States of America\ne Department of Nutrition, University of Maryland Medical Center, Baltimore, MD 21201, United States of America\nf Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland Medical Center, Baltimore, MD 21201, United States of America\ng Division of Genetics, Department of Pediatrics, University of Maryland Medical Center, Baltimore, MD 21201, United States of America\nh Department of OB GYN and Reproductive Services, University of Maryland Medical Center, Baltimore, MD 21218, United States of America\ni Kennedy Kreiger Institute, 707 North Broadway, Baltimore MD 21205, United States of America\n⁎ Corresponding author at: Kennedy Kreiger Institute, 707 North Broadway, Baltimore MD 21205, United States of America bekimbrell@gmail.comkimbrell@kennedykrieger.org\n13 12 2020 \n12 2020 \n13 12 2020 \n25 10068517 11 2020 18 11 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Maple Syrup Urine Disease (MSUD) is a rare inherited disorder of branched chain amino acid metabolism characterized by cerebral edema and death in uncorrected metabolic crisis. It is conventionally treated with intensive nutritional therapy to prevent and correct metabolic crisis. This paper reports the use of growth hormone as a pharmacologic rescue agent in the case of an 11-year-old male with MSUD and metabolic crisis refractory to standard interventions. The initiation of short courses of growth hormone correlated with corrected mental status, resolution of metabolic acidosis, and improvement in plasma leucine levels on two occasions during an admission to the pediatric intensive care unit. This is the first known case report of the use of growth hormone in MSUD since contemporary dietary management became available. The discussion includes a literature review of the use of growth hormone in inherited diseases of amino acid metabolism and a brief discussion of protein anabolic pharmacotherapeutic agents shown to improve net protein balance in pediatric burn patients. We propose that growth hormone and other protein anabolic agents may be valuable adjuvants to standard therapy in children with inherited metabolic disease.\n\nHighlights\n• Growth hormone was used to treat acute MSUD metabolic crisis refractory to standard interventions.\n\n• Protein anabolic pharmacotherapy such as growth hormone has been studied in pediatric burn victims.\n\n• Protein anabolic pharmacotherapy warrants further study in inherited metabolic disease.\n\n\n\nKeywords\nMaple syrup urine diseaseGrowth hormoneMetabolic crisisInherited metabolic diseaseAnabolic pharmacologyBranched-chain alpha-ketoacid dehydrogenation deficiency\n==== Body\n1 Introduction\nMaple Syrup Urine Disease is an inherited metabolic disorder of amino acid metabolism in caused by deficiency in branched chain ketoacid dehydrogenase enzyme leading to the accumulation of branched chain amino acids (BCAA) such as leucine, isoleucine, and valine. Untreated, the buildup of these acids leads to progressive metabolic ketoacidosis, encephalopathy, and cerebral edema. The condition is typically detected on metabolic newborn screen and is treated by limiting dietary intake of natural protein containing branched chain amino acids while providing adequate essential non branched chain amino acids via special medical food [1]. Metabolic crisis can be triggered by catabolic states releasing branched chain amino acids from skeletal muscles or by decreased natural protein tolerance due to physiologic stress. In individuals with MSUD, acute illness can lead to a metabolic crisis, cerebral edema, and irreversible neurologic injury. Although MSUD has been known for decades, it is a rare disease and only recently have guidelines for its management been published [2,3]. This report discusses a case in which a child's metabolic crisis was not controlled by the strategies included in these guidelines. We report the use of growth hormone as an adjuvant therapy, which is referenced by older literature for MSUD [4] and some recent case series in other inherited metabolic disorders [[5], [6], [7], [8]] and is supported by recent research in pediatric burn patients [9].\n\nThe Nutritional Management Guidelines for Maple Syrup Urine Disease published in 2014 and guidelines published by Genetic Metabolic Dietitians International in 2013 provide recommendations for care of patients in metabolic crisis based around aggressive nutritional management to promote anabolism including supplying up to 150% of usual energy intake, BCAA free protein for 1–2 days, supplementation of valine and isoleucine, and electrolytes. In addition to these nutritional management strategies, seriously ill patients may need insulin infusion, dialysis, hemofiltration, parenteral nutrition and/or tube feeding while the source of the decompensation is addressed [2,3]. Protein anabolic pharmacotherapy has potential to complement nutritional management and ideally reduce the need for dialysis and other invasive interventions during periods of metabolic stress. Because inherited metabolic disease is rare, the literature on protein anabolic pharmacotherapy in this population is limited [4,10]. However, the protein catabolic state of severely burned children has been well documented, and several high-quality studies have been performed on protein anabolic pharmacotherapy in that population [9]. This paper proposes that this body of literature represents a valuable fund of knowledge which could be applied to the care of children with inherited metabolic disease.\n\n2 Case summary\nKP is a 11-year-old Hispanic male with MSUD detected on newborn metabolic screen and confirmed by blood amino acids with characteristic elevations including allosioleucine and the absence of elevation of glycine and alpha-ketoglutarate. DNA testing was offered and not pursued after family decided that they would not attempt any future pregnancy. Biopsy for enzyme assay was not requested since amino acid levels clearly indicated classical MSUD. Because he had an early episode of sepsis and congenital nystagmus, we screened for congenital disorders of glycosylation by analysis of transferrin with normal results. Nystagmus gradually resolved after surgery for exotropia. Growth was normal, there were no dysmorphic features and development was typical for a child with MSUD with history of episodes of MSUD crisis; therefore, other diagnostic genetic or endocine testing was undertaken. He had two significant episodes of severe metabolic decompensation before age 7. One episode was complicated by significant cerebral edema which required intensive care unit stay and use of mannitol. He had not received dialysis in the past. He has baseline learning and behavioral issues that are suspected to be related to MSUD and attention deficit hyperactivity disorder (ADHD). Prior to admission, his nutritional prescription was as follows: 45 kcal/kg total calories, 2.2 g/kg total protein, 0.18–0.2 g/kg/day natural protein, 275–500 mg/kg leucine, 240–450 mg/kg isoleucine, 325-500 mg/kg valine. He demonstrated good dietary compliance with the assistance of his mother and had stable blood amino acids for several months prior to admission with goal intake of 7 g of natural protein daily. He had normal growth velocity along the 10th percentile (Table 1).Table 1 KP's anthropometrics prior to admission.\n\nTable 1Anthropometrics prior to admission\tPercentile\tZ- score\t\nWeight\t38.2 kg\t40th\t−0.25\t\nHeight\t136 cm\t4th\t−1.75\t\nBMI\t20.7\t84th\t0.98\t\n\n\nHe presented in septic shock and metabolic crisis with cerebral edema in May 2019 which required intubation, hemodialysis, and insulin continuous infusion in the Pediatric Intensive Care Unit (PICU). He was found to have pancreatitis and pneumonia with cavitary Group A Streptococcus infection of the lung. He was provided with trophic feeds of BCAA free formula for bowel rest in the setting of pancreatitis and abdominal distention while on vasopressor support. Dextrose and intravenous lipid provided caloric supplementation and BCAA free total parental nutrition was provided. During the initial 6 days, natural protein was held because of persistently elevated levels of leucine. This prolonged restriction later lead to concern for negative amino acid balance, especially in the setting of recent hemodialysis. His recovery was complicated by pulmonary thrombosis and renal infarction due to hypercoagulable state during the metabolic crisis. Renal function was normal. He received three doses of dexamethasone peri-extubation without signs of worsened metabolic status post steroid treatment despite the risk of steroids to worsen metabolic status in MSUD due to net catabolic effect. After his neurologic and metabolic states stabilized, he was transferred to the pediatric progressive care unit to complete his course of antibiotics, resumption of his home feeds, and weaning off intravenous (IV) fluids. Because the patient's leucine levels remained high, his natural protein was restricted to 3.5–4 g/day with periodic attempts to increase back to 7 g. During this period his weight decreased by 1.1 kg. Weight was expected to be an inaccurate measure of nutritional status given major fluid shifts but decrease may be a reflection of negative nitrogen balance due to muscle wasting because of inactivity and possibly prolonged catabolism due to over restriction of leucine on admission.\n\nWhile on the progressive care unit, he developed increased work of breathing, biphasic stridor, and tracheal tugging concerning for subglottic or tracheal stenosis. He was transferred back to the PICU for close monitoring in preparation for laryngoscopy and possible intervention under anesthesia. In preparation for the physiologic stress of the procedure, his IV fluids were increased to twice maintenance with D10W+ 0.9%NS. He went to the operating room (OR) on June 5th and was found to have 70% stenosis of the sub-subglottic region and underwent tracheostomy. A nasogastric tube was placed in the OR for continued administration of BCAA free formula. Because he was at high risk for decannulation due to his impulsive ADHD, his otolaryngologist required that he have sedation and muscle relaxation for a full 7 days until his first trach change. During that period, natural protein of 4 g/day was provided via PediaSure®, valine and isoleucine supplements were continued, intralipids were resumed daily for extra calories, and glucose infusion rate of no less than 6 mg/kg/min was maintained with D10W+ 0.9%NS. His amino acids, including all essential amino acids, were followed closely once or twice daily to monitor for catabolic shifts in the setting of post-operative physiologic stress and prolonged immobility.\n\nDespite aggressive nutritional management, his amino acids trended up and continuous insulin infusion and increased dextrose to 8 mg/kg/min were started on June 8th to stimulate anabolism while he remained immobilized. He was hemodynamically stable, required only continuous airway pressure for respiratory support, and was without sign of end organ dysfunction on laboratory monitoring. In the evening on June 11th his AA levels were found to be markedly elevated with leucine 1050 nmol/mL and he developed a metabolic acidosis to 7.23 with an anion gap of 15 indicating a catabolic state (Fig. 1). He had altered mental status with decreased ability to follow commands. Dialysis was considered but would have been counterproductive overall given his negative protein balance over the course of admission. After consultation with other metabolic genetics colleagues and review of the available case reports and short case series reporting the use of growth hormone in children with inherited metabolic disease [[4], [5], [6], [7], [8]], a 3-day course of growth hormone was started and his natural protein was increased to 7 g to facilitate protein anabolism. No changes to respiratory support or infusions were made. Within 24 h he had normalizations of his anion gap and metabolic acidosis, his ability to follow commands improved, but his AA levels remained stably elevated. His first trach change was completed the next day on June 12th and sedation and paralysis were weaned. During airway interventions his branched chain amino acid free formula was held for most of the day and natural protein was again decreased to 3.5 g daily given his high AA levels (leucine still >1100 nmol/mL). As his activity level increased on June 13th, his serum branched chain amino acids began slowly down trending but leucine remained close to 1000 despite continuous insulin infusion and optimization of nutritional management.Fig. 1 Graphical representation of metabolic crisis and response to interventions. Branched chain amino acid levels trended up and remained markedly elevated despite standard interventions including natural protein restriction, caloric supplementation with dextrose, and continuous insulin infusion to stimulate anabolism. Clinical signs of metabolic crisis and altered mental status were treated with short courses of growth hormone which correlated with improved mental status and improved branch chain amino acid levels.\n\nFig. 1\n\nHis BCAA levels began rising again on June 16th and he became lethargic on June 17th with a leucine level of 1322 nmol/mL. There was concern for possible infection as he had up-trending serum white blood cells and platelets, with red and white blood cells in his urine. Urine culture grew 25,000 Enterobacter cloacae, and he was treated with IV antibiotics. Serum ESR and CRP were elevated but overall down trending from his recent surgery. His renal ultrasound was normal and serum creatinine remained normal. Again, dialysis was discussed for treatment of metabolic crisis with altered mental status, but his mother did not consent. Continued literature search regarding protein anabolic pharmacotherapy options lead the authors to a body of literature reporting the use of growth hormone to treat the protein catabolic state of severely burned children with positive protein balance kinetics measured by radioisotope tracers [9]. A second course of growth hormone was started, this time for 7 days in conjunction with physical therapy as tolerated. BCAA levels stabilized then down trended sharply on June 19th to leucine 519 nmol/mL, isoleucine 70 nmol/mL, and valine 169 nmol/mL. His natural protein was increased to 7 g/day and his BCAA levels did not rise. He passed a modified barium swallow study and was transitioned back to his home MSUD formula orally with nasogastric (NG) supplementation. He was allowed to take solids foods with mom keeping a protein count with a goal of 7 g per day so that natural protein provision was transitioned from formula to solid food. Enteral formula was supplemented as needed to achieve protein goal for the day. Insulin and dextrose were weaned off. By the completion of his second course of growth hormone on June 24th, his AA levels had normalized and he was tolerating his home nutrition and supplement regimen. He had regained his admission weight and continued to gain weight along the 50-60th percentile. He required prolonged admission for tracheostomy training and physical rehabilitation.\n\nAfter resolution of his metabolic crisis, he displayed increased natural protein tolerance and was discharged on 12 g/day of natural protein. His natural protein prescription was gradually decreased to 8 g/day over a twelve-month period with close monitoring of his serum amino acid levels and growth curves. This period of increased natural protein tolerance is attributed to correction of his hospital acquired muscle wasting as well as the onset of puberty. He is scheduled for a laryngoscopy for evaluation of laryngotracheal reconstruction. Parental informed consent was obtained for the publication of this case report.\n\n3 Results and discussion\n3.1 Discussion of nutritional management\nCurrent pediatric critical care guidelines recommend estimating the Resting Energy Expenditure (REE) as using the Schofield equation without stress factors, in the absence of indirect calorimetry [11]. For KP, his REE is estimated at 1340 kcal/day, or 44 kcal/kg. Estimated protein needs during critical illness are at least 1.5 g/kg [12]. We initiated nutritional support immediately upon admission. He was transitioned from parental to enteral, then to oral nutrition while maintaining calorie provision from 150 to 200% of REE. The calories provided well exceeded typical provision for critical illness, and later, his ambulatory state. Non BCAAs were also provided in excess of the recommended need for pediatric critical illness. This intensive approach was taken for KP with the intent to reverse catabolism and promote anabolism, which would result in the reduction of plasma leucine. However, his leucine levels remained persistently elevated despite seamless provision of aggressive nutrition support. Table 2 compares the protein and energy provided to standard of care ranges in ambulatory and acute illness [[11], [12]].Table 2 Comparison of recommended and provided nutrition in ambulatory and acute illness settings. KP was consistently provided with energy and protein in excess of recommended guidelines to promote anabolism.\n\nTable 2\tAmbulatory goal in MSUD\tAmbulatory goals for KP prior to admission\tRecommendations for child in critical care\tRecommendations for acutely ill ambulatory child\tProvision during acute and critical illness for KP\t\nNatural Protein (g/day)\t5–8 g/day\t7 g/day\tNot applicable\tNot applicable\t0–7 g/day\t\nTotal Protein (g/kg)\t1.2–1.8 g/kg\t1–1.5 g/kg\t>1.5 g/kg\tNot available\t2–3.5 g/kg\t\nEnergy (Kcal/kg)\t40–90 kcal/kg\t45–55 kcal/kg\t34 kcal/kg\t44 kcal/kg\t52–68 kcal/kg\t\nPercent Resting Energy Expenditure\tNot applicable\tNot applicable\t100% REE\t130% REE\t150% REE\t\n\n\n3.2 Discussion of response to growth hormone\nThis case demonstrates that growth hormone can be used as a rescue intervention when standard of care nutritional therapy and use of insulin are unable to reverse metabolic crisis. Use of growth hormone to treat metabolic crisis in maple syrup urine disease has been mentioned in medical literature as early as 1968 [4]. However, this is the first recent case report documenting the protein anabolic response to growth hormone in inherited metabolic disease. The administration of growth hormone during the first course was effective at correcting clinical signs of metabolic encephalopathy, resolving his acidosis, and stabilizing his plasma leucine levels. In contrast, the rapid decline in his plasma amino acid levels with the second course, even in the setting of increase natural protein intake, was attributed to the protein anabolic effects of growth hormone augmented by the physiologic stimulus of physical activity Figure 1.\n\n3.3 Discussion of pharmacology and safety\nThere are no known studies on the most appropriate dose of growth hormone in metabolic crisis. In this case, we used the standard dose approved for the available manufacturer for prepubertal children, which is 0.3 mg/kg/week divided by 7 for a daily dose of 0.04 mg/kg/day [13]. This dose represented a large volume and eight subcutaneous injections daily because the concentration/product available for use on our hospital's formulary. The product on formulary Genotropin MiniQuick® (somatropin) 0.2 mg injections. Several of the injections were able to be given while patient was still under sedation. By the time patient was off sedation, he only had a couple of days left of the somatropin, so the hospital was unable to purchase another somatropin product. The large number of injections may limit the feasibility of the use of this project in some clinical scenarios, but other products can be used to avoid this limitation.\n\nThere are no studies of the safety profile of growth hormone for short term use. The clinical practice guidelines for the use of growth hormone for growth hormone deficiency and idiopathic short stature discusses rare side effects of chronic administration. These rare side effects include: decreased insulin sensitivity, changes in cortisol metabolism which could theoretically unmask an undiagnosed adrenal insufficiency, theoretical increase risk of neoplasm in susceptible children, and problems associated with rapid linear growth including slipped capital femoral epiphysis (SCFE), increased scoliosis, and intracranial hypertension. The incidence of these adverse effects is reportedly <3% in children undergoing long term therapy and do not require specific surveillance [14]. Of these potential adverse reactions, decreased insulin sensitivity and altered cortisol metabolism would pose the greatest risk to a child in metabolic crisis. These effects have not been specifically studied or reported with acute administration of growth hormone.\n\nThe use of growth hormone in critically ill children has very limited evidence. Dysregulation of GH and insulin like growth factor 1 axis has been demonstrated in critically ill adults and children [15,16]. After the development of recombinant GH in the 1985, several studies in critically ill adults showed positive safety profiles and improvement in nitrogen balance [17]. However in 1999 a pair of prospective, double blind, randomized control trials of high dose growth hormone in adults with critical illness including surgery, trauma, and sepsis showed increased morbidity and mortality in the treatment group despite improved nitrogen balance [18]. The source of this increased mortality is unclear with some groups speculating that there may have been inadequate nutritional support, specifically glycine supplementation [17]. After this study, further exploration of GH in critical care settings has been limited. The Growth Hormone Research Society published a critical evaluation of the safety of recombinant GH administration in the Journal of Clinical Endocrinology and Metabolism in 2001. It states “Any GH treatment other than replacement in those who have GH deficiency should be considered as pharmacological. In specific conditions where pharmacological treatment with GH is being considered, standard safety data should be collected and protocols for new drug development followed. The detrimental outcome of high-dose GH treatment in intensive care patients cannot be extrapolated to other conditions, which may potentially benefit from GH treatment [19].”\n\n3.4 Focused literature review\nA literature search of pharmacologic effects of growth hormone on protein anabolism lead the author to a useful literature review by Diaz et al. discussing the catabolic state of burn victims and the effects of various pharmacologic agents on protein kinetics in severely burned children. We found this review to be relevant to our patient because it demonstrates the net protein anabolic effect of growth hormone. They report that growth hormone administered at 0.2 mg/kg once daily for 19 days increased the net protein balance of treated children by 67% compared to controls. Our patient responded well to standard dosing approved for treating growth hormone deficiency, however it is worth noting that the dose reported in the burn literature is five times greater than the dose used in our patient. Diaz et al. also summarized results of studies of metformin, insulin, and testosterone in burned adults as well as oxandrolone, insulin, propranolol, and ketoconazole in burned children. Insulin, which has been a staple of treatment of metabolic crisis in children with MSUD for decades, was reported to increase both muscle protein breakdown and synthesis with a net increase in protein balance by 120% after treatment with 0.432 units/kg/h for 7 days in burned children. Ketoconazole showed no significant effect. Propranolol showed increase in net protein balance by 183% in burned children after treatment with 6.3 mg/kg/day divided in four doses per day for 2 weeks. Oxandrolone is a synthetic testosterone analogue with minimal virilizing effects which was shown to increase net protein balance by 107% after treatment with 0.1 mg/kg twice daily for 5 days [9].\n\nSpecific searches of the literature for studies of these drugs in MSUD revealed that metformin has a single study published [20]. This study demonstrated decrease in branched chain amino acid derived ketoacidosis and improvement in mitochondrial metabolic function in cultured patient fibroblasts and reports that the effects were preserved in a MSUD mouse model. There are no published clinical trials or case reports of metformin or any of the other reviewed pharmacotherapies in patients with MSUD.\n\nLiterature search for evidence supporting the use of growth hormone in children with MSUD revealed a single case report from 1968 which described MSUD metabolic crisis and states “The use of human growth hormone at such times has been considered. A fall in plasma amino acid levels has been observed following its administration but its value in clinical use is not yet established” [4]. More recently a physician William Nyhan published an article online for MSUD Family Support Group on the treatment of the acute crisis in MSUD. He described the use of insulin and glucose to promote anabolism and reverse catabolic states. He adds “More recently we have been using human growth hormone, a very powerful anabolic agent in this situation. At first, we only turned to growth hormone when amino acids plus insulin had not turned things around. More recently I have employed growth hormone earlier and have not needed to use insulin” [10].\n\nLiterature review of growth hormone in the treatment of other inherited disorders of metabolism revealed a few limited case series. D. Marsden et al. studied five patients with organic acidemias, two of which demonstrated decreased growth hormone secretion to stimulation challenge and reported increased protein tolerance of 20–60% with growth hormone treatment [5]. M. Al-Owain et al. report improved linear growth but no change in serum methylmalonic acid concentrations in two children with methylmalonic acidemia found to have growth hormone secretory deficiency [6]. C—H Kao et al. reports the use of growth hormone in four neonates with methylmalonic acidemia and observed weight gain and distinct improvement in skin erosions with indeterminant effect on serum propionyl carnitine levels [7]. H. Niinikoski et al. treated four patients with lysinuric protein intolerance with growth hormone for 3–4.5 years and reported improvement in height standard deviation scores and no episodes of hyperammonemias [8].\n\n4 Conclusion\nThis case report demonstrates positive response to the use growth hormone as a pharmacologic rescue in MSUD metabolic crisis refractory to standard therapy. Literature search suggests that more research is needed into protein anabolic pharmacology in inherited metabolic disease and that studies performed in pediatric burn patients may be relevant to this inquiry. Randomized controls trials of protein anabolic pharmacotherapy have been performed in the pediatric burn population as reviewed by Diaz et al. [9]. Promising interventions from these studies could be assessed for application in inherited metabolic disease to reverse catabolic processes and improve nitrogen balance. Although metabolic disease and severe burns are not typically considered together, these apparently disparate catabolic conditions may unlock clinical and biochemical insight to understand their pathophysiology and improve metabolic care for both populations. The use of protein anabolic pharmacotherapy in inherited metabolic disease could reduce the need for dialysis and other invasive interventions in the management of acute metabolic crisis. Thus, protein anabolic pharmacotherapy with acceptable safety profiles and improvement in net protein balance should be considered as candidates for further study as adjuvants to standard of care management in inherited disorders of amino acid metabolism.\n==== Refs\nReferences\n1 Strauss K.A. Carson V.J. Soltys K. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): treatment, biomarkers, and outcomes Mol. Genet. Metab. 129 3 2020 193 206 10.1016/j.ymgme.2020.01.006 31980395 \n2 Frazier D.M. Allgeier C. Homer C. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach Mol. Genet. Metab. 112 3 2014 210 217 10.1016/j.ymgme.2014.05.006 24881969 \n3 Singh R. Rohr F. Nutrition Management Guidelines for MSUD https://southeastgenetics.org/ngp/guidelines.php/105/MSUD 2013 \n4 Hatcher G.W. Maple syrup urine disease J. R. Soc. Med. 61 3 1968 287 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1902282/?page=1 (Accessed June 16, 2020) \n5 Marsden D. Barshop B. Capistranoestrada S. Anabolic effect of human growth hormone: management of inherited disorders of catabolic pathways Biochem. Med. Metabolic Biol. 52 2 1994 145 154 10.1006/bmmb.1994.1047 \n6 Al-Owain M. Freehauf C. Bernstein L. Kappy M. Thomas J. Growth hormone deficiency associated with methylmalonic acidemia J. Pediatr. Endocrinol. Metab. 17 2 2004 239 243 10.1515/jpem.2004.17.2.239 15055362 \n7 Kao C.H. Liu M.Y. Liu T.T. Growth hormone therapy in neonatal patients with methylmalonic acidemia J. Chin. Med. Assoc. 72 9 2009 462 467 10.1016/S1726-4901(09)70408-3 19762313 \n8 Niinikoski H. Lapatto R. Nuutinen M. Tanner L. Simell O. Näntö-Salonen K. Growth hormone therapy is safe and effective in patients with lysinuric protein intolerance JIMD Rep. 1 2011 43 47 10.1007/8904_2011_15 23430827 \n9 Diaz E.C. Herndon D.N. Porter C. Sidossis L.S. Suman O.E. Børsheim E. Effects of pharmacological interventions on muscle protein synthesis and breakdown in recovery from burns Burns. 41 4 2015 649 657 10.1016/j.burns.2014.10.010 25468473 \n10 Nyhan W.L. Treatment of the Acute Crisis in Maple Syrup Urine Disease http://msud-support.org/index.php?view=article&catid=38:volume-21-2&id=265:treatment-of-the-acute-crisis-in-maple-syrup-urine-disease&option=com_content&Itemid=62 July 20, 2009 \n11 Mehta N.M. Skillman H.E. Irving S.Y. Coss-Bu J.A. Vermilyea S. Farrington E.S. McKeever L. Hall A.M. Goday P.S. Braunschweig C. Guidelines for the provision and assessment of nutrition support therapy in the pediatric critically ill patient: society of critical care medicine and American society of parenteral and enteral nutrition JPEN 41 5 2017 707 742 \n12 Corkin M.R. The ASPEN Pediatric Nutrition Support Core Curriculum 2015 \n13 Genotropin® Subcutaneous Injection, Somatropin (rDNA Origin) Subcutaneous Injection 2020 Pharmacia & Upjohn Company New York, NY \n14 Grimberg A. Divall S.A. Polychronakos C. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency Hormone Res. Pediatr. 86 6 2016 361 397 10.1159/000452150 \n15 Gardelis J.G. Hatzis T.D. Stamogiannou L. Dona A.A. Fotinou A.D. Brestas P.S. Constantopoulos A.G. Activity of the growth hormone/insulin-like growth factor-I Axis in critically ill children J. Pediatr. Endocrinol. Metab. 18 4 2005 363 372 10.1515/jpem.2005.18.4.363 15844470 \n16 Bentham J. Rodriguez-Arnao J. Ross R. Acquired growth hormone resistance in patients with hypercatabolism Horm. Res. 40 1–3 1993 87 91 10.1159/000183772 7507879 \n17 Elijah I.E. Branski L.K. Finnerty C.C. Herndon D.N. The GH/IGF-1 system in critical illness Best Pract. Res. Clin. Endocrinol. Metab. 25 5 2011 759 767 10.1016/j.beem.2011.06.002 21925076 \n18 Takala J. Roukomen E. Wesbser N. Nielsen M. Zandstra D. Vundelinkx Hinds C. Increased mortality associated with growth hormone treatment in critically ill adults N. Engl. J. Med. 341 1999 785 792 10.1056/NEJM199909093411102 10477776 \n19 Critical evaluation of the safety of recombinant human growth hormone administration: statement from the growth hormone research society J. Clin. Endocrinol. Metabolism 86 5 2001 1868 1870 10.1210/jcem.86.5.7471 \n20 Sonnet D.S. O’Leary M.N. Gutierrez M.A. Nguyen S.M. Mateen S. Hsu Y. Mitchell K.P. Lopez A.J. Vockley J. Kennedy B.K. Ramanathan A. Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD Sci. Rep. 6 2016 28775 10.1038/srep28775 27373929\n\n",
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"issue": "25()",
"journal": "Molecular genetics and metabolism reports",
"keywords": "Anabolic pharmacology; Branched-chain alpha-ketoacid dehydrogenation deficiency; Growth hormone; Inherited metabolic disease; Maple syrup urine disease; Metabolic crisis",
"medline_ta": "Mol Genet Metab Rep",
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"pubdate": "2020-12",
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"title": "Growth hormone as a rescue treatment in maple syrup urine disease with lessons from pediatric burn literature, case report and brief literature review.",
"title_normalized": "growth hormone as a rescue treatment in maple syrup urine disease with lessons from pediatric burn literature case report and brief literature review"
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"abstract": "BACKGROUND\nThe benefits of adjuvant chemotherapy for elderly patients with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. This study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in patients > 65 years of age after laparoscopic D2 gastrectomy.\n\n\nMETHODS\nThis was a single-center retrospective cohort study of elderly patients (> 65 years) with stage II/III GC who underwent curative laparoscopic D2 gastrectomy with R0 resection between 2004 and 2018. The adjuvant chemotherapy regimens included monotherapy (oral capecitabine) and doublet chemotherapy (oral capecitabine plus intravenous oxaliplatin [XELOX] or intravenous oxaliplatin, leucovorin, and 5-fluorouracil [FOLFOX]). The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The patients were divided as surgery alone and surgery plus adjuvant chemotherapy (chemo group). The overall survival (OS), disease-free survival (DFS), chemotherapy duration, and toxicity were examined.\n\n\nRESULTS\nThere were 270 patients included: 169 and 101 in the surgery and chemo groups, respectively. There were 10 (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1-/3-/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1-/3-/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357-0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322-0.811, P = 0.004) in stage III patients.\n\n\nCONCLUSIONS\nThis study suggested that adjuvant chemotherapy significantly improves OS and DFS compared with surgery alone in elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.",
"affiliations": "Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China. liang.yanrui@qq.com.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.;Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515, China.",
"authors": "Liang|Yanrui|Y|;Zhao|Liying|L|;Chen|Hao|H|;Lin|Tian|T|;Chen|Tao|T|;Zhao|Mingli|M|;Hu|Yanfeng|Y|;Yu|Jiang|J|;Liu|Hao|H|;Li|Guoxin|G|",
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"doi": "10.1186/s12885-021-07919-0",
"fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407 BioMed Central London \n\n7919\n10.1186/s12885-021-07919-0\nResearch Article\nSurvival analysis of elderly patients over 65 years old with stage II/III gastric cancer treated with adjuvant chemotherapy after laparoscopic D2 gastrectomy: a retrospective cohort study\nLiang Yanrui liang.yanrui@qq.com Zhao Liying Chen Hao Lin Tian Chen Tao Zhao Mingli Hu Yanfeng Yu Jiang Liu Hao Li Guoxin grid.416466.7Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510-515 China \n25 2 2021 \n25 2 2021 \n2021 \n21 19612 8 2020 16 2 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe benefits of adjuvant chemotherapy for elderly patients with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. This study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in patients > 65 years of age after laparoscopic D2 gastrectomy.\n\nMethods\nThis was a single-center retrospective cohort study of elderly patients (> 65 years) with stage II/III GC who underwent curative laparoscopic D2 gastrectomy with R0 resection between 2004 and 2018. The adjuvant chemotherapy regimens included monotherapy (oral capecitabine) and doublet chemotherapy (oral capecitabine plus intravenous oxaliplatin [XELOX] or intravenous oxaliplatin, leucovorin, and 5-fluorouracil [FOLFOX]). The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The patients were divided as surgery alone and surgery plus adjuvant chemotherapy (chemo group). The overall survival (OS), disease-free survival (DFS), chemotherapy duration, and toxicity were examined.\n\nResults\nThere were 270 patients included: 169 and 101 in the surgery and chemo groups, respectively. There were 10 (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1−/3−/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1−/3−/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357–0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322–0.811, P = 0.004) in stage III patients.\n\nConclusions\nThis study suggested that adjuvant chemotherapy significantly improves OS and DFS compared with surgery alone in elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12885-021-07919-0.\n\nKeywords\nGastric cancerGastrectomyAdjuvant chemotherapyOverall survivalThe State's Key Project of Research and Development Plan2017YFC0108300Li Guoxin The National Natural Science Foundation of China81672446Li Guoxin The Southern Medical University Clinical Research Start-Up ProjectLC2016ZD003Li Guoxin The Key Clinical Specialty Discipline Construction Program[2012]121Li Guoxin issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nGastric cancer (GC), as the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide, was responsible for over 1,000,000 new cases and an estimated 783,000 deaths in 2018 [1]. The markedly elevated incidence rates of GC in Eastern Asia (China, Japan, and Korea) indicate that GC is a significant public health threat, especially to the elderly, since over 60% of the GC diagnoses and 70% of GC-related mortality occur in elderly patients (aged 65 years or older) [2, 3]. As the population continues to age, the proportion of the population aged 60 years and over will increase from 12.4% in 2010 to 28% in 2040 [4]. Longer life expectancy also results in an increasing number of the elderly (aged 65 years or older) undergoing cancer operation and chemotherapy.\n\nThe survival benefits from gastrectomy plus chemotherapy have been confirmed in patients with advanced GC [5–7]. In the United States of America, chemoradiotherapy after gastrectomy has been confirmed to improve overall survival (OS) by the INT-0116 trial [8], while the progression-free survival (PFS) and OS benefits of perioperative chemotherapy have been shown by the MAGIC and FLOT4 trials [9, 10]. The adjuvant chemotherapy following D2 gastrectomy is a standard treatment for stage II/III GC in East Asia [11–13]. Although prior randomized controlled studies (RCTs) indicated that postoperative adjuvant treatment in patients who underwent D2 gastrectomy could improve the 5-year disease-free survival (DFS) and OS, the subgroup analyses showed that the survival benefits decreased with increasing age. Furthermore, the ACTS-GC study showed no statistically significant effects of postoperative chemotherapy on DFS and OS for patients older than 70 years (DFS: hazard ratios (HR) = 0.779, 95% confidence interval (CI): 0.527–1.151; OS: HR = 0.706, 95% CI: 0.490–1.017) [11]. Similar results for OS were observed in the CLASSIC study for patients older than 65 (HR = 0.70, 95% CI: 0.4–1.12) [12]. These results might be due to the considerably higher incidence of comorbidities, higher risk of complications, and shorter life expectancy of elderly patients [14]. Nevertheless, when considering those conflicting results, whether to give or not adjuvant chemotherapy to elderly patients with GC after D2 gastrectomy remains a dilemma for physicians. Therefore, the International Society of Geriatric Oncology suggested that specific trials for older patients with cancer should be conducted [15].\n\nLaparoscopic gastrectomy has gained popularity worldwide for its safety and effectiveness [16, 17]. The Chinese Laparoscopic Gastrointestinal Surgery (CLASS) group recently reported the primary endpoints of the CLASS-01 trial, which suggested that laparoscopic distal gastrectomy for advanced gastric cancer was non-inferior to open surgery in terms of 3-year DFS and safety, with significant minimally invasive benefits [18, 19]. A previous study by our group indicated the potential benefits of laparoscopic gastrectomy for elderly patients with resectable GC [20]. Ushimaru et al. [21] reported that laparoscopic gastrectomy might improve the OS by reducing mortality from respiratory diseases. Still, the benefit of adjuvant chemotherapy after laparoscopic D2 gastrectomy in elderly patients is unknown.\n\nAs the elderly patients (over 65 years of age) are underrepresented in most RCTs, the present study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy retrospectively in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy, based on a prospectively registered database in China. Those results could help shed some light on this controversy.\n\nMethods\nStudy design and patients\nThis was a retrospective cohort study conducted in the Department of General Surgery of Nanfang Hospital in patients treated between June 2004 and June 2018. This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.\n\nThe inclusion criteria were: 1) over 65 years of age; 2) histologically confirmed stage II or III gastric adenocarcinoma, according to American Joint Committee on Cancer (AJCC, 7th Edition); 3) received curative laparoscopic gastrectomy with D2 nodal dissection at Nanfang Hospital; and 4) at least 15 lymph nodes were available to ensure adequate disease classification. The exclusion criteria were: 1) residual tumors (R1/R2 resections or palliative surgery; 2) death within 1 month after surgery; 3) a previous history of primary or secondary tumor beside the current GC; 4) neoadjuvant chemotherapy or adjuvant radiotherapy; or 5) incomplete medical record .\n\nThe enrolled patients were divided into surgery alone group (surgery group) and the surgery plus adjuvant chemotherapy group (chemo group).\n\nAdjuvant chemotherapy protocols\nThe adjuvant chemotherapy regimens administered during the study period included monotherapy and doublet chemotherapy. The initial dose of each regimen was reduced to 75% of the original value to minimize toxic effects in elderly patients. For monotherapy, the patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months if tolerated. For doublet chemotherapy, the patients received oral capecitabine plus intravenous oxaliplatin (XELOX) or 2-week cycles of intravenous oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX). For the XELOX regimen, patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months if tolerated. The FOLFOX regimen was administered as follows: intravenous (IV) treatment with 63.75 mg/m2 of oxaliplatin, 300 mg/m2 of leucovorin and IV push administration of 300 mg/m2 of fluorouracil on day 1, and 900 mg/m2 of fluorouracil IV by continuous infusion for 24 h on days 1 and 2. This regimen was repeated every 14 days and lasted for 6 months if tolerated. In all regimens, the dose of each drug was reduced to the next lower dose increment in case of grade 4 neutropenia or thrombocytopenia, or grade 3 or above febrile neutropenia.\n\nData collection\nThe data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The database includes patient characteristics (age at diagnosis, sex, etc.), clinical variables (postoperative stay, circulating tumor cells [CTCs] collected at postoperative two weeks, etc.), pathological features (tumor size, histological grade, etc.), chemotherapy (regimen, duration, cycles of chemotherapy, and grade 3 or above toxicity events), and follow-up. All data are routinely updated after each routine follow-up visit, either at the outpatient clinic or by phone. For the present study, the last follow-up data were collected on May 30th, 2018.\n\nOutcomes\nThe observation outcomes of this study were OS and DFS. The OS was calculated from the date of operation to either the date of death or the date of the last follow-up visit. The DFS was calculated from the date of resection to the date of the first recurrence detected, or the last follow-up visit. Recurrence was determined as the appearance of any new lesion either locally, regionally, or distant. All grade 3 or above hematological and non-hematological toxicity events were recorded. Toxicities were graded according to the National Cancer Institute common toxicity criteria version 3.0 [22].\n\nStatistical analysis\nAll statistical analyses were performed using SPSS 24.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Those with a normal distribution were expressed as means ± standard deviations (SD) and were analyzed using Student’s t-test; otherwise, they were presented as medians (ranges) and analyzed using the Mann-Whitney U-test. Categorical variables were reported as numbers with percentages and analyzed using the chi-square test with the Yates correction or Fisher’s exact test, as appropriate. The OS and DFS rates were compared between the surgery and chemo groups using unadjusted Kaplan-Meier curves and the log-rank test. The OS and DFS rates of different clinicopathological characteristics and different chemotherapy regimen were compared. HR and 95% CI were used to estimate the role of each independent predictor of survival. The Cox regression model was used for univariable and multivariable analyses. We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts. Variables with P < 0.1 in the univariable analysis were included in the multivariable analysis. The level of significance was set at a two-tailed P-value of 0.05.\n\nResults\nPatient characteristics\nAt first, 298 patients were eligible, but 28 were excluded because of the presence of residual tumors (R1/R2 resections and palliative surgery), death within 1 month of surgery, primary or secondary tumor history, neoadjuvant chemotherapy, adjuvant radiotherapy, or incomplete medical record. The remaining 270 patients were included in the analysis; 169 and 101 were classified in the surgery and chemo groups, respectively (Fig. 1).\nFig. 1 Patient flowchart\n\n\n\nTable 1 presents the characteristics of the patients. The median age in the surgery and chemo groups was 70 years (69–75 years) and 69 years (66–72 years), respectively (P = 0.001). The male-to-female ratio was 2.1:1 in the surgery group and 3.2:1 in the chemo group (P = 0.152). Most patients in the two groups had an ECOG score and a Charlson comorbidity score of < 1 (ECOG: 88.2 and 89.1%; Charlson score: 94.7 and 96.0%; all P > 0.05). The number of CTCs in the surgery group was 5 (2–16), while 4 (1–7) in the chemo group (P = 0.328). In the surgery group, there were 56 patients with AJCC stage II and 113 with AJCC stage III, while in the chemo group, there were 25 patients with AJCC stage II and 76 with AJCC stage III (P = 0.147). In the chemo group, six patients received monotherapy, and 95 patients received platinum-based doublet chemotherapy therapy; 57 patients received adjuvant chemotherapy for less than 3 months, while 44 patients received 3–6 months of adjuvant chemotherapy. The median follow-up in the surgery and chemo groups was 25 (IQR 13–44) months, and 22 (IQR 11–54.5) months, respectively (P = 0.452).\nTable 1 Baseline information of patients\n\nCharacteristics\tSurgery N = 169\tChemotherapy N = 101\tp\t\nClinical characteristics\t\n Age at diagnosis (years), median (IQR)\t70 (67–75)\t69 (66–72)\t0.001\t\n 65–70, n (%)\t92 (54.4)\t64 (63.4)\t0.152\t\n > 70, n (%)\t77 (45.6)\t40 (39.6)\t\n Time of surgery, n (%)\t\t\t0.684\t\n 2005–2014\t81 (47.9)\t51 (50.5)\t\t\n 2015–2018\t88 (52.1)\t50 (49.5)\t\nSex, n (%)\t\t\t0.152\t\n Male\t115 (68.0)\t77 (76.2)\t\t\n Female\t54 (32.0)\t24 (23.8)\t\n ECOG score\t\t\t0.281\t\n 0\t78 (46.2)\t54 (63.5)\t\n 1\t71 (42.0)\t36 (35.6)\t\n 2\t14 (8.3)\t9 (8.9)\t\n 2+\t6 (3.5)\t2 (2.0)\t\nCharlson score\t\t\t0.711\t\n 0\t128 (75.7)\t74 (73.3)\t\t\n 1\t32 (18.9)\t23 (22.8)\t\n 2\t8 (4.8)\t3 (2.9)\t\n 2+\t1 (0.6)\t1 (1.0)\t\nTumour location\t\t\t0.524\t\n Gastroesophageal junction\t58 (34.3)\t39 (38.6)\t\t\n Antrum\t88 (52.1)\t49 (48.5)\t\n Other\t23 (13.6)\t13 (12.9)\t\n Hospital stays (days), median (IQR)\t11 (8–16)\t10.0 (8–15)\t0.328\t\n CTC (number), median (IQR)\t5 (2–16)\t4 (1–7)\t0.270\t\nPathological characteristics\t\n TMN stage, n (%)\t\t\t0.147\t\n II\t56 (33.1)\t25 (24.8)\t\t\n III\t113 (66.9)\t76 (75.2)\t\nT stage, n (%)\t\t\t0.286\t\n T1–2\t13 (7.7)\t5 (5.0)\t\t\n T3\t35 (20.7)\t18 (17.8)\t\n T4\t121 (71.6)\t78 (77.2)\t\nN stage, n (%)\t\t\t0.285\t\n N0\t45 (26.6)\t17 (16.8)\t\t\n N1\t18 (10.7)\t17 (16.8)\t\n N2\t44 (26.0)\t26 (25.8)\t\n N3\t62 (36.7)\t41 (40.6)\t\n Retrieved lymph nodes (number), median (IQR)\t40 (25–55.5)\t38 (24–54)\t0.516\t\nGrade, n (%)\t\t\t0.051\t\n Well or moderately differentiated\t123 (72.8)\t84 (83.2)\t\t\n Poorly differentiated or undifferentiated\t46 (27.2)\t17 (16.8)\t\n Lymphatic, blood vessel or perineural invasion, n (%)\t100 (59.2)\t62 (61.4)\t0.720\t\n Tumour size (cm), mean ± SD\t4.0 (3.0–5.5)\t4.5 (3.2–6.0)\t0.121\t\n ≤ 5 cm\t104 (61.5)\t51 (50.5)\t0.076\t\n > 5 cm\t65 (38.5)\t50 (49.5)\t\nDrug delivery and toxicities\t\n Adjuvant chemotherapy regimen\t\t\t\t\n Mono chemotherapy\t\t6 (5.9)\t\n Doublet chemotherapy\t\t95 (94.1)\t\nLength of adjuvant chemotherapy\t\n < 3 months\t\t57 (56.4)\t\t\n 3–6 months\t\t44 (43.6)\t\nToxicities (grade 3 or more)\t\n Monotherapy\t\t1 (1.0)\t\t\n Non-hematological adverse events\t\t1 (1.0)\t\t\n Hematological adverse events\t\t0\t\t\n Double therapy\t\t15 (14.9)\t\t\n Non-hematological adverse events\t\t9 (8.9)\t\t\n Hematological adverse events\t\t6 (5.9)\t\t\nIQR interquartile range, ECOG Eastern Cooperative Oncology Group, CTC circulating tumor cells\n\n\n\nFactors associated with OS and DFS in all patients\nThe univariable and multivariable Cox proportional hazards models for all patients are shown in Table 2. In the multivariable analysis, age > 70 years (HR = 1.640, 95% CI: 1.119–2.403, P = 0.011) and stage III GC (HR = 2.738, 95% CI: 1.677–4.471, P < 0.001) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004), surgery performed in 2015–2018 (HR = 0.586, 95% CI: 0.376–0.912, P = 0.018), and stage III GC (HR = 2.345, 95% CI: 1.466–3.751, P < 0.001) were independently associated with DFS. Therefore, stage III GC was independently associated with both OS and DFS.\nTable 2 Association factors of OS and DFS in the total patients\n\n\tOverall survival\tDisease-free survival\t\nUnivariable analysis\tMultivariable analysis\tUnivariable analysis\tMultivariable analysis\t\nFactors\tHR (95% CI)\tp\tHR (95% CI)\tp\tHR (95% CI)\tp\tHR (95% CI)\tp\t\nTreatment\t\n Surgery alone\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t1 (Reference)\t–\t\n Surgery/adjuvant chemotherapy\t0.733 (0.486–1.106)\t0.139\t\t\t0.673 (0.447–1.012)\t0.057\t0.511 (0.322–0.811)\t0.004\t\nAge of diagnosis\t\n 65–70 years\t1 (Reference)\t–\t1 (Reference)\t–\t1 (Reference)\t–\t\t\t\n > 70 years\t1.560 (1.021–2.385)\t0.028\t1.640 (1.119–2.403)\t0.011\t1.422 (0.978–2.067)\t0.065\t\t\t\nTime of surgery\t\n 2004–2014\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t1 (Reference)\t–\t\n 2015–2018\t0.967 (0.632–1.478)\t0.876\t\t\t0.713 (0.475–1.069)\t0.102\t0.586 (0.376–0.912)\t0.018\t\nSex\t\n Male\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n Female\t0.903 (0.589–1.383)\t0.638\t\t\t0.895 (0.588–1.361)\t0.603\t\t\t\nECOG score\t\n 0\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n 1\t1.325 (0.879–1.996)\t0.179\t\t\t1.468 (0.982–2.194)\t0.062\t\t\t\n 2\t1.006 (0.504–2.008)\t0.987\t\t\t1.105 (0.554–2.202)\t0.777\t\t\t\n 2+\t2.016 (0.797–5.100)\t0.139\t\t\t2.017 (0.798–5.097)\t0.138\t\t\t\nCharlson score\t\n 0\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n 1\t1.029 (0.631–1.679)\t0.909\t\t\t1.068 (0.661–1.724)\t0.788\t\t\t\n 2\t0.992 (0.363–2.710)\t0.988\t\t\t1.182 (0.479–2.961)\t0.716\t\t\t\n 2+\t1.135 (0.158–8.174)\t0.900\t\t\t1.368 (0.190–9.852)\t0.756\t\t\t\nTumor location\t\n Gastroesophageal junction\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n Antrum\t1.304 (0.841–2.023)\t0.236\t\t\t1.321 (0.861–2.027)\t0.203\t\t\t\n Other\t1.511 (0.832–2.724)\t0.175\t\t\t1.497 (0.840–2.670)\t0.171\t\t\t\nRetrieved lymph node\t1.002 (0.9931.011)\t0.656\t\t\t0.999 (0.990–1.008)\t0.841\t\t\t\nHospital stays\t1.003 (0.983–1.023)\t0.793\t\t\t1.006 (0.987–1.025)\t0.550\t\t\t\nAJCC stage\t\n II\t1 (Reference)\t–\t1 (Reference)\t–\t1 (Reference)\t–\t1 (Reference)\t–\t\n III\t2.626 (1.610–4.284)\t< 0.001\t2.738 (1.677–4.471)\t< 0.001\t2.345 (1.466–3.751)\t< 0.001\t2.345 (1.466–3.751)\t< 0.001\t\nHistologic Grade\t\n Well or moderately differentiated\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n Poorly differentiated or undifferentiated\t1.293 (0.809–2.068)\t0.283\t\t\t1.247 (0.788–1.975)\t0.346\t\t\t\nLymphatic, blood vessel or perineural invasion\t\n Yes\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n No\t0.857 (0.581–1.7266\t0.439\t\t\t0.740 (0.505–1.083)\t0.121\t\t\t\nTumor size\t\n ≤ 5 cm\t1 (Reference)\t–\t1 (Reference)\t\t1 (Reference)\t–\t\t\t\n > 5 cm\t1.610 (1.099–2.356)\t0.014\t1.356 (0.921–1.996)\t0.123\t1.440 (0.991–2.091)\t0.560\t\t\t\nCTC\t0.937 (0.802–1.096)\t0.416\t\t\t1.007 (0.924–1.088)\t0.866\t\t\t\nHR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee, CTC circulating tumor cells\n\nWe adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts\n\n\n\nOverall survival\nUnadjusted Kaplan-Meier survival curves were constructed for all patients in the two groups. The 1-, 3-, and 5-year OS rates of the surgery group were 72.9, 51.8, and 48.3%, compared with 90.1, 66.4, and 48.6% for the chemo group, respectively (HR = 0.61, 95% CI: 0.42–0.92, P = 0.135) (Fig. 2a). In the stage II cohort, the 1-, 3-, and 5-year OS rates of the surgery group were 96.3, 80.4, and 72.7%, compared with 90.5, 73.8, and 50.9% for the chemo group, respectively (HR = 1.26, 95% CI: 0.483–3.29, P = 0.637) (Fig. 2b). For stage III patients, the 1-, 3-, and 5-year OS rates of the surgery group were 83.7, 40.7, and 28.7%, compared with 89.9, 61.2, and 43.6% for the chemo group, respectively (HR = 0.58, 95% CI: 0.38–0.90, P = 0.016) (Fig. 2c).\nFig. 2 Survival curves for overall survival (OS) and disease-free survival (DFS) in all the patients a, d, stage II patients b, e, and stage III patients c, f\n\n\n\nDisease-free survival\nThe 1-, 3-, and 5-year DFS rates of the surgery group were 72.9, 51.8, and 48.4%, compared with 81.3, 65.1, and 53.6% for the chemo group, respectively (HR = 0.682, 95% CI: 0.463–1.005, P = 0.053) (Fig. 2d). In the stage II cohort, the 1-, 3-, and 5-year DFS rates of the surgery group were 85.3, 78.5, and 74.2%, compared with 91.8, 64.4, and 64.4% for the chemo group, respectively (HR = 1.02, 95% CI: 0.416–2.54, P = 0.950 (Fig. 2e). In stage III patients, the 1-, 3-, and 5-year DFS rates of the surgery group were 66.5, 37.7, and 34.8%, compared with 77.9, 60.0, and 49.0% for the chemo group, respectively (HR = 0.55, 95% CI: 0.36–0.83, P = 0.007) (Fig. 2f). The OS and DFS in the stage III subgroup were significantly different between the surgery and Chemo groups.\n\nSubgroup survival analysis in stage III patients\nThe univariable and multivariable Cox proportional hazards models in stage III patients are shown in Table 3. Surgery plus adjuvant chemotherapy (HR = 0.568, 95% CI: 0.357–0.903, P = 0.017) and age > 70 years (HR = 1.573, 95% CI: 1.029–2.405, P = 0.036) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004) and surgery performed in 2015–2018, HR = 0.586, 95% CI: 0.376–0.912, P = 0.018) were independently associated with DFS.\nTable 3 Association factors of OS and DFS in stage III patients\n\n\tOverall survival\tDisease-free survival\t\nUnivariable analysis\tMultivariable analysis\tUnivariable analysis\tMultivariable analysis\t\nFactors\tHR (95% CI)\tp\tHR (95% CI)\tp\tHR (95% CI)\tp\tHR (95% CI)\tp\t\nTreatment\t\n Surgery alone\t1 (Reference)\t–\t1 (Reference)\t–\t1 (Reference)\t–\t1 (Reference)\t–\t\n Surgery/adjuvant chemotherapy\t0.572 (0.360–0.910)\t0.018\t0.568 (0.357–0.903)\t0.017\t0.542 (0.342–0.859)\t0.009\t0.511 (0.322–0.811)\t0.004\t\nAge of diagnosis\t\n 65–70 years\t1 (Reference)\t–\t1 (Reference)\t–\t1 (Reference)\t–\t\t\t\n > 70 years\t1.560 (1.021–2.385)\t0.040\t1.573 (1.029–2.405)\t0.036\t1.409 (0.926–1.943)\t0.109\t\t\t\nTime of surgery\t\n 2004–2014\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t1 (Reference)\t–\t\n 2015–2018\t0.895 (0.565–1.417)\t0.636\t\t\t0.630 (0.405–0.980)\t0.041\t0.586 (0.376–0.912)\t0.018\t\nSex\t\n Male\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n Female\t0.987 (0.609–1.602)\t0.959\t\t\t0.957 (0.591–1.55)\t0.860\t\t\t\nECOG score\t\n 0\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n 1\t1.345 (0.848–2.132)\t0.207\t–\t–\t1.493 (0.948–2.351)\t0.083\t\t\t\n 2\t1.201 (0.576–2.507)\t0.625\t\t\t1.335 (0.643–2.773)\t0.438\t\t\t\n 2+\t2.810 (1.098–7.188)\t0.031\t\t\t2.715 (1.061–6.950)\t0.037\t\t\t\nCharlson score\t\n 0\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n 1\t1.038 (0.609–1.771)\t0.890\t\t\t1.119 (0.664–1.885)\t0.674\t\t\t\n 2\t1.000 (0.364–2.749)\t0.999\t\t\t1.186 (0.477–2.946)\t0.713\t\t\t\n 2+\t–\t–\t\t\t\t\t\t\t\nTumor location\t\n Gastroesophageal junction\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n Antrum\t1.347 (0.838–2.166)\t0.219\t\t\t1.368 (0.858–2.183)\t0.188\t\t\t\n Other\t1.862 (0.917–3.780)\t0.086\t\t\t1.521 (0.753–3.073)\t0.242\t\t\t\nRetrieved lymph node\t1.001 (0.991–1.010)\t0.853\t\t\t0.999 (0.989–1.009)\t0.782\t\t\t\nHospital stays\t1.001 (0.980–1.023)\t0.905\t\t\t1.005 (0.986–1.025)\t0.600\t\t\t\nT stage\t\n T1–2\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n T3\t0.596 (0.130–2.729)\t0.505\t\t\t0.464 (0.103–2.098)\t0.318\t\t\t\n T4\t0.722 (0.176–2.958)\t0.651\t\t\t0.576 (0.141–2.358)\t0.443\t\t\t\nN stage\t\n N0\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n N1\t0.223 (0.040–1.231)\t0.085\t\t\t0.234 (0.042–1.288)\t0.095\t\t\t\n N2\t0.517 (0.121–2.207)\t0.373\t\t\t0.555 (0.131–2.357)\t0.425\t\t\t\n N3\t1.071 (0.261–4.398)\t0.924\t\t\t1.065 (0.259–4.375)\t0.930\t\t\t\nHistologic Grade\t\n Well or moderately differentiated\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n Poorly differentiated or undifferentiated\t1.035 (0.609–1.759)\t0.899\t\t\t1.043 (0.615–1.769)\t0.877\t\t\t\nLymphatic, blood vessel or perineural invasion\t\n Yes\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n No\t0.899 (0.581–1.389)\t0.631\t\t\t0.741 (0.484–1.134)\t0.167\t\t\t\nTumor size\t\n ≤ 5 cm\t1 (Reference)\t–\t\t\t1 (Reference)\t–\t\t\t\n > 5 cm\t1.209 (0.793–1.843)\t0.377\t\t\t1.147 (0.756–1.738)\t0.519\t\t\t\nHR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee\n\nWe adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, T stage, N stage, histologic grade, lymphatic, blood vessel or perineural invasion, and tumor size\n\n\n\nChemotherapy regimens, duration, and toxicity\n In stage III patients, the platinum-based doublet chemotherapy led to better OS and DFS compared with monotherapy (OS: P = 0.037; DFS: P = 0.013) (Supplementary Fig. S2 A, C), but the differences were not statistically significant in stage II patients (P = 0.473 and P = 0.499) (Supplementary Fig. S1A, C). No significant differences in OS and DFS were observed in relation to chemotherapy duration (all P > 0.05) (Supplementary Fig. S1 B,D; Supplementary Fig. S2 B, D). There were 10 patients with grade 3 or above non-hematological toxicity adverse events, and six with grade 3 hematological toxicity adverse events (neutropenia) (Table 1).\n\nAnalysis in patients with available CTC data\nForty-three patients had a CTC count before surgery, and 40 of them were positive. There were no significant differences in OS and DFS between the surgery and chemo groups among CTC-tested patients (Supplementary Fig. S3 A, C) and CTC-positive patients (all P > 0.05) (Supplementary Fig. S3 B,D).\n\nDiscussion\nThe benefits of adjuvant chemotherapy for elderly patients (age over 65) with GC remain unknown because the elderly patients are underrepresented in most clinical trials [15]. Therefore this study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy. The results strongly suggest that adjuvant chemotherapy improves the OS and DFS of elderly patients with stage III GC operated using D2 laparoscopic gastrectomy compared with surgery alone.\n\nPreviously, there were a few single-center retrospective studies that focused on adjuvant chemotherapy for elderly patients after gastrectomy [23, 24]. Still, those previous studies might not represent the current status of advanced GC treatment since laparoscopic D2 gastrectomy became popular relatively recently [18]. In the present study, only elderly gastric patients who underwent laparoscopic D2 gastrectomy were included. Among them, 41% received adjuvant chemotherapy in the 65–70 age group and only 33% in the > 70 age group. This finding is similar to other cancers [25, 26]. This may be due to two reasons. First, there is no solid evidence to prove the efficacy of adjuvant chemotherapy in elderly patients with GC. Second, with a high comorbidity rate, older patients may prefer not to undergo chemotherapy treatment in their relatively limited lifetime [27].\n\nChemotherapy toxicity is another concern of the elderly who just underwent surgery. In the CLASSIC study, 56% of the patients who received the fluoropyrimidine-platinum chemotherapy regimen experienced grade 3–4 adverse events [12]. In the ACTS-GC study, 22.8% of patients with mono-chemotherapy experienced grade 3–4 adverse events [11]. In the present study, 95 (94.0%) patients in the chemo group received platinum-based doublet chemotherapy, including XELOX and FOLFOX, and 15 (15.6%) patients suffered from grade 3–4 adverse events. In the monotherapy group, one patient suffered from grade 3–4 non-hematological adverse events. The adverse event rate in our cohort is similar to a retrospective study from Korea [24]. Low rates of grade 3–4 adverse events may be due to the low Charlson comorbidity score in the present study since the patients were required to be able to tolerate laparoscopic D2 gastrectomy. The result indicates that adjuvant chemotherapy is tolerable in elderly patients who were suitable for gastrectomy. Still, it is possible that the adverse events were underestimated or not measured strictly in this retrospective study.\n\nIn the present study, adjuvant chemotherapy could significantly improve the OS in stage III elderly patients. Jin et al. [23] revealed an OS benefit (P = 0.003) of adjuvant chemotherapy in elderly patients in a single-center retrospective study. A single-center retrospective study of elderly patients with GC (over 70 years) in Korea reported a DFS benefit (P = 0.03) after adjuvant chemotherapy, but without an OS benefit (P = 0.242, 24]. Nevertheless, by analyzing elderly patients with resected GC in the SEER-Medicare database, Hoffman et al. [28] reported that elderly patients might not gain a survival benefit from adjuvant chemotherapy, but most cases in this database underwent D0 or D1 gastrectomy. Up to now, no standard adjuvant chemotherapy regimens were established for the elderly. Some reports suggest that patients might benefit from adjuvant chemotherapy, no matter which chemotherapy regimen is used [29]. The CLASSIC study indicated that the fluoropyrimidine and oxaliplatin combination reduced both locoregional and distant recurrences, but had a smaller effect on peritoneal recurrences [12]. Kim et al. [30] reported that there were no significant improvements in OS and RFS when using longer treatments of fluoropyrimidine-based adjuvant chemotherapy in patients with stage II or III GC. Similar results were also observed in stage III colon cancer with 3 vs. 6 months of XELOX [31]. On the other hand, Feng et al. [32] reported that additional oral capecitabine for 6 months after eight cycles of XELOX improved the DFS and OS for stage IIIA GC. Still, those previous studies were not focused on elderly patients with GC. Elderly patients may prefer to undergo fewer treatments or treatments with fewer adverse effects in their relatively limited lifetime [27].\n\nThere are several limitations to this study. First, this study was based on retrospective data, with inherent shortcomings. For example, immortal time bias in the adjuvant group could not be completely avoided in a retrospective study. Secondly, it was a single center study, and it is unknown whether the results are valid externally. In addition, this was a strictly selected group of patients, excluding those with previous cancers, R1/2 resections and post-operative death. Consequently, the survival rates in both groups might not reflect real-world data. Finally, differences between the < 65 and ≥ 65 year-old groups were not assessed. Further prospective studies are needed to address those issues.\n\nConclusions\nIn this retrospective, single-institution study, the OS and DFS benefited from adjuvant chemotherapy in elderly patients with stage III GC after D2 laparoscopic gastrectomy. Well-designed prospective studies are needed to confirm these findings. Elderly patients are highly variable in their functional status and comorbidities. Thus, cofactors regarding the functional, social, and mental status should also be considered. Further studies are needed to identify the elderly who can tolerate and benefit from adjuvant chemotherapy.\n\nContribution to the field statement\nThe benefits of adjuvant chemotherapy for elderly patients (age > 65) with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. A total of 270 patients included for analysis. There were ten (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1−/3−/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1−/3−/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357–0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322–0.811, P = 0.004) in stage III patients. CTC > 0 had no significant impact on the benefits of adjuvant chemotherapy on OS and DFS. These findings suggested that adjuvant chemotherapy significantly improves OS and DFS for elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.\n\nSupplementary Information\n\nAdditional file 1: Supplementary Figure S1. Subgroup survival analysis for stage II patients in the chemotherapy group.\n\n Additional file 2; Supplementary Figure S2. Subgroup survival analysis for stage III patients in the chemotherapy group.\n\n Additional file 3: Supplementary Figure S3. Subgroup survival analysis in patients who had been tested for circulating tumor cells (CTCs) (A, C), and for those with positive CTCs (B, D).\n\n \n\nAbbreviations\nGCGastric cancer\n\nOSOverall survival\n\nDFSDisease-free survival\n\nCTCsCirculating tumor cells\n\nPFSProgression-free survival\n\nRCTsRandomized controlled studies\n\nHRHazard ratios\n\nCIConfidence interval\n\nCLASSThe chinese laparoscopic gastrointestinal surgery\n\nAJCCAmerican Joint Committee on Cancer\n\nSDStandard deviations\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nYanrui Liang, Liying Zhao and Hao Chen contributed equally to this work.\n\nThe authors would like to thank all study participants who were enrolled in this study.\n\nAuthors’ contributions\nYR L, LY Z and HC carried out the studies, participated in collecting data, and drafted the manuscript. TL, TC, ML Z, YF H and JY performed the statistical analysis and participated in its design. HL and GX L participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe project was supported by grants from the State’s Key Project of Research and Development Plan (2017YFC0108300), the National Natural Science Foundation of China (81672446), the Southern Medical University Clinical Research Start-Up Project (LC2016ZD003), and the Key Clinical Specialty Discipline Construction Program ([2012]121). The funding bodies had no rule in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nAll authors declare no conflict of interest associated with this manuscript.\n==== Refs\nReferences\n1. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 394 424 10.3322/caac.21492 30207593 \n2. Yancik R Ries LA Cancer in older persons. Magnitude of the problem--how do we apply what we know? Cancer. 1994 74 1995 2003 10.1002/1097-0142(19941001)74:7+<1995::AID-CNCR2820741702>3.0.CO;2-Y \n3. Joharatnam-Hogan N Shiu KK Khan K Challenges in the treatment of gastric cancer in the older patient Cancer Treat Rev 2020 85 101980 10.1016/j.ctrv.2020.101980 32065879 \n4. WHO. China country assessment report on ageing and health. . https://wwww.hoint/ageing/publications/china-country-assessment/en/. 2015.\n5. Hu JK Chen ZX Zhou ZG Zhang B Tian J Chen JP Wang L Wang CH Chen HY Li YP Intravenous chemotherapy for resected gastric cancer: meta-analysis of randomized controlled trials World J Gastroenterol 2002 8 1023 1028 10.3748/wjg.v8.i6.1023 12439918 \n6. Wu DM Wang S Wen X Han XR Wang YJ Shen M Fan SH Zhang ZF Zhuang J Shan Q Survival Benefit of Three Different Therapies in Postoperative Patients With Advanced Gastric Cancer: A Network Meta-Analysis Front Pharmacol 2018 9 929 10.3389/fphar.2018.00929 30210338 \n7. NCCN Clinical Prtactice guidelines in Oncolofy (NCCN guidelines). Gastric Cancer 2020 Fort Washington National Comprehensive Cancer Network \n8. Macdonald JS Smalley SR Benedetti J Hundahl SA Estes NC Stemmermann GN Haller DG Ajani JA Gunderson LL Jessup JM Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction N Engl J Med 2001 345 725 730 10.1056/NEJMoa010187 11547741 \n9. Cunningham D Allum WH Stenning SP Thompson JN Van de Velde CJ Nicolson M Scarffe JH Lofts FJ Falk SJ Iveson TJ Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med 2006 355 11 20 10.1056/NEJMoa055531 16822992 \n10. Al-Batran SE Homann N Pauligk C Goetze TO Meiler J Kasper S Kopp HG Mayer F Haag GM Luley K Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial Lancet (London, England) 2019 393 1948 1957 10.1016/S0140-6736(18)32557-1 \n11. Sasako M Sakuramoto S Katai H Kinoshita T Furukawa H Yamaguchi T Nashimoto A Fujii M Nakajima T Ohashi Y Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer J Clin Oncol 2011 29 4387 4393 10.1200/JCO.2011.36.5908 22010012 \n12. Noh SH Park SR Yang HK Chung HC Chung IJ Kim SW Kim HH Choi JH Kim HK Yu W Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial Lancet Oncol 2014 15 1389 1396 10.1016/S1470-2045(14)70473-5 25439693 \n13. Yoshida K Kodera Y Kochi M Ichikawa W Kakeji Y Sano T Nagao N Takahashi M Takagane A Watanabe T Addition of Docetaxel to Oral Fluoropyrimidine improves efficacy in patients with stage III gastric Cancer: interim analysis of JACCRO GC-07, a randomized controlled trial J Clin Oncol 2019 37 1296 1304 10.1200/JCO.18.01138 30925125 \n14. Saif MW Makrilia N Zalonis A Merikas M Syrigos K Gastric cancer in the elderly: an overview Eur J Surg Oncol 2010 36 709 717 10.1016/j.ejso.2010.05.023 20542657 \n15. Wildiers H Mauer M Pallis A Hurria A Mohile SG Luciani A Curigliano G Extermann M Lichtman SM Ballman K End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer--Alliance for clinical trials in oncology--international society of geriatric oncology position article J Clin Oncol 2013 31 3711 3718 10.1200/JCO.2013.49.6125 24019549 \n16. Wei Y Yu D Li Y Fan C Li G Laparoscopic versus open gastrectomy for advanced gastric cancer: a meta-analysis based on high-quality retrospective studies and clinical randomized trials Clin Res Hepatol Gastroenterol 2018 42 577 590 10.1016/j.clinre.2018.04.005 30146236 \n17. Beyer K Baukloh AK Kamphues C Seeliger H Heidecke CD Kreis ME Patrzyk M Laparoscopic versus open gastrectomy for locally advanced gastric cancer: a systematic review and meta-analysis of randomized controlled studies World J Surg Oncol 2019 17 68 10.1186/s12957-019-1600-1 30987645 \n18. Yu J Huang C Sun Y Su X Cao H Hu J Wang K Suo J Tao K He X Effect of laparoscopic vs open distal Gastrectomy on 3-year disease-free survival in patients with locally advanced gastric Cancer: the CLASS-01 randomized clinical trial JAMA. 2019 321 1983 1992 10.1001/jama.2019.5359 31135850 \n19. Hu Y Huang C Sun Y Su X Cao H Hu J Xue Y Suo J Tao K He X Morbidity and mortality of laparoscopic versus open D2 distal Gastrectomy for advanced gastric Cancer: a randomized controlled trial J Clin Oncol 2016 34 1350 1357 10.1200/JCO.2015.63.7215 26903580 \n20. Yu J Hu J Huang C Ying M Peng X Wei H Jiang Z Du X Liu Z Liu H The impact of age and comorbidity on postoperative complications in patients with advanced gastric cancer after laparoscopic D2 gastrectomy: results from the Chinese laparoscropic gastrointestinal surgery study (CLASS) group Eur J Surg Oncol 2013 39 1144 1149 10.1016/j.ejso.2013.06.021 23850088 \n21. Ushimaru Y Kurokawa Y Takahashi T Saito T Yamashita K Tanaka K Makino T Yamasaki M Nakajima K Mori M Is laparoscopic Gastrectomy more advantageous for elderly patients than for young patients with Resectable advanced gastric Cancer? World J Surg 2020 44 2332 2339 10.1007/s00268-020-05486-2 32236729 \n22. Trotti A Colevas AD Setser A Rusch V Jaques D Budach V Langer C Murphy B Cumberlin R Coleman CN CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Semin Radiat Oncol 2003 13 176 181 10.1016/S1053-4296(03)00031-6 12903007 \n23. Jin Y Qiu MZ Wang DS Zhang DS Ren C Bai L Luo HY Wang ZQ Wang FH Li YH Adjuvant chemotherapy for elderly patients with gastric cancer after D2 gastrectomy PLoS One 2013 8 e53149 10.1371/journal.pone.0053149 23359796 \n24. Jo JC Baek JH Koh SJ Kim H Min YJ Lee BU Kim BG Jeong ID Cho HR Kim GY Adjuvant chemotherapy for elderly patients (aged 70 or older) with gastric cancer after a gastrectomy with D2 dissection: a single center experience in Korea Asia-Pac J Clin Oncol 2015 11 282 287 10.1111/ajco.12349 25856172 \n25. Merchant SJ Nanji S Brennan K Karim S Patel SV Biagi JJ Booth CM Management of stage III colon cancer in the elderly: practice patterns and outcomes in the general population Cancer. 2017 123 2840 2849 10.1002/cncr.30691 28346663 \n26. Samet J Hunt WC Key C Humble CG Goodwin JS Choice of cancer therapy varies with age of patient JAMA. 1986 255 3385 3390 10.1001/jama.1986.03370240055036 3712698 \n27. Dudeja V Habermann EB Zhong W Tuttle TM Vickers SM Jensen EH Al-Refaie WB Guideline recommended gastric cancer care in the elderly: insights into the applicability of cancer trials to real world Ann Surg Oncol 2011 18 26 33 10.1245/s10434-010-1215-9 20645007 \n28. Hoffman KE Neville BA Mamon HJ Kachnic LA Katz MS Earle CC Punglia RS Adjuvant therapy for elderly patients with resected gastric adenocarcinoma: population-based practices and treatment effectiveness Cancer. 2012 118 248 257 10.1002/cncr.26248 21692071 \n29. Liu TS Wang Y Chen SY Sun YH An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer Eur J Surg Oncol 2008 34 1208 1216 10.1016/j.ejso.2008.02.002 18353606 \n30. Kim SG Hwang SH The association between the duration of fluoropyrimidine-based adjuvant chemotherapy and survival in stage II or III gastric cancer World J Surg Oncol 2016 14 102 10.1186/s12957-016-0845-1 27039375 \n31. Grothey A Sobrero AF Shields AF Yoshino T Paul J Taieb J Souglakos J Shi Q Kerr R Labianca R Duration of adjuvant chemotherapy for stage III Colon Cancer N Engl J Med 2018 378 1177 1188 10.1056/NEJMoa1713709 29590544 \n32. Feng WM Tang CW Guo HH Bao Y Fei MY Prolonged adjuvant capecitabine chemotherapy improved survival of stage IIIA gastric cancer after D2 gastrectomy Biomed Pharmacother 2015 72 140 143 10.1016/j.biopha.2015.03.003 26054688\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "21(1)",
"journal": "BMC cancer",
"keywords": "Adjuvant chemotherapy; Gastrectomy; Gastric cancer; Overall survival",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D017024:Chemotherapy, Adjuvant; D005260:Female; D005743:Gastrectomy; D006801:Humans; D010535:Laparoscopy; D008297:Male; D009367:Neoplasm Staging; D012189:Retrospective Studies; D013274:Stomach Neoplasms",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "196",
"pmc": null,
"pmid": "33632161",
"pubdate": "2021-02-25",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Survival analysis of elderly patients over 65 years old with stage II/III gastric cancer treated with adjuvant chemotherapy after laparoscopic D2 gastrectomy: a retrospective cohort study.",
"title_normalized": "survival analysis of elderly patients over 65 years old with stage ii iii gastric cancer treated with adjuvant chemotherapy after laparoscopic d2 gastrectomy a retrospective cohort study"
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"abstract": "BACKGROUND\nThe FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged.\n\n\nMETHODS\nWe describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy.\n\n\nCONCLUSIONS\nWe found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.",
"affiliations": "Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium. Annick.de.weerdt@uza.be.;Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Radiology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Gastroenterology, Heilig Hart Hospital, Lier, Belgium.;Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.",
"authors": "De Weerdt|Annick|A|http://orcid.org/0000-0002-9346-3797;Dendooven|Amélie|A|;Snoeckx|Annemie|A|;Pen|Jan|J|;Lammens|Martin|M|;Jorens|Philippe G|PG|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D009944:Organoplatinum Compounds; D003520:Cyclophosphamide; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-017-3576-y",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 357610.1186/s12885-017-3576-yCase ReportPrognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient http://orcid.org/0000-0002-9346-3797De Weerdt Annick +32 3 821 36 35Annick.de.weerdt@uza.be 1Dendooven Amélie Amelie.Dendooven@uza.be 2Snoeckx Annemie Annemie.Snoeckx@uza.be 3Pen Jan Jan.Pen@hhzhlier.be 4Lammens Martin Martin.Lammens@uza.be 2Jorens Philippe G. Philippe.Jorens@uza.be 11 Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium 2 Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium 3 Department of Radiology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium 4 Department of Gastroenterology, Heilig Hart Hospital, Lier, Belgium 29 8 2017 29 8 2017 2017 17 58614 7 2016 22 8 2017 © The Author(s). 2017\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\nThe FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged.\n\nCase presentation\nWe describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived.\n\nWe performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy.\n\nConclusions\nWe found that for the 45 cases with available data, the median age was 70 years, and the male–female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.\n\nKeywords\nFOLFOXOxaliplatin toxicityChemotherapy lungInterstitial lung diseaseInterstitial pneumoniaDrug induced pulmonary toxicityImmune globulinsCyclophosphamideCase report and reviewissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nSince the middle of the previous century, 5-fluorouracil (5-FU) has been the cornerstone in the treatment of colorectal cancer. The initial addition of folinic acid (leucovorin) and subsequent addition of oxaliplatin (OX) resulted in improved response rates, longer remissions and an increase in patient survival [1, 2]. Subsequently, the combination of folinic acid, 5-fluorouracil and oxaliplatin, i.e., the so-called FOLFOX regimen, became a well-established treatment for colorectal malignancy either as in monotherapy or as an adjuvant to surgery [1]. With the widespread use of this triple chemotherapeutic combination therapy, reports of increased toxicity (e.g., peripheral neuropathy, neutropenia, thrombocytopenia, vomiting) compared with the 5-FU/leucovorin treatment emerged [3]. Additionally, interstitial lung disease has been reported. In the majority of cases, the noxious pulmonary effects occur rather late in the course of therapy [4–9], although there have been exceptions to this rule [10–14]. Although pulmonary toxicity in conjunction with FOLFOX therapy is uncommon (≤ 1.5%) [15], it can be lethal despite the immediate discontinuation of the chemotherapeutic drugs and the initiation of immunotherapy (i.e., corticosteroids). Indirect arguments designating oxaliplatin as the causative pulmonary toxic agent can be found in more than one publication [4, 7, 12, 14, 16–19].\n\nWe describe a patient with profound pulmonary toxicity secondary to FOLFOX who was successfully treated with a combination of acetylcysteine, corticosteroids, immune globulins and cyclophosphamide. Additionally we reviewed all other reports of similar cases.\n\nCase presentation\nA 49-year-old non-smoking female patient, who received a diagnosis of rectosigmoidal carcinoma 4 months prior and was treated with (laparoscopic) rectosigmoidal resection and adjuvant FOLFOX chemotherapy, was admitted to the hospital due to progressive dyspnoea approximately 3 weeks after the sixth chemotherapy session. CT examination of the lungs revealed extensive abnormalities in both lungs with diffuse ground glass abnormalities in both the upper (Fig. 1a) and lower lobes (Fig. 1b) and areas of consolidation at the level of the lower lobes (Fig. 1b). Antibiotics were empirically prescribed (moxifloxacin) from day one. Hypoxic respiratory insufficiency arose and necessitated intubation 1 week after admission. Immediately thereafter, she was referred to our university hospital. On admission to our intensive care unit (ICU), 70% oxygen (PEEP 8 cm H20) was needed to prevent frank hypoxemia. The serum white blood cell count amounted to 19 × 10 9/L (the normal value is up to 10 × 10 9/L). Predominantly, neutrophils (78.8%, 14.97 × 10 9/L) and to a lesser extent lymphocytes (16.3%, 3.10 × 10 9/L), were present. There was no peripheral eosinophilia. The C-reactive protein (CRP) level was low (1.2 mg/dl), and there were no biochemical signs of other organ failure (i.e., serum creatinine 0.55 mg/dl).Fig. 1 axial CT images of the chest in the lung window setting at the levels of the upper lobes (images in a, c and e) and the lower lobes (images in b, d and f). CT examination at the time of diagnosis revealed extensive abnormalities in both lungs with diffuse ground glass abnormalities in both the upper (a) and lower lobes (b). Associated areas of consolidation at the lower lobe level were present. Follow-up images 11 weeks after multimodal therapy for ILD revealed a good resolution of the ground glass abnormalities and consolidation with only minor parenchymal changes in the upper lobes, some small foci of ground glass abnormalities and some parenchymal bands (c). In the lower lobes, the nodular area (d asterisk) was consistent with loculated postoperative fluid due to the open-lung biopsy. The most recent examination more than 4 years after the event (e, f) showed no abnormalities\n\n\n\n\nShortly after admittance to our ICU, a bronchoalveolar lavage (BAL) was performed in the right middle lobe and revealed a white blood cell count of 44/m3 that mostly consisted of neutrophils (90%) in addition to 4% lymphocytes, 6% macrophages and no eosinophils, which suggested infectious lung disease or acute diffuse lung injury [20]. However, no microorganisms (e.g., (myco)bacteria, moulds, fungi, or viruses (entero-, rhino-, parainfluenza, adeno-, herpes simplex, or cytomegalovirus)) were detected. PCR on the BAL fluid for herpes simplex, cytomegalovirus, Epstein-Barr virus, Chlamydia pneumoniae, Mycoplasma pneumoniae and Bordetella pertussis also proved negative. Additional histopathological examination of the lavage liquid did not reveal malignant cells. There was no family history of interstitial lung disease (ILD), and there were no coexisting medical conditions that favoured the development of ILD. Moreover, there had been no occupational exposure to pulmonary toxins and no prior use of potential ILD-causing drugs (e.g., bleomycin, busulphan, gemcitabine, mitomycin, paclitaxel, docetaxel, nitrofurantoin, amiodarone), with the exception of the FOLFOX chemotherapy.\n\nGiven the proof of the absence of pulmonary infection, at 48 h after admission, high-dose corticosteroids (methylprednisolone 4 × 250 mg per day) were administered intravenously (IV) over 5 consecutive days followed by a tapering scheme. This therapy was initiated while considering the possibility of an autoimmune disease or chemotherapy-related pulmonary toxicity [21]. Meanwhile, IV acetylcysteine (1800 mg per day) had been administered from day one in our hospital with the initial intention of preventing contrast-induced nephropathy in this CT-scanned patient.\n\nIn view of the fact that screening for autoimmune and systemic diseases (e.g., anti-nuclear antibodies, anti-neutrophil cytoplasmatic antibodies, complement factors, circulating immune complexes, lupus anticoagulant, immune globulin dosage, retinal fundoscopy) revealed no aberrations, and based on the absence of a favourable respiratory evolution after 14 days of therapy, a surgical (open) lung biopsy (right middle lobe) and a tracheotomy were performed.\n\nAn initial quick examination of the lung biopsy fragments revealed an interstitial pattern of disease with widening of the alveolar septa. While awaiting further microscopic characterization, immune globulins (Sandoglobulin 0.4 g/kg) were administered intravenously during a five-day period in an attempt to reduce the pulmonary inflammation that led to fibrosis [22–24]. Approximately a fortnight later, a single dose of cyclophosphamide (10.5 mg/kg = 1000 mg, Endoxan, Baxter, Braine-l-Alleud Walloon Brabant, Lessines Hainaut, Belgium) was administered due to the persistent need for ventilatory support and the possibility of an unspecified immunological process. The intravenous administration of acetylcysteine was continued. After these therapeutic interventions, the oxygen demand gradually fell. The definite histopathological findings validated the presence of on-going damage of the alveolar epithelium with evolving pulmonary fibrosis. Thickened alveolar septa with lymphocytic inflammatory infiltrate and fibrosis and an exudate in the alveolar lumina lined with reactive cuboid pneumocytes were present. There were no arguments for concomitant vasculitis, infection or malignancy (Fig. 2).Fig. 2 lung tissue (day 14, open-lung biopsy, staining Hematoxylin Eosin) exhibiting a pattern compatible with on-going damage of the alveolar epithelium with evolving pulmonary fibrosis. a magnification 37×: histology (wedge biopsy) revealing lung tissue with a disturbed architecture. The alveolar septa are thickened in a non-specific interstitial pneumonia (NSIP) pattern with lymphocytic inflammatory infiltrate and fibrosis. b magnification 185×: the alveolar lumina exhibit the presence of an exudate. c Magnification 380×: reactive cuboid pneumocytes line the alveolar lumina. This picture is consistent with interstitial pneumonitis\n\n\n\n\nThe interstitial pattern on chest X-ray and follow-up CT gradually dissolved. A follow-up CT-scan 13 weeks after admittance to our ICU revealed a good resolution of the ground glass abnormalities and consolidation with only minor residual parenchymal changes in the upper lobes (Fig. 1c).\n\nThe patient remained dependent upon mechanical ventilation until day 80 due to intercurrent ventilator-associated pulmonary infections that were treated with broad-spectrum antibiotics, acute bilateral pulmonary embolism, critical illness myopathy (secondary to the glucocorticoid treatment) and polyneuropathy (electromyographically confirmed), all of which contributed to the general neuromuscular weakness and failure to wean from mechanical ventilation.\n\nOn day 101, she was referred to the department of respiratory medicine for further care still receiving oral methylprednisolone at a dosage of 20 mg per day and acetylcysteine in a daily dosage of 1200 mg.\n\nShe left the hospital 8 months after admission and resumed work 1 year after discharge. She remained under medical supervision and, in a diagnostic work up for evolving carcinoembryonic antigen, underwent computed tomography of the lungs more than 4 years later. No residual pulmonary abnormalities were found (Fig. 1 e-f).\n\nMethods\nA systematic literature search was performed in PubMed for all publications (case reports and case series) regarding FOLFOX-related pulmonary toxicity with or without pulmonary fibrosis, respiratory insufficiency, intubation and artificial ventilation. To reduce/eliminate the chance of bias, we excluded all reported cases that were not treated solely with FOLFOX (e.g., FOLFOX/bevacizumab) or not solely attributable to FOLFOX. The corresponding authors of the reports that did not mention the ventilation or intubation statuses of their patients were contacted by e-mail or telephone to provide this information because it was our aim to describe and compare treatment strategies in the dramatic cases, i.e., the respiratory insufficient, intubated patients. Forty-five cases were identified [4–19, 25–39]. The data were analyzed using Student’s t-tests. Values of p < 0.05 were considered statistically significant.\n\nResults\nInterstitial lung disease associated with FOLFOX therapy seems to be a global problem. Physicians on nearly every continent (Table 1) have published reports regarding this topic. Including our own, there are currently 45 reports about FOLFOX-related pulmonary toxicity, including 18 from Asia, 16 from Europe, 5 from North America, 3 from South America and 3 from Oceania.Table 1 Overview of all reported cases of FOLFOX therapy related pulmonary toxicity\n\nReference\tPatient gender/age (years)\tOncologic diagnosis\tNumber of FOLFOX cycles\tTotal dose OX (mg/m2)\tPresumed lung disease (Radiology/Laboratory)\tPathology\tILD treatment other than discontinuation of FOLFOX\tArtificial Ventilation\tOutcome\t\n2001 Trisolini Italy\tM/60\tColorectal cancer\t7\t910\tILD\tBAL: DAD cells\nTBB: fibroblastic plugs in alveolar spaces, DAD cells\tCorticosteroids\tNo\tComplete resolution\t\n2002 Gagnadoux France\tF/60\tColorectal cancer\t8\t680\tEP\tTBB: no abnormalities\tNone\tNo\tComplete resolution\t\n2006 Ruiz-Casado Spain\tM/67\tHepatocellular cancer\tNA\t1100\tPF\tNA\tNone\tNo\tImprovement\t\n2005 Hernandez Yagüe Spain\tF/68\tColorectal cancer\t6\t510\tPF\tLB: IP + DAD\tCorticosteroids\tYes\tDeath\t\n2006 Jung Korea\tM/64\tGastric cancer\t2\t200\tPF\tTBB: organizing pneumonia\tCorticosteroids\tNo\tImprovement\t\n2006 Jung Korea\tM/75\tGastric cancer\t1\t100\tILD\tTBB: DAD with hyaline membranes\tCorticosteroids\tNo\tImprovement\t\n2006 Pasetto Italy\tM/74\tColorectal cancer\t6\t510\tARDS\tTBB: no infection\tCorticosteroids\tNA\tDeath\t\n2007 Garrido Chile\tF/30\tColorectal cancer\t6\t510\tILD\tLB: COP\tCorticosteroids\tNo\tComplete resolution\t\n2008 Wilcox USA\tM/71\tColorectal cancer\t6\t600\tILD\tNA\tCorticosteroids\tYes\tDeath\t\n2008 Wilcox USA\tF/77\tColorectal cancer\t12\t1200\tIP\tNA\tNone\tNo\tImprovement\t\n2008 Wilcox USA\tM/69\tColorectal cancer\t6\tNA\tILD\tTBB: COP\tAcetylcysteine Corticosteroids\tNo\tImprovement\t\n2007 Mundt Germany\tM/66\tColorectal cancer\t12\t1020\tInfectious pneumonia\tNecropsy: DAD, PF\tCorticosteroids\tNA\tDeath\t\n2009 Muneoka Japan\tM/82\tColorectal cancer\t10\t850\tIP\tNA\tCorticosteroids\tNo\tComplete resolution\t\n2008 Arevalo Lobera Spain\tF/73\tColorectal cancer\t4\t340\tPF\tNecropsy: DAD\tCorticosteroids\tNo\tDeath\t\n2008 Arevalo Lobera Spain\tM/71\tColorectal cancer\t4\t340\tILD\tNecropsy: interstitial inflammatory infiltrate, PF, bilateral bronchopneumonia\tCorticosteroids Cyclophosphamide Immune globulins\tYes\tDeath\t\n2009 Pena Alvarez Spain\tM/62\tColorectal cancer\t7\t700\tILD\tNA\tCorticosteroids\tNo (family refused ICU admission)\tDeath\t\n2009 Pena Alvarez Spain\tM/77\tColorectal cancer\t7\t700\tILD\tNA\tCorticosteroids\tNo\tSymptomatic resolution\t\n2012 Hannan Australia\tM/74\tColorectal cancer\t6\t600\tILD\tNecropsy: DAD\tCorticosteroids\tNo (patient refused intubation)\tDeath\t\n2010 Han Lim Korea\tM/64\tGastric cancer\t8\t680\tILD/PF\tNA\tCorticosteroids\tYes\tDeath\t\n2013 Shogbon USA\tF/78\tColorectal cancer\t2\t170\tCOP\tNA\tCorticosteroids\tNo\tImprovement\t\n2010 Shimura Japan\tM/56\tColorectal cancer\t6\t510\tILD\tNA\tCorticosteroids\tNA\tImprovement\t\n2010 Shimura Japan\tM/71\tColorectal cancer\t13\t1105\tILD\tNA\tCorticosteroids\tNA\tDeath\t\n2010 Shimura Japan\tM/73\tColorectal cancer\t3\t255\tILD\tNA\tCorticosteroids\tNA\tImprovement\t\n2010 Shimura Japan\tM/76\tColorectal cancer\t5\t425\tILD\tNA\tCorticosteroids\tNA\tImprovement\t\n2010 Shimura Japan\tM/73\tColorectal cancer\t10\t850\tILD\tNA\tCorticosteroids\tNA\tDeath\t\n2011 Joo Lee Korea\tM/57\tColorectal cancer\t8\t680\tILD\tLB: organizing pneumonia\tCorticosteroids\tNo\tImprovement\t\n2009 Ohori Japan\tM/69\tColorectal cancer\t11\t782\tIP\tNA\tCorticosteroids\tYes\tComplete resolution\t\n2009 Ohori Japan\tM/72\tColorectal cancer\t11\t935\tIP\tNA\tCorticosteroids\tNo\tComplete resolution\t\n2012 Prochilo Italy\tM/61\tGastric cancer\t3\t255\tIP\tNA\tCorticosteroids\tNo\tImprovement\t\n2011 Watkins USA\tM/69\tColorectal cancer\t11\t795\tEP\tNecropsy: DAD\tCorticosteroids\tYes\tDeath\t\n2011 Ishizone Japan\tM/74\tColorectal cancer\t22\t1716\tIP\tNA\tCorticosteroids\tYes\tDeath\t\n2014 Cheong Soon UK\tF/54\tColorectal cancer\t12\t1200\tILD\tNA\tCorticosteroids\tNo\tImprovement\t\n2011 Ryu en Jung Korea\tM/55\tColorectal cancer\t13\t1105\tIP\tNA\tCorticosteroids\tYes\tDeath\t\n2011 Ryu Jung Korea\tM/73\tColorectal cancer\t8\t680\tIP\tNA\tCorticosteroids\tYes\tDeath\t\n2011 Homma Japan\tM/79\tColorectal cancer\t12\t1020\tCOP\tNA\tCorticosteroids\tNo\tImprovement\t\n2008 Piccolo Australia\tM/70\tColorectal cancer\t11\t1100\tIP\tNA\tCorticosteroids Cyclophosphamide\tNo\tImprovement\t\n2008 Piccolo Australia\tM/62\tColorectal cancer\t12\t1200\tIP\tNA\tCorticosteroids\tNo\tImprovement\t\n2010 Park Korea\tM/76\tColorectal cancer\t10\t1000\tILD\tNA\tNone\tNo\tStable disease\t\n2014 Basyigit Turkey\tM/60\tColorectal cancer\t6\t510\tIP\tNA\tNone\tNo\tImprovement\t\n2009 Dahlqvist Belgium\tF/74\tColorectal cancer\t12\t1020\tILD\tBAL: alveolitis\nTBB: BOOP\tCorticosteroids\tNo\tImprovement\t\n2014 Hoon Choi Korea\tF/76\tColorectal cancer\t8\t800\tSarcoidosis\tNA\tCorticosteroids\tNo\tImprovement\t\n2012 Pontes Brazil\tM/75\tGastric cancer\t9\t765\tILD\tBAL: no malignant cells\tCorticosteroids\tYes\tDeath\t\n2012 Pontes Brazil\tM/64\tColorectal cancer\t12\t1020\tILD\tLB: DAD, inflammatory infiltrate, diffuse thickening of interalveolar septa\tCorticosteroids\tYes\tDeath\t\n2013 Wildner Germany\tM/62\tColorectal cancer\t1\t85\tInfectious pneumonia\tLB: granulomatous inflammation\tCorticosteroids\tYes\tComplete resolution\t\n2015 De Weerdt Belgium\tF/49\tColorectal cancer\t6\t580\tILD\tLB: IP\tAcetylcysteine Corticosteroids Immune globulins Cyclophosphamide\tYes\tComplete resolution\t\n\nARDS Adult Respiratory Distress Syndrome, BOOP Bronchiolitis Obliterans Organizing Pneumonia, COP Cryptogenic Organizing Pneumonitis, DAD Diffuse Alveolar Damage, EP Eosinophilic Pneumonia, ILD Interstitial Lung Disease, IP Interstitial Pneumonia, LB Lung Biopsy, OX Oxaliplatin, PF Pulmonary Fibrosis, TBB Transbronchial Biopsy, NA Not Available\n\n\n\n\nAn overview of all of the reported FOLFOX-related pulmonary disease cases (Table 1) revealed that there seems to be an overwhelming male preponderance (male (M) 35/45 = 77,8%; female (F) 10/45 = 22,2%). Although the overall incidence of digestive cancer is higher in men [40–42], the incidence of oxaliplatin-related non-pulmonary toxic symptoms (e.g., neurotoxicity) is higher in women [43], which thus leaves the question of a possible increase in male gender-related pulmonary toxicity unresolved.\n\nThe mean age of all patients who developed pulmonary toxicity was 67.6 years (Y), with mean ages of 68.7 Y for the males and 63.9 Y for the women.\n\nOn average, ILD attributable to FOLFOX occurred after a median of 8 cycles of FOLFOX therapy (range 1–22 cycles) and a mean dose of 729.8 mg/m2 OX (range 85–1200 mg/m2, median 700 mg/m2). The men who developed pulmonary toxicity did so after a mean of 8.2 therapy cycles (range 1–22 cycles, median 8 cycles) and a mean OX dose of 738.3 mg/m2 (range 85–1716 mg/m2, median 732.5 mg/m2). The women who developed ILD did so after a mean of 7.6 cycles (range 2–12 cycles, median 7 cycles) and a mean OX dose of 701 mg/m2 (range 170–1200 mg/m2, median 630 mg/m2). These differences in mean age, number of cycles and mean dose were not significant between the men and women (all Ps > 0.5).\n\nFive of the 45 patients (11.1%) with evidence of ILD on imaging studies received no other therapy other than the discontinuation of FOLFOX. These patients only exhibited mild symptoms (Table 2). None of these patients died. The other 40 patients (40/45 = 88.9%) with more marked symptoms were treated with corticosteroids, and 36 (36/40 = 90%) of these patients were treated with corticosteroids as a monotherapy (36/45 = 80% of the total study population). Twenty of the 36 patients treated with corticosteroids as monotherapy (55.6%) exhibited improvement, and 16 (44.4%) of these patients died.Table 2 Clinical characteristics of patients with FOLFOX therapy related pulmonary disease treated with discontinuation of chemotherapy\n\nReference\tPatient Gender/Age\tPreexisting lung disease with the exception of lung metastasis\tSmoking\tSymptomes\t0xygen supplement\tPulmonary function tests\t\nGagnadoux\tF/60\tNone\tNo\tCough, progressive dyspnea on exertion\tNone\tFEV1 1.980 L (90%) TLC 4.207 L (90%)\nDLCO 4.4 ml/mmHg/min (59%)\t\nRuiz Casado\tM/67\tCT: some signs of pulmonary fibrosis in the basal portions\tNA\tNone\tNone\tNA\t\nWilcox\tF/77\tNone\tNo\tDry cough, dyspnea on exertion\tNone\tNormal lung volumes\nDLCO 9.3 ml/mmHg/min (54%)\t\nPark\tM/76\tBronchial asthma\tEx-smoker 40 pack years\tGeneral systemic weakness, loss of appetite\tNone\tFVC 2.26 L (95%)\nFEV 1 1.46 L (92%)\nDLCO 10,8 ml/min/mmHg (109%)\t\nBasyigit\tM/60\tNone\tEx-smoker 14 pack years\tDyspnea on exertion\tNone\tNA\t\n\nFEV1 Forced Expiratory Volume In One Second, FVC Forced Vital Capacity, TLC Total Lung Capacity, DL\nCO Diffusing Capacity of carbon monoxide, NA Not Available\n\n\n\n\nIn the group of patients who exhibited improvement after treatment with corticosteroids as monotherapy, the mean number of FOLFOX therapy cycles was 6.95 (range 1–12 cycles, median 7 cycles). These patients had been treated with a mean OX dose of 630.35 mg/m2 (range 85–1200 mg/m2, median 690 mg/m2). Despite the fact that steroids have a much shorter half life in women than in men [44], five of the 7 female patients (71.4%) who were treated with corticosteroids as monotherapy exhibited improvement as opposed to only 15 of the 29 male patients (51.7%). This difference might be explained by the fact that females exhibit a greater sensitivity to corticosteroids [44].\n\nThe patients who died in this group had received a mean 9.56 cycles of therapy (range 4–22, median 8.5 cycles) and a mean OX dose of 812.25 mg/m2 (median 732.5 mg/m2).\n\nThree of the 4 (75%) patients who were treated with a multimodal therapy regimen exhibited improvement. One patient was treated with a combination of corticosteroids and acetylcysteine, another was treated with a combination of corticosteroids and cyclophosphamide. One patient who was treated with a combination of corticosteroids, cyclophosphamide and immune globulins died. Prior to the FOLFOX treatment, he was diagnosed with Wegener’s disease with lung involvement, which probably contributed to the severity of the progression of ILD and his demise [10]. Our own patient was treated with a combination of corticosteroids, acetylcysteine, immune globulins and cyclophosphamide and exhibited improvement.\n\nInformation regarding intubation or not was available for 38 of the 45 patients (84.4%). Twenty-five of these patients did not receive mechanical ventilation (25/38 = 65.8%): 23 of them did not require it (23/25 = 92%), two of them were not intubated due to patient or family refusal.\n\nThe patients who were intubated had been treated with a mean OX dose of 742.92 mg/m2 (range 85–1716 mg/m2, median 680 mg/m2). The patients who were not intubated had been treated with a mean OX dose of 740.83 mg/m2 (range 100–1200 mg/m2, median 750 mg/m2).\n\nTen of the 13 patients (10/13 = 76.9%) who were intubated died. They had been treated with a mean OX dose of 821.10 mg/m2 (range 340–1716 mg/m2, median 722.5 mg/m2). The intubated patients who survived had received a mean OX dose of 482.33 mg/m2 (range 85–782 mg/m2, median 580 mg/m2).\n\nNine of the 10 intubated patients who died (90%) were treated with corticosteroids as monotherapy. The tenth intubated patient who died was the one with Wegener’s disease.\n\nTwo of the intubated patients who survived (2/3 = 66.67%) were treated with corticosteroids as monotherapy. The third patient who survived was our patient and was treated with acetylcysteine, corticosteroids, immune globulins and cyclophosphamide. All of the patients who had been intubated and survived developed complete resolution of their respiratory symptoms.\n\nSeventeen out of the 45 (37.8%) patients died. The patients who died had been treated (mean of 9.24 episodes) with a mean dose of OX dose of 784. 47 mg/m2 (range 340–1716 mg/m2, median 700 mg/m2). The patients who survived had received a mean OX dose of 695.44 mg/m2 (range 85–1200 mg/m2, median 700 mg/m2) over a mean of 7 therapy cycles. Again, these differences were not significant.\n\nIn summary, we found that the discontinuation of the precipitating drug resulted in a 100% regression of the symptoms in the patients whose respiration was not too strongly affected, and we demonstrated that intubation heralded death in the majority of cases even with corticosteroid treatment.\n\nDiscussion\nInterstitial lung disease has diverse origins (e.g., autoimmune or systemic disease, exposure to drugs or herbs, infection, radiation, inhaled organic and inorganic substances, the late phase of the adult respiratory distress syndrome, cryptogenic) [45, 46] and often leads to death.\n\nThe diagnosis of a drug-induced lung disorder is considered when diagnostic algorithms have excluded all other potential aetiologies and when a distinct temporal association between exposure to the drug(s) and the development of respiratory complaints can be established [47]. In our patient, the respiratory symptoms arose after the 6th chemotherapy session, were rapidly progressive in nature, and were without microbial, autoimmune or environmental explanation. No infectious causes triggering the clinical picture were identified, although the high neutrophil count in the bronchoalveolar lavage fluid was initially strongly suggestive of microbial disease. In retrospect, we found that this finding was also compatible with drug-induced lung disease [20]. In view of the fact that an autoimmune disease could not be diagnosed, the administration of FOLFOX was considered to be the probable and most plausible cause of the biopsy-proven interstitial pneumonitis. Similar histological findings have been reported in three other cases of FOLFOX-related ILD [10, 32, 39].\n\nTo which of the three components of the FOLFOX regimen should the development of ILD be attributed? Thus far, there have been no reports linking folinic acid (leucovorin) in monotherapy to pulmonary toxicity. Five-fluorouracil is a thymidilate synthase inhibitor whose antimetabolite properties are enhanced by folates. It is one of the most frequently used chemotherapeutic agents and is applied in mono- and combined therapy for various solid malignancies of the head, neck, breast, lungs, gastrointestinal tract, prostate and bladder. Known side effects include alopecia, stomatitis, emesis, coronary spasms, hand-foot syndrome, diarrhoea and myelosuppression [48, 49]. There has only been one (Japanese) report of pulmonary toxicity accompanying the administration of 5-FU as monotherapy [50]. Oxaliplatin is a third-generation platinum derivative (diaminocyclohexane, containing platinum) that blocks DNA replication and transcription through the induction of intrastrand or interstrand lesions and DNA protein cross links [51]. Oxaliplatin is active against breast, gastric and colon cancers, renal cell carcinoma, sarcoma and cisplatin-resistant cell lines and tumour models including lung, ovarian, cervix, colon and leukaemia cell lines [51]. Known side effects include alopecia, peripheral sensory neuropathy (limb dysesthesia or paresthesia), haematological abnormalities (anaemia, thrombocytopenia, neutropenia), electrolyte disturbances (hyponatraemia, kalaemia), hepatocellular injury, nausea and vomiting, ototoxicity and laryngeal dysesthesia [6, 52, 53]. An important indirect argument pointing in the direction of oxaliplatin as “the” pulmonary toxicity-inducing culprit lies in the observation that respiratory symptoms present during FOLFOX therapy do not recur after rechallenge with a 5-FU- and leucovorin-containing but oxaliplatin-deprived chemotherapy cocktail [4, 7, 12, 14, 16–19].\n\nWhen ILD is thought to be secondary to a chemical insult, discontinuation of the causative agent should be the first therapeutic intervention. Although sufficient for some, not all patients will experience improvement or full recovery after the cessation of the culprit compound. In our patient, the FOLFOX administration had already been discontinued, and acetylcysteine (supplying glutathione) was administered from day one in our hospital. Given that arguments linking oxaliplatin administration to glutathione depletion exist [30, 32], it seemed logical to continue glutathione supplementation because this molecule plays an important role in protecting the lungs against oxidative damage, which is a possible and probable contributing factor to the emergence of interstitial pneumonitis and subsequent evolution to pulmonary fibrosis.\n\nAccounting for the severity of the illness, corticosteroid therapy, which is a well-established therapy modality, was initiated shortly after disease onset. Because no favourable respiratory evolution over a 14-day steroid course was observed, and no autoimmune disease had been diagnosed in the meantime, intravenous immune globulins (IVIgs) were given in an attempt to reduce the deposition of excessive amounts of extracellular proteins (particularly collagen-I) in the lung and thus prohibit the progression of the lung fibrosis already observed in the patient’s lung biopsy. These IVIgs were administered over a five-day period. The rationale for this treatment was found in experimental data that indicated that IVIgs are capable of preventing and treating bleomycin-induced pulmonary fibrosis in mice through the reduced expression of collagen-I protein in the affected lungs [23, 24]. Postulated mechanisms of this anti-fibrotic action of IVIg include modulation of cytokine production, inhibition of the complement reaction and inhibition of the CD95 receptor (Fas) activity through the presence of anti-Fas antibodies in IVIg [23, 54, 55]. Subsequently, one dose of cyclophosphamide, a nitrogen mustard alkylating and lymphocyte-modulating agent, was administered. This immunosuppressive steroid-sparing agent is used to treat autoimmune inflammatory disorders and associated interstitial lung disease and is frequently added to corticosteroid therapy to enhance the clinical response due to the additional suppression of immunoreactions that cause lung damage [56]. In our patient, an intravenous pulse was administered because at that moment, an unspecified immunological process (possibly with vasculitis) leading to pulmonary fibrosis seemed possible.\n\nIn our analysis of the 45 reported cases of FOLFOX-related pulmonary disease, we found that the administered treatments were variable in terms of the drugs used and highly variable in terms of the durations and dosages of the corticosteroids used. Hence, it was impossible to determine the exact contribution of each individual drug or drug dosage to the recoveries of the patients. Moreover, in some patients, ILD regression was observed without special treatment but “merely” after discontinuation of FOLFOX. The fact that our patient exhibited no improvement after the withdrawal of the causative agent and developed a full clinical and radiographic recovery after the introduction of acetylcysteine, corticosteroids, immune globulins and cyclophosphamide, led us to believe that a causal relationship between this multimodal therapy and respiratory progress exists.\n\nConsidering the frequency with which FOLFOX therapy is used worldwide, the reported incidence of ILD seems extremely low. We wondered why this is. Are not all cases of FOLFOX related pulmonary toxicity reported, or are only a small number of people genetically or otherwise predisposed? Are there age, gender, ethnic or geographical differences in the concentrations of innate NO, glutathione or profibrotic agents (e.g., type 2 CD4-positive lymphocytes, CD40 receptor and ligand interactions, interleukin-4, interleukin-10, interleukin–13, Th3-type cytokine-transforming growth factor beta 1, and platelet-derived growth factor) [22–24] that contribute to the development of pulmonary toxicity? Could there be interindividual differences in oxaliplatin metabolism that lead to toxicity? Indeed, the biotransformation of oxaliplatin leads to the formation of aquated platinum forms in the blood. Three compounds can be found: total platinum, free (ultrafiltrable) platinum, and erythrocyte platinum [57]. Platinum is rapidly cleared from the plasma by renal elimination. However, what if the erythrocyte platinum is not as harmless as generally accepted but rather exhibits toxic effects in isolated cases, and what if the clearance of erythrocyte platinum is delayed in a minority of patients?\n\nConclusions\nFOLFOX therapy related pulmonary toxicity is uncommon but often lethal in respiratory insufficient patients. We urge oncologists and critical care physicians not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroid therapy and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents (e.g., immune globulins and cyclophosphamide) whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside.\n\nAbbreviations\n5 – FU5-fluorouracil\n\nBALBronchoalveolar lavage\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nICUIntensive care unit\n\nILDInterstitial lung disease\n\nIPInterstitial pneumonia\n\nIVIgIntravenous immune globuline\n\nOXOxaliplatin\n\nPCRPolymerase chain reaction\n\nPEEPPositive end expiratory pressure\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article are included within the article.\n\nAuthors’ contributions\nADW: treated the patient, drafted and designed the article, analyzed and interpreted the data. AD: provided the description of the pathology specimens and revised the manuscript critically for important intellectual content. AS: provided and interpreted the CT- images and revised the manuscript critically for important intellectual content. JP: provided data and revised the manuscript critically for important intellectual content. ML: provided the description of the pathology specimens and revised the manuscript critically for important intellectual content. PHJ: helped to draft the manuscript and the statistical analysis, revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication was obtained from the patient described in the case report. A copy of the written consent is available for review by the Editor-in-Chief of the journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Saltz L Systemic therapy for metastatic colorectal cancer Journal of the National Comprehensive Cancer Network : JNCCN 2013 11 649 652 10.6004/jnccn.2013.0193 23704235 \n2. Ocvirk J Advances in the treatment of metastatic colorectal carcinoma Radiol Oncol 2009 43 1 8 10.2478/v10019-009-0004-1 \n3. Chen ML Fang CH Liang LS Dai LH Wang XK A meta-analysis of chemotherapy regimen fluorouracil/leucovorin/oxaliplatin compared with fluorouracil/leucovorin in treating advanced colorectal cancer Surg Oncol 2010 19 38 45 10.1016/j.suronc.2009.02.015 19345093 \n4. 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Molina V Haj-Yahia S Solodeev I Levy Y Blank M Shoenfeld Y Immunomodulation of experimental pulmonary fibrosis by intravenous immunoglobulin (IVIG) Autoimmunity 2006 39 711 717 10.1080/08916930601061272 17178568 \n25. Basyigit I, Onyilmaz TA, Boyaci H, Temiz S, Inan N, Baris SA, et al. Interstitial pneumonitis associated with FOLFOX-6 chemotherapy. Translational Medicine. 2014;4\n26. Choi JH Shin JA Park HK Kim SY Jung H Lee SS Sarcoidosis associated with oxaliplatin-based chemotherapy for colorectal cancer Case reports in oncological medicine 2014 2014 203027 10.1155/2014/203027 24716039 \n27. Ishizone S Koide N Akita N Karasawa F Kobayashi N Koizumi T Fatal interstitial pneumonia associated with oxaliplatin-based therapy in a patient with metastatic rectal cancer Clin J Gastroenterol 2011 4 157 161 10.1007/s12328-011-0217-x 26189347 \n28. Lee EJ Lee SY In KH Kim CH Park S Organizing pneumonia associated with oxaliplatin-combined chemotherapy: a case report Med Princ Pract 2012 21 89 92 10.1159/000331898 22025010 \n29. Mundt P Mochmann HC Ebhardt H Zeitz M Duchmann R Pauschinger M Pulmonary fibrosis after chemotherapy with oxaliplatin and 5-fluorouracil for colorectal cancer Oncology 2007 73 270 272 10.1159/000127425 18424892 \n30. Park S Jung JJ Kim GB Yoon HS Ko SH Ko JE Interstitial lung disease associated with combination chemotherapy of oxaliplatin, 5-fluorouracil, and leucovorin Korean J Gastroenterol 2010 55 340 343 10.4166/kjg.2010.55.5.340 20697195 \n31. Piccolo D Feeney KT Tribe AE Thompson PJ Millward MJ van Hazel GA Oxaliplatin-induced interstitial lung disease Asia-Pacific Journal of Clinical Oncology 2008 4 175 180 10.1111/j.1743-7563.2008.00187.x \n32. Pontes LB Armentano DP Soares A Gansl RC Fatal pneumonitis induced by oxaliplatin: description of three cases Case reports in oncology. 2012 5 104 109 10.1159/000337030 22539922 \n33. Ruiz-Casado A Garcia MD Racionero MA Pulmonary toxicity of 5-fluoracil and oxaliplatin Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2006 8 624 10.1007/s12094-006-0072-2 \n34. Ryu CG Jung EJ Kim G Kim SR Hwang DY Oxaliplatin-induced Pulmonary Fibrosis: Two Case Reports Journal of the Korean Society of Coloproctology 2011 27 266 269 10.3393/jksc.2011.27.5.266 22102978 \n35. Soon WC West K Gibeon D Bowen EF Pulmonary Fibrosis Secondary to FOLFOX Chemotherapy: A Case Report Case reports in oncology 2014 7 662 668 10.1159/000368185 25408660 \n36. Trisolini R Lazzari Agli L Tassinari D Rondelli D Cancellieri A Patelli M Acute lung injury associated with 5-fluorouracil and oxaliplatinum combined chemotherapy Eur Respir J 2001 18 243 245 11510798 \n37. Watkins J Slade JH Phan A Eng C Weissferdt A Overman MJ Fatal diffuse alveolar damage associated with oxaliplatin administration Clin Colorectal Cancer 2011 10 198 202 21855043 \n38. Wilcox BE Ryu JH Kalra S Exacerbation of pre-existing interstitial lung disease after oxaliplatin therapy: a report of three cases Respir Med 2008 102 273 279 10.1016/j.rmed.2007.09.001 17945475 \n39. Yague XH Soy E Merino BQ Puig J Fabregat MB Colomer R Interstitial pneumonitis after oxaliplatin treatment in colorectal cancer Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2005 7 515 517 10.1007/BF02717006 \n40. Abotchie PN Vernon SW Du XL Gender differences in colorectal cancer incidence in the United States, 1975-2006 J Women's Health (Larchmt) 2012 21 393 400 10.1089/jwh.2011.2992 22149014 \n41. Brenner H Rothenbacher D Arndt V Epidemiology of stomach cancer Methods Mol Biol 2009 472 467 477 10.1007/978-1-60327-492-0_23 19107449 \n42. Wu CY Lin JT The changing epidemiology of Asian digestive cancers: From etiologies and incidences to preventive strategies Best Pract Res Clin Gastroenterol 2015 29 843 853 10.1016/j.bpg.2015.09.016 26651247 \n43. Wiela-Hojenska A Kowalska T Filipczyk-Cisarz E Lapinski L Nartowski K Evaluation of the toxicity of anticancer chemotherapy in patients with colon cancer Adv Clin Exp Med 2015 24 103 111 10.17219/acem/38154 25923094 \n44. Schmetzer O, Florcken A. Sex differences in the drug therapy for oncologic diseases. Handb Exp Pharmacol. 2012:411–42.\n45. Ferguson EC Berkowitz EA Lung CT: Part 2, The interstitial pneumonias--clinical, histologic, and CT manifestations AJR Am J Roentgenol 2012 199 W464 W476 10.2214/AJR.10.7309 22997396 \n46. Ryu JH Daniels CE Hartman TE Yi ES Diagnosis of interstitial lung diseases Mayo Clin Proc 2007 82 976 986 10.4065/82.8.976 17673067 \n47. Camus P Fanton A Bonniaud P Camus C Foucher P Interstitial lung disease induced by drugs and radiation Respiration; international review of thoracic diseases 2004 71 301 326 10.1159/000079633 15316202 \n48. Alter P Herzum M Soufi M Schaefer JR Maisch B Cardiotoxicity of 5-fluorouracil Cardiovasc Hematol Agents Med Chem 2006 4 1 5 10.2174/187152506775268785 16529545 \n49. Mosseri M Fingert HJ Varticovski L Chokshi S Isner JM In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle Cancer Res 1993 53 3028 3033 8391384 \n50. Andou H Itoh K Tsuda T A case of fluorouracil-induced pneumonitis Nihon Kyobu Shikkan Gakkai Zasshi 1997 35 1080 1083 9465619 \n51. Raymond E Faivre S Chaney S Woynarowski J Cvitkovic E Cellular and molecular pharmacology of oxaliplatin Mol Cancer Ther 2002 1 227 235 12467217 \n52. Raymond E Chaney SG Taamma A Cvitkovic E Oxaliplatin: a review of preclinical and clinical studies Ann Oncol 1998 9 1053 1071 10.1023/A:1008213732429 9834817 \n53. Vietor NO George BJ Oxaliplatin-induced hepatocellular injury and ototoxicity: a review of the literature and report of unusual side effects of a commonly used chemotherapeutic agent J Oncol Pharm Pract 2012 18 355 359 10.1177/1078155212437901 22333669 \n54. Amemiya K Semino-Mora C Granger RP Dalakas MC Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin Clin Immunol 2000 94 99 104 10.1006/clim.1999.4823 10637094 \n55. Fouque A Debure L Legembre P The CD95/CD95L signaling pathway: a role in carcinogenesis Biochim Biophys Acta 1846 2014 130 141 \n56. Ge Y Peng Q Zhang S Zhou H Lu X Wang G Cyclophosphamide treatment for idiopathic inflammatory myopathies and related interstitial lung disease: a systematic review Clin Rheumatol 2015 34 99 105 10.1007/s10067-014-2803-z 25367345 \n57. Burz C Berindan-Neagoe IB Balacescu O Tanaselia C Ursu M Gog A Clinical and pharmacokinetics study of oxaliplatin in colon cancer patients Journal of gastrointestinal and liver diseases : JGLD 2009 18 39 43 19337632\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "17(1)",
"journal": "BMC cancer",
"keywords": "Case report and review; Chemotherapy lung; Cyclophosphamide; Drug induced pulmonary toxicity; FOLFOX; Immune globulins; Interstitial lung disease; Interstitial pneumonia; Oxaliplatin toxicity",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007167:Immunotherapy; D002955:Leucovorin; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011379:Prognosis; D012121:Respiration, Artificial; D012811:Sigmoid Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "586",
"pmc": null,
"pmid": "28851379",
"pubdate": "2017-08-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10637094;11510798;12151971;12467217;15062597;15316202;15564013;15585934;16373064;16391408;16529545;16952855;17007064;17044215;17178568;17673067;17945475;18079234;18424892;19015075;19107449;19223749;19337632;19345093;19451069;19856057;20146958;20305036;20697195;21358098;21855043;22025010;22102978;22149014;22333669;22539922;22842502;22873503;22997396;23027461;23412544;23467619;23691384;23704235;24716039;24780723;25367345;25408660;25923094;26189347;26651247;8391384;9465619;9834817",
"title": "Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient.",
"title_normalized": "prognosis and treatment of folfox therapy related interstitial pneumonia a plea for multimodal immune modulating therapy in the respiratory insufficient patient"
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"companynumb": "BE-FRESENIUS KABI-FK201708130",
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"abstract": "There is an unmet need for a treatment for psoriasis that results in complete skin clearance with a reliably quick response. Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. We aimed to compare the efficacy and safety of bimekizumab with placebo and ustekinumab in patients with moderate to severe plaque psoriasis over 52 weeks.\n\n\n\nBE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries in Asia, Australia, Europe, and North America. Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator's Global Assessment [IGA] score ≥3 on a five point scale) were included. Randomisation was stratified by geographical region and previous exposure to biologics; patients, investigators, and sponsors were masked to treatment assignment. Patients were randomly assigned (4:2:1) using an interactive response technology to bimekizumab 320 mg every 4 weeks, ustekinumab 45 mg or 90 mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. At week 16, patients receiving placebo switched to bimekizumab 320 mg every 4 weeks. All study treatments were administered as two subcutaneous injections. Coprimary endpoints were the proportion of patients with 90% improvement in the PASI (PASI90) and the proportion of patients with an IGA response of clear or almost clear (score 0 or 1) at week 16 (non-responder imputation). Efficacy analyses included the intention-to-treat population; safety analysis included patients who received at least one dose of study treatment. This trial was registered at ClinicalTrials.gov, NCT03370133 (completed).\n\n\n\nBetween Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were enrolled and randomly assigned (bimekizumab 320 mg every 4 weeks n=321, ustekinumab 45 mg or 90 mg every 12 weeks n=163, placebo n=83). At week 16, 273 (85%) of 321 patients in the bimekizumab group had PASI90 versus 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI 27-43]; p<0·0001) and four (5%) of 83 in the placebo group (risk difference 80 [74-86]; p<0·0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI 22-39]; p<0·0001) and four (5%) in the placebo group (risk difference 79 [73-85]; p<0·0001). Over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group (including those who switched from placebo at week 16) and 13 (8%) of 163 in the ustekinumab group.\n\n\n\nBimekizumab was more efficacious than ustekinumab and placebo in the treatment of moderate to severe plaque psoriasis. The bimekizumab safety profile was consistent with that observed in previous studies.\n\n\n\nUCB Pharma.",
"affiliations": "Center for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: k.reich@uke.de.;Probity Medical Research and K Papp Clinical Research, Waterloo, ON, Canada.;Oregon Medical Research Center, Portland, OR, USA.;Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, NS, Canada.;Keck School of Medicine of USC, Dermatology, Los Angeles, CA, USA.;The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, University of Manchester, Manchester, UK.;Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.;Department of Dermatology, Tokyo Medical University, Tokyo, Japan.;UCB Pharma, Raleigh, NC, USA.;UCB Pharma, Raleigh, NC, USA.;UCB Pharma, Raleigh, NC, USA.;UCB Pharma, Brussels, Belgium.;Icahn School of Medicine, New York, NY, USA.",
"authors": "Reich|Kristian|K|;Papp|Kim A|KA|;Blauvelt|Andrew|A|;Langley|Richard G|RG|;Armstrong|April|A|;Warren|Richard B|RB|;Gordon|Kenneth B|KB|;Merola|Joseph F|JF|;Okubo|Yukari|Y|;Madden|Cynthia|C|;Wang|Maggie|M|;Cioffi|Christopher|C|;Vanvoorden|Veerle|V|;Lebwohl|Mark|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; C000625981:bimekizumab; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(21)00125-2",
"fulltext": null,
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"issn_linking": "0140-6736",
"issue": "397(10273)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D000069549:Ustekinumab",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "487-498",
"pmc": null,
"pmid": "33549193",
"pubdate": "2021-02-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial.",
"title_normalized": "bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis be vivid efficacy and safety from a 52 week multicentre double blind active comparator and placebo controlled phase 3 trial"
} | [
{
"companynumb": "DE-JNJFOC-20210543993",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
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{
"abstract": "Splenic marginal zone lymphoma (SMZL) accounts for only 1-2.7% of all lymphomas. Almost all patients have bone marrow (BM) involvement but only one-third has liver involvement. The higher prevalence of hepatitis C virus (HCV) infection in these patients has led to the hypothesis of viral involvement in lymphomagenesis. In this report, we present a case of a 48-year-old woman, with cured hepatitis C, presenting with fever, weight loss, nausea, abdominal pain, and jaundice. She had leucocytosis with lymphocytosis, a progressively worsening cytocholestasis, and hepatosplenomegaly. Liver biopsy, immunophenotyping, and BM biopsy were performed, resulting in the diagnosis of SMZL. The patient started chemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone) with an initial good response, but later progression to high-grade lymphoma and was recommended to undergo salvage chemotherapy followed by auto-transplant. Despite the unusual liver involvement, we should consider hepatic infiltration by lymphomas, such as SMZL, especially in patients with a history of HCV infection.",
"affiliations": "Internal Medicine, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT.;Hematology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT.;Pathology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT.;Internal Medicine, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT.;Internal Medicine, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT.",
"authors": "Silva|Leonor|L|;Alpoim|Mafalda|M|;Ribeiro|Ana|A|;Caiano Gil|Pedro|P|;Lopes Caçola|Rute|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.18667",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18667\nInternal Medicine\nInfectious Disease\nHematology\nHepatic Infiltration by Splenic Marginal Zone Lymphoma in a Patient With Cured Hepatitis C\nMuacevic Alexander\nAdler John R\nSilva Leonor 1\nAlpoim Mafalda 2\nRibeiro Ana 3\nCaiano Gil Pedro 1\nLopes Caçola Rute 1\n1 Internal Medicine, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT\n2 Hematology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT\n3 Pathology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, PRT\nLeonor Silva leonorpsilva@gmail.com\n11 10 2021\n10 2021\n13 10 e1866711 10 2021\nCopyright © 2021, Silva et al.\n2021\nSilva et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/68206-hepatic-infiltration-by-splenic-marginal-zone-lymphoma-in-a-patient-with-cured-hepatitis-c\nSplenic marginal zone lymphoma (SMZL) accounts for only 1-2.7% of all lymphomas. Almost all patients have bone marrow (BM) involvement but only one-third has liver involvement. The higher prevalence of hepatitis C virus (HCV) infection in these patients has led to the hypothesis of viral involvement in lymphomagenesis.\n\nIn this report, we present a case of a 48-year-old woman, with cured hepatitis C, presenting with fever, weight loss, nausea, abdominal pain, and jaundice. She had leucocytosis with lymphocytosis, a progressively worsening cytocholestasis, and hepatosplenomegaly. Liver biopsy, immunophenotyping, and BM biopsy were performed, resulting in the diagnosis of SMZL. The patient started chemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone) with an initial good response, but later progression to high-grade lymphoma and was recommended to undergo salvage chemotherapy followed by auto-transplant.\n\nDespite the unusual liver involvement, we should consider hepatic infiltration by lymphomas, such as SMZL, especially in patients with a history of HCV infection.\n\nnon-hodgkin lymphoma\nmarginal zone lymphoma\nhepatitis c\nliver disease\ndiffuse large b-cell lymphoma\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nSplenic marginal zone lymphoma (SMZL) is an indolent B-cell neoplasia involving the spleen, bone marrow (BM), and blood [1,2]. It represents 1-2.7% of all lymphomas and 10% of non-Hodgkin's lymphomas (NHL) [2-4]. Most patients are asymptomatic, although splenomegaly (75%), adenomegaly, and BM involvement may be present [4]. SMZL has been associated with hepatitis C virus (HCV) infection, raising the hypothesis of viral involvement in lymphomagenesis [5].\n\nWe discuss a rare case of a 48-year-old woman, with cured hepatitis C, diagnosed with SMZL presenting with uncommon hepatic infiltration initially and later progression to high-grade lymphoma.\n\nCase presentation\n\nA 48-year-old Caucasian woman presented with an eight-month history of anorexia, weight loss (25 Kg), nocturnal hypersudoresis, nausea, and food vomiting, which had exacerbated in the last two months. Three days before admission, she had developed intense abdominal pain on both flanks and afternoon-predominance fever (38.5 ºC); she was admitted to the ER.\n\nHer medical history included untreated chronic hepatitis C (diagnosed 16 years ago) and cholecystectomy. She was medicated with alprazolam 1 mg and diazepam 10 mg once daily. She was a current smoker (4.5 pack-years), former drug addict (intravenous heroin usage between 20-28 years of age), and had discontinued her alcohol abuse (one year ago). She had had contact with a vaccinated cat. She denied any recent travel, transfusions, or risky sexual behavior.\n\nIn the ER, she appeared slightly jaundiced with abdominal pain on palpation of both flanks with spleen’s inferior pole palpable on the left flank and palpable hepatic edge 3 cm from the costal margin. The remainder of the general examination was normal.\n\nOn admission, she had normal haemoglobin (Hb) (12.6 g/dL) and platelet count (156 x 10E3/uL) with leucocytosis (13.9 x 103/uL). Lactate dehydrogenase (LDH) (690 U/L), total bilirubin (TB) (1.72 mg/dL), direct bilirubin (DB) (1.30 mg/dL), glutamic-oxalacetic transaminase (GOT) (196 U/L), glutamic-pyruvic transaminase (GPT) (224 U/L), and C-reactive protein (CRP) (6.80 mg/dL) were elevated. Coagulation study [international normalized ratio (INR): 1.16, activated partial thromboplastin time (aPTT): 31 seconds], ionogram, and renal function were normal.\n\nThe patient was admitted to the Internal Medicine Service for further investigation. During hospitalization, she maintained fever, nausea, vomiting, and abdominal pain, with a progressive exacerbation of cholestasis (maximum TB: 12.7 mg/dL, DB: 12.0 mg/dL, alkaline phosphatase: 826 U/L, and gamma-glutamyl transferase: 157 U/L), although GOT/GPT returned to normal levels. Leukocytosis reached 15.3 x 103/uL with lymphocytosis. CRP increased to a maximum of 25 mg/dL and procalcitonin was 0.78 ng/mL (Table 1). She had hypoalbuminemia.\n\nTable 1 Blood exams including admission and maximum values during inpatient investigation\n\nVariables\tAdmission results\tMaximum values\tNormal values\t\nLeukocytes\t13.9 x 103/uL\t15.3 x 103/uL\t3.6–11 x 103/uL\t\nLymphocytes\t14.7 x 103/uL\t14.9 x 103/uL\t1–4.8 x 103/uL\t\nLactate dehydrogenase (LDH)\t690 U/L\t851 U/L\t135–214 U/L\t\nTotal bilirubin (TB)\t1.72 mg/dL\t12.7 mg/dL\t0.1–1.1 mg/dL\t\nDirect bilirubin (DB)\t1.30 mg/dL\t12 mg/dL\t0.1–0.3 mg/dL\t\nGlutamic-oxalacetic transaminase (GOT)\t196 U/L\t224 U/L\t4–27 U/L\t\nGlutamic-pyruvic transaminase (GPT)\t224 U/L\t285 U/L\t4–34 U/L\t\nAlkaline phosphatase\t469 U/L\t826 U/L\t35–104 U/L\t\nGamma-glutamyl transferase\t162 U/L\t157 U/L\t5–61 U/L\t\nAlbumin\t1.9 g/dL\t2.9 g/dL\t3.4–4.8 g/dL\t\nProcalcitonin\t---\t0.78 ng/mL\t<0.5 ng/mL\t\nC-reactive protein (CRP)\t6.80 mg/dL\t25 mg/dL\t<0.5 mg/dL\t\n\nSerum protein electrophoresis and immunoglobulin assay were normal and there was no complement consumption. Antinuclear antibodies presented a homogeneous pattern (titer: 1/160). Antineutrophil cytoplasmic, anti-hepatic, anti-mitochondrial, anti-double-stranded DNA, and anti-extractable nuclear antigens antibodies were negative.\n\nSerologies showed a positive HCV antibody with undetectable viral load, previous hepatitis A and cytomegalovirus infection, and reactive varicella-zoster IgM antibody (non-reactive IgG antibody). HIV, hepatitis B virus (HBV), Epstein-Barr virus, Treponema pallidum, Leptospira, Borrelia, and mononucleosis serological tests were negative. Blood and urine cultures were also negative.\n\nCervical-thoracic-abdominal-pelvic CT scan (Figure 1) confirmed the pathologic findings in abdominal ultrasound (Figure 2), revealing a ganglion formation (18 x 11 mm) anteriorly to the pericardium, suggestive features of chronic liver disease, splenomegaly (17.5 cm), and signs of portal hypertension, as well as discreetly prominent main bile duct (10 mm) secondary to cholecystectomy and several ganglia in the hepatic hilum (largest: 28 x 17 mm).\n\nFigure 1 Cervical-thoracic-abdominal-pelvic CT scan\n\nA. Suggestive features of chronic liver disease, splenomegaly (17.5 cm), and signs of portal hypertension; discreetly prominent main bile duct (10 mm) secondary to cholecystectomy. B. Ganglion formation (18 x 11 mm) anteriorly to the pericardium. C. Several ganglia in the hepatic hilum (largest: 28 x 17 mm)\n\nCT: computed tomography\n\nFigure 2 Abdominal ultrasound at ER admission\n\nA. Hepatomegaly (22.7 cm). B. Slight prominence of the intrahepatic biliary tract and main biliary ectasia (10 mm) without obstructive cause. C. Globular splenomegaly (18 cm)\n\nER: emergency room\n\nPET scan (Figure 3A) presented intense anomalous 18F-fluorodeoxyglucose (FDG) uptake, with heterogeneous distribution in the spleen [maximum standardized uptake value (SUV): 7.7] and discrete increased uptake in humerus, pelvis, and femur diaphyses. There was no FDG uptake in the liver.\n\nFigure 3 PET scan at diagnosis and revaluation PET scans\n\nA. PET scan at diagnosis. B. Revaluation PET scan after six cycles of R-CHOP. C. PET scan two months after chimeric antigen receptor T-cell therapy showing complete remission\n\nPET: positron emission tomography; R-CHOP: rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone\n\nPeripheral blood (PB) smear (Table 2) showed lymphocytes with cytoplasmic extensions and irregularly nucleated mononuclear cells, chromatin laxa, and rare vacuolization. PB immunophenotyping demonstrated a monoclonal small B-lymphoid population (99%) with SMZL-compatible immunophenotyping.\n\nHepatic biopsy (Table 2; Figures 4, 5) presented a preserved trabecular architecture, slight fibrosis of portal spaces with portal space expansion by atypical lymphoid population, ductulitis lesions, and mild/moderate interface lesions. It also showed a small lymphocyte population with PAX-5 and BCL2 expression and a small plasmacytic population with CD138, MUM-1, and lambda light chain expression restriction. A low proliferation index was observed based on Ki67/MIB-1 immunostain (Figure 5C). The immunophenotyping revealed a monoclonal lymphoid B population with lambda light chain and strong CD11c expression.\n\nBM biopsy (Table 2; Figure 6) showed hypercellularity with atypical nodular small lymphocytes infiltration (60%) expressing CD20 and PAX-5, compatible with infiltration by SMZL.\n\nTable 2 Histological, immunochemistry, and immunophenotyping results of peripheral blood smear and liver, subcutaneous nodule, lymph node, and bone marrow biopsies\n\n \tHistology\tImmunochemistry\tImmunophenotyping\t\nPeripheral blood smear\tLymphocytes with cytoplasmic extensions; irregularly nucleated mononuclear cells with chromatin laxa and rare vacuolization; Gumprecht patches\t \tMonoclonal small B-lymphocytes (99%): immunophenotyping compatible with marginal zone splenic non-Hodgkin's lymphoma B\t\nHepatic biopsy\tSlight fibrosis; portal spaces: 1) expansion by atypical lymphoid population; 2) ductulitis lesions; 3) mild to moderate interface lesions \tAtypical lymphocyte population: PAX-5 and BCL2 expression; no expression of CD10, CD5, BCL6, CD23, or cyclin D1. Small plasmacytic population: CD138 and MUM-1 expression; restriction of lambda light chain expression\tMonoclonal lymphoid population (52%): strong CD11c expression; lambda light chain expression; no expression of CD5 or CD10\t\nBone marrow biopsy\tHypercellularity; atypical nodular lymphoid infiltration; predominance of small lymphocytes\tSmall lymphocytes (60%): CD20 and PAX-5 expression; no expression of CD3, CD5, CD10, BCL6, BCL2, CD23, cyclin D1, or annexin A\t \t\nSubcutaneous nodule biopsy\t \t \tB lymphocytes population (56%): CD19, CD20, CD38, CD81, BCL2, and lambda light chain expression; no expression of CD5 or CD10\t\nLymph node biopsy\tLarge and atypical lymphoid cells tissue infiltration; several areas of necrosis\tLarge, atypical lymphoid population: PAX-5, CD79A, CD38, and MUM-1 expression; CD23 expression does not show dendritic follicular network; no expression of CD20, CD3, BCL2, BCL6, CD10, c-MYC, CD5, CD3, or cyclin D1\t \t\n\nFigure 4 Hepatic biopsy - hematoxylin and eosin (H&E)\n\nA. Hepatic parenchyma with nodular lymphoplasmacytic infiltrate centered in the portal spaces ('hepatitis-like' and extension to the adjacent parenchyma) (10x). B. The lymphoplasmacytic population has predominantly small cells (40x)\n\nFigure 5 Liver biopsy (immunochemistry)\n\nA. Left (4x): PAX-5; right (4x): CD3; there is a predominance of B lymphocytes. B. Left (10x): light chain lambda; right (10x): light chain kappa; the lambda predominance is striking. C. Ki67/MIB-1 immunostain (left 2x, right 20x); the proliferation index is low. D. Aberrant CD138 expression in epithelium evidences a ‘hepatitis-like’ pattern of the infiltrate (4x)\n\nFigure 6 Bone marrow trephine biopsy\n\nA. (H&E) on the left side (2x), there is hypercellular medullary space. On the right side (20x), hematopoietic tissue is present with architectural disarray. B. (immunohistochemistry, 20x) CD20 (left) and CD3 (right); it is evident that a dense lymphoid infiltrate, predominantly B-cell, with nodular and paratrabecular distribution is present\n\nH&E: hematoxylin and eosin\n\nB symptoms and splenomegaly favored lymphoma diagnosis. Jaundice and cytocholestasis are uncommon; however, portal space expansion conditioning ductilitis and interface lesions may justify these findings. Hepatic, BM, and PB immunophenotyping demonstrated the presence of monoclonal B-lymphoid population expressing CD20, PAX-5, BCL2, and CD11c, all frequent in SMZL and lymphoplasmacytic lymphoma. CD138/MUM-1 small plasmacytic population with lambda light chain expression restriction may be present in both lymphomas. The absence of CD10 and BCL6 excluded follicular lymphoma and the absence of CD5 and cyclin D1 excluded mantle cell lymphoma [1,6]. Hairy cell leukemia was ruled out as CD103 and CD25 were negative [7]. Since serum protein electrophoresis and immunoglobulin were normal, associated with small lymphocytes with cytoplasmic extensions and atypical nodular lymphoid infiltration in BM, SMZL seemed the most likely diagnosis.\n\nIn the presence of a rapid clinical and analytical deterioration, the patient was started on prednisolone (60 mg/day for eight days) resulting in nausea and abdominal pain resolution with a slight improvement in cytocholestasis, despite maintaining fever. Due to the suspicion of transformation to diffuse large B-cell lymphoma (rapid clinical progression and high LDH and SUV), combined with splenic biopsy risks, she was also started on R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone). After the first cycle, she developed anaemia (Hb: 6.3 g/dL), leukopenia (2.21 x 103/uL), and thrombocytopenia (12 x 103/uL). She was discharged from inpatient service, continuing treatment in a day hospital unit. Twenty-one days after R-CVP initiation, the patient underwent the first cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone) with a 50% reduction in doxorubicin and vincristine. The second cycle of R-CHOP had 100% of the doxorubicin dose and 50% of the vincristine dose, while the third and fourth cycles were full doses. The fifth and sixth cycle, due to neuropathy, was performed with vincristine 1 g. The patient initially had a good response, being asymptomatic, without fever or pancytopenia with improved cytocholestasis [normal GOT, GPT, and bilirubin; high AP (117-173 U/L)] and normalization of inflammatory markers six months after discharge. HCV viral load remained negative three months after discharge.\n\nDespite the initial good response, the disease progressed to high-grade lymphoma. Revaluation PET (Figure 3B) showed a reduction of the affected areas but intensely avid FDG foci in the spleen (qSUVmax=12.2) and lateroaortic adenopathies, reflecting refractory disease.\n\nThree months after the sixth R-CHOP cycle, the patient presented with stiff and painful subcutaneous nodules at occipital, abdominal, and infra-mammary regions. Subcutaneous nodule biopsy immunophenotyping (Table 2) and cervical lymph node biopsy were performed, revealing a diffuse large B-cell lymphoma (Figure 7).\n\nFigure 7 Cervical lymph node biopsy\n\nA. Lymph node completely replaced by atypical lymphoid infiltration (H&E, 4x); no normal lymph node is observed. B. Atypical cells are medium to large with abundant images of apoptosis (H&E, 10x). C. Atypical cells are medium to large with centroblastic morphology (H&E, 20x). D. Expression of PAX-5 is noticed in most cells (immunohistochemistry, 4x). No expression of CD20 is observed (secondary to administration of rituximab?). E. Cells presents an expression of MUM-1 in the absence of CD10 and BCL6 expression (non-GCB immunophenotype – Hans algorithm) (immunohistochemistry, 4x)\n\nH&E: hematoxylin and eosin\n\nIn the presence of a high-grade lymphoma under first-line treatment, the patient accomplished two cycles with ifosfamide, etoposide, and carboplatin with persistent disease, and then underwent rituximab, dexamethasone, cytarabine, and cisplatin followed by chimeric antigen receptor T-cell therapy. Two months later, the PET showed complete remission (Figure 4C).\n\nDiscussion\n\nSMZL is a rare B-cell neoplasia with a female predominance, and the average age at diagnosis is between 65-69 years [2-4,6]. The median overall survival is 10-11 years [4]. BM involvement is common at diagnosis but only one-third has liver involvement [3]. Hepatomegaly is less common and lymphadenopathy is rare (abdominal: 25%) [3,7]. Anaemia, thrombocytopenia, and leucocytosis occur in 25% of patients [3].\n\nThe prevalence of HCV in patients with SMZL is higher than that in the general population, and patients with HCV presented with SMZL in 4.2% of cases [4,8]. Although the mechanism is not completely understood, lymphoma development may be related to HCV chronic antigenic stimulation [9]. The causal role of HCV in lymphomagenesis is supported by the phenomenon of lymphoma regression after HCV eradication [2].\n\nOur patient, at diagnosis, had spontaneously cured hepatitis C. Although the exact date of cure is unknown, we speculate whether the risk of developing SMZL in such patients is similar to the general population or higher due to previous HCV infection. On the other hand, given that the disease is cured in some cases after hepatitis C treatment, we also wonder whether the mechanism behind the cure may be related to the pharmacological mechanisms as well as HCV eradication.\n\nDifferential diagnosis with respect to lymphoplasmacytic lymphoma is difficult as SMZL may present with plasmacytic differentiation and serum monoclonal paraproteinemia (28%) [1,3]. If lymphocytes are organized in marginal zone pattern or intrasinusoidal involvement, as observed in our patient's BM biopsy, SMZL should be suspected [3].\n\nSMZL does not have a specific immunophenotyping (usually positive for CD20, CD79a, PAX-5/BSAP, IGM, and BCL2 surface immunoglobulins and negative for CD5, CD10, BCL6, cyclin D1/BCL1, CD43, annexin A1, LEF1, CD103, and CD123); therefore, it is often a diagnosis of exclusion [1,2].\n\nThere is no consensus on the treatment of this condition: splenectomy, chemotherapy, rituximab, or antiretroviral treatment may be employed in HCV patients [2]. Due to the significant morbidity associated, risk of infection, and no impact on BM disease, splenectomy may be an unreasonable option [10-13]. Rituximab monotherapy has been associated with high response rates, higher five-year progression-free survival rates, and a favorable safety profile [10-15].\n\nConclusions\n\nAlthough liver involvement in SMZL is uncommon, this diagnosis should be considered in patients with hepatic abnormalities, especially if associated with HCV infection. SMZL is usually indolent; however, sometimes, there is transformation into high-grade lymphomas, which are more aggressive and associated with shorter survival periods.\n\nWe would like to thank Dr. Gonçalo Ferreira for kindly providing us with the PET scan images.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Coexistence of splenic marginal zone lymphoma with hepatocellular carcinoma: a case report Diagn Pathol Zhang SH Xu AM Zheng JM He MX 1 7 2 2007 17212821\n2 Splenic marginal zone lymphoma: from genetics to management Blood Arcaini L Rossi D Paulli M 2072 2081 127 2016 26989207\n3 Splenic marginal zone lymphoma Best Pract Res Clin Haematol Piris MA Onaindía A Mollejo M 56 64 30 2017 https://doi.org/10.1016/j.beha.2016.09.005 28288718\n4 Marginal zone lymphoma: clinicopathologic variations and approaches to therapy Curr Oncol Rep Ayyappan S William BM 33 20 2018 29572581\n5 Hepatitis C virus - associated B cell non-Hodgkin's lymphoma World J Gastroenterol Mihăilă RG 6214 6223 22 2016 27468211\n6 A peculiar case of splenic marginal zone lymphoma and review of literature Iran J Immunol Mishra MN Pandey R Dinda A Nityanand S 186 189 10 2013 https://iji.sums.ac.ir/article_16835_bcbad4de6f7ba4caa1a0e36e9c9ce656.pdf 24076596\n7 Effective management strategies for patients with marginal zone lymphoma Future Oncol Rosand CB Valla K Flowers CR Koff JL 1213 1222 14 2018 29260925\n8 Important diagnostic clues for diagnosing splenic marginal zone lymphoma in absence of splenic histology J Clin Diagn Res Mohanpuria A Kumar V Suteri P Marwah S Nigam AS 0 7 11 2017\n9 Prevalence of hepatitis B and hepatitis C viral infections in various subtypes of B-cell non-Hodgkin lymphoma: confirmation of the association with splenic marginal zone lymphoma Blood Cancer J Xiong W Lv R Li H 0 7 2017\n10 Lymphoma remission by interferon-free HCV eradication without chemotherapy ACG Case Rep J Lim LY La D Cserti-Gazdewich CM Shah H 69 70 3 2015 26504885\n11 Diagnosis of splenic B-cell lymphomas in the bone marrow: a review of histopathologic, immunophenotypic, and genetic findings Arch Pathol Lab Med Behdad A Bailey NG 1295 1301 138 2014 25268192\n12 Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma Br J Haematol Else M Marín-Niebla A de la Cruz F 322 328 159 2012 23016878\n13 Outcomes in splenic marginal zone lymphoma: analysis of 107 patients treated in British Columbia Br J Haematol Xing KH Kahlon A Skinnider BF 520 527 169 2015 25854936\n14 Unusual course of splenic marginal zone lymphoma World J Oncol Tun NT Mi K Smith J 205 209 4 2013 29147357\n15 Immunophenotypic profile and role of adhesion molecules in splenic marginal zone lymphoma with bone marrow involvement Leuk Lymphoma Florena AM Tripodo C Porcasi R 49 57 47 2006 16321827\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": "diffuse large b-cell lymphoma; hepatitis c; liver disease; marginal zone lymphoma; non-hodgkin lymphoma",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e18667",
"pmc": null,
"pmid": "34786250",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "29572581;27468211;28362442;23016878;28288718;16321827;28892912;25268192;29260925;29147357;26504885;24076596;17284308;25854936;26989207",
"title": "Hepatic Infiltration by Splenic Marginal Zone Lymphoma in a Patient With Cured Hepatitis C.",
"title_normalized": "hepatic infiltration by splenic marginal zone lymphoma in a patient with cured hepatitis c"
} | [
{
"companynumb": "PT-CELLTRION HEALTHCARE HUNGARY KFT-2021PT015921",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"druga... |
{
"abstract": "Extracorporeal membrane oxygenation is considered a relative contraindication for patients with severe neurological injury manifested by fixed and dilated pupils. The inability to provide adequate cardiopulmonary support while attempting to treat the underlying neurologic disease results in a fatal outcome. The impairment of cerebral perfusion, compounded by the underlying neurologic condition, results in signs of brainstem dysfunction often equated with a fatal prognosis. As a result, these patients are not considered to be candidates for initiation of extracorporeal membrane oxygenation. We present a case series of three patients with complex neurologic conditions with fixed and dilated pupils, who received extracorporeal membrane oxygenation. All three patients achieved a significant neurologic recovery. Two survived with a cerebral performance category scale of 1, and the third succumbed to multi-organ failure after achieving a Glasgow Coma Scale of 11T. The decision to initiate extracorporeal membrane oxygenation should be based upon the pathophysiology of the underlying neurologic condition and not solely upon isolated clinical findings. Extracorporeal membrane oxygenation use is normally reserved for patients with reversible underlying processes, and a neurologic exam with fixed and dilated pupils is often interpreted as an irreversible neurologic injury. The implementation and success of extracorporeal membrane oxygenation in this patient population require understanding of complex neurologic diseases, rapid recognition of neurocardiogenic shock, and expeditious initiation of cardiopulmonary support in carefully selected patients. The patients described demonstrate that fixed and dilated pupils are not a contraindication for extracorporeal support in select patients.",
"affiliations": "Medical Critical Care Service, Department of Medicine, INOVA Fairfax Hospital, Falls Church, VA, USA.;Medical Critical Care Service, Department of Medicine, INOVA Fairfax Hospital, Falls Church, VA, USA.;Medical Critical Care Service, Department of Medicine, INOVA Fairfax Hospital, Falls Church, VA, USA.;Medical Critical Care Service, Department of Medicine, INOVA Fairfax Hospital, Falls Church, VA, USA.;INOVA Cardiac and Thoracic Surgery, INOVA Fairfax Hospital, Falls Church, VA, USA.;INOVA Cardiac and Thoracic Surgery, INOVA Fairfax Hospital, Falls Church, VA, USA.;INOVA Heart and Vascular Institute, Falls Church VA, USA.;Medical Critical Care Service, Department of Medicine, INOVA Fairfax Hospital, Falls Church, VA, USA.",
"authors": "Desai|Mehul|M|0000-0002-5036-9477;Wang|Jing|J|0000-0002-3294-3746;Zakaria|Asma|A|;Dinescu|Dan|D|;Bogar|Linda|L|;Singh|Ramesh|R|;Dalton|Heidi|H|;Osborn|Erik|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0267659120915386",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0267-6591",
"issue": "35(8)",
"journal": "Perfusion",
"keywords": "extracorporeal membrane oxygenation; extracorporeal support; fixed and dilated pupils",
"medline_ta": "Perfusion",
"mesh_terms": "D000328:Adult; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D012164:Retinal Diseases",
"nlm_unique_id": "8700166",
"other_id": null,
"pages": "814-818",
"pmc": null,
"pmid": "32404027",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fixed and dilated pupils, not a contraindication for extracorporeal support: a case series.",
"title_normalized": "fixed and dilated pupils not a contraindication for extracorporeal support a case series"
} | [
{
"companynumb": "US-PFIZER INC-2021195114",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Purpose: Defining the risk of neoplasia associated with gender-affirming hormone therapy (GAHT) is a priority for transgender medical research. The purposes of this article are to present a unique case of breast neoplasia in a transgender individual and to review the existing evidence base on GAHT as a potential risk for breast pathology. Methods: We present the case of a 76-year-old transgender patient who developed an estrogen receptor-positive mammary myofibroblastoma (MFB) after 13 months of treatment on feminizing hormones. To our knowledge, this is the first reported case of MFB occurring in a transgender individual. A literature review was conducted to identify all reported cases of breast neoplasia among transgender individuals receiving feminizing GAHT. Information was abstracted from each of the included cases to describe the existing body of literature and to compare published cases to the case reported in this study. Results: We identified a total of 19 malignant and 3 benign cases of breast neoplasia among transgender women. Ours is the first reported case of MFB in a transgender individual receiving feminizing hormones and the first reported case of breast neoplasia associated with GAHT administered via the estradiol patch. Conclusion: This case reinforces the need for additional reporting of breast neoplasia presenting in transgender individuals treated with feminizing hormones. The relationship between estrogen exposure and breast neoplasia in the transgender population remains poorly defined, and additional research is needed to define risks and inform clinical practice.",
"affiliations": "Bassett Healthcare/Research Institute, Cooperstown, New York.;The Gender Wellness Center/Susquehanna Family Practice, AO Fox Hospital/Bassett Healthcare Network, Oneonta, New York.;Department of Hematology/Oncology, AO Fox Hospital/Bassett Healthcare Network, Oneonta, New York.",
"authors": "O'Bryan|Jane|J|;Wolf-Gould|Carolyn|C|;Matsuo|Yoshiro|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/trgh.2017.0026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2380-193X",
"issue": "3(1)",
"journal": "Transgender health",
"keywords": "breast neoplasms; hormones; myofibroblastoma; transgender adult",
"medline_ta": "Transgend Health",
"mesh_terms": null,
"nlm_unique_id": "101691357",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "29344575",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "10632490;3037930;7796003;25428790;11482575;23904280;25264275;20878100;25994431;15200048;22096693;25611459;10460666;28421153;28055103;27000661;22906135;24828032;25415740;26825469;10337665;19898907;25445423;10048088;26790021;23402485;12117397;21364939;9563783;11147176;10849093;12927427;15695086;24010586;25291864;27525142;26674598;2832627;21266549;18976021;16488803;5689553",
"title": "Mammary Myofibroblastoma in a Transgender Patient on Feminizing Hormones: Literature Review and Case Report.",
"title_normalized": "mammary myofibroblastoma in a transgender patient on feminizing hormones literature review and case report"
} | [
{
"companynumb": "US-MYLANLABS-2018M1009863",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TAMSULOSIN"
},
"drugadditional": null,
... |
{
"abstract": "Both developmental and acquired stuttering are related to the function of the basal ganglia-thalamocortical loop, which includes the putamen. Here, we present a case of stuttering- and palilalia-like dysfluencies that manifested as an early symptom of multiple system atrophy-parkinsonian type (MSA-P) and bilateral atrophy of the putamen. The patient was a 72-year-old man with no history of developmental stuttering who presented with a stutter for consultation with our otorhinolaryngology department. The patient was diagnosed with MSA-P based on parkinsonism, autonomic dysfunction, and bilateral putaminal atrophy revealed by T2-weighted magnetic resonance imaging. Treatment with levodopa improved both the motor functional deficits related to MSA-P and stuttering-like dysfluencies while reading; however, the palilalia-like dysfluencies were much less responsive to levodopa therapy. The patient died of aspiration pneumonia two years after his first consultation at our hospital. In conclusion, adult-onset stuttering- and palilalia-like dysfluencies warrant careful examination of the basal ganglia-thalamocortical loop, and especially the putamen, using neuroimaging techniques. Acquired stuttering may be related to deficits in dopaminergic function.",
"affiliations": "Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kikuci@med.kyushu-u.ac.jp.;Voice and Swallowing Center, Fukuoka Sanno Hospital, Fukuoka, Japan; International University of Health and Welfare, Fukuoka, Japan.;Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Voice and Swallowing Center, Fukuoka Sanno Hospital, Fukuoka, Japan.;Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Kikuchi|Yoshikazu|Y|;Umezaki|Toshiro|T|;Uehara|Taira|T|;Yamaguchi|Hiroo|H|;Yamashita|Koji|K|;Hiwatashi|Akio|A|;Sawatsubashi|Motohiro|M|;Adachi|Kazuo|K|;Yamaguchi|Yumi|Y|;Murakami|Daisuke|D|;Kira|Jun-Ichi|JI|;Nakagawa|Takashi|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jfludis.2017.11.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-730X",
"issue": "57()",
"journal": "Journal of fluency disorders",
"keywords": "Basal ganglia; Neurogenic stuttering; Parkinsonism; Putamen; l-Dopa",
"medline_ta": "J Fluency Disord",
"mesh_terms": "D000368:Aged; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D019578:Multiple System Atrophy; D020734:Parkinsonian Disorders; D011699:Putamen; D013342:Stuttering",
"nlm_unique_id": "7601744",
"other_id": null,
"pages": "51-58",
"pmc": null,
"pmid": "29157667",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A case of multiple system atrophy-parkinsonian type with stuttering- and palilalia-like dysfluencies and putaminal atrophy.",
"title_normalized": "a case of multiple system atrophy parkinsonian type with stuttering and palilalia like dysfluencies and putaminal atrophy"
} | [
{
"companynumb": "JP-IMPAX LABORATORIES, INC-2018-IPXL-00149",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"dru... |
{
"abstract": "We retrospectively studied the long-term (2-year) outcome of 50 consecutive patients admitted to our inpatient headache program because of chronic daily headache (CDH) associated with the overuse of analgesics, ergotamine, or both. They had been detoxified, given repetitive intravenous dihydroergotamine (IV DHE) and prophylactic medications as part of the program, and had become headache-free on this regimen. At the time of admission, 37 of the 50 patients had transformed migraine (TM), 12 had new daily persistent headache (NDPH), and 1 had chronic tension-type headache; 29 of the patients with TM, 7 of those with NDPH, and the single patient with chronic tension-type headache had coexistent migraine. Substances abused, alone or in combination, included: caffeine in 39 patients (av. 441 mg/d), acetaminophen in 32 (av. 2187 mg/d), aspirin in 24 (av. 1807 mg/d), ibuprofen in 9 (av. 1156 mg/d), narcotics in 7 (av. 10.1 mg morphine equivalents/d) and ergotamine in 11 (av. 2.3 mg/d). Twenty patients were using preventive medication at the time of admission. Follow-up evaluations were performed at 3, 6, 12, and 24 months after discharge. Forty-three patients were analyzed at 3 months. Of these, 44% had an excellent or good result and 28% a fair result; 3 were overusing analgesics. At 24 months, 39 patients were analyzed: 59% had a good or excellent result and 28% a fair result; 5 were overusing analgesics, 4 of whom were doing poorly.(ABSTRACT TRUNCATED AT 250 WORDS)",
"affiliations": "Temple University School of Medicine, Philadelphia, Pennsylvania.",
"authors": "Silberstein|S D|SD|;Silberstein|J R|JR|",
"chemical_list": "D004087:Dihydroergotamine",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1526-4610.1992.hed3209439.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "32(9)",
"journal": "Headache",
"keywords": null,
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D000368:Aged; D002908:Chronic Disease; D004087:Dihydroergotamine; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006261:Headache; D006760:Hospitalization; D006801:Humans; D007275:Injections, Intravenous; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019966:Substance-Related Disorders; D013997:Time Factors",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "439-45",
"pmc": null,
"pmid": "1446987",
"pubdate": "1992-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE.",
"title_normalized": "chronic daily headache long term prognosis following inpatient treatment with repetitive iv dhe"
} | [
{
"companynumb": "US-PFIZER INC-2015436478",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAFFEINE"
},
"drugadditional": null,
... |
{
"abstract": "Solid organ transplant recipients have an increased incidence of skin infections resulting from immunosuppression. Common pathogens include herpes simplex virus, varicella zoster virus, Gram-positive bacteria and dermatophytes; however, the contribution of multicellular parasitic organisms to dermatologic disease in this population remains less studied. Demodex folliculorum and brevis are commensal mites that reside on human skin. Proliferation of Demodex mites, or demodicosis, is associated with rosacea and rosacea-like disorders, particularly in immunocompromised populations, although their ability to cause disease is still the subject of debate. We present a case series of four renal transplant recipients with the singular chief complaint of acne rosacea who we diagnosed with demodicosis. Although one of the four patients showed complete resolution following initial antiparasitic therapy, the other three required subsequent antibacterial treatment to fully resolve their lesions. We suggest that demodicosis may be more prevalent than once thought in solid organ transplant recipients and showed that Demodex-associated acne rosacea can be effectively treated in this population.",
"affiliations": "Yale Transplant Dermatology Clinic, New Haven, CT.;Yale Transplant Dermatology Clinic, New Haven, CT.",
"authors": "Chovatiya|R J|RJ|;Colegio|O R|OR|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.13462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "16(2)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008924:Mite Infestations; D008925:Mites; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D012393:Rosacea; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "712-6",
"pmc": null,
"pmid": "26431451",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Demodicosis in Renal Transplant Recipients.",
"title_normalized": "demodicosis in renal transplant recipients"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP000065",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "A 47-year-old woman with a large ostium secundum atrial septal defect (ASD) and severe pulmonary artery hypertension underwent device closure of ASD under transesophageal echocardiography guidance. She developed a massive esophageal hematoma which was diagnosed 4 days after the procedure. The use of dual antiplatelets after the device closure further aggravated the hematoma. As the patient remained stable and the site of leak could not be identified by contrast studies, she was managed conservatively with nil per mouth, broad-spectrum antibiotics, and continuous nasogastric aspiration. We were faced with the risk of thromboembolism after stopping antiplatelets versus the risk of increasing peri-esophageal hematoma if they were continued. With careful monitoring for thrombus formation on the device, the antiplatelets were stopped and the hematoma resolved. The hematoma resolved by 10 days, and the antiplatelets were restarted gradually. Iatrogenic esophageal injury is an important cause of esophageal perforation, which is a condition with high mortality and morbidity. Esophageal perforation following device closure of ASD is particularly challenging as the scenario is worsened by the use of antiplatelets and they have to be discontinued with the attendant risk of thromboembolism.",
"affiliations": "Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.;Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.",
"authors": "Sasikumar|Deepa|D|;Mahadevan|Krishnamoorthy K|KK|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/echo.13088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-2822",
"issue": "33(1)",
"journal": "Echocardiography (Mount Kisco, N.Y.)",
"keywords": "atrial septal defect; device closure; esophageal perforation; transesophageal echocardiography",
"medline_ta": "Echocardiography",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017548:Echocardiography, Transesophageal; D004935:Esophageal Diseases; D004947:Esophagus; D005260:Female; D006344:Heart Septal Defects, Atrial; D006406:Hematoma; D006801:Humans; D008875:Middle Aged; D011183:Postoperative Complications; D055989:Septal Occluder Device; D013396:Suction; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "8511187",
"other_id": null,
"pages": "141-4",
"pmc": null,
"pmid": "26494543",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Large Esophageal Hematoma Following Transesophageal Echocardiography-Guided Device Closure of Atrial Septal Defect.",
"title_normalized": "large esophageal hematoma following transesophageal echocardiography guided device closure of atrial septal defect"
} | [
{
"companynumb": "IN-DRREDDYS-USA/IND/16/0068234",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditiona... |
{
"abstract": "PURPOSE We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). PATIENTS AND METHODS Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m(2), thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone-specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). CONCLUSION To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.",
"affiliations": "Cattedra di Ematologia, Via Genova 3, 10126 Torino, Italy. marco.ladetto@unito.it",
"authors": "Ladetto|Marco|M|;Pagliano|Gloria|G|;Ferrero|Simone|S|;Cavallo|Federica|F|;Drandi|Daniela|D|;Santo|Loredana|L|;Crippa|Claudia|C|;De Rosa|Luca|L|;Pregno|Patrizia|P|;Grasso|Mariella|M|;Liberati|Anna Marina|AM|;Caravita|Tommaso|T|;Pisani|Francesco|F|;Guglielmelli|Tommasina|T|;Callea|Vincenzo|V|;Musto|Pellegrino|P|;Cangialosi|Clotilde|C|;Passera|Roberto|R|;Boccadoro|Mario|M|;Palumbo|Antonio|A|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2009.23.7172",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "28(12)",
"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; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D003907:Dexamethasone; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D018365:Neoplasm, Residual; D016133:Polymerase Chain Reaction; D011719:Pyrazines; D033581:Stem Cell Transplantation; D013792:Thalidomide; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2077-84",
"pmc": null,
"pmid": "20308672",
"pubdate": "2010-04-20",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma.",
"title_normalized": "major tumor shrinking and persistent molecular remissions after consolidation with bortezomib thalidomide and dexamethasone in patients with autografted myeloma"
} | [
{
"companynumb": "IT-TAKEDA-2017MPI007091",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "As a result of infection control regulations during the coronavirus disease 2019 (COVID-19) pandemic, anticoagulation clinics have been required to adjust their practices in order to continue providing safe and effective services for their patients. In accordance with a guidance document issued by the Anticoagulation Forum, The Brooklyn Hospital Center (TBHC) anticoagulation clinic in Brooklyn, New York implemented measures including telemedicine follow-ups instead of in-person clinic visits, extending the interval of INR testing, and reviewing eligible candidates for transition from warfarin to direct oral anticoagulants. This study describes the outcomes of one hospital-based clinic location in the 3 months before and after COVID-19 became a significant concern in the New York City area. The primary outcome of time-in-therapeutic range (TTR) for patients receiving warfarin was 60.6 % and 65.8 % in the pre-COVID and post-COVID groups, respectively (p = 0.21). For secondary outcomes, there was no difference in percent of therapeutic INRs (51.5 % pre-COVID v. 44.8 % post-COVID, p = 0.75) or percent of INRs ≥ 4.5 (2.3 % pre-COVID v. 4 % post-COVID, p = 0.27). Based on the data reported in this study, the short-term changes implemented at TBHC's anticoagulation clinic did not appear to cause reductions in safety and efficacy of chronic warfarin therapy management.",
"affiliations": "The Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 1 University Plaza, Brooklyn, NY, 11201, USA. rebecca.cope@liu.edu.;The Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 1 University Plaza, Brooklyn, NY, 11201, USA.;The Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 1 University Plaza, Brooklyn, NY, 11201, USA.;The Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 1 University Plaza, Brooklyn, NY, 11201, USA.;The Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 1 University Plaza, Brooklyn, NY, 11201, USA.",
"authors": "Cope|Rebecca|R|http://orcid.org/0000-0001-9962-0995;Fischetti|Briann|B|;Eladghm|Nourhan|N|;Elaskandrany|Mahy|M|;Karam|Nardine|N|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-021-02410-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "52(3)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Anticoagulation Clinic; COVID-19; Vitamin K Antagonist; Warfarin",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000553:Ambulatory Care; D000925:Anticoagulants; D001777:Blood Coagulation; D000086382:COVID-19; D019033:Delivery of Health Care, Integrated; D016903:Drug Monitoring; D057915:Drug Substitution; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D009518:New York; D010044:Outpatient Clinics, Hospital; D010595:Pharmacists; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D017216:Telemedicine; D014859:Warfarin",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "754-758",
"pmc": null,
"pmid": "33677744",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": "32291542;32085846;32838219;32440883;29382672;32425265;32419766",
"title": "Outpatient management of chronic warfarin therapy at a pharmacist-run anticoagulation clinic during the COVID-19 pandemic.",
"title_normalized": "outpatient management of chronic warfarin therapy at a pharmacist run anticoagulation clinic during the covid 19 pandemic"
} | [
{
"companynumb": "US-MYLANLABS-2021M1093661",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
... |
{
"abstract": "Cytomegalovirus (CMV) is a common posttransplant infection, most commonly seen in settings of excessive immunosuppression. Before the advent of CMV specific antiviral therapies, the standard treatment approaches for CMV disease were immunosuppression reductions to let the transplant recipient mount an immunologic response against CMV. Additionally, CMV is rarely identified as causing stricturing enteritis and has not previously been reported as causing stricturing enteritis in an adult transplant recipient. All identified reports of stricturing CMV enteritis have been reported in either pediatric patient populations or those with severe immunosuppression from human immunodeficiency virus and acquired immune deficiency syndrome. Our report presents the unusual case of an adult liver transplant recipient many years after transplant and on minimal immunosuppression with mycophenolate alone who developed stricturing CMV enteritis.",
"affiliations": "James D. Eason Transplant Institute at Methodist University Hospital, Memphis, TN, USA.;James D. Eason Transplant Institute at Methodist University Hospital, Memphis, TN, USA.",
"authors": "Helmick|Ryan A|RA|;Agbim|Uchenna A|UA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jscr/rjz356",
"fulltext": "\n==== Front\nJ Surg Case RepJ Surg Case RepjscrJournal of Surgical Case Reports2042-8812Oxford University Press 10.1093/jscr/rjz356rjz356Case ReportStricturing CMV enteritis in an adult liver transplant recipient Helmick Ryan A 12Agbim Uchenna A 121 \nJames D. Eason Transplant Institute at Methodist University Hospital, Memphis, TN, USA2 \nThe University of Tennessee Health Science Center, Memphis, TN, USACorrespondence address. James D. Eason Transplant Institute at Methodist University Hospital, 1211 Union Avenue STE 340, Memphis, TN 38104, USA. Tel: 1-901-478-9183; E-mail: ryan.helmick.md@gmail.com or rhelmick@uthsc.edu12 2019 17 12 2019 17 12 2019 2019 12 rjz3562 10 2019 23 8 2019 17 10 2019 10 11 2019 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2019.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nCytomegalovirus (CMV) is a common posttransplant infection, most commonly seen in settings of excessive immunosuppression. Before the advent of CMV specific antiviral therapies, the standard treatment approaches for CMV disease were immunosuppression reductions to let the transplant recipient mount an immunologic response against CMV. Additionally, CMV is rarely identified as causing stricturing enteritis and has not previously been reported as causing stricturing enteritis in an adult transplant recipient. All identified reports of stricturing CMV enteritis have been reported in either pediatric patient populations or those with severe immunosuppression from human immunodeficiency virus and acquired immune deficiency syndrome. Our report presents the unusual case of an adult liver transplant recipient many years after transplant and on minimal immunosuppression with mycophenolate alone who developed stricturing CMV enteritis.\n\nCytomegalovirusSmall bowel strictureLiver transplant\n==== Body\nINTRODUCTION\nInvasive cytomegalovirus (CMV) disease is a well-recognized complication following solid organ transplant; however CMV is infrequently reported to cause significant small bowel pathology. Most commonly CMV manifests as a viral syndrome with fever and neutropenia, with common gastrointestinal manifestations including esophagitis, gastritis, colitis, or hepatitis [1]. Further, the reported cases and series of CMV causing gastrointestinal stricturing are often reported in pediatric patient groups, generally with birth prematurity [2, 3]. Adult cases of CMV-associated stricture are unusual and have heretofore been reported only in those with acquired immune deficiency syndrome and severe immunodeficiency, but these reports highlight esophageal strictures due to CMV [4, 5]. To our knowledge, there are no reported instances of CMV-associated small intestinal stricture in a relatively immunocompetent adult.\n\nCASE REPORT\nOur patient is a 69-year-old gentleman who underwent orthotopic liver transplant in April of 2010 for cryptogenic cirrhosis. His maintenance therapy consisted of rapamune due to chronic kidney disease but was transitioned to mycophenolate mofetil (MMF) monotherapy in 2014 and continued to have normal allograft function. In the spring of 2018, he developed CMV viremia; immunosuppression was held, and CMV therapy was initiated with valganciclovir. Within a month he had cleared the CMV viremia and was restarted on MMF for immunosuppression; however he proceeded to be readmitted to the hospital service approximately six times over the following 2 months for intolerance of solid foods. He was ultimately taken to surgery for lysis of adhesions, where a strictured segment of the ileum was identified 20 cm from the ileocecal value. Six centimeters of the small intestine were resected, and primary bowel anastomosis was performed. The mucosal surface was remarkable for a centrally located area of stricture with 60% luminal narrowing. Pathology of the resected segment showed no ischemic changes but ulcerations of the mucosa causing the stricture, with immunostaining positive for invasive CMV disease. The patient has subsequently had no recurrence of or readmittance for small bowel obstruction or food intolerance.\n\nDISCUSSION\nCMV disease is a well-reported posttransplant infection, most frequently causing allograft hepatitis and infrequently causing biliary strictures [6, 7]. Stricturing manifestations of intestinal CMV disease more commonly present in term or preterm neonates [2]. Series reporting episodes of CMV enteritis demonstrate about a 40% incidence of small intestinal disease, with the esophagus and colon compromising an equal percent of cases [8]. To our knowledge, there is one report of CMV enteritis an adolescent liver transplant recipient, who presented with duodenal bleeding requiring pancreas preserving duodenectomy but no stricture [9]. The reports of intestinal CMV infections in children emphasize that all patients had significant causes for immunodeficiency, such as HIV, prematurity, or age less than 6 months. There appears to be no other report in the literature of adult posttransplant patients suffering from CMV stricturing small bowel enteritis.\n==== Refs\nREFERENCES\n1. \nFishman JA \nChapter 31 - Infection in Kidney Transplant Recipients A2 - Morris, Peter J In: Knechtle SJ , ed. Kidney Transplantation–Principles and Practice , 7th edn \nPhiladelphia (PA) :\nContent Repository , 2014 , 491 –510 . Available from : http://www.sciencedirect.com/science/article/pii/B9781455740963000313 (July 2016, date last accessed).\n2. \nGoelz R , Hamprecht K , Klingel K , Poets CF \nIntestinal manifestations of postnatal and congenital cytomegalovirus infection in term and preterm infants . J Clin Virol 2016 ;83 :29 –36 .27529309 \n3. \nSrinivasjois RM , Kava MP , Thomas A , Rao SC \nCytomegalovirus-associated ileal stricture in a preterm neonate . J Paediatr Child Health 2008 ;44 :80 –2 .18086043 \n4. \nSheth A , Boktor M , Diamond K , Lavu K , Sangster G \nComplete esophageal obliteration secondary to cytomegalovirus in AIDS patient . Dis Esophagus 2010 ;23 :E32 –4 .20659143 \n5. \nWilcox CM \nEsophageal strictures complicating ulcerative esophagitis in patients with AIDS . Am J Gastroenterol 1999 ;94 :339 –43 .10022626 \n6. \nPedersen M , Seetharam A \nInfections after orthotopic liver transplantation . J Clin Exp Hepatol 2014 ;4 :347 –60 .25755581 \n7. \nKowdley KV , Fawaz KA , Kaplan MM \nExtrahepatic biliary stricture associated with cytomegalovirus in a liver transplant recipient . Transpl Int 1996 ;9 :161 –3 .8639259 \n8. \nArnold M , Itzikowitz R , Young B , Machoki SM , Hsiao NY , Pillay K , et al. \nSurgical manifestations of gastrointestinal cytomegalovirus infection in children: clinical audit and literature review . J Pediatr Surg 2015 ;50 :1874 –9 .26265193 \n9. \nVincenzi R , Fonseca EA , Chapchap P , Machado MCC , Roda KMO , Candido HL , et al. \nPancreas-preserving duodenectomy after living donor liver transplantation for invasive cytomegalovirus disease . Pediatr Transplant 2017 ;21 . doi: 10.1111/petr.13059 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2042-8812",
"issue": "2019(12)",
"journal": "Journal of surgical case reports",
"keywords": "Cytomegalovirus; Liver transplant; Small bowel stricture",
"medline_ta": "J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101560169",
"other_id": null,
"pages": "rjz356",
"pmc": null,
"pmid": "31867097",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "20659143;8639259;10022626;25755581;28881059;27529309;18086043;26265193",
"title": "Stricturing CMV enteritis in an adult liver transplant recipient.",
"title_normalized": "stricturing cmv enteritis in an adult liver transplant recipient"
} | [
{
"companynumb": "US-APOTEX-2020AP006798",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",... |
{
"abstract": "Chronic granulomatous disease (CGD) is a genetic disease caused by structural mutations in the enzyme NADPH oxidase that results in severe immunodeficiency. End-stage renal disease occurs in this patient population and is attributed to various factors, including infections, amyloidosis, and nephrotoxic anti-infective agents. In this report, we present our experience in transplantation for a patient with CGD complicated by isolated hepatic tuberculosis abscess. The course of the case demonstrates the absolute requirements for a multidisciplinary and compulsive approach before, during, and after transplantation. This case report also highlights the unexpectedly benign effects of immunosuppressive therapy in this patient population.",
"affiliations": "Division of Pediatric Infectious Diseases, Department of Pediatrics, Istanbul University, Istanbul, Turkey. Electronic address: drbaharbudan@gmail.com.;Division of Nephrology, Department of Internal Medicine, Istanbul University, Istanbul, Turkey.;Department of Pathology, Istanbul University, Istanbul, Turkey.;Division of Nephrology, Department of Internal Medicine, Istanbul University, Istanbul, Turkey.;Division of Nephrology, Department of Internal Medicine, Istanbul University, Istanbul, Turkey.;Division of Nephrology, Department of Internal Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Caliskan|B|B|;Yazici|H|H|;Gulluoglu|M|M|;Caliskan|Y|Y|;Turkmen|A|A|;Sever|M S|MS|",
"chemical_list": "D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D006105:Granulomatous Disease, Chronic; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008100:Liver Abscess; D008297:Male",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "158-60",
"pmc": null,
"pmid": "25480525",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal transplantation in a patient with chronic granulomatous disease: case report.",
"title_normalized": "renal transplantation in a patient with chronic granulomatous disease case report"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-106657",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Systemic capillary leak syndrome is a rare, underdiagnosed and life-threatening disease characterized by periodic episodes of hypovolaemic shock due to leakage of plasma from the intravascular to the extravascular space. It is associated with haemoconcentration, hypoalbuminaemia and generalized oedema. We report the case of a patient with a history of emergent extensive small and large bowel resection and several episodes of hypovolaemic shock with acute renal injury, who presented with abdominal pain, headache and generalized oedema. Severe systemic capillary leak syndrome was diagnosed after a complex diagnostic approach. This case report describes the acute and prophylactic treatment administered to the patient and the 4-year follow-up. We highlight the importance of timely recognition and prompt treatment, as well as the need for new investigations to prevent the serious and unusual complications seen in this case.\nIdiopathic systemic capillary leak syndrome (ISCLS) should be suspected in the presence of the triad of hypotension, haemoconcentration and hypoalbuminaemia; the diagnostic work-up is challenging and requires exclusion of several causes of hypotension and shock of uncertain aetiology.Acute mesenteric ischaemia leading to extensive and emergent bowel resection is an irreversible but atypical complication of ISCLS; other complications include myocardial oedema and deep vein thrombosis.ISCLS is characterized by three phases; supportive as well as prophylactic treatment adapted to each phase is crucial for prognosis and to avoid end-organ damage.",
"affiliations": "Internal Medicine Department, Centro Hospitalar São João, Porto, Portugal.;Internal Medicine Department, Centro Hospitalar São João, Porto, Portugal.;Internal Medicine Department, Centro Hospitalar São João, Porto, Portugal.;Internal Medicine Department, Centro Hospitalar São João, Porto, Portugal.",
"authors": "Correia|Cristina Pires|CP|;Guiomar|Veronica|V|;Coelho|Fátima|F|;Almeida|Jorge|J|",
"chemical_list": null,
"country": "Italy",
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"doi": "10.12890/2019_001156",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_001156156-1-8331-2-10-20190620ArticlesNon-occlusive Mesenteric Ischaemia and Acute Kidney Injury: A Case Report of Severe Idiopathic Systemic Capillary Leak Syndrome Correia Cristina Pires Guiomar Veronica Coelho Fátima Almeida Jorge Internal Medicine Department, Centro Hospitalar São João, Porto, Portugal2019 24 6 2019 6 7 00115619 5 2019 28 5 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseSystemic capillary leak syndrome is a rare, underdiagnosed and life-threatening disease characterized by periodic episodes of hypovolaemic shock due to leakage of plasma from the intravascular to the extravascular space. It is associated with haemoconcentration, hypoalbuminaemia and generalized oedema.\n\nWe report the case of a patient with a history of emergent extensive small and large bowel resection and several episodes of hypovolaemic shock with acute renal injury, who presented with abdominal pain, headache and generalized oedema. Severe systemic capillary leak syndrome was diagnosed after a complex diagnostic approach. This case report describes the acute and prophylactic treatment administered to the patient and the 4-year follow-up. We highlight the importance of timely recognition and prompt treatment, as well as the need for new investigations to prevent the serious and unusual complications seen in this case.\n\nLEARNING POINTS\nIdiopathic systemic capillary leak syndrome (ISCLS) should be suspected in the presence of the triad of hypotension, haemoconcentration and hypoalbuminaemia; the diagnostic work-up is challenging and requires exclusion of several causes of hypotension and shock of uncertain aetiology.\n\nAcute mesenteric ischaemia leading to extensive and emergent bowel resection is an irreversible but atypical complication of ISCLS; other complications include myocardial oedema and deep vein thrombosis.\n\nISCLS is characterized by three phases; supportive as well as prophylactic treatment adapted to each phase is crucial for prognosis and to avoid end-organ damage.\n\nIdiopathic systemic capillary leak syndrome (ISCLS)hypovolaemic shockmonoclonal gammopathy of unknown significance (MGUS)non-occlusive mesenteric ischaemiaacute kidney injury\n==== Body\nCASE REPORT\nA 48-year-old man with a medical history of smoking and significant bowel resection 2 years previously presented to the emergency department complaining of intense headache and abdominal pain that had started 2 days earlier. He also reported dyspnoea, generalized oedema, asthenia and a decrease in urinary output in the last week. He did not describe fever or other neurological, respiratory, digestive or genitourinary symptoms. He worked as a hairdresser and denied allergies, exposure to new substances, drugs, ticks, animals or recent travels.\n\nHe had been submitted to extensive small and large bowel partial resection 2 years previously, which had resulted in post-surgical short bowel syndrome and a colostomy. At that time, he had presented with non-specific abdominal pain, hypotension, elevated plasma lactate levels, an elevated haematocrit consistent with haemoconcentration, and metabolic acidosis. Plasma creatine phosphokinase levels were normal. After abdominal CT arteriography had excluded several causes of shock including arterial occlusion and venous thrombosis, intensive haemodynamic support and monitoring was provided. Emergent abdominal exploration and bowel resection was then carried out. The diagnostic approach included exclusion of several causes of end-organ damage including cardiovascular disease, sepsis and drugs. Non-occlusive mesenteric ischaemia was identified as the most likely cause.\n\nThe patient required two more surgeries for partial bowel resection. Post-surgery care was complicated by catheter-related superior vena cava thrombosis associated with the implantation of a vascular access system for parenteral nutrition, which resulted in the patient needing 3 months of hypocoagulation.\n\nThe patient also reported three previous hospitalizations for oliguric acute renal injury before his bowel surgery. In the first episode, 3 years previously, he presented with hypovolaemic shock and metabolic acidaemia requiring intensive care unit (ICU) admission for ionotropic support, renal replacement treatment and broad spectrum empiric antibiotics as the primary cause remained unknown. The episodes were all preceded by a 2-day prodrome of intense headache and diffuse abdominal discomfort associated with physical exercise and heat exposure.\n\nPhysical examination in the present hospital admission showed the patient was haemodynamically unstable with hypotension (85/45 mmHg) and a heart rate of 120 bpm, but without respiratory failure or fever. He presented with generalized oedema, but no skin flushing, urticaria, focal angioedema, stridor or lymphadenopathy was detected (Fig. 1). His abdominal, neurological, cardiac and pulmonary evaluations were normal.\n\nArterial blood gas analysis revealed severe metabolic acidaemia (pH 7.27, HCO3 10.6). Laboratory findings showed haemoconcentration with Hgb 22.4 g/dl (normal 13.5–18.0 g/dl), haematocrit 61% (normal >49–50% in men), 20.08 K/μl leucocytes (normal 4–10 K/μl), uraemia (90 mg/dl; normal 6–23 mg/dl) with elevated creatinine (2.20 mg/dl; normal 0.50–1.20 mg/dl) and hypoalbuminaemia (2.0 g/dl; normal 3.5–5.2 g/dl). Creatine phosphokinase (CPK), coagulation and liver function were normal. Elevated BNP (222.5 pg/ml) with a normal troponin level was documented. An electrocardiogram did not show any relevant disturbances. A thoracic x-ray, urinary study with 24-hour urine collection, a contrast-enhanced thoracoabdominal CT scan, and abdominal and renal ultrasound were all normal (Fig. 2).\n\nThe patient started intensive fluid replacement therapy and was admitted to the Internal Medicine Department after haemodynamic stabilization with renal function recovery.\n\nInflammatory studies including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) did not show any relevant changes. A complete infectious study involving serologies, blood and urinary cultures was performed and was negative.\n\nIn light of the several episodes of severe hypovolaemic shock with acute renal injury, generalized oedema and laboratory findings of haemoconcentration and hypoalbuminaemia, the diagnosis of idiopathic systemic capillary leak syndrome (ISCLS) was suspected. The prodromes of intense headache and abdominal pain, as well as the association with previous heat exposure, supported this diagnosis.\n\nThe differential diagnosis also included sepsis, anaphylaxis and some drug reactions. Several causes of distributive, cardiogenic, hypovolaemic and obstructive shock were considered and excluded.\n\nStudies of thyroid, gonadal and adrenal steroid function, and immune and metabolic function tests were unremarkable. Complement studies including C3, C4 and CH50 as well as C1 esterase inhibitor levels and function to exclude types I and II hereditary angioedema, were requested and were normal.\n\nA complete cardiac study was performed to identify causes of hypotension or shock of uncertain aetiology, and to investigate dangerous cardiovascular complications associated with ISCLS, especially in the recruitment phase. Transthoracic echocardiography and cardiovascular MRI did not show any relevant changes (Fig. 2).\n\nA whole endoscopic study was requested because of the severe gastrointestinal presentation and the association between neuroendocrine tumours and acute severe hypovolaemic episodes, but did not show any relevant changes (Fig. 3).\n\nSince ISCLS is related to monoclonal gammopathies, a complete study with serum protein electrophoresis, urine protein electrophoresis, immunofixation and serum free light chain assay was performed and revealed a monoclonal gamma/lambda gammopathy (IgG1) of unknown significance with lambda light chains (Fig. 4).\n\nImmunocytochemical evaluation of a bone marrow biopsy specimen did not show any disturbances.\n\nAfter the diagnosis was made, intravenous immunoglobulin (IVIG) (1 g/kg) was administered, resulting in considerable improvement in the patient’s clinical status. He maintained nutritional supplementation due to the short bowel syndrome and was discharged 1 month later.\n\nDuring follow-up, the patient reported several episodes of oedema of the extremities and fatigue due to partial leaks and therefore started prophylactic treatment with terbutaline and theophylline, requiring periodic plasma level evaluations for 2 years.\n\nThe patient avoided physical exercise and heat exposure, but still needed two more hospital admissions for acute exacerbation associated with subtherapeutic theophylline levels. He then started prophylactic administration of 1 g/kg/month IVIG, which he maintained for 1 year with good results.\n\nDISCUSSION\nThis case report is remarkable for both its rarity and the severe systemic manifestations, difficult diagnostic approach and unusual irreversible complications. It concerns a patient with a history of major and emergent bowel resection and several episodes of hypovolaemic shock with acute renal injury, who presented with abdominal pain, acute headache and generalized oedema. A complex diagnosis of ISCLS (also known as Clarkson disease) was made after exclusion of other rare disorders such as hereditary angioedema and neuroendocrine tumours.\n\nAlthough <500 cases of ISCLS have been reported in the literature since 1960, the condition is probably under-diagnosed due to lack of awareness and a high mortality rate without treatment[1]. It typically begins in midlife and diagnosis relies on the triad of severe hypotension, hypoalbuminaemia and haemoconcentration[1, 2].\n\nDespite the association of ISCLS with monoclonal gammopathy of unknown significance, evolution to myeloma is not inevitable[1]. However, this can influence treatment strategies, like the administration of IVIG, as in the follow-up of this patient[3].\n\nProdromes with intense headache and abdominal pain with previous heat exposure have been reported but are less frequent than those which include upper respiratory infections. Prodrome symptoms and their triggers are under study but have not yet been defined[1,2].\n\nThis case is also unusual because of the severe episodes of multiple organ failure and end-organ complications, such as the need for nutritional supplementation after bowel resection and deep venous thrombosis. The most commonly reported gastrointestinal consequences are compartment syndrome during both the extravasation and recovery phases and ischaemic hepatitis due to prolonged hypoperfusion.\n\nThis report underlines the importance of cardiovascular evaluation because myocardial dysfunction is frequent in patients with SCLS and because overly aggressive fluid resuscitation can lead to pulmonary oedema and compartment syndrome in the recovery (fluid recruitment) phase[4].\n\nWe emphasise that the cornerstone of acute treatment remains supportive care with intense haemodynamic stabilization and monitoring, although other treatments are under investigation, including the administration of high doses of IVIG, intravenous aminophylline and terbutaline, as well as anti-vascular endothelial growth factor (VEGF) antibody[3,4]. The administration of IVIG was effective in our patient.\n\nNon-occlusive mesenteric ischaemia remains a rare emergent condition, especially in young patients without known risk factors, and requires early recognition and timely treatment in order to prevent serious consequences[5]. Non-occlusive mesenteric ischaemia has a mortality rate of 70–90%, which has changed little over time despite new treatments.\n\nThis case report describing a patient requiring a prompt laparotomy which disclosed massive bowel necrosis, emphasises the importance of identifying ISCLS as a predisposing disease underlying mesenteric ischaemia. In addition to the high degree of clinical suspicion and emergent haemodynamic support required, we also underline the severe and permanent gastrointestinal consequences in our patient which included malabsorption syndrome, a colostomy and associated infective, thrombotic and haemodynamic comorbidities (Fig. 5).\n\nDetailed observational studies combined with personalized investigation are crucial and may provide a better understanding of the immunology underlying the exaggerated microvascular response leading to capillary leak syndrome, as well as improve the diagnosis, treatment and prophylaxis of non-occlusive mesenteric ischaemia and ISCLS.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Physical examination revealed significant and generalized oedema\n\nFigure 2 Top panels: cardiovascular MRI did not show any relevant changes. Bottom panel: contrast-enhanced CT image of the abdomen without signs of acute ischaemic or non-viable gastrointestinal segments\n\nFigure 3 Upper and small bowel capsule endoscopy did not show any lesions or other relevant changes\n\nFigure 4 Serum protein electrophoresis revealing monoclonal gamma/lambda gammopathy (IgG1) of unknown significance with lambda light chains, confirmed by an immunofixation study\n\nFigure 5 A colostomy bag after emergent and significant bowel resection resulting in short bowel syndrome\n==== Refs\nREFERENCES\n1 Druey KM Parikh SM Idiopathic systemic capillary leak syndrome (Clarkson disease) J Allergy Clin Immunol 2017 140 663 28012935 \n2 Gousseff M Arnaud L Lambert M The systemic capillary leak syndrome: a case series of 28 patients from a European registry Ann Intern Med 2011 154 464 21464348 \n3 Pineton de Chambrun M Gousseff M Mauhin W Intravenous immunoglobulins improve survival in monoclonal gammopathy-associated systemic capillary-leak syndrome Am J Med 2017 130 1219.e19 \n4 Pineton de Chambrun M Luyt CE Beloncle F The clinical picture of severe systemic capillary-leak syndrome episodes requiring ICU admission Crit Care Med 2017 45 1216 28622216 \n5 Clair DG Beach JM Mesenteric ischemia N Engl J Med 2016 374 959 26962730\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(7)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Idiopathic systemic capillary leak syndrome (ISCLS); acute kidney injury; hypovolaemic shock; monoclonal gammopathy of unknown significance (MGUS); non-occlusive mesenteric ischaemia",
"medline_ta": "Eur J Case Rep Intern Med",
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"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001156",
"pmc": null,
"pmid": "31410358",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "21464348;26962730;28012935;28602874;28622216",
"title": "Non-occlusive Mesenteric Ischaemia and Acute Kidney Injury: A Case Report of Severe Idiopathic Systemic Capillary Leak Syndrome.",
"title_normalized": "non occlusive mesenteric ischaemia and acute kidney injury a case report of severe idiopathic systemic capillary leak syndrome"
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"abstract": "To describe the presentation and management of a patient with epithelial versus fibrous downgrowth following trabeculectomy surgery and review relevant literature regarding this complication after intraocular surgery.\nA 52-year-old monocular African-American woman was referred for management of presumed epithelial versus fibrous downgrowth following trabeculectomy surgery. The patient was initially treated with intracameral injections of 5-fluorouracil (x2) and bevacizumab (x1). Cataract extraction, membranectomy, and a third intracameral 5-fluorouracil injection were performed. Intraocular pressure (IOP) elevation was subsequently managed with a superotemporal Ahmed FP7 glaucoma drainage device in the sulcus, followed by an inferonasal Baerveldt 350 glaucoma drainage device in the sulcus. The downgrowth has not progressed and the intraocular pressure remains controlled at the most recent follow-up.\nThis case underscores the risk of this complication following trabeculectomy, the role of a combined medical and surgical approach to management, and the possible need for multiple surgical interventions to control IOP. A review of the literature regarding epithelial and fibrous downgrowth after intraocular surgery was conducted, which highlighted the aggressive nature of these conditions and the range of therapeutic approaches that have been described.",
"affiliations": "Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.;Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.;Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.;Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.;Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.",
"authors": "Theophanous|Christos N|CN|;Avdagic|Ema|E|;Farooq|Asim V|AV|;Skondra|Dimitra|D|;Qiu|Mary|M|",
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"country": "United States",
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"doi": "10.1016/j.ajoc.2021.101183",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00192-4\n10.1016/j.ajoc.2021.101183\n101183\nCase Report\nManagement of severe epithelial versus fibrous downgrowth following trabeculectomy: Case report and literature review\nTheophanous Christos N.\nAvdagic Ema\nFarooq Asim V.\nSkondra Dimitra\nQiu Mary maryqiu@bsd.uchicago.edu\n∗\nDepartment of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA\n∗ Corresponding author. Department of Ophthalmology and Visual Science University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, IL, 60637, USA. maryqiu@bsd.uchicago.edu\n27 7 2021\n9 2021\n27 7 2021\n23 10118318 11 2020\n4 5 2021\n25 7 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPurpose\n\nTo describe the presentation and management of a patient with epithelial versus fibrous downgrowth following trabeculectomy surgery and review relevant literature regarding this complication after intraocular surgery.\n\nObservations\n\nA 52-year-old monocular African-American woman was referred for management of presumed epithelial versus fibrous downgrowth following trabeculectomy surgery. The patient was initially treated with intracameral injections of 5-fluorouracil (x2) and bevacizumab (x1). Cataract extraction, membranectomy, and a third intracameral 5-fluorouracil injection were performed. Intraocular pressure (IOP) elevation was subsequently managed with a superotemporal Ahmed FP7 glaucoma drainage device in the sulcus, followed by an inferonasal Baerveldt 350 glaucoma drainage device in the sulcus. The downgrowth has not progressed and the intraocular pressure remains controlled at the most recent follow-up.\n\nConclusions\n\nThis case underscores the risk of this complication following trabeculectomy, the role of a combined medical and surgical approach to management, and the possible need for multiple surgical interventions to control IOP. A review of the literature regarding epithelial and fibrous downgrowth after intraocular surgery was conducted, which highlighted the aggressive nature of these conditions and the range of therapeutic approaches that have been described.\n\nKeywords\n\nTrabeculectomy\nEpithelial downgrowth\nFibrous downgrowth\n==== Body\n1 Introduction\n\nEpithelial downgrowth is a rare complication of intraocular surgery or trauma characterized by invasion of surface epithelial cells into the anterior chamber (AC) of the eye.1 The membranous spread of these conjunctival or corneal epithelial cells can be difficult to control and lead to devastating consequences including end-stage glaucoma and permanent vision loss.2 Fibrous downgrowth is a similar but somewhat less aggressive condition characterized by fibrovascular connective tissue invading into the eye. Patients with these conditions can present with decreasing visual acuity, pain, tearing, photophobia, foreign body sensation or flashes of light.2 Previous reports have described epithelial downgrowth following glaucoma surgery.3, 4, 5, 6, 7 Herein, we report the medical and surgical management of a case of severe epithelial versus fibrous downgrowth following prior trabeculectomy surgery.\n\n2 Case report\n\nA monocular 52-year-old African American woman with primary open angle glaucoma (POAG) was referred to the anterior segment service for evaluation of a membrane growing into the AC from a superior trabeculectomy site in her only-seeing left eye (OS) performed 10 months prior. Visual acuity (VA) was 20/125 and intraocular pressure (IOP) was 24 mmHg on four topical antihypertensive agents. She was also using prednisolone acetate 1 % and cyclopentolate 0.5 % once daily for low-grade AC inflammation. She had previously undergone selective laser trabeculoplasty (SLT) OS with initial improvement in IOP; however, after being lost to follow-up for 18 months, the IOP had increased to 29 mmHg so she underwent a superior fornix-based ab externo trabeculectomy with subconjunctival injection of mitomycin-C (MMC) (0.1 mL of 0.4mg/mL). Her post-operative course was notable for hypotony with IOP of 7 mmHg, a shallow AC, self-limited choroidal effusions, and persistent low-grade AC inflammation. Five months after surgery, the angle was documented to be synechially closed for 360-degrees.\n\nOn slit lamp examination, a membrane covering the anterior lens capsule was noted, originating from the superior trabeculectomy site with neovascularization on the membrane. This was concerning for an inflammatory membrane, fibrous downgrowth, or epithelial downgrowth (Fig. 2). An inflammatory workup for Lyme disease, syphilis, tuberculosis, and sarcoidosis was negative. Diagnostic argon laser applied to the iris surface was consistent with the diagnosis of epithelial downgrowth. Confocal microscopy did not reveal a retro-corneal membrane.Fig. 1 A) Pre-trabeculectomy Humphrey Visual Field 24-2 of left eye. B) Post-treatment Humphrey Visual Field 24-2 of left eye.\n\nFig. 1\n\nFig. 2 Gonioscopic photograph of left eye demonstrating membranous growth from trabeculectomy site.\n\nFig. 2\n\nThe patient underwent intracameral injection of 0.05mL of 5-Fluorouracil (5-FU) followed by intracameral injection of 0.05mL of bevacizumab two weeks later, and a second intracameral injection of 0.05mL of 5-FU one month later. Her IOP OS increased to 29 mmHg, so topical prednisolone acetate was discontinued due to a concern for steroid response. Over the next eight months, the appearance of the fibrous membrane remained stable, the patient's VA OS fluctuated between 20/300 and count fingers, and IOP ranged from 15 to 23 mmHg.\n\nThe patient subsequently underwent membranectomy, cataract extraction with implantation of a one-piece intraocular lens in the capsular bag, and another intracameral injection of 0.05mL of 5-FU. The membranectomy involved visco-dissection and excision of the membrane using a cystotome and MST scissors. Histopathologic analysis identified the sample as a hypocellular collagenous tissue with small vessels and focal pigment deposition (Fig. 3).Fig. 3 Histopathology image of membrane resected during combined membranectomy and cataract extraction with intraocular lens implant from left eye stained with hematoxylin and eosin at 10x magnification.\n\nFig. 3\n\nOne month after surgery, the patient's IOP OS was 38 mmHg on four topical antihypertensive medications, and she was referred to a new glaucoma provider (MQ). Steroid response was considered given prolonged use of prednisolone acetate. Gonioscopy revealed 360-degrees of synechial closure with fibrous tissue extending from the trabeculectomy sclerostomy site to the superior aspect of the anterior capsule. Oral acetazolamide 500mg twice a day was started, but IOP remained elevated at 33 mmHg. The patient underwent implantation of a superotemporal Ahmed FP7 glaucoma drainage device (New World Medical, Rancho Cucamonga, CA) with the tube tip in the sulcus, scleral patch graft, and Kenalog 20mg injected intra-tenons over the plate to reduce encapsulation. The following day, IOP was 17 mmHg OS.\n\nBy post-operative week five, IOP increased to 25 mmHg on 4 topical antihypertensive medications and oral acetazolamide 250mg four times per day, so the patient underwent implantation of an inferonasal Baerveldt 350 implant (Johnson & Johnson Vision Care Inc., Jacksonville, FL) with the tube tip in the inferonasal sulcus, split thickness half-moon corneal patch graft, and 3-0 Prolene ripcord suture in the tube lumen to prevent hypotony when the ligating suture dissolves, which is this surgeon's standard protocol for Baerveldt tubes. Concurrent revision of the Ahmed FP7 was also performed by excising the capsule over the plate and injecting Kenalog 20mg to reduce aqueous outflow resistance and future encapsulation. The goal was to achieve early IOP lowering in the first 6 weeks before the Baerveldt opened.\n\nAt post-operative week one, the IOP was 12 mmHg; however, one week later, the IOP decreased to 3 mmHg, the ripcord suture was absent although the patient did not recall removing it herself, and there was a robust AC inflammatory reaction with fibrinous material at the tip of the inferonasal tube, not occluding the tube (Fig. 2). The patient was treated medically with frequent topical steroid and atropine. By post-operative week three, the IOP increased to 16 mmHg, and the AC inflammation subsided. Throughout this period, the AC remained deep, and no choroidal effusions or suprachoroidal hemorrhage were seen. By post-operative week six, the ligating suture dissolved, as expected, and the inferonasal Baerveldt tube was fully functioning. By postoperative month seven, the patient's best-corrected VA was 20/50, and the IOP was 11 mmHg on five topical antihypertensives (brinzolamide/brimonidine 3x per day, Timolol 2x per day, netarsudil/latanoprost at bedtime) and no oral agents. No recurrence of the downgrowth was noted, the fibrinous AC reaction had resolved, and both tube tips were patent in the sulcus (Fig. 4). A new 24-2 Humphrey Visual Field, this time with a size V stimulus, demonstrated that she still retained a central island of vision in this eye (Fig. 1).Fig. 4 Post-operative slit lamp photographs showing (A) superotemporal and inferonasal tube insertions in sulcus and superior trabeculectomy site; (B) fibrinous deposit at inferonasal tube tip; (C) inferonasal Baerveldt 350 tube with corneal patch graft; (D) superotemporal Ahmed FP7 tube with tutoplast scleral patch graft.\n\nFig. 4\n\n3 Discussion\n\nEpithelial or fibrous downgrowth after glaucoma surgery is rare. Most cases of epithelial downgrowth occur after trauma or intraocular surgery such as phacoemulsification, penetrating keratoplasty, and Descemet stripping automated endothelial keratoplasty.8, 9, 10 Rare cases have been reported after aqueous aspiration and pterygium removal.2 A 30-year pathologic review of epithelial downgrowth by Weiner et al. found that 82 % of cases present within a year of intraocular surgery. In the study, a retro-corneal membrane was the most common presenting sign, followed by glaucoma, corneal edema, and a positive Seidel sign.2 Fibrous downgrowth present similarly but differs by the histopathologic presence of fibroblastic instead of epithelial cells.11\n\nThis case describes epithelial versus fibrous downgrowth identified ten months after trabeculectomy that was successfully treated with a staged medical and surgical approach. One case of epithelial downgrowth after trabeculectomy with MMC was previously reported by Ruderman et al. in a retrospective case series of 43 trabeculectomies.7 In that case, a leak at the flap was seen and treated with a pressure patch, but after a subsequent conjunctival leak was found and the patient refused treatment, the eye eventually became phthisical.7\n\nEpithelial downgrowth after implantation of a glaucoma drainage device has been reported. Jewelewitz et al. described a case of tissue confirmed epithelial downgrowth in an 84-year-old patient seen four months after Ahmed FP7 implantation.4 Hu et al. described a case of epithelial downgrowth presenting as a peritubular vascular membrane after Ahmed FP7 implantation.3 Giaconi et al. reported epithelial downgrowth presenting as a cyst after goniotomy and Ahmed valve revisions in a child with congenital glaucoma that was treated by ab externo drainage and repeated cryotherapy after recurrence.12\n\nOn histopathology, epithelial downgrowth typically appears as a multilayered membrane of nonkeratinized, stratified, squamous epithelial sheets.1 It may also be seen as cysts or scattered islands of cells. Clinically, these sheets appear as a translucent or gray membrane with a smooth border and rolled edges. These membranes can occlude the trabecular meshwork or cause peripheral anterior synechiae formation leading to secondary angle closure glaucoma. Fibrous downgrowth, the spread of fibrocytes through a fistula, can present similarly but the membranes are typically thicker with irregular borders. They tend to grow more slowly and carry a more favorable prognosis.1 In this case, although no epithelial cells were seen on histopathology, it is unclear whether this is due to treatment with 5-FU or if epithelial cells were never present. Epithelial downgrowth was more suspected due to the characteristic whitening of the membrane with argon laser and smooth iris appearance with loss of normal architecture.\n\nVarious treatments have been attempted for epithelial and fibrous downgrowth including surgical excision, cryotherapy, irradiation, and laser photocoagulation.13,14 Hu et al. employed tube shunt explanation with surgical excision of the fibrovascular membrane with no noted recurrence 6 weeks post-operatively.3 Several reports have noted successful use of 5-FU.15, 16, 17, 18, 19 Sivaraman et al. reported three patients with localized epithelial downgrowth treated with partial lamellar sclero-kerato-uvectomy.20 Yu et al. reported successful use of MMC for cystic epithelial downgrowth after cataract surgery.21\n\nThe initial treatment of the downgrowth with intracameral injections of 5-FU, followed by bevacizumab, followed by a second dose of 5-FU, did not resolve the membrane, which was not unexpected given the extent of AC invasion. However, the sheet did not progress after these treatments, and given the aggressiveness of epithelial downgrowth, we deem halting the spread as a demonstration of treatment success. Of note, intracameral or intravitreal methotrexate was considered, but since the membrane was not progressing after the 5-FU injections, methotrexate was not deemed necessary.\n\nThe patient was originally noted to have PAOG, however after the trabeculectomy, the angle had become synechially closed, potentially due to AC shallowing after the trabeculectomy or the persistent AC inflammation and downgrowth. The elevated IOP prior to Ahmed implantation may also have been due in part to steroid response from use of prednisolone acetate after the cataract extraction and membranectomy. A valved Ahmed FP7 implant was preferred to a non-valved Baerveldt 350 implant since the advanced stage of her glaucoma demanded rapid pressure reduction. A second trabeculectomy was considered but deemed likely to fail in the setting of active neovascularization and persistent inflammation. Considering the synechial angle closure, sulcus placement of the Ahmed tube tip was preferred.\n\nAlthough initially successful, the IOP increased again after the Ahmed FP7, likely due to encapsulation of the plate and possible steroid response. A Baerveldt 350 implant was deemed more likely to achieve better long-term IOP control than a second Ahmed FP7,22,23 and concurrent revision of the Ahmed capsule could achieve early IOP lowering before the Baerveldt opened, with less risk of hypotony than aggressive fenestrating slits in the Baerveldt. This patient experienced early transient hypotony due to suspected inadvertent removal of her own ripcord suture. Fortunately, the AC never shallowed, there were never any chorioretinal folds, choroidal effusions, or suprachoroidal hemorrhage, and the transient fibrinous AC reaction resolved with topical steroids and never occluded the tube lumen. Ultimately, this case emphasizes the aggressiveness of membranous downgrowth following trabeculectomy surgery, the possible need for a combined medical and surgical approach to management, and the potential necessity for multiple surgical interventions to control IOP after this complication.\n\nPatient consent\n\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nAcknowledgements and Disclosures\n\nNo funding or grant support was received. The following authors have no financial disclosures: (CT, EA, DS, MQ). One author is a consultant to GlaxoSmithKline in a capacity unrelated to this manuscript (AF). All authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n\n1 Chen S.H. Pineda R. Epithelial and fibrous downgrowth: mechanisms of disease Ophthalmol Clin North Am 15 1 2002 41 48 12064080\n2 Weiner M.J. Trentacoste J. Pon D.M. Epithelial downgrowth: a 30-year clinicopathological review Br J Ophthalmol 73 1989 6 11 2920156\n3 Hu J. Goldstein D.A. Leiderman Y.I. Epithelial downgrowth after Ahmed implantation presenting as a peritubular fibrovascular membrane J Glaucoma 22 6 2013 e11 e13 23899696\n4 Jewelewicz D. Rosenfeld S. Litinsky S. Epithelial downgrowth following insertion of an Ahmed glaucoma implant Arch Ophthalmol 121 2003 285 286 12583803\n5 Smith M.F. Doyle J.W. Glaucoma secondary to epithelial and fibrous downgrowth Semin Ophthalmol 9 4 1994 248 253 10155645\n6 Sidoti P.A. Minckler D.S. Baerveldt G. Epithelial ingrowth and glaucoma drainage implants Ophthalmology 101 1994 872 875 8190473\n7 Ruderman J.M. Fundingsland B. Meyer M.A. Combined phacoemulsification and trabeculectomy with mitomycin-C J Cataract Refract Surg 22 8 1996 1085 1090 8915813\n8 Vargas L.G. Vroman D.T. Solomon K.D. Epithelial downgrowth after clear cornea phacoemulsification: report of two cases and review of the literature Ophthalmology 109 12 2002 2331 2335 12466179\n9 Mihail Z. Alina-Cristina S. Speranta S. Retrocorneal membranes after penetrating keratoplasty Rom J Ophthalmol 59 4 2015 230 234 29450312\n10 Koenig S.B. Covert D.J. Epithelial ingrowth after descemet-stripping automated endothelial keratoplasty Cornea 27 6 2008 727 729 18580268\n11 Jakobiec F.A. Bhat P. Retrocorneal membranes: a comparative immunohistochemical analysis of keratocytic, endothelial, and epithelial origins Am J Ophthalmol 150 2 2010 230 242.e2 20579631\n12 Giaconi J.A. Coleman A.L. Aldave A.J. Epithelial downgrowth following surgery for congenital glaucoma Am J Ophthalmol 138 6 2004 1075 1077 15629317\n13 Stark W.J. Michels R.G. Maumenee A.E. Surgical management of epithelial ingrowth Am J Ophthalmol 85 1978 772 780 567013\n14 Jadav D.S. Rylander N.R. Vold S.D. Endoscopic photocoagulation in the management of epithelial downgrowth Cornea 27 5 2008 601 604 18520512\n15 Ni N. Goldberg M.A. Eagle R.C. Jr. Epithelial downgrowth after intraocular surgery treated with intracameral 5-Fluorouracil Case Rep Ophthalmol Med 2015 2015 325485 26106497\n16 Abdollah Z. Mohd Zahidin A.Z. Ahem A. Successful treatment of epithelial downgrowth with endoscopic photocoagulation and intracameral 5-fluorouracil after prolonged limbal wound leak Int J Ophthalmol 11 4 2018 703 704 29675395\n17 Lai M. Haller J. Resolution of epithelial ingrowth in a patient treated with 5-fluorouracil Am J Ophthalmol 133 2002 562 564 11931795\n18 Shaikh A. Damji K. Mintsioulis G. Bilateral epithelial downgrowth managed in one eye with intraocular 5-fluorour- acil Arch Ophthalmol 120 2002 1396 1398 12365927\n19 Wong R.K. Greene D.P. Shield D.R. 5-Fluorouracil for epithelial downgrowth after Descemet stripping automated endothelial keratoplasty Cornea 32 12 2013 1610 1612 24113368\n20 Sivaraman K.R. Snyder M.E. Partial lamellar sclerokeratouvectomy for management of epithelial downgrowth Cornea 35 12 2016 1589 1593 27261941\n21 Yu C.S. Chiu S.I. Tse R.K. Treatment of cystic epithelial downgrowth with intralesional administration of mitomycin C Cornea 24 7 2005 884 886 16160512\n22 Christakis P.G. Zhang D. Budenz D.L. ABC-AVB study groups. Five-year pooled data analysis of the ahmed Baerveldt comparison study and the ahmed versus Baerveldt study Am J Ophthalmol 176 2017 118 126 28104418\n23 Christakis P.G. Kalenak J.W. Tsai J.C. The ahmed versus Baerveldt study: five-year treatment outcomes Ophthalmology 123 10 2016 2093 2102 27544023\n\n",
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"abstract": "Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions.\n\n\n\nA 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples.\n\n\n\nThe patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC.\n\n\n\nThis is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment.",
"affiliations": "Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China.;Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China.;Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China.;Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China.;Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.;Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China.;Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China.;Center for Brain Disorders Research, Capital Medical University, Beijing Institute for Brain Disorders, Beijing, 100069, China.;Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853, China. zouliping21@hotmail.com.",
"authors": "Lu|Qian|Q|;Shi|Xiu-Yu|XY|;Wang|Yang-Yang|YY|;Zhang|Meng-Na|MN|;Wang|Wen-Ze|WZ|;Wang|Jing|J|;Wang|Qiu-Hong|QH|;Chen|Hui-Min|HM|;Zou|Li-Ping|LP|",
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"fulltext": "\n==== Front\nOrphanet J Rare Dis\nOrphanet J Rare Dis\nOrphanet Journal of Rare Diseases\n1750-1172 BioMed Central London \n\n1396\n10.1186/s13023-020-01396-7\nResearch\nJuvenile xanthogranuloma as a new type of skin lesions in tuberous sclerosis complex\nLu Qian drluqian@163.com 1 Shi Xiu-Yu shixiuyu@sina.com 1 Wang Yang-Yang schopenhauersays@gmail.com 1 Zhang Meng-Na zhangmengna2014@sina.com 1 Wang Wen-Ze wwzvssxy@126.com 2 Wang Jing 13671158819@139.com 1 Wang Qiu-Hong 13562081183@163.com 1 Chen Hui-Min 2572068137@qq.com 3 Zou Li-Ping zouliping21@hotmail.com 13 1 grid.414252.40000 0004 1761 8894Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing, 100853 China \n2 grid.506261.60000 0001 0706 7839Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 China \n3 grid.24696.3f0000 0004 0369 153XCenter for Brain Disorders Research, Capital Medical University, Beijing Institute for Brain Disorders, Beijing, 100069 China \n12 6 2020 \n12 6 2020 \n2020 \n15 1477 3 2020 4 5 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Objective\nTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions.\n\nMethods\nA 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples.\n\nResults\nThe patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC.\n\nConclusion\nThis is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment.\n\nKeywords\nTuberous sclerosis complexJuvenile xanthogranulomaSubependymal giant cell astrocytomaPathologySirolimusWhole-exome sequencingthe National Natural Science Foundation of China8147132981771389Shi Xiu-Yu Zou Li-Ping issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nTSC is a rare autosomal dominant genetic disease with an incidence rate of approximately 1/6000 [1]. TSC has many manifestations and involves any organ in the body. The most common findings are benign tumors of the skin, brain, heart, kidneys and lung. Skin lesions include hypomelanotic macules (90% of patients), facial angiofibromas (75% of patients), fibrous cephalic plaques (25% of patients) and shagreen patches (> 50% of patients) [1]. Some studies have reported the use of sirolimus on specific TSC manifestations [2–4].\n\nJXG is a common form of non-Langerhans cell histiocytosis in infants and children. It is characterized by spontaneous formation of cutaneous nodules on the scalp, face, trunk and extremities. Approximately 71% of JXG cases occur during the first year of life [5]. The pathogenesis of JXG is unknown.\n\nHere, we report a 7-month-old TSC boy who presented with a 2-month history of a gradual growth of multiple cutaneous nodules, which through biopsy and whole-exome sequencing finally identified JXG as a new type of skin lesions in TSC.\n\nMethod\nPatients and diagnosis\nA 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. The diagnosis was made by at least two experienced specialists based on the 2012 TSC Consensus Conference updated diagnostic criteria [6]. We obtained written consent from his parents. This study was approved by the Ethics Committee of Chinese PLA General Hospital (Beijing, China).\n\nWe performed a biopsy of cutaneous nodules. Existing family members underwent testing all exons and introns of TSC1 and TSC2 genes. Paraffin block tissue and whole blood sample were collected from the patient to obtain genomic DNA for whole-exome sequencing.\n\nWe gave the patient sirolimos orally at the 8 months of age. The initial dose of sirolimus was 1 mg/(m2·day), and this dose was adjusted according to the blood concentration to maintain the blood concentration at 5–10 μg/L. He was administered oral sirolimus regularly for 1 year.\n\nResults\nOne week before birth, examination revealed a strong echo mass in the heart of the fetus (patient), indicating cardiac rhabdomyoma (Fig. 1a). A regular follow-up was recommended to observe changes in the cardiac rhabdomyoma. The patient’s mother had seizures since 4 years old. During pregnancy, she took lamotrigine and valpromide tablets but still had seizures every month. She had multiple skin lesions, including hypomelanotic macules, shagreen patches and facial angiofibromas. The patient’s uncle had seizures and died of “brain tumor” at 25 years old. The patient’s grandfather had hypomelanotic macules, shagreen patches and facial angiofibromas. When the patient was 4 months old, the mother was hospitalized. Existing family members had underwent testing for all exons and introns of TSC1 and TSC2 genes. Test results identified TSC1 mutation (c.2356C > T, p.R786*) in the patient, his mother and grandfather (Fig. 1b). The nonsense mutation has been reported in a previous study [7]. Based on both clinical signs and genetic testing, our patient was definitely diagnosed with TSC.\nFig. 1 a The timeline of the patient. b Family pedigree. The black square indicates TSC patient. The square with slash indicates the person is died. Sequence chromatograms show TSC1 mutation (c.2356C > T, p.R786*) in both paraffin block tissue and blood samples. The mutation is also found in blood of his mother and grandfather. c-d Nodules on the scalp and abdomen (white arrow) and hypomelanotic macule on the abdomen (black arrow) before treatment. e-f The multiple nodules disappeared and hypomelanotic macule in the abdomen was no change (black arrow) after 3 months of sirolimus\n\n\n\nThe cutaneous nodules of the patient first appeared behind the right ear without evident cause or tenderness and gradually growth multiple nodules at 5-month old. After 2 months, he was admitted into our department. Physical examination showed multiple nodules on the scalp, eyelids, trunk and limbs of the patient which are papules or yellow and erythematous nodules without inflammation or ulceration (Fig. 1c-d). He had one hypomelanotic macule on the abdomen (Fig. 1d). Brain computed tomography (CT) showed multiple punctate, flaky and round-like high-density holes in the bilateral lateral ventricles and bilateral subependymal. A large lesion (51 mm × 46 mm) located in the posterior corner of the left lateral ventricle was diagnosed as subependymal giant cell astrocytoma (SEGA) (Fig. 2a). Head magnetic resonance imaging (MRI) showed nodules in the posterior corners of bilateral ventricles on T1- and T2-weighted images (Fig. 2b–c). Chest CT showed the presence of a pulmonary subpleural nodule in the lower left lobe (Fig. 2d). Cardiac ultrasound showed cardiac rhabdomyoma in the left ventricular cavity, which was approximately 15 mm × 12 mm. Abdominal ultrasonography was normal. Ophthalmologic evaluation was not performed, because the patient was too young to cooperatate. Laboratory blood tests showed that the patient had normal lipid level. He had no facial angiofibromas, shagreen patches or seizures, and his development was normal.\nFig. 2 a Brain CT shows multiple punctate, flaky, and round-like high-density holes in the bilateral lateral ventricles and bilateral subependymal. A large lesion located in the posterior corner of the left lateral ventricle was diagnosed as SEGA. b-c Head MRI shows nodules in the posterior corners of bilateral ventricles on T1- and T2-weighted images. d Chest CT showed pulmonary subpleural nodule (white arrow)\n\n\n\nThe cutaneous nodules were different from common TSC skin lesions. We performed biopsy on the cutaneous nodules. Histopathological examination showed typical histiocytosis in the dermis with many multinucleated giant cells and inflammatory cells (Fig. 3a–b). Cluster differentiation 68 (CD68) and CD163 were positive (Fig. 3c–d) and S100, CD1a, langerin, human melanoma black 45 (HMB-45) and Melan-A were negative in immunohistochemical staining (Fig. 3e, f, g, and i). The Ki-67 (Fig. 3h) proliferation index was 15%. The pathological finding of cutaneous nodules was consistent with JXG. We believed that JXG and TSC simultaneously occurred in the patient.\nFig. 3 Histomorphologic examination. a-b Show typical histiocytosis findings in the dermis, with the presence of many multinucleated giant cells and inflammatory cells. c-i Show immunostainings results that are positive for CD68 (c) and CD168 (d). S-100 (e), CD1a (f), Lagerin (g) and Melan-A (i) are negative. The Ki-67 proliferation index is 15% (h)\n\n\n\nWe gave the patient sirolimus orally to treat TSC. After 3 months, the multiple nodules disappeared and hypomelanotic macule in the abdomen did not show any change (Fig. 1e-f). We were surprised that sirolimus had a significant effect on JXG. We performed whole-exome sequencing and identified TSC1 mutation (c.2356C > T, p.R786*) in both paraffin block tissue and blood samples (Fig. 1b). No other disease-causing mutations were found. We considered JXG to be a new skin lesion of TSC.\n\nSirolimus was well tolerated without evident adverse reactions. After 1 year of administering sirolimus, no cutaneous nodule appeared. Cardiac ultrasound showed a reduction of cardiac rhabdomyoma in the left ventricular cavity (2 mm × 4 mm). Blood routine, liver functions, kidney functions and serum electrolytes were normal. The patient continued oral sirolimus and followed up regularly every 6 months.\n\nDiscussion\nRegarding to cutaneous nodules, a broad spectrum of differential diagnosis should be considered by immunohistochemical staining. S100, CD1a, Langerin are negative, thereby distinguishing the condition from Langerhans cell histiocytosis. S-100, HMB-45 and Melan-A are negative, thereby distinguishing the condition from malignant melanoma. The pathological finding is consistent with JXG.\n\nThrough whole-exome sequencing in paraffin block tissue, we overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC. The pathogenesis of JXG is unknown. Previously reported on patients with JXG have not performed whole-exome gene sequencing. Thus, no TSC1 or TSC2 mutations have been reported in JXG patients in previous studies.\n\nThe etiology of TSC involves the mutation in TSC1 (9q34, encoding hamartin) or TSC2 (16p13.3, encoding tuberin). Hamartin and tuberin form a functional unit that is involved in inhibiting the mammalian target of rapamycin (mTOR) pathway [8]. JXG patients have a prevalence of neurofibromatosis type 1 (NF1) that reached 18–30% [9]. Study reported that the mTOR pathway is hyperactivated in NF1 patients and mouse models [10]. We hypothesize that JXG may be related to mTOR pathway. Considering the finding in our case, we recommend that JXG patients should perform histopathological examination and genetic testing. Further studies are needed to find the relationship between JXG and the mTOR pathway.\n\nSirolimus selectively inhibits mTOR signaling. Clinical trials and scientific evidence support the use of sirolimus in TSC patients with specific manifestations, including SEGA and skin lesions [2–4]. Darcy AK et al. conducted a multicenter clinical investigation on the safety of mTOR inhibitors in TSC patients before the age of 2 years [11]. Sirolimus has been used to treat fetus with TSC and presenting cardiac rhabdomyoma [12]. Our patient started sirolimus treatment at the age of 8 months and the symptoms improved significantly, especially the JXG skin lesions.\n\nThe patient had pulmonary isolated subpleural nodule in the left lower lobe as observed via chest CT. The round mass in pulmonary nodules could be a sign of lung tumors or lesions. The lesion was not confirmed, because the parents of patient refused to perform lung biopsy. Annual CT test was recommended to the patient.\n\nConclusion\nThis is the first report of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. The abovementioned findings expand the phenotype of skin in TSC and contribute to the elucidation of JXG pathogenesis and treatment.\n\nAbbreviations\nJXGJuvenile xanthogranuloma\n\nTSCTuberous sclerosis complex\n\nSEGASub-ependymal giant cell astrocytoma\n\nCTComputed tomography\n\nMRIMagnetic resonance imaging\n\nCD68Cluster differentiation 68\n\nHMB45Langerin, human melanoma black 45\n\nmTORMammalian target of rapamycin\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors are grateful to the patient and his relatives for their efforts.\n\nAuthors’ contributions\nQL and LPZ participated in the study design, clinical evaluation of patients, data analysis, and manuscript drafting. XYS contributed in the data analysis and manuscript drafting. YYW, MNZ, WZW, JW, QHW and HMC conducted data collection. All authors read and approved the final manuscript.\n\nFunding\nThis work is supported by the National Natural Science Foundation of China (81471329 and 81771389).\n\nAvailability of data and materials\nAll the data in this study were included in the published article.\n\nEthics approval and consent to participate\nThis study is performed according the international rules of acceptable clinical trials, and informed consent is obtained from the parents of the patient.\n\nConsent for publication\nThe parents of the patient have signed consent for publication.\n\nCompeting interests\nThe authors report no disclosures relevant to the manuscript.\n==== Refs\nReferences\n1. Henske EP Jozwiak S Kingswood JC Sampson JR Thiele EA Tuberous sclerosis complex Nat Rev Dis Primers 2016 2 16035 10.1038/nrdp.2016.35 27226234 \n2. Cardamone M Flanagan D Mowat D Kennedy SE Chopra M Lawson JA Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex J Pediatr 2014 164 5 1195 1200 10.1016/j.jpeds.2013.12.053 24518170 \n3. Wataya-Kaneda M Ohno Y Fujita Y Yokozeki H Niizeki H Ogai M Sirolimus gel treatment vs placebo for facial angiofibromas in patients with tuberous sclerosis complex: a randomized clinical trial JAMA Dermatol 2018 154 7 781 788 10.1001/jamadermatol.2018.1408 29800026 \n4. Gupta N, Lee HS, Young LR, Strange C, Moss J, Singer LG, et al. Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis. Eur Respir J. 2019;53(4):1802066.\n5. Meyer M Grimes A Becker E Browning J Assanasen C Libow L Systemic juvenile xanthogranuloma: a case report and brief review Clin Exp Dermatol 2018 43 5 642 644 10.1111/ced.13403 29427327 \n6. Northrup H Krueger DA Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference Pediatr Neurol 2013 49 4 243 254 10.1016/j.pediatrneurol.2013.08.001 24053982 \n7. van Slegtenhorst M de Hoogt R Hermans C Nellist M Janssen B Verhoef S Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34 Science 1997 277 5327 805 808 10.1126/science.277.5327.805 9242607 \n8. Samuels JA Treatment of renal angiomyolipoma and other hamartomas in patients with tuberous sclerosis complex Clin J Am Soc Nephrol 2017 12 7 1196 1202 10.2215/CJN.08150816 28302901 \n9. Ferrari F Masurel A Olivier-Faivre L Vabres P Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type 1 JAMA Dermatol 2014 150 1 42 46 10.1001/jamadermatol.2013.6434 24258576 \n10. Helfferich J Nijmeijer R Brouwer OF Boon M Fock A Hoving EW Neurofibromatosis type 1 associated low grade gliomas: a comparison with sporadic low grade gliomas Crit Rev Oncol Hematol 2016 104 30 41 10.1016/j.critrevonc.2016.05.008 27263935 \n11. Krueger DA Capal JK Curatolo P Devinsky O Ess K Tzadok M Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): multicentre clinical experience Eur J Paediatr Neurol 2018 22 6 1066 1073 10.1016/j.ejpn.2018.06.007 30005812 \n12. Park H, Chang CS, Choi SJ, Oh SY, Roh CR. Sirolimus therapy for fetal cardiac rhabdomyoma in a pregnant woman with tuberous sclerosis. Obstet Gynecol Sci. 2019;62(4):280–4.\n\n",
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"abstract": "We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection.\n\n\n\nPatients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed.\n\n\n\nSixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin).\n\n\n\nConsecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.",
"affiliations": "Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.;Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.",
"authors": "Liu|Jing|J|;Ji|Chao-Ran|CR|;Li|Yue-Yue|YY|;Qiao|Chen|C|;Hu|Jun-Nan|JN|;Wan|Meng|M|;Lin|Min-Juan|MJ|;Lin|Bo-Shen|BS|;Wang|Juan|J|;Zha|Jing|J|;Li|Li-Xiang|LX|;Zuo|Xiu-Li|XL|0000-0001-9556-8771",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/ctg.0000000000000391",
"fulltext": "\n==== Front\nClin Transl Gastroenterol\nClin Transl Gastroenterol\nCLTG\nCT9\nCT9\nClinical and Translational Gastroenterology\n2155-384X\nWolters Kluwer Philadelphia, PA\n\n34397042\nCTG-20-0628\n10.14309/ctg.0000000000000391\n00010\nArticle\nStomach\nTwo Different 1-Week Quadruple Therapies Given Back-to-Back Consecutive Therapy for Difficult-to-Treat Helicobacter pylori Infection: A Pilot Study\nLiu Jing MD 1231158600694@qq.com\n\nJi Chao-Ran MD 123jichaoran6@163.com\n\nLi Yue-Yue MD 123lyynqj@126.com\n\nQiao Chen MD 123sduqiaoch@163.com\n\nHu Jun-Nan MD 123hujn0222@163.com\n\nWan Meng BD 12317865192519@163.com\n\nLin Min-Juan BD 12317853138356@163.com\n\nLin Bo-Shen BD 123tvxqshinee2012@163.com\n\nWang Juan BD 123wjwangjuan163@163.com\n\nZha Jing BD 1232818443872@qq.com\n\nLi Li-Xiang PhD 123\nhttp://orcid.org/0000-0001-9556-8771\nZuo Xiu-Li MD, PhD 123\n1 Department of Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China;\n2 Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China;\n3 Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Jinan, Shandong, China.\nCorrespondence: Xiu-Li Zuo, MD, PhD. E-mail: zuoxiuli@sdu.edu.cn.\n8 2021\n16 8 2021\n12 8 e0039115 12 2020\n09 7 2021\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology\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-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\nINTRODUCTION:\n\nWe aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection.\n\nMETHODS:\n\nPatients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed.\n\nRESULTS:\n\nSixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3–7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin).\n\nDISCUSSION:\n\nConsecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nThe global prevalence of Helicobacter pylori is approximately 40% (1). As a common pathogen leading to various gastrointestinal diseases, H. pylori eradication alleviates gastric atrophy and prevents metachronous gastric cancer (2–5). However, with increasing antibiotic resistance, H. pylori eradication has become a therapeutic challenge (6,7).\n\nCurrently, 14-day bismuth-containing quadruple therapies (BQTs) are recommended as the first-line therapeutic regimen in areas where antibiotic resistance is high (8–10). After BQT failure, fewer options of subsequent rescue regimens are available. Currently, traditional treatment regimens fail to achieve satisfactory cure rates (11). The posttreatment resistance rates of H. pylori to clarithromycin (58.3%), metronidazole (99.2%), and levofloxacin (52.3%) have increased significantly in China (12), reducing the efficacy of all non-BQTs. For this reason, in a certain proportion of patients, the infection cannot be eliminated after multiple rounds of treatment, and they are often left untreated because there are no other conventional options (13).\n\nIn clinical trials involving patients with refractory H. pylori infection, antimicrobial susceptibility-guided therapies failed to achieve satisfactory efficacies. We conducted a randomized controlled trial (RCT) for the second-line or third-line therapy of H. pylori to compare the efficacy of antimicrobial susceptibility-guided with empirical BQTs. The eradication rates in both groups were <80% in intention-to-treat (ITT) analysis (14). However, antimicrobial susceptibility testing is time-consuming, expensive, and has certain technical prerequisites.\n\nA novel rescue regimen is urgently required to solve this therapeutic dilemma in China. The aim of this pilot study was to evaluate the efficacy and tolerability of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in Chinese patients with difficult-to-treat H. pylori infection.\n\nMETHODS\n\nStudy design and participants\n\nThis pilot study was approved by the Ethics Committee of Qilu Hospital of Shandong University (number 2019186), and the Declaration of Helsinki was followed. All patients provided written informed consent before recruitment (Clinical Trials.gov, number NCT03658733).\n\nConsecutive patients aged 18–70 years were eligible for this study if they were confirmed to have persistent H. pylori infection and had failed >3 rounds of standard quadruple regimens in previous eradication attempts. Before enrollment, H. pylori infection was diagnosed using at least 2 of the following tests: 13C‐urea breath test (13C‐UBT), histology, and rapid urease test. Exclusion criteria were as follows: (i) history of gastrectomy, acute gastrointestinal bleeding, or gastric malignancy; (ii) unclear previous eradication regimens; (iii) contraindication or allergy to any study drugs administered in the regimens; (iv) pregnancy or lactation; (v) severe concurrent diseases; (vi) alcohol abuse or drug addiction; (vii) use of proton pump inhibitors (PPIs), histamine-2 receptor antagonists, bismuth-containing drugs, or antibiotics in the preceding 4 weeks; (viii) unwillingness or intolerance to gastroscopy or H. pylori culture; (ix) compliance of <90% during any previous eradication; and (x) inability to sign informed consent.\n\nProcedures\n\nPatient demographics, characteristics, and previous eradication regimens were recorded at entry. Previous antibiotic use was defined as the continuous use of antibiotics whether oral or intravenous for >14 days for any reason besides H. pylori eradication. In addition, physical examinations, vital signs, hematology, serum chemistry, and electrocardiography were performed before gastroscopy. All patients underwent gastroscopy, H. pylori culture, and antimicrobial susceptibility testing before treatment.\n\nH. pylori culture and antimicrobial susceptibility testing\n\nAt gastroscopy, 2 biopsy specimens were obtained from antrum and corpus for H. pylori culture. The specimens were maintained at −80 °C in brain-heart infusion broth (Oxoid, Basingstoke, UK) and then immediately sent to Zhiyuan Medical Inspection Institute (Hangzhou, Zhejiang, China). Specimens were fully ground and then cultured on brain-heart infusion agar medium (Oxoid, Basingstoke, UK) with 5% sheep blood at 37 °C under microaerophilic conditions (85% N2, 10% CO2, 5% O2) for 3–7 days. The H. pylori colonies were identified by Gram-negative staining and positivity for urease, cytochrome oxidase, and catalase activity.\n\nSusceptibility to commonly used antibiotics against H. pylori was evaluated using the standard agar plate dilution method. After 72 hours of cultivation at 37 °C under microaerophilic conditions, the minimal inhibitory concentration was determined based on the lowest antibiotic concentration that inhibited visible bacterial growth. The reference strain ATCC43504 (NCTC11637) was included as a quality control. The minimal inhibitory concentrations of clarithromycin (1 μg/mL), metronidazole (8 μg/mL), amoxicillin (1 μg/mL), levofloxacin (1 μg/mL), furazolidone (1 μg/mL), and tetracycline (1 μg/mL) were in accordance with the criteria of the US Clinical and Laboratory Standards Institute.\n\nEradication therapy and follow-up\n\nPatients were randomly assigned to receive either esomeprazole or rabeprazole in a ratio of 1:1 according to a predetermined random number sequence generated by a computer. All patients were administered consecutive therapy containing esomeprazole 40 mg/rabeprazole 20 mg, amoxicillin 1,000 mg, furazolidone 100 mg, and tetracycline 500 mg for the first 7 days, followed by colloidal bismuth pectin 200 mg in place of furazolidone for another 7 days. PPIs and colloidal bismuth pectin were administrated 30 minutes before breakfast and dinner; amoxicillin was administrated 30 minutes after breakfast and dinner; tetracycline was given 4 times daily (30 minutes after breakfast/lunch/dinner and before bed); and furazolidone 3 times daily (30 minutes after breakfast/lunch/dinner).\n\nBefore treatment, patients received both oral and written medical instructions, including detailed therapy regimens, possible treatment-emergent adverse events (TEAEs), and the importance of rational medication use. Patients who experienced discomforts were instructed to contact the investigators immediately. All patients were asked to return within 3 days of the end of treatment. Adherence and adverse symptoms were evaluated using their medication diaries and laboratory tests.\n\nOutcomes\n\nEight weeks after completion of the regimen, H. pylori infection status was evaluated using 13C-UBT, whereas of histamine-2 blocker, PPIs, antimicrobials, and bismuth-containing drugs for at least 4 weeks. Successful H. pylori eradication was defined as a negative 13C-UBT result with a delta‐over‐baseline value of <0.4%. The primary endpoint was the H. pylori cure rate. The secondary outcomes were the rates of drug-related TEAEs, compliance, and resistance to antibiotics. Physical examinations, vital signs, hematology, and serum chemistry were performed after the treatment. TEAEs and concomitant medications were observed synchronously during therapeutic sessions. All TEAEs were coded and categorized (MedDRA v.19.0) for system organ class and preferred term among patients who received a minimum of 1 dose of the study drug. The relationships of the TEAEs to the study drugs were also recorded, as were their severity and the necessity of early treatment discontinuation. Low compliance was identified when <90% of the pills had been taken.\n\nStatistical analysis\n\nWe assumed that the eradication rate of consecutive therapy was 88% (15). Given a 95% confidence interval of 79.8%–96.2%, a sample size of 61 patients was required. Assuming that 5% would be lost to follow-up, a minimum of 65 patients was required.\n\nContinuous variables were described as mean ± SD, and percentages were calculated for categorical variables. The H. pylori eradication rates were calculated on an ITT basis and a per-protocol (PP) basis. All eligible patients were included in the ITT analysis. All protocol violators, for whom a posttreatment 13C‐UBT was unavailable, were excluded from PP analysis, as were those with low compliance. Data were analyzed using R software (version 3.6.0; R Foundation for Statistical Computing, Vienna, Austria).\n\nThis pilot study was approved by the Ethics Committee of Qilu Hospital of Shandong University (number 2019186).\n\nRESULTS\n\nPatients\n\nThe study flow is shown in Figure 1. From December 2018 to August 2020, 102 patients were screened for eligibility. Of these, 65 met the selection criteria and received consecutive treatments at Qilu Hospital of Shandong University. The demographic and clinical characteristics of the study population in the ITT analysis are listed in Table 1. On average, patients had undergone 3.6 previous H. pylori treatment courses (range 3–7). Among their medication histories, multiple antibiotics had previously been administered, including clarithromycin, amoxicillin, metronidazole, and levofloxacin. In total, 87.7% of the enrolled patients reported a previous history of furazolidone medication and 43.1% had a history of tetracycline medication. One patient withdrew from this study, and 2 patients discontinued treatment. One patient with poor compliance was excluded from PP analysis, despite a negative follow-up 13C-UBT.\n\nFigure 1. Consolidated standards of reporting trials flowchart of this study. ITT, intention-to-treat; PP, per-protocol.\n\nTable 1. Demographic and clinical characteristics of the enrolled patients\n\nCharacteristic\tConsecutive therapy (N = 65)\t\nAge (yr; mean ± SD)\t49.7 ± 8.8\t\nMale\t41 (63.1%)\t\nSmokinga\t5 (7.7%)\t\nDrinkingb\t9 (13.9%)\t\nBMI, kg/m2, mean ± SD\t23.3 ± 3.4\t\nNSAID user\t3 (4.6%)\t\nComplication\t7 (10.8%)\t\n Diabetes mellitus\t4 (6.2%)\t\n Hypertension\t5 (7.7%)\t\nEndoscopic finding\t\t\n Atrophy gastritis\t42 (64.6%)\t\n Peptic ulcer\t4 (6.2%)\t\n Gastric intraepithelial neoplasia\t3 (4.6%)\t\nFamilial history of gastric cancer\t12 (18.5%)\t\nTimes of eradication failure\t\t\n 3\t37 (56.9%)\t\n 4\t18 (27.7%)\t\n ≥5\t10 (15.4%)\t\nPrevious clarithromycin usec\t65 (100%)\t\nPrevious amoxicillin usec\t65 (100%)\t\nPrevious metronidazole usec\t65 (100%)\t\nPrevious levofloxacin usec\t65 (100%)\t\nPrevious furazolidone usec\t57 (87.7%)\t\nPrevious tetracycline usec\t28 (43.1%)\t\nClarithromycin resistanced\t31 (60.8%)\t\nAmoxicillin resistanced\t1 (2.0%)\t\nMetronidazole resistanced\t51 (100%)\t\nLevofloxacin resistanced\t36 (70.6%)\t\nFurazolidone resistanced\t0\t\nTetracycline resistanced\t0\t\nBMI, body mass index; NSAID, nonsteroidal anti-inflammatory drug.\n\na An individual who smoked more than 1 cigarette every day for more than 1 yr was considered as a smoker.\n\nb An individual who drank alcohol more than once per week for at least 12 mo was defined as a drinker.\n\nc Previous antibiotic use was identified in patients who had continuous antibiotics (oral or intravenous agents for ≥14 d) for any reason besides H. pylori eradication.\n\nd Strains were isolated from 51 patients.\n\nEradication rates\n\nSuccessful H. pylori eradication was confirmed in 59 patients. The overall eradication rates of consecutive therapy using ITT and PP analyses were 90.8% (59/65) and 95.1% (58/61), respectively. The eradication rates of esomeprazole-based and rabeprazole-based regimens were 90.6% (29/32) and 90.9% (30/33), respectively, using ITT analysis and 96.7% (29/30) and 93.6% (29/31) using PP analysis. The eradication rate was 92.2% (47/51) in H. pylori-isolated participants. The eradication rates based on the number of previous failed regimens are listed in Table 2. Notably, H. pylori strains from 28 patients were resistant to at least 3 commonly used antibiotics, and 92.9% of these patients achieved successful eradication. The eradication rates were similar between the fourth- and fifth-line attempts, and they were not decreased when the regimen was prescribed after 5 or more eradication failures.\n\nTable 2. Eradication rates of consecutive therapy according to previous regimen failures\n\nVariable\tOverall eradication rates\t4th-line\t≥5th-line\t\nITT analysis\t90.8% (59/65)\t86.5% (32/37)\t96.4% (27/28)\t\nPP analysis\t95.1% (58/61)\t91.4% (32/35)\t100% (26/26)\t\nITT, intention-to-treat; PP, per-protocol.\n\nAdverse effects and compliance\n\nIn the safety analysis, the incidence of TEAEs was 39.1% (25/64), with 35.9% of patients (23/64) reporting only mild TEAEs and 3.1% (2/64) reporting TEAEs of moderate severity. No serious adverse events (SAEs) were observed. None of the patients received drug or nonpharmaceutical treatment for TEAEs. Two patients experienced TEAEs that led to study drug discontinuation, and they refused to undergo follow-up UBT; 1 patient had drug-related headache, dizziness, nausea, and vomiting on the ninth day of medications. The others reported headache, arthralgia, pyrexia, abdominal pain, diarrhea, nausea, and vomiting on day 2 after eating expired food and then was diagnosed with acute gastroenteritis by investigators, which was unrelated to the eradication therapy.\n\nOverall, 23.4% (15/64) of patients reported drug-related TEAEs judged by investigators as having a reasonable suspected causal relationship to the study drug. Gastrointestinal disorders (nausea and abdominal pain) were the most common drug-related SOCs with an incidence of 14.1% (9/64). The incidences of drug-related TEAEs for the first week (furazolidone-based) and second week (bismuth-based) quadruple therapy were 15.6% (10/64) and 10.9% (7/64), respectively. All drug-related symptoms resolved spontaneously after treatment completion or premature drug cessation.\n\nRegarding laboratory abnormalities, 2 patients showed mild liver function abnormality, which was caused by nonalcoholic fatty liver disease in 1 patient. A 46-year-old man had mild leukopenia (white cell count 2.1 × 109/L and neutrophils 1.3 × 109/L), which was considered to be related to esomeprazole. All TEAEs disappeared at the posttreatment week 4 visit, and no drug intervention was conducted. No clinically relevant changes were observed in electrocardiogram or vital signs.\n\nPatients with good compliance accounted for 95.3% (61/64). An overview of TEAEs and compliance with consecutive therapy is listed in Table 3.\n\nTable 3. TEAEs and patient compliance with 14-day consecutive therapy\n\nVariable\tConsecutive therapy\t\nTotal no. of TEAEs\t41\t\nNo. of drug-related TEAEs\t46.3% (19/41)\t\nMild\t84.2% (16/19)\t\nModerate\t15.8% (3/19)\t\nSevere\t0\t\nSerious adverse events\t0\t\nNo. of patients with TEAEs\t39.1% (25/64)\t\nNo. of patients with drug-related TEAEs\t23.4% (15/64)\t\nHeadache\t3.1% (2/64)\t\nDizziness\t1.6% (1/64)\t\nNausea\t6.3% (4/64)\t\nAbdominal pain\t3.1% (2/64)\t\nDiarrhea\t3.1% (2/64)\t\nDyspepsia\t3.1% (2/64)\t\nVomiting\t1.6% (1/64)\t\nFatigue\t1.6% (1/64)\t\nLeukopenia\t1.6% (1/64)\t\nEyelid edema\t1.6% (1/64)\t\nVision blurred\t1.6% (1/64)\t\nAST increased\t1.6% (1/64)\t\nDropout because of TEAEs\t3.1% (2/64)\t\nDrug-related dropout\t1.6% (1/64)\t\nCompliance\t95.3% (61/64)\t\nCompliance was indicative of patients taking at least 90% of the pills.\n\nAST, aspartate aminotransferase; TEAE, treatment-emergent adverse event.\n\nSusceptibility results\n\nOverall, H. pylori were successfully isolated in 78.5% (51/65) of the patients. The resistance rates of H. pylori isolates toward clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to furazolidone or tetracycline (Table 1). The overall triple drug resistance rate (clarithromycin, metronidazole, and levofloxacin) was 54.9% (28/51) and further increased to 71.4% (5/7) among patients with 5 previous therapy failures.\n\nDISCUSSION\n\nFailure to cure H. pylori infection presents a difficult clinical therapeutic problem, especially in patients with precancerous lesions who have experienced several failed attempts with combined common antibiotics. In this pilot study, consecutive eradication therapy containing 3 antibiotics known to have the highest resistance barrier was developed to treat those who had experienced >3 previous eradication failures; the results showed that the regimen achieved good therapeutic efficacy (95.1% by PP and 90.8% by ITT), it was tolerable by most patients, and compliance was good in China. The incidence of drug-related TEAEs was similar to that of previously reported TEAEs (15,16).\n\nFactors that may cause treatment failure include presence of multiple antibiotic resistance, inadequate suppression of gastric acid secretion, poor compliance, and inadequate therapy duration. The enrolled patients had already failed multiple quadruple eradication regimens involving key antibiotics. Moreover, 96.9% of patients (63/65) had received failed quadruple eradication with at least 2 low-resistance antibiotics, such as amoxicillin, furazolidone, and tetracycline. Of these, 14 patients (21.5%) have experienced failed regimens containing amoxicillin, tetracycline, and a PPI. In China, the resistant rates of H. pylori to amoxicillin, tetracycline, and furazolidone are lower than 5% (14,17), and reuse of these antibiotics rarely results in subsequent resistance. The consecutive regimen includes 3 antibiotics known to have the highest resistance barrier to achieve satisfactory efficacy in a difficult-to-treat group. In addition, 57 patients (87.7%) had received at least 1 failed eradication attempt containing amoxicillin 1,000 mg and furazolidone 100 mg twice daily. Regimens containing an increased dose of furazolidone (100 mg 3 or 4 times daily), based on previous data (18–20), could achieve satisfactory efficiency. This should be taken into account because the short duration of these treatments did not increase SAEs (21,22). Without increasing the total dose (<2.8 g), the daily dose of furazolidone was increased to 300 mg for 7 days in this study. Finally, amoxicillin 500 mg 4 times daily may further increase the eradication rate, although it may also lower patient compliance because it involves complex regimens. Consecutive therapy achieved a cure rate of 95.1% in the PP population, an encouraging result when considering that almost every patient received the same 2 low-resistance antibiotics previously used. This may be because no drug resistance was noted for these 3 antimicrobials. Moreover, the efficacy did not decrease with an increasing number of previous failures.\n\nPrevious studies have shown that double-dose esomeprazole regimens increase the efficacy of H. pylori eradication therapy (23,24). Esomeprazole-based and rabeprazole-based regimens have shown little difference in efficacy among different CYP2C19 genotypes and are recommended for rescue therapies in Asian populations (25–28). Thus, in this preliminary study, we selected esomeprazole 40 mg and rabeprazole 20 mg twice daily to obtain adequate acid suppression. However, as a novel potassium-competitive acid blocker, vonoprazan exhibits a more rapid, sustained, and profound acid-inhibitory effect compared with esomeprazole and rabeprazole in Japanese individuals, regardless of CYP2C19 polymorphisms. Further studies will undertake vonoprazan because of the established importance of acid suppression in improving the efficacy of amoxicillin against H. pylori.\n\nThe furazolidone-containing regimen showed no increased risk of drug-related TEAEs or SAEs compared with other antibiotic regimens, despite variable daily doses, medication duration, and regimen forms (29,30). Liang et al. (19) showed that the regimens containing 300 mg of furazolidone per day were well tolerated and achieved ≥90% cure rates. Severe TEAEs are more common in regimens containing high doses (≥200 mg twice daily) or long durations (>7 days). Tetracycline-containing and furazolidone-containing regimens may have good efficacy with only occasionally SAEs (31,32). The incidence of SAEs is rare (0.4‰), and penicillin allergy cannot be completely ruled out (30). Meanwhile, amoxicillin-based and furazolidone-based therapies have also demonstrated high cure rates with a favorable safety profile (19,33). Significantly, dual therapies including high doses of PPIs and amoxicillin have proven to be safe and effective (34,35). Our current findings showed that consecutive therapy was well tolerated in the study population. A similar incidence of drug-related TEAEs has been observed previously (15,31). One-week furazolidone quadruple therapy has a higher incidence of drug-related TEAEs probably because of the increased daily dose of furazolidone 300 mg. Notably, all adverse events were mild-to-moderate with a low occurrence of drug-related discontinuation. The most common drug-related TEAEs were nausea (6.3%), and similar results have been reported in previous studies.\n\nGood compliance with treatment could improve the H. pylori cure rate (36,37). Despite the slightly complex regimen, good compliance was achieved in 95.3% of the patients, probably attributed to the detailed education by investigators, high motivation of patients, and exclusion of patients with poor compliance during previous therapies.\n\nThe success rate of H. pylori isolation (78.5%, 51/65) was not ideal. Previous studies found that patients with autoimmune gastritis are often misdiagnosed with false-positive results in 13C-UBT and rapid urease test because of the presence of other urease-containing bacteria (38–40). Furthermore, bacteria with structural similarity to H. pylori may led to the false-positive histology result (41). No patients with pernicious anemia were found in our study population. Antiparietal cell antibody and anti-intrinsic factor antibody tests were not performed, and prolonged transport may influence the optimal recovery of the organisms from gastric biopsy specimens. Finally, among patients with good compliance, the eradication rates were similar in the positive-culture and negative-culture groups (95.8% vs 92.3%).\n\nThere were some methodological weaknesses that may restrict the validity of our results. First, as this study was a single-arm pilot study, it was not possible to compare the eradication efficacy. The occurrence of drug-related TEAEs was similar between consecutive therapy in this study and bismuth-containing quadruple therapy in a previous study (15). Large-scale, multicenter RCTs must be conducted to confirm these results in regions with different patterns of resistance. Second, CYP2C19 polymorphisms were not tested before initiating treatment. Nevertheless, esomeprazole 40 mg or rabeprazole 20 mg twice daily was selected to ensure sufficient acid suppression because CYP2C19 has a minimal significant effect on the esomeprazole-based or rabeprazole-based therapies. However, it remains a major weakness of our study because both esomeprazole and rabeprazole were used simultaneously. Third, although drug-related TEAEs were carefully assessed, the dynamic changes of gut microbiota were not monitored while the relatively broad-spectrum antibiotics were used. It is still unknown whether this regimen affects the antimicrobial resistance of Escherichia coli and its metabolic parameters. Finally, tetracycline, furazolidone, and bismuth compounds are not always available in many areas. Considering the relatively low cost of these drugs, reasonable application of these drugs could effectively reduce the cost of eradication.\n\nThis pilot study showed that even after >previous H. pylori eradication failures in a specific population with high levels of multiple antimicrobial resistance, consecutive therapy including amoxicillin, tetracycline, and furazolidone, was feasible to achieve a good eradication rate (>90%) with acceptable tolerability and good compliance, regardless of a medication history of these 3 antibiotics. These findings should be further elucidated using multicenter RCTs for clinical application in Chinese patients.\n\nCONFLICTS OF INTEREST\n\nGuarantor of the article: Xiu-Li Zuo, MD, PhD.\n\nSpecific author contributions: Jing Liu, MD, and Chao-Ran Ji, MD, contributed equally to this work. J.L., C-R.J., and Y-Y.L.: research design and drafting of the article. C.Q., J-N.H., M.W., B-S.L., M-J.L., J.W., and J.Z.: data collection. J.L. and C-R.J.: analysis and interpretation of data. X-L.Z. provided critical revision of the article. All authors read and approved the final article.\n\nFinancial support: This investigation was funded by the National Natural Science Foundation of China (81770538, 81570485) and Key Research and Development Program of Shandong Province (2017CXGC1215). This work was independent of the funding.\n\nPotential competing interests: None to report.\n\nInstitutions participating in the study: The endoscopy unit, Qilu Hospital of Shandong University, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China.\n\nTrial identification number:ClinicalTrials.gov ID: NCT03658733, https://clinicaltrials.gov/ct2/show/NCT03658733Study Highlights\n\nWHAT IS KNOWN\n\n✓ The posttreatment resistance rates of Helicobacter pylori are increasing.\n\n✓ Traditional fourth-line regimens fail to achieve satisfactory cure rates of H. pylori infection.\n\nWHAT IS NEW HERE\n\n✓ Consecutive therapy achieves a good cure rate in difficult-to-treat H. pylori infections.\n==== Refs\nREFERENCES\n\n1. Zamani M Ebrahimtabar F Zamani V . Systematic review with meta-analysis: The worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther 2018;47 :868–76.29430669\n2. Choi IJ Kim CG Lee JY . Family history of gastric cancer and Helicobacter pylori treatment. N Engl J Med 2020;382 :427–36.31995688\n3. Chiang TH Chang WJ Chen SL Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: A long-term cohort study on Matsu Islands. Gut 2020;70 :243–250.32792335\n4. Choi IJ Kook MC Kim YI . Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N Engl J Med 2018;378 :1085–95.29562147\n5. Kim HJ Kim YJ Seo SI . Impact of the timing of Helicobacter pylori eradication on the risk of development of metachronous lesions after treatment of early gastric cancer: A population-based cohort study. Gastrointest Endosc 2020;92 :613–22.e1.32473251\n6. Savoldi A Carrara E Graham DY . Prevalence of antibiotic resistance in Helicobacter pylori: A systematic review and meta-analysis in world health organization regions. Gastroenterology 2018;155 :1372–82.e17.29990487\n7. Fallone CA Moss SF Malfertheiner P . Reconciliation of recent Helicobacter pylori treatment guidelines in a time of increasing resistance to antibiotics. Gastroenterology 2019;157 :44–53.30998990\n8. Chey WD Leontiadis GI Howden CW . ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 2017;112 :212–39.28071659\n9. Fallone CA Chiba N van Zanten SV . The toronto consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology 2016;151 :51–69.e14.27102658\n10. Malfertheiner P Megraud F O'Morain CA . Management of Helicobacter pylori infection-the Maastricht V/florence consensus report. Gut 2017;66 :6–30.27707777\n11. Graham DY Fischbach L . Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010;59 :1143–53.20525969\n12. Liu DS Wang YH Zhu ZH Characteristics of Helicobacter pylori antibiotic resistance: Data from 4 different populations. Antimicrob Resist Infect Control 2019;8 :192–8.31798838\n13. Gisbert JP Pajares JM . Review article: Helicobacter pylori “rescue” regimen when proton pump inhibitor-based triple therapies fail. Aliment Pharmacol Ther 2002;16 :1047–57.12030945\n14. Ji CR Liu J Li YY Susceptibility-guided quadruple therapy is not superior to medication history-guided therapy for the rescue treatment of Helicobacter pylori infection: A randomized controlled trial. J Dig Dis 2020; 21 :549–557.32833285\n15. Yang J Zhang Y Fan L . Eradication efficacy of Modified dual therapy compared with bismuth-containing quadruple therapy as a first-line treatment of Helicobacter pylori. Am J Gastroenterol 2019;114 :437–45.30807294\n16. Gisbert JP Castro-Fernandez M Perez-Aisa A Fourth-line rescue therapy with rifabutin in patients with 3 Helicobacter pylori eradication failures. Aliment Pharmacol Ther 2012;35 :941–7.22372560\n17. Zamani M Rahbar A Shokri-Shirvani J . Resistance of Helicobacter pylori to furazolidone and levofloxacin: A viewpoint. World J Gastroenterol 2017;23 :6920–2.29085236\n18. Lu H Zhang W Graham DY . Bismuth-containing quadruple therapy for Helicobacter pylori: Lessons from China. Eur J Gastroenterol Hepatol 2013;25 :1134–40.23778309\n19. Liang X Xu X Zheng Q . Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study. Clin Gastroenterol Hepatol 2013;11 :802–7.e1.23376004\n20. Cheng H Hu FL . Furazolidone, amoxicillin, bismuth and rabeprazole quadruple rescue therapy for the eradication of Helicobacter pylori. World J Gastroenterol 2009;15 :860–4.19230048\n21. Mohammadi M Attaran B Malekzadeh R . Furazolidone, an underutilized drug for H. pylori eradication: Lessons from Iran. Dig Dis Sci 2017;62 :1890–6.28577244\n22. Mokhtare M Hosseini V Tirgar Fakheri H . Comparison of quadruple and triple Furazolidone containing regimens on eradication of Helicobacter pylori. Med J Islam Repub Iran 2015;29 :195.26157713\n23. De Francesco V Ridola L Hassan C Two-week triple therapy with either standard or high-dose esomeprazole for first-line H. pylori eradication. J Gastrointestin Liver Dis 2016;25 :147–50.27308644\n24. Graham DY Lu H Dore MP . Relative potency of proton-pump inhibitors, Helicobacter pylori therapy cure rates, and meaning of double-dose PPI. Helicobacter 2019;24 :e12554.30440097\n25. McNicholl AG Linares PM Nyssen OP . Meta-analysis: Esomeprazole or rabeprazole vs. first-generation pump inhibitors in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 2012;36 :414–25.22803691\n26. Wu IC Wu DC Hsu PI . Rabeprazole- versus esomeprazole-based eradication regimens for H. pylori infection. Helicobacter 2007;12 :633–7.18001406\n27. Kuo CH Wang SS Hsu WH . Rabeprazole can overcome the impact of CYP2C19 polymorphism on quadruple therapy. Helicobacter 2010;15 :265–72.20633187\n28. Lima JJ Thomas CD Barbarino J Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther 2020;109 :1417–1423.32770672\n29. Zhuge L Wang Y Wu S . Furazolidone treatment for Helicobacter pylori infection: A systematic review and meta-analysis. Helicobacter 2018;23 :e12468.29480532\n30. Ji CR Liu J Li YY . Safety of furazolidone-containing regimen in Helicobacter pylori infection: A systematic review and meta-analysis. BMJ Open 2020;10 :e037375.\n31. Zhang Y Gao W Cheng H . Tetracycline- and furazolidone-containing quadruple regimen as rescue treatment for Helicobacter pylori infection: A single center retrospective study. Helicobacter 2014;19 :382–6.24849129\n32. Song C Qian X Zhu Y . Effectiveness and safety of furazolidone-containing quadruple regimens in patients with Helicobacter pylori infection in real-world practice. Helicobacter 2019;24 :e12591.31111641\n33. Zhang YW Hu WL Cai Y . Outcomes of furazolidone- and amoxicillin-based quadruple therapy for Helicobacter pylori infection and predictors of failed eradication. World J Gastroenterol 2018;24 :4596–605.30386109\n34. Yang JC Lin CJ Wang HL . High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection. Clin Gastroenterol Hepatol 2015;13 :895–905.e5.25460556\n35. Tai WC Liang CM Kuo CM . A 14 day esomeprazole- and amoxicillin-containing high-dose dual therapy regimen achieves a high eradication rate as first-line anti-Helicobacter pylori treatment in Taiwan: A prospective randomized trial. J Antimicrob Chemother 2019;74 :1718–24.30768161\n36. Al-Eidan FA McElnay JC Scott MG Management of Helicobacter pylori eradication-the influence of structured counselling and follow-up. Br J Clin Pharmacol 2002;53 :163–71.11851640\n37. Wang T Yang X Li Y . Twice daily short-message-based re-education could improve Helicobacter pylori eradication rate in young population: A prospective randomized controlled study. Helicobacter 2019;24 :e12569.30848868\n38. Furuta T Baba S Yamade M High incidence of autoimmune gastritis in patients misdiagnosed with 2 or more failures of H. pylori eradication. Aliment Pharmacol Ther 2018;48 :370–7.29920721\n39. Terao S Suzuki S Yaita H . Multicenter study of autoimmune gastritis in Japan: Clinical and endoscopic characteristics. Dig Endosc 2020;32 :364–72.31368581\n40. Sabbagh P Mohammadnia-Afrouzi M Javanian M . Diagnostic methods for Helicobacter pylori infection: Ideals, options, and limitations. Eur J Clin Microbiol Infect Dis 2019;38 :55–66.30414090\n41. Patel SK Pratap CB Verma AK . Pseudomonas fluorescens-like bacteria from the stomach: A microbiological and molecular study. World J Gastroenterol 2013;19 :1056–67.23466902\n\n",
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"title": "Two Different 1-Week Quadruple Therapies Given Back-to-Back Consecutive Therapy for Difficult-to-Treat Helicobacter pylori Infection: A Pilot Study.",
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"abstract": "Enterovesical fistula (EVF) is a rare complication of diverticulitis, as well as Crohn's disease, intestinal malignancy, radiotherapy and trauma. EVF formation is associated with inflammation of the involved bowel segments. The current study presents the case of a 35-year-old man with non-Hodgkin's lymphoma who developed pneumaturia, fecaluria and recurrent urinary tract infections following chemotherapy, accompanied by regressive change of the lymphoma. Abdominal computed tomography scans revealed that the terminal ileum had adhered to the bladder wall. The patient underwent exploratory laparotomy and partial resection of the terminal ileum, and EVF was confirmed. Histological examination revealed an inflammatory response but no evidence of residual lymphoma. The diagnosis of EVF is occasionally difficult and requires appropriate radiographic examination. Surgical treatment is recommended.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, R.O.C.;Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, R.O.C.; Department of Radiology, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.;Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, R.O.C.;Division of Hematology and Oncology, Department of Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 32551, Taiwan, R.O.C.;Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, R.O.C.;Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, R.O.C.; Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.",
"authors": "Lee|Yu-Ting|YT|;Chen|Ying-Yuan|YY|;Wu|Chia-Yun|CY|;Chen|Hung-Ming|HM|;Tzeng|Cheng-Hwai|CH|;Chiou|Tzeon-Jye|TJ|",
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"keywords": "complication of chemotherapy; enterovesical fistula; ileovesical fistula; intestinal fistula; non-Hodgkin's lymphoma; urinary fistula",
"medline_ta": "Oncol Lett",
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"title": "Enterovesical fistula caused by regressive change of non-Hodgkin's lymphoma: A case report.",
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"abstract": "We describe a case of atrial fibrillation in which an intracardiac thrombus that could not be prevented with \"low-dose\" dabigatran treatment was resolved by switching to apixaban treatment. Thrombolysis using direct oral anticoagulants (DOACs) could be a therapeutic option for patients with intracardiac thrombi, although the efficacies of different DOACs seem to differ and need further examination.",
"affiliations": "Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.;Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.;Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.;Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.;Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.;Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.;Department of Cardiology Fukuoka Wajiro Hospital Fukuoka Japan.",
"authors": "Koyama|Taku|T|;Otsuka|Yoritaka|Y|0000-0002-0485-8966;Kawahara|Masaaki|M|;Imoto|Yuki|Y|;Nakamura|Keita|K|;Kodama|Sunao|S|;Noguchi|Hiroo|H|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 2846988110.1002/ccr3.933CCR3933Case ReportCase ReportsA left atrial appendage thrombus that developed during prophylactic low‐dose dabigatran treatment resolved after switching to apixaban T. Koyama et al.Koyama Taku \n1\nOtsuka Yoritaka http://orcid.org/0000-0002-0485-8966yotsuka@sugi-hosp.jp \n1\n\n2\nKawahara Masaaki \n1\nImoto Yuki \n1\nNakamura Keita \n1\nKodama Sunao \n1\nNoguchi Hiroo \n1\n1 Department of CardiologyFukuoka Wajiro HospitalFukuokaJapan2 Division of CardiologySugi HospitalFukuokaJapan* Correspondence\n\nYoritaka Otsuka, Division of Cardiology, Sugi Hospital, 950‐1, Takuma, Omuta, Fukuoka, 837‐0916, Japan. Tel: +81‐944‐56‐1119; Fax: +81‐944‐56‐2077; E‐mail: yotsuka@sugi-hosp.jp\n31 3 2017 5 2017 5 5 10.1002/ccr3.2017.5.issue-5711 713 27 9 2016 13 2 2017 05 3 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nWe describe a case of atrial fibrillation in which an intracardiac thrombus that could not be prevented with “low‐dose” dabigatran treatment was resolved by switching to apixaban treatment. Thrombolysis using direct oral anticoagulants (DOACs) could be a therapeutic option for patients with intracardiac thrombi, although the efficacies of different DOACs seem to differ and need further examination.\n\nAnticoagulantsatrial fibrillationleft atrial appendagethrombus source-schema-version-number2.0component-idccr3933cover-dateMay 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:18.05.2017\n==== Body\nIntroduction\nLeft atrial appendage (LAA) or left atrium (LA) thrombi are usually associated with atrial fibrillation (AF) and cause systemic thromboembolism complications. Therefore, patients with AF, particularly those at a high risk of thromboembolism, should receive anticoagulant therapy. Transesophageal echocardiography (TEE) is useful for the detection of LAA thrombi.\n\nCompared to placebo or anti‐platelet therapy, warfarin is more effective in preventing thromboembolism complications in patients with AF 1, 2, 3. Recently, direct oral anticoagulants (DOACs) have been introduced as alternative prophylactics for thromboembolism in patients with nonvalvular AF. DOACs are associated with reduced risk of both stroke and bleeding compared to the standard warfarin 4, 5, 6. However, the differences in the efficacy of various DOACs for preventing intracardiac thrombi have not been studied, although some case reports have shown resolution of LAA thrombi with DOACs 7, 8, 9, 10. Here, we describe a case in which a LAA thrombus was resolved by replacing “low‐dose” dabigatran with apixaban.\n\nCase Report\nA 78‐year‐old man with a history of hypertension was admitted to our hospital for aphasia, dysarthria, and numbness of the left leg. The patient initially received anticoagulant therapy with warfarin, but it was switched to 220 mg/day dabigatran by a private practice doctor over a year ago. A 12‐lead electrocardiogram at admission showed AF along with ST depression and negative T wave in leads V4–V6 and left ventricular hypertrophy. The CHADS2 and CHA2DS2‐VASc scores before cerebral infarction development were 2 and 3, respectively. Transthoracic echocardiography showed normal left ventricular wall motion and was unable to detect an intracardiac thrombus. Brain diffusion‐weighted magnetic resonance imaging on admission showed hyperintense areas in the frontal lobes on both sides, but magnetic resonance angiography showed no stenosis or occlusion in the cerebral arteries. The patient was diagnosed with acute cerebral infarction due to cardiogenic embolism. On day 11 after admission, TEE was performed after treatment of the acute phase of cerebral infarction and showed a large LAA thrombus (16 × 26 mm; Fig. 1A). The patient's weight was 63 kg; serum creatinine level, 0.81 mg/dL (normal range, 0.80–1.20); estimated creatinine clearance, 66 mL/min; and estimated glomerular filtration rate, 69.7 mL/min/1.73 m2. We decided to switch from dabigatran to other DOACs. The patient was eligible for standard‐dose apixaban therapy and did not fulfill any dose reduction criteria. Therefore, 220 mg/day dabigatran was switched to 10 mg/day apixaban on day 15 after admission. The patient was carefully monitored using serial TEE and physical examinations. TEE conducted on day 7 after initiation of apixaban treatment showed no change in the size of the LAA thrombus (Fig. 1B), but that conducted on day 24 did (Fig. 1C); further, TEE conducted on day 56 after initiation of apixaban treatment showed complete resolution of the thrombus (Fig. 1D). The patient had no recurrent stroke and is currently alive without any complications.\n\nFigure 1 Transesophageal echocardiogram (TEE). (A) Left atrial appendage (LAA) thrombus (white arrow) was observed at first presentation. (B) No change of thrombus of LAA on day 7 after apixaban treatment. (C) Reduction in thrombus of LAA (white dotted arrow) on day 24 after apixaban treatment. (D) Complete resolution of LAA thrombus was achieved on day 56 after apixaban treatment.\n\nDiscussion\nNumerous reports have described the resolution of LAA thrombi in patients treated with oral warfarin 1, 2, 3. Contrastingly, it has been reported that warfarin is not very effective in resolving large intracardiac thrombi, and LAA thrombi persist in 44% of patients treated with this drug 11. In addition, patients with persistent LAA thrombi have a poor prognosis 11. Therefore, optimal anticoagulant management is critical in patients with LAA thrombi.\n\nDOACs are superior to warfarin in preventing stroke or systemic embolism in patients with AF and are associated with less bleeding and lower mortality 4, 5, 6. In contrast to the indirect action of warfarin, DOACs directly inhibit thrombin or factor Xa in the coagulant cascade. The inhibition of thrombin prevents its binding to fibrin and fibrin degradation products, whereby DOACs have thrombolytic properties 12. Inhibition of factor Xa blocks the generation of thrombin. Thus, DOACs have the potential not only to prevent de novo thrombi but also to resolve established thrombi. In fact, some case reports have confirmed resolution of LAA or LA thrombi with DOACs 7, 8, 9, 10. In two studies, rivaroxaban 7 and apixaban 10 were used as the first choice of anticoagulant therapy, and two others reported that dabigatran 9 and rivaroxaban 8 were used as the second choice of treatment after failure of warfarin. To the best of our knowledge, this is the first documented case report of LAA thrombus resolution with a switch to apixaban after failed “low‐dose” dabigatran treatment.\n\nIt is important to consider why dabigatran failed to prevent thrombus development, but apixaban effectively dissolved it the thrombus in the present case. First, the mean plasma trough concentration of dabigatran shows a fivefold range of variation 13, 14. In other words, the range of plasma concentrations of dabigatran varies widely among individuals. Second, a low dose of dabigatran may not have been adequate to prevent and resolve the LAA thrombus in our patient, unlike the standard dose of apixaban. Third, direct factor Xa inhibitors and direct thrombin inhibitors may have different in vivo effects on thrombolysis. Recently, it has been reported that direct factor Xa inhibitors inhibit thrombin generation and platelet aggregation derived via the tissue factor pathway to a greater extent than direct thrombin inhibitors do 15. Switching to other DOACs may be an alternative option if a DOAC fails to prevent and resolve LAA thrombi. However, these findings need to be confirmed through more large‐scale studies.\n\nIn conclusion, we described a case of AF in which an LAA thrombus that could not be prevented with “low‐dose” dabigatran treatment was resolved by switching to apixaban treatment. Thrombolysis using DOACs could be a therapeutic option for patients with intracardiac thrombi, although the efficacies of different DOACs seem to differ and need further examination.\n\nAuthorship\nTK: drafted the manuscript and contributed to treating the patient. YO: contributed to treating the patient and critically revised and edited the manuscript. MK, YI, KN, SK, and HN: contributed to treating the patient. All authors have read and approved the final manuscript.\n\nConflict of Interest\nThere is no real or potential conflict of interest for any author. No author has relationships relevant to the contents of this manuscript to disclose.\n==== Refs\nReferences\n1 \n\nHart , R. G. \n, \nL. A. \nPearce \n, and \nM. I. \nAguilar \n. 2007 \nMeta‐analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation . Ann. Intern. Med. \n146 :857 –867 .17577005 \n2 \n\nConnolly , S. J. \n, \nJ. \nPogue \n, \nR. G. \nHart \n, \nS. H. \nHohnloser \n, \nM. \nPfeffer \n, \nS. \nChrolavicius \n, et al. 2009 \nEffect of clopidogrel added to aspirin in patients with atrial fibrillation . N. Engl. J. Med. \n360 :2066 –2078 .19336502 \n3 \n\nConnolly , S. \n, \nJ. \nPogue \n, \nR. \nHart \n, \nM. \nPfeffer \n, \nS. \nHohnloser \n, \nS. \nChrolavicius \n, et al. 2006 \nClopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial . Lancet \n367 :1903 –1912 .16765759 \n4 \n\nConnolly , S. J. \n, \nM. D. \nEzekowitz \n, \nS. \nYusuf \n, \nJ. \nEikelboom \n, \nJ. \nOldgren \n, \nA. \nParekh \n, et al. 2009 \nDabigatran versus warfarin in patients with atrial fibrillation . N. Engl. J. Med. \n361 :1139 –1151 .19717844 \n5 \n\nPatel , M. R. \n, \nK. W. \nMahaffey \n, \nJ. \nGarg \n, \nG. \nPan \n, \nD. E. \nSinger \n, \nW. \nHacke \n, et al. 2011 \nRivaroxaban versus warfarin in nonvalvular atrial fibrillation . N. Engl. J. Med. \n365 :883 –891 .21830957 \n6 \n\nGranger , C. B. \n, \nJ. H. \nAlexander \n, \nJ. J. \nMcMurray \n, \nR. D. \nLopes \n, \nE. M. \nHylek \n, \nM. \nHanna \n, et al. 2011 \nApixaban versus warfarin in patients with atrial fibrillation . N. Engl. J. Med. \n365 :981 –992 .21870978 \n7 \n\nHammersting , C. \n, \nB. \nPötzsch \n, and \nG. \nNickenig \n. 2013 \nResolution of giant left atrial appendage thrombus with rivaroxaban . Thromb. Haemost. \n109 :583 –584 .23348106 \n8 \n\nTakasugi , J. \n, \nH. \nYamagami \n, \nT. \nOkata \n, \nK. \nToyoda \n, and \nK. \nNagatsuka \n. 2013 \nDissolution of the left atrial appendage thrombus with rivaroxaban therapy . Cerebrovasc. Dis. \n36 :322 –323 .24192983 \n9 \n\nMorita , S. \n, \nY. \nAjiro \n, \nY. \nUchida \n, and \nK. \nIwade \n. 2013 \nDabigatran for left atrial thrombus . Eur. Heart J. \n34 :2745 .23698566 \n10 \n\nKawakami , T. \n, \nH. \nKobayakawa \n, \nH. \nOhno \n, \nN. \nTanaka \n, and \nH. \nIshihara \n. 2013 \nResolution of left atrial appendage thrombus with apixaban . Thromb. J. \n11 :26 .24359320 \n11 \n\nBernhardt , P. \n, \nH. \nSchmidt \n, \nC. \nHammerstingl \n, \nM. \nHackenbroch \n, \nT. \nSommer \n, \nB. \nLüderitz \n, et al. 2004 \nFate of left atrial thrombi in patients with atrial fibrillation determined by transesophageal echocardiography and cerebral magnetic resonance imaging . Am. J. Cardiol. \n94 :801 –804 .15374795 \n12 \n\nYeh , C. H. \n, \nJ. C. \nFredenburgh \n, and \nJ. I. \nWeitz \n. 2012 \nOral direct factor Xa inhibitors . Circ. Res. \n111 :1069 –1078 .23023509 \n13 \n\nCohen , D. \n\n2014 \nDabigatran: how the drug company withheld important analyses . BMJ \n349 :g4670 .25055829 \n14 \n\nReilly , P. A. \n, \nT. \nLehr \n, \nS. \nHaertter \n, \nS. J. \nConnolly \n, \nS. \nYusuf \n, \nJ. W. \nEikelboom \n, et al. 2014 \nThe effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE‐LY Trial (Randomized Evaluation of Long‐Term Anticoagulation Therapy) . J. Am. Coll. Cardiol. \n63 :321 –328 .24076487 \n15 \n\nWan , H. \n, \nY. \nYang \n, \nJ. \nZhu \n, \nS. \nWu \n, \nZ. \nZhou \n, \nB. \nHuang \n, et al. 2016 \nAn in‐vitro evaluation of direct thrombin inhibitor and factor Xa inhibitor on tissue factor‐induced thrombin generation and platelet aggregation: a comparison of dabigatran and rivaroxaban . Blood Coagul. Fibrinolysis \n27 :882 –885 .26757012\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(5)",
"journal": "Clinical case reports",
"keywords": "Anticoagulants; atrial fibrillation; left atrial appendage; thrombus",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "711-713",
"pmc": null,
"pmid": "28469881",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports",
"references": "25055829;17577005;24076487;23023509;15374795;24192983;19717844;23698566;23348106;24359320;26757012;21870978;16765759;19336502;21830957",
"title": "A left atrial appendage thrombus that developed during prophylactic low-dose dabigatran treatment resolved after switching to apixaban.",
"title_normalized": "a left atrial appendage thrombus that developed during prophylactic low dose dabigatran treatment resolved after switching to apixaban"
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"abstract": "A 46-year-old woman was referred to the endocrinology clinic for evaluation of progressive fatigue, dizziness and treatment-resistant hypothyroidism. Initial laboratory results revealed hypothyroidism, hyponatraemia and hyperkalaemia. Liothyronine sodium (Cytomel) was initiated, which exacerbated her fatigue and dizziness. Suspecting adrenal insufficiency, an 08:00 cortisol level was obtained and found to be low with failure to increase following cosyntropin stimulation test. Diagnosis of primary adrenal insufficiency was confirmed via CT abdomen and pelvis revealing diminutive adrenal glands and elevated 21-hydroxylase antibody. Treatment was initiated with hydrocortisone 10 mg every morning and 5 mg at 16:00/day, with plan for patient follow-up in 3 weeks to assess need for mineralocorticoid replacement. Polyglandular syndromes are rare and have a wide variety of presentation. Thus, we recommend screening patients with a single autoimmune disorder who do not respond to conventional therapy to prevent possible life-threatening adrenal crisis.",
"affiliations": "College of Osteopathic Medicine, Des Moines University, Des Moines, Iowa, USA.;Endocrinology, Covenant Clinic, Waterloo, Iowa, USA.",
"authors": "Hoener|Katherine|K|;Sharma|Tulsi|T|",
"chemical_list": "D013974:Thyroxine",
"country": "England",
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"doi": "10.1136/bcr-2019-230760",
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"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "Thyroid Disease; adrenal disorders; general practice/family medicine; medical management",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007037:Hypothyroidism; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune; D013974:Thyroxine; D014057:Tomography, X-Ray Computed",
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"pubdate": "2019-08-21",
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"references": "19411300;17375512;12050123;11498494;3085775;15918231;9920103;15270837;31080849;7024719",
"title": "Type II polyglandular autoimmune syndrome: a case of Addison's disease precipitated by use of levothyroxine.",
"title_normalized": "type ii polyglandular autoimmune syndrome a case of addison s disease precipitated by use of levothyroxine"
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"abstract": "We report the case of a 43-year-old woman presenting with nocturnal episodes of pain and screaming during sleep starting at age 30. There was no childhood or family history of parasomnia. The events had gradually become more frequent over the years, occurring in the first half of the night within 2 h of sleep onset. There were no triggers, and she had partial amnesia for the events. A diagnosis of adult-onset sleep terrors was made on clinical grounds and supported polysomnographically. Seizures and periodic limb movements were excluded as triggering factors. There was some mild sleep disordered breathing (predominantly non-desaturating hypopnea with a propensity for REM sleep of debatable significance). Imaging of the brain and spine and neurophysiological investigations ruled out lesions, entrapments, or neuropathies as possible causes of pain. Treatment (clonazepam, paroxetine, or gabapentin) was poorly tolerated and made no difference to the nocturnal episodes, while trazodone worsened them. This is the first report of hypnopompic psychic pain in association with a NREM parasomnia. We hypothesize that the pain may represent a sensory hallucination analogous to the more commonly recognized visual NREM parasomnia-associated hypnopompic visual hallucinations and that, as such, it may arise during arousal of the sensory neocortex as confabulatory response.",
"affiliations": "National Hospital for Neurology and Neurosurgery, Epilepsy Department, Queen Square, London, UK. l.mantoan@ion.ucl.ac.uk",
"authors": "Mantoan|Laura|L|;Eriksson|Sofia H|SH|;Nisbet|Angus P|AP|;Walker|Matthew C|MC|",
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"delete": false,
"doi": "10.5665/sleep.2392",
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"issue": "36(2)",
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"keywords": null,
"medline_ta": "Sleep",
"mesh_terms": "D000328:Adult; D017668:Age of Onset; D005260:Female; D006212:Hallucinations; D006801:Humans; D020184:Night Terrors; D010146:Pain; D020447:Parasomnias; D017286:Polysomnography; D012894:Sleep Stages",
"nlm_unique_id": "7809084",
"other_id": null,
"pages": "287-90",
"pmc": null,
"pmid": "23372277",
"pubdate": "2013-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10221293;11317618;18758883;9797572;16636516;16809057;19444452;16331401",
"title": "Adult-onset NREM parasomnia with hypnopompic hallucinatory pain: a case report.",
"title_normalized": "adult onset nrem parasomnia with hypnopompic hallucinatory pain a case report"
} | [
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"companynumb": "GB-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK014998",
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"abstract": "Objective: To describe a temporal association between COVID-19 vaccine administration and multiple sclerosis (MS) relapses. Methods: This case series study was collected in four MS Centres in Central Italy, using data from 16 MS patients who received COVID-19 vaccination and presented both clinically and radiologically confirmed relapses between March and June 2021. We collected patients' relevant medical history, including demographics, MS clinical course, disease-modifying treatment (DMT) received (if applicable), and data from MRI scans obtained after the COVID-19 vaccination. Results: Three out of 16 patients received a diagnosis of MS with a first episode occurring after COVID-19 vaccination; 13 had already a diagnosis of MS and, among them, 9 were on treatment with DMTs. Ten patients received BNT162b2/Pfizer-BioNTech, 2 patients mRNA-1273/Moderna, and 4 patients ChAdOx1 nCoV-19/AstraZeneca. All MS relapses occurred from 3 days to 3 weeks after receiving the first dose of the COVID-19 vaccination or the booster. All patients had evidence of radiological activity on MRI. Discussion: Clinical and radiological findings in these cohort of MS patients confirmed disease re/activation and suggested a temporal association between disease activity and COVID-19 vaccination. The nature of this temporal association, whether causative or incidental, remains to be established.",
"affiliations": "Neurology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;Neurology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;Neurology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;Neurology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;Institute of Advanced Biomedical Technologies (ITAB), Department of Neurosciences, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.;MS Centre, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;MS Centre, Department of Neurology, Fabrizio Spaziani Hospital, Frosinone, Italy.;MS Centre, Department of Clinical Neurology, SS. Annunziata University Hospital, Chieti, Italy.;MS Centre, Department of Neurosciences, S. Camillo-Forlanini Hospital, Rome, Italy.;Institute of Advanced Biomedical Technologies (ITAB), Department of Neurosciences, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.;Neurology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.",
"authors": "Nistri|Riccardo|R|;Barbuti|Elena|E|;Rinaldi|Virginia|V|;Tufano|Laura|L|;Pozzilli|Valeria|V|;Ianniello|Antonio|A|;Marinelli|Fabiana|F|;De Luca|Giovanna|G|;Prosperini|Luca|L|;Tomassini|Valentina|V|;Pozzilli|Carlo|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2021.765954",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295\nFrontiers Media S.A.\n\n10.3389/fneur.2021.765954\nNeurology\nCase Report\nCase Report: Multiple Sclerosis Relapses After Vaccination Against SARS-CoV2: A Series of Clinical Cases\nNistri Riccardo 1\n\nBarbuti Elena 1\n\nRinaldi Virginia 1\n\nTufano Laura 1\nPozzilli Valeria 2 3\n\nIanniello Antonio 4\n\nMarinelli Fabiana 5\nDe Luca Giovanna 3\nProsperini Luca 6\n\nTomassini Valentina 2 3\nPozzilli Carlo 1 4 *\n\n1Neurology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy\n2Institute of Advanced Biomedical Technologies (ITAB), Department of Neurosciences, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy\n3MS Centre, Department of Clinical Neurology, SS. Annunziata University Hospital, Chieti, Italy\n4MS Centre, Sant'Andrea Hospital, Sapienza University, Rome, Italy\n5MS Centre, Department of Neurology, Fabrizio Spaziani Hospital, Frosinone, Italy\n6MS Centre, Department of Neurosciences, S. Camillo-Forlanini Hospital, Rome, Italy\nEdited by: Jorge Correale, Fundación Para la Lucha Contra las Enfermedades Neurológicas de la Infancia (FLENI), Argentina\n\nReviewed by: Johann Sellner, Landesklinikum Mistlbach-Gänserndorf, Austria; Gustavo C. Roman, Houston Methodist Research Institute, United States\n\n*Correspondence: Carlo Pozzilli carlo.pozzilli@uniroma1.it\nThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n22 10 2021\n2021\n22 10 2021\n12 76595427 8 2021\n21 9 2021\nCopyright © 2021 Nistri, Barbuti, Rinaldi, Tufano, Pozzilli, Ianniello, Marinelli, De Luca, Prosperini, Tomassini and Pozzilli.\n2021\nNistri, Barbuti, Rinaldi, Tufano, Pozzilli, Ianniello, Marinelli, De Luca, Prosperini, Tomassini and Pozzilli\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: To describe a temporal association between COVID-19 vaccine administration and multiple sclerosis (MS) relapses.\n\nMethods: This case series study was collected in four MS Centres in Central Italy, using data from 16 MS patients who received COVID-19 vaccination and presented both clinically and radiologically confirmed relapses between March and June 2021. We collected patients' relevant medical history, including demographics, MS clinical course, disease-modifying treatment (DMT) received (if applicable), and data from MRI scans obtained after the COVID-19 vaccination.\n\nResults: Three out of 16 patients received a diagnosis of MS with a first episode occurring after COVID-19 vaccination; 13 had already a diagnosis of MS and, among them, 9 were on treatment with DMTs. Ten patients received BNT162b2/Pfizer-BioNTech, 2 patients mRNA-1273/Moderna, and 4 patients ChAdOx1 nCoV-19/AstraZeneca. All MS relapses occurred from 3 days to 3 weeks after receiving the first dose of the COVID-19 vaccination or the booster. All patients had evidence of radiological activity on MRI.\n\nDiscussion: Clinical and radiological findings in these cohort of MS patients confirmed disease re/activation and suggested a temporal association between disease activity and COVID-19 vaccination. The nature of this temporal association, whether causative or incidental, remains to be established.\n\nSARS-CoV2 infection\nCOVID-19 vaccine\nmultiple sclerosis relapse\nMRI activity\nlesions\nadverse event\n==== Body\npmcIntroduction\n\nPatients with multiple sclerosis (MS) have an increased risk of respiratory infections, especially patients presenting severe disability and on disease-modifying treatments (DMTs) (1). Infections can trigger MS relapses (2), and thus, vaccination in MS patients should be pursued as a general policy in order to reduce the risk of infections (3). Despite the long-standing debate over an increased risk of relapse occurrence after vaccination, the existence of this phenomenon has not been confirmed (4).\n\nThe ongoing coronavirus pandemic led to an unprecedented vaccination campaign that included MS patients. In Italy, two types of vaccines were available: (i) mRNA-vaccines (BNT162b2 Pfizer/BioNTech and mRNA-1273 Moderna) (5); (ii) adenovirus-vectored vaccine (ChsdOx1 nCoV-19, AZD12222, AstraZeneca) (6).\n\nHere, we describe 16 cases of clinically and radiologically confirmed MS re/activation that occurred after the administration of COVID-19 vaccines in MS patients regularly followed in four MS Centres in Central Italy from March to June 2021 (Table 1).\n\nTable 1 Demographic and clinical baseline characteristics of the MS patients.\n\nNo. cases\tAge\tSex\tEDSS\tDMT\tYear of last relapse\tDisease duration\tType of vaccine\tDose\tTime of symptom onset after vaccine\tSteroids use\tNo. new MRI lesions\tTiming of MRI after symptom onset\t\n1\t45\tM\t2.5\tOcrelizumab\t2020\t9 years\tChAdOx1 nCoV-19\t1\t21 days\tYes\t2 brain Gd-, 1 spine Gd-\t50 days\t\n2\t48\tF\t2.0\tNone\tNew diagnosis\tND\tChAdOx1 nCoV-19\t1\t8 days\tYes\t1 brain Gd+\t18 days\t\n3\t54\tF\t2.5\tNone\t2014\t28 years\tChAdOx1 nCoV-19\t1\t3 days\tNo\t1 spine Gd+\t17 days\t\n4\t66\tF\t2.5\tNone\tNew diagnosis\tND\tChAdOx1 nCoV-19\t1\t7 days\tYes\t4 brain Gd+\t17 days\t\n5\t42\tf\t4.0\tOcrelizumab\t2019\t2 years\tmRNA-1273\t1\t14 days\tNo\t1 brain Gd+\t17 days\t\n6\t57\tF\t6.0\tNone\t2015\t20 years\tmRNA-1273\t2\t14 days\tYes\t1 brain Gd+\t13 days\t\n7\t49\tF\t1.5\tDMF\t2013\t8 years\tBNT162b2/Pfizer-BioNTech\t1\t5 days\tYes\t1 brain Gd+, 1 spine Gd+\t7 days\t\n8\t39\tM\t2.0\tDMF\t2018\t7 years\tBNT162b2/Pfizer-BioNTech\t1\t10 days\tYes\t2 brain Gd+, 1 spine Gd-\t7 days\t\n9\t39\tF\t1.0\tNone\tnew diagnosis\tND\tBNT162b2/Pfizer-BioNTech\t1\t3 days\tYes\t1 brain Gd+\t9 days\t\n10\t60\tF\t3.5\tDMF\t2014\t23 years\tBNT162b2/Pfizer-BioNTech\t1\t2 days\tNo\t1 brain Gd+\t3 days\t\n11\t30\tF\t1.5\tCladribine\t2020\t3 years\tBNT162b2/Pfizer-BioNTech\t2\t20 days\tYes\t2 brain Gd+\t36 days\t\n12\t58\tF\t5.0\tNone\t2018\t21 years\tBNT162b2/Pfizer-BioNTech\t1\t3 days\tYes\t1 brain ring Gd+\t38 days\t\n13\t34\tF\t2.5\tNone\t2021\t3 months\tBNT162b2/Pfizer-BioNTech\t2\t4 days\tYes\t3 brain Gd+, 1 spine Gd-\t16 days\t\n14\t35\tF\t2.0\tDMF\t2019\t16 years\tBNT162b2/Pfizer-BioNTech\t2\t1 day\tYes\t3 brain Gd+\t13 days\t\n15\t54\tM\t2.0\tTeriflunomide\t2020\t18 years\tBNT162b2/Pfizer-BioNTech\t1\t7 days\tYes\t2 brain Gd+\t4 days\t\n16\t37\tM\t1.5\tDMF\t2019\t2 years\tBNT162b2/Pfizer-BioNTech\t2\t10 days\tYes\t1 brain Gd+\t9 days\t\nNo., number of; EDSS, expanded disability status scale; M, male; F, female; DMT, disease modifying treatment; DMF, dimethyl fumarate; ND, new diagnosis; Gd, gadolinium-enhancing lesion; MRI, magnetic resonance imaging.\n\nCase Series\n\nCase 1\n\nA 45-year-old man received a diagnosis of MS (7) in 2012 and was started on teriflunomide and then from April 2020 with Ocrelizumab with radiological and clinical stability, as confirmed in November 2020. He received his first ChAdOx1 nCoV-19 on February 19, 2021. He experienced dysesthesia in both legs 3 weeks later. He underwent a scan on April 30, 2021 which showed two new lesions in the temporal gyri and a new spinal cord lesion at T3 level (Figure 1A).\n\nFigure 1 New MRI lesions associated with the MS episodes occurred after ChAdOx1 nCoV-19 (AZD12222), mRNA-1273, Moderna and BNT162b2, Pfizer/BioNTech vaccine. The lesions are shown on T2 weighted images or on post-contrast T1 weighted images and are indicated by yellow arrows. (A) Case 1: C3 lesion; (B) Case 2: new enhancing lesion in corpus callosum and multiple white matter unenhanced lesions in periventricular areas and in the mesial occipital lobe; (C) Case 3: new enhancing lesion in the thoracic cord; (D) Case 4: multiple hyperintense lesions in the supra and infratentorial white matter, four of which are with contrast enhancement; (E) Case 5: new brain lesion with contrast enhancement. (F) Case 6: enhancing bulbar lesion; (G) Case 7: C3 lesion with contrast enhancement; (H) Case 8: new brain enhancing lesion; (I) Case 9: a new contrast enhancing lesion in the mesencephalon. (L) Case 10: new enhancing brain lesion. (M) Case 11: enhancing brain lesion with conspicuous oedema; (N) Case 12: a new active lesion with ring enhancement in the left frontal white matter. (O) Case 13: three new brain enhancing lesions, one of which is indicated by the arrow; (P) Case 14: three new enhancing lesions in the left temporal lobe and one, indicated here, in the left centrum semiovale; (Q) Case 15: two ring-enhancing lesions localized in the white matter adjacent to the left frontal horn and in the left middle periventricular region. (R). Case 16: new enhancing lesions, one of which is tumefactive, localized in the white matter of the left centrum semiovale.\n\nCase 2\n\nA 48-year-old woman received on March 5 her first dose of ChAdOx1 nCoV-19. 8 days later, she developed visual acuity deficit from her right eye. She underwent MRI scan on March 31, where an enhancing lesion in the corpus callosum, multiple white matter unenhanced lesions, and lesions in the occipital lobe were detected (Figure 1B). Diagnosis of MS was made, and she was treated with high dose of intravenous methylprednisolone (IVMP), with marked improvement of the visual deficit.\n\nCase 3\n\nA 54-year-old woman was diagnosed with MS in 1993. She remained clinically stable without any therapy up to 2021. On February 27, 2021, 3 days after the first ChAdOx1 nCoV-19 dose, the patient developed hypoesthesia below the T6 level. She underwent a new MRI showing one enhancing lesion in the spinal cord (Figure 1C). She was treated with IVMP with complete recovery.\n\nCase 4\n\nA 66-year-old woman received the first dose of ChAdOx1 nCoV-19 on April 11, 2021 and, 1 week later, complained visual disturbance and postural instability on the right limbs. A brain MRI on May 4 showed multiple white matter lesions, four of them enhancing in the left paratrigonal and periventricular white matter (Figure 1D). Her CSF showed oligoclonal bands. Diagnosis of MS (7) was made, and she was treated with IVMP with partial improvement.\n\nCase 5\n\nIn 2019 a 42-year-old woman experienced a progressive weakness on the right side of her body. After an MRI scan performed in February 2020, showing multiple lesions with dissemination in space and time, she started treatment with Ocrelizumab on May 8, 2020. She received the first dose of mRNA-1273 vaccine on March 22, 2021. Two weeks later, she experienced slight weakness of the left upper limb. On April 19, 2021, she received the booster, and after 3 days, her follow-up MRI showed an enhancing brain lesion in the right corona radiata (Figure 1E).\n\nCase 6\n\nA 57-year-old man had a diagnosis of MS in 2001. He was treated initially with injectables, then with teriflunomide, and, in 2015, with mitoxantrone. Since then, he remained clinically and radiologically stable without any treatment. On May 11, 2021, he received the booster of mRNA-1273 vaccine. Two weeks later, he experienced a severe motor deficit in both legs that made him bed bound. He was admitted to hospital where he underwent an MRI on June 7, 2021, showing an enhancing pontine lesion (Figure 1F). He was treated with IVMP with only partial recovery.\n\nCase 7\n\nA 49-year-old woman was diagnosed with MS in November 2013. She has been on treatment with dimethyl fumarate (DMF) since July 2014, with clinical and radiological stability. On April 1, 2021, she underwent a brain and spinal cord MRI scan, which was stable. On April 8, she received her first BNT162b2 dose of vaccine. Five days after, she developed numbness on the left hand and left side of her head. On April 20, she underwent a new scan, which detected a periventricular lesion and a spinal lesion at C3 level, both enhancing (Figure 1G). She was treated with IVMP with almost complete recovery.\n\nCase 8\n\nIn 2014, after the onset of hypoesthesia on his left side, a 39-year-old man underwent an MRI scan, which showed multiple lesions on brain and spinal cord. He started treatment with injectables switched to DMF in 2017. After almost 3 years of clinical and radiological stability, on April 27, 2021, he received his first dose of BNT162b2 vaccine, followed, 10 days later, by the onset of paraesthesia on his left leg. He underwent an MRI scan on May 13 that showed three new lesions, two of which were enhancing in the left parietal lobe and in the periventricular white matter (Figure 1H). He was treated with oral steroids with partial recovery.\n\nCase 9\n\nA 39-year-old woman suffered from her first clinical episode in August 2019 with a complete recovery. A diagnosis of clinically isolated syndrome was made, and she was monitored by serial MRI that confirmed a radiological stability up to January 2021. On April 29, she received her first dose of BNT162b2 vaccine followed, 3 days later, by dysesthesia on her right hand and foot. A scan performed on May 11, 2021 showed a new enhancing lesion in the mesencephalon (Figure 1I). She was treated with IV methylprednisolone with a good recovery. A diagnosis of MS was made, and a DMT was planned.\n\nCase 10\n\nA 60-year-old female patient received a diagnosis of MS in 1998. In 2001, she started treatment with injectables switched to DMF in 2015. She was clinically and radiologically stable for 6 years. In April 2021, she performed the first BNT162b2 dose of vaccine presenting few days later with fatigue and numbness in both legs. A scan was performed, and one enhancing brain lesion was detected in the left periventricular white matter (Figure 1L).\n\nCase 11\n\nA 30-year-old woman was diagnosed with MS in 2018, after a clinical onset with optic neuritis and MRI suggestive of dissemination in space and time. She was treated with DMF between September 2018 and August 2020 and then she started Cladribine. A baseline MRI at the end of October 2020 was stable. She received the BNT162b2 booster on April 8, 2021. Twenty days later, she complained of a language disturbance. A brain MRI performed on June 3, 2021 revealed the presence of two enhancing brain lesions, one in the right corona radiata and one with conspicuous oedema in the left centrum semiovale (Figure 1M).\n\nCase 12\n\nA 58-year-old woman was diagnosed with MS in August 2000. She was treated with injectables and then, in 2018, with DMF that was stopped after 1 year for lymphopenia. She performed an MRI scan in February 2020 that was stable. She had her first BNT162b2 dose on March 26, 2021. Three days later, she complained headache, balance disturbances, urinary incontinence, difficulties in walking, and dysphagia. She performed an MRI on May 27, 2021 that showed a new area with ring enhancement in the white matter of the left frontal lobe (Figure 1N). She started IVMP with benefit.\n\nCase 13\n\nA 34-year-old woman developed numbness and hyposthenia on her right hand in February 2021. An MRI scan showed multiple lesions and one enhancing cord lesion at C3 level. Diagnosis of MS was made. She was treated with IVMP with almost complete recovery. A treatment with Ocrelizumab was planned. On May 18, she received the BNT162b booster. Four days later, she complained of neck pain and hypoesthesia on her right arm. She performed an MRI scan on June 7 showing three brain enhancing lesions (one right posterior paraventricular and two in the left periventricular white matter) and a new unenhanced lesion on spinal cord (Figure 1O).\n\nCase 14\n\nA 35-year-old woman received a diagnosis of MS in the 2005. She was treated with injectables, and in February 2019, she started DMF. She remained clinically and radiologically stable until May 24, 2021, when she received the BNT162b2 booster. The day after the vaccination, she developed paraesthesia on the left side of the body. She underwent a scan 13 days later, which showed three enhancing lesions in the left temporal lobe and left centrum semiovale (Figure 1P).\n\nCase 15\n\nA 54-year-old man was diagnosed with MS in 2003. He was treated with injectables and switched to teriflunomide in November 2020. He was clinically stable and without new lesions on MRI performed on February 25, 2021. On April 7, 2021, 1 week after the first dose of BNT162b2 vaccine (March 31, 2021), he developed a right hemiparesis. A brain scan showed two ring-enhancing lesions located in the left periventricular white matter (Figure 1Q). IVMP was administered with full recovery. He received the BNT162b2/Pfizer-BioNTech booster on May 11, 2021. without any further medical problem.\n\nCase 16\n\nA 37-year-old man was diagnosed with MS in 2019. In April 2020, he started DMF with clinical stability. On June 4, 2021, he had the BNT162b2 booster. On June 15, the patient presented with weakness on his right limbs. On June 24, he underwent a brain MRI that, compared with a previous routine scan of May 20, 2021, showed a new tumefactive contrast-enhancing lesion in the left fronto-parietal white matter (Figure 1R). The patient was treated with IVMP with partial recovery.\n\nDiscussion\n\nThere have been few cases reported of neurological complications associated with COVID-19 vaccination. These include cases of transverse myelitis (8), of Bell's palsy (9), of unusual variant of Guillain-Barre syndrome, and of cerebral venous sinus thrombosis (10, 11). In MS, there are suggestions of an unchanged rate of relapse in vaccinated, when compared to non-vaccinated, patients following the vaccination (12). However, this latter finding has not been supported by radiological evidence of disease activity and the period of observation was limited.\n\nOnly two cases of acute relapse after COVID-19 vaccination have been reported so far (13, 14), both having a good outcome.\n\nHere, we describe a series of 16 patients with MS relapses occurring from 3 days to 3 weeks after their COVID-19 vaccination, between March and June 2021. During this period, at least 2500 patients with MS accessed the four MS Centres. During this period, a total of 69 verified (i.e., treated with high dose IV steroids) relapses were observed in the Centers, while 52 relapses were measured in the preceding 4 months. Although seasonal variation in relapse rate associated with monthly hours of sunshine should be taken into account (15), an increase in the total number of relapses was observed during the SARS-COV-2 vaccination campaign.\n\nOut of 16 cases, 3 received a diagnosis of MS after COVID-19 vaccination; the remaining 13 had already a diagnosis of MS made from few months to several years before the vaccine administration. Nine patients were on DMTs; four patients were no longer on DMTs, although they had used them in the past, and were clinically and radiologically stable. Disease reactivation is reported after both the first vaccine administration (n = 10) and the booster (n = 6). All patients had evidence of radiological activity on MRI to support the relapse diagnosis. Age, sex, and level of disability reflect what may be expected for a relapsing MS cohort. The characteristics of the enhancing lesions varied from small to large lesions, in both the brain and the spinal cord.\n\nThe role of vaccines on the risk of developing MS and MS relapses remains to be elucidated, with no sufficient data to support or refute an association between the development of MS and the antiviral vaccinations (16, 17). Therefore, currently, there are no contraindications for vaccination in patients with MS, with the only exception regarding live-attenuated vaccines that are contraindicated for MS patients who receive immunosuppressive or immunomodulating treatments. Unless the risk of infection outweighs the risk of adverse reactions induced by the vaccine, MS relapses are not a contraindication for vaccination, but they are a reason to delay vaccination until remission (17).\n\nAlthough the evidence of an association between vaccination and MS activity is still debated (18), a link between them has been suggested, within the first 30 days after immunization, given the possibility of vaccines to accelerate the transition from subclinical to clinical disease through a stimulation of the immune system (19). In a previous case series, we have looked into the safety of receiving the influenza vaccine in MS patients by clinical and MRI studies, adding a note of caution in those subjects with evidence of recent disease activity (20).\n\nThe exact mechanisms through which autoimmune reactions can be triggered by vaccination are not fully understood, although they probably vary according to the type of vaccine and individual genetic susceptibility (21, 22).\n\nImmunological studies have shown that coordinated interactions between T and B lymphocytes of the adaptive immune system are necessary for the successful generation of immunological memory and the production of neutralizing antibodies following recognition of antigens by the innate immune cells (3). However, the T/B cell interaction may be altered in MS even in the absence of DMTs (23, 24). In addition, new technologies currently used for mounting an immune response to the COVID-19 vaccine, such as mRNA vaccines, have not been tested in populations suffering from autoimmune conditions before the vaccination campaign.\n\nAlthough the clinical cases described here experienced neurological symptoms that were temporally associated with administration of the vaccine, causality cannot be assumed. Indeed, it cannot be disentangled whether radiologically confirmed relapses occurring after vaccination are triggered by the vaccination-induced inflammatory state or are relapses that would have happened anyway, independently from vaccination.\n\nAfter the authorization of vaccines against SARS-CoV-2 in Italy, MS patients were prioritized for vaccination starting in March 2021. The availability of COVID-19 vaccines met the willingness of approximately 80% of European MS patients to receive vaccination (ref). The greatest interest in vaccination was observed in older patients and in those with comorbidities (25). This evidence is reflected in our case series, where mean age was 46.7 ± 10.3 and median EDSS score was 2.5. Immunosenescence increases the risk of adverse events in older adults. Beyond reduced response to vaccines, changes that take place in the immune system with aging generally result in higher susceptibility to infections and prevalence of autoimmunity (26), factors that can precipitate reactivations in MS patients. During mass immunization campaign, such as that occurred in France between 1995 and 1997, several cases of MS were reported a few weeks after HBV vaccination, suggesting that vaccine may accelerate the transition from subclinical to clinical disease (27). However, two subsequent case-control studies showed a non-significant increase in risk of developing MS following the HBV vaccine (ref). Therefore, conclusions derived from case reports and case series are not free from biases and should not influence vaccine hesitancy (28).\n\nAdverse events of vaccination can occur in rare cases, but benefits generally outweigh adverse effects, given that acute infections may have dangerous consequences (29). Indeed, patients with MS have an increased mortality risk from COVID-19, especially if older and with significant disability and/or comorbidities (30).\n\nConclusion\n\nThe elevated number of MS patients with relapse after COVID-19 vaccine coming to our observation during a relative short period of time suggests the need for robust post-vaccination surveillance in patients with MS. Large prospective controlled studies are required to estimate the frequency of MS relapses, both clinically and MRI proved, which might occur during the post-vaccine period when a new COVID-19 vaccination program will be planned.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nCP and RN wrote the manuscript with support from EB, AI, LT, FM, LP, GD, VP, and VT. CP and VR conceived of the presented idea. All authors have collected the data.\n\nConflict of Interest\n\nFM has received consulting fees, speaker honoraria, and/or travel grants from Biogen, Sanofi Genzyme, Novartis, and Roche; GD served on scientific advisory boards for Merck, Sanofi-Genzyme, and Roche, and has received travel and/or speaker honoraria from Merck, Roche, Teva, Biogen, Novartis, and Sanofi-Genzyme. LP has received consulting fees from Celgene, Biogen, and Novartis; speaker honoraria and/or travel grants from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme. VT has received consulting fees and/or travel grants and/or research grants from Bristol Myer Squibb, Biogen, Novartis, Sanofi Genzyme, Merck Serono, and Roche; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and the MS Society UK, and from the Italian Ministry of Health. CP has served on scientific advisory boards for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, and Actelion; received funding for travel and speaker honoraria from Biogen, Teva, Sanofi Genzyme, Actelion, and Novartis; received research support from Biogen, Teva, Novartis, and Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\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==== Refs\nReferences\n\n1. Persson R Lee S Yood MU Wagner Usn Mc CM Minton N Niemcryk S . Infections in patients diagnosed with multiple sclerosis: a multi-database study. Mult Scler Relat Disord. (2020) 41 :101982. 10.1016/j.msard.2020.101982 32070858\n2. Cahill JF Izzo A Garg N . Immunization in patients with multiple sclerosis. Neurological Bulletin. (2010) 2 :17–21. 10.7191/neurol_bull.2010.1020\n3. Coyle PK Gocke A Vignos M Newsome SD . Vaccine considerations for multiple sclerosis in the COVID-19 Era. Adv Ther. (2021) 38 :3550–88. 10.1007/s12325-021-01761-3 34075554\n4. Mailand MT Frederiksen JL . Vaccines and multiple sclerosis: a systematic review. J Neurol. (2017) 264 :1035–50. 10.1007/s00415-016-8263-4 27604618\n5. Schlake T Thess A Fotin-Mleczek M Kallen KJ . Developing mRNA-vaccine technologies. RNA Biol. (2012) 9 :1319–30. 10.4161/rna.22269 23064118\n6. Du L Zhao G Lin Y Sui H Chan C Ma S . Intranasal vaccination of recombinant adeno-associated virus encoding receptor-binding domain of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein induces strong mucosal immune responses and provides long-term protection against SARS-CoV infection. J Immunol. (2008) 180 :948–56. 10.4049/jimmunol.180.2.948 18178835\n7. Thompson AJ Banwell BL Barkhof F Carroll WM Coetzee T Comi G . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. (2018) 17 :162–73. 10.1016/S1474-4422(17)30470-2 29275977\n8. Knoll MD Wonodi C . Oxford-AstraZeneca COVID-19 vaccine efficacy. Lancet. (2021) 397 :72–4. 10.1016/S0140-6736(20)32623-4 33306990\n9. Goss AL Samudralwar RD Das RR Nath A . ANA investigates: neurological complications of COVID-19 vaccines. Ann Neurol. (2021) 89 :856–7. 10.1002/ana.26065 33710649\n10. Allen CM Ramsamy S Tarr AW Tighe PJ Irving WL Tanasescu R . Guillain-Barré syndrome variant occurring after SARS-CoV-2 vaccination. Ann Neurol. (2021) 90 :315–8. 10.1002/ana.26144 34114269\n11. European Medicines Agency EMA. AstraZeneca's COVID-19 Vaccine: EMA Finds Possible Link to Very Rare Cases of Unusual Blood Clots With Low Blood Platelets (2021). Available online at: https://anmj.org.au/update-astrazeneca-covid-19-vaccine-blood-clots-with-low-platelet-counts/ (accessed April 2021).\n12. Achiron A Dolev M Menascu S Zohar DN Dreyer-Alster S Miron S . COVID-19 vaccination in patients with multiple sclerosis: what we have learnt by February 2021. Mult Scler. (2021) 27 :864–70. 10.1177/13524585211003476 33856242\n13. Etemadifar M Sigari AA Sedaghat N Salari M Nouri H . Acute relapse and poor immunization following COVID-19 vaccination in a rituximab-treated multiple sclerosis patient. Hum Vaccin Immunother. (2021) 20 :1–3. 10.1080/21645515.2021.1928463 34015240\n14. Maniscalco GT Manzo V Di Battista ME Salvatore S Moreggia O Scavone C . Severe multiple sclerosis relapse after COVID-19 vaccination: a case report. Front Neurol. (2021) 12 :721502. 10.3389/fneur.2021.721502 34447349\n15. Harding K Tilling K MacIver C Willis M Joseph F Ingram G . Seasonal variation in multiple sclerosis relapse. Neurol. (2017) 264 :1059–67. 10.1007/s00415-017-8485-0 28424900\n16. Lebrun C Vukusic S French group for recommendations in multiple sclerosis (France4MS) The Société Francophone De La Sclérose En Plaques (SFSEP). Immunization and multiple sclerosis: recommendations from the French multiple sclerosis society. Mult Scler Relat Disord. (2019) 31 :173–88. 10.1016/j.msard.2019.04.004 31159998\n17. Farez MF Correale J Armstrong MJ Rae-Grant A Gloss D Donley D . Practice guideline update summary: vaccine-preventable infections and immunization in multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the american academy of neurology. Neurology. (2019) 93 :584–94. 10.1212/WNL.0000000000008157 31462584\n18. Zrzavy T Kollaritsch H Rommer PS Boxberger N Loebermann M Wimmer I . Vaccination in multiple sclerosis: friend or foe? Front Immunol. (2019) 10 :1883. 10.3389/fimmu.2019.01883 31440255\n19. Langer-Gould A Qian L Tartof SY Brara SM Jacobsen SJ Beaber BE . Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol. (2014) 71 :1506–13. 10.1001/jamaneurol.2014.2633 25329096\n20. Salvetti M Pisani A Bastianello S Millefiorini E Buttinelli C Pozzilli C . Clinical and MRI assessment of disease activity in patients with multiple sclerosis after influenza vaccination. J Neurol. (1995) 242 :143–6. 10.1007/BF00936886 7751856\n21. Kivity S Agmon-Levin N Blank M Shoenfeld Y . Infections and autoimmunity: Friends or foes? Trends Immunol. (2009) 30 :409–14. 10.1016/j.it.2009.05.005 19643667\n22. Chen RT Pless R Destefano F . Epidemiology of autoimmune reactions induced by vaccination. J Autoimmun. (2001) 16 :309–18. 10.1006/jaut.2000.0491 11334497\n23. Hartmut Wekerle . B cells in multiple sclerosis. Autoimmunity. (2017) 50 :57–60. 10.1080/08916934.2017.1281914 28166681\n24. Severson C Hafler DA . T-Cells in Multiple Sclerosis. Results Probl Cell Differ. Berlin; Heidelberg: Springer-Verlag (2009). 10.1007/400_2009_12\n25. Serrazina F Pinho AS Cabral G Salavisa M Correia AS . Willingness to be vaccinated against COVID-19: an exploratory online survey in a Portuguese cohort of multiple sclerosis patients. Mult Scler Relat Disord. (2021) 51 :102880. 10.1016/j.msard.2021.102880 33740481\n26. Dema M Eixarch H Villar LM Montalban X Espejo C . Review. Immunosenescence in multiple sclerosis: the identification of new therapeutic targets. Autoimmunity Rev. (2021) 20 :102893. 10.1016/j.autrev.2021.102893 34237417\n27. Ascherio A Zhang SM Hernán MA Olek MJ Coplan PM Brodovicz K . Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med. (2001) 344 :327–32. 10.1056/NEJM200102013440502 11172163\n28. Diem L Friedli C Chan A Salmen A Hoepner R . Vaccine hesitancy in patients with multiple sclerosis: preparing for SARS-Cov 2 vaccination challenge. Neurol Neuroimmunol Neuroinflamm. (2021) 8 :e991. 10.1212/NXI.0000000000000991 33811158\n29. Sirbu CA Florea AA Ghinescu MC Docu-Axelerad A Sirbu AM Bratu OG . Vaccination in multiple sclerosis - challenging practices (Review). Exp Ther Med. (2020) 20 :217. 10.3892/etm.2020.9347 33149781\n30. Barzegar M Mirmosayyeb O Gajarzadeh M Afshari-Safavi A Nehzat N Vaheb S . COVID-19 among patients with multiple sclerosis: a systematic review. Neurol Neuroimmunol Neuroinflamm. (2021) 8 :e1001. 10.1212/NXI.0000000000001001 34016734\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "12()",
"journal": "Frontiers in neurology",
"keywords": "COVID-19 vaccine; MRI activity; SARS-CoV2 infection; adverse event; lesions; multiple sclerosis relapse",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "765954",
"pmc": null,
"pmid": "34744992",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "34114269;27604618;19582415;33856242;23064118;25329096;7751856;31159998;34015240;33149781;33740481;11334497;31440255;33811158;28166681;11172163;19643667;34016734;29275977;32070858;34447349;33710649;28424900;33306990;18178835;31462584;34237417;34075554",
"title": "Case Report: Multiple Sclerosis Relapses After Vaccination Against SARS-CoV2: A Series of Clinical Cases.",
"title_normalized": "case report multiple sclerosis relapses after vaccination against sars cov2 a series of clinical cases"
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"companynumb": "IT-PFIZER INC-202101625315",
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"activesubstancename": "DIMETHYL FUMARATE"
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{
"abstract": "A woman aged 44 underwent elective standard abdominoplasty and bilateral mastopexy (superiorly based pedicle with vertical scar) following weight loss of 8.5 stone (53.9 kg) over a 5-year period. She had type 2 diabetes and her antidiabetic medications included metformin, liraglutide and empagliflozin. Towards the end of the first postoperative day, she reported gradual onset of nausea, vomiting and abdominal pain. Her condition continued to deteriorate overnight, becoming tachycardic and tachypnoeic. Urgent investigations showed severe diabetic ketoacidosis with euglycaemia. She was managed with fluid resuscitation, insulin infusion and intravenous sodium bicarbonate in the high dependency unit. She made a complete clinical and biochemical recovery and was discharged on day 9 postoperatively. This case illustrates a diagnostic challenge of a serious life-threatening complication of diabetes in the postoperative period associated with a novel class of antidiabetic medications, sodium-glucose cotransporter 2 inhibitors.",
"affiliations": "Department of Plastic Surgery, The Ulster Hospital, Belfast, UK.;Department of Plastic Surgery, The Ulster Hospital, Belfast, UK.;Department of Plastic Surgery, Royal Victoria Hospital, Belfast, UK.",
"authors": "Sleiwah|Aseel|A|;McBride|Michael|M|;Black|Claire E|CE|",
"chemical_list": "D007328:Insulin; D017693:Sodium Bicarbonate",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220253",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "diabetes; drugs: endocrine system; endocrine system; plastic and reconstructive surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061645:Abdominoplasty; D000328:Adult; D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007297:Inpatients; D007328:Insulin; D007662:Ketosis; D011183:Postoperative Complications; D017693:Sodium Bicarbonate",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28794087",
"pubdate": "2017-08-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11229425;21418041;25216510;25851664;25944304;26078479;26519331;27042263;27351797;4197425;4197963;8180418",
"title": "Euglycaemic ketoacidosis: a potential new hazard to plastic surgery day case and inpatient procedures.",
"title_normalized": "euglycaemic ketoacidosis a potential new hazard to plastic surgery day case and inpatient procedures"
} | [
{
"companynumb": "GB-NOVOPROD-559656",
"fulfillexpeditecriteria": "1",
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{
"abstract": "BACKGROUND\nMycophenolate mofetil (MMF) is recommended as a first-line immunosuppressant to treat lupus nephritis (LN). Prognosis and therapeutic response in LN are known to vary depending on race. We investigated the benefits of MMF and therapeutic drug monitoring (TDM) in the treatment of Japanese LN patients.\n\n\nMETHODS\nIn this retrospective cohort study, a total of 20 patients with LN who started MMF treatment were included. Clinical data were collected regularly after MMF administration. We evaluated complete remission (CR) rate as the primary outcome. Predictors of CR were identified using univariate and multivariate analyses. In the research of TDM, the correlation with the area under the curve (AUC) was analyzed at MMF dose, single-point value, treatment response, and adverse events.\n\n\nRESULTS\nOverall, 70% of cases showed CR; both flare-ups and refractory cases had favorable results. Cases of LN with nephrotic syndrome (NS) or class III/IV + V showed a significantly lower CR rate (p < 0.005). The ratio of maintaining CR after MMF therapy was as high as 85.7%. In multivariate analysis, NS was an independent negative predictor of CR (HR 0.09, 95% confidence interval 0.01-0.81; p = 0.03). The relationship between AUC and MMF dose was low, and AUC correlated with trough level (r = 0.73). AUC tended to be high in the treatment responder (p = 0.09), but did not correlate with adverse events of infection (p = 0.92).\n\n\nCONCLUSIONS\nMMF is a beneficial treatment option for Japanese LN patients, and further investigation on TDM-based therapy is needed.",
"affiliations": "Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. katsu11@med.nagoya-u.ac.jp.;Department of Internal Medicine, Eijinkai Sato Hospital, Konan, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.",
"authors": "Katsuno|Takayuki|T|;Ozaki|Takenori|T|;Ozeki|Takaya|T|;Hachiya|Asaka|A|;Kim|Hangsoo|H|;Kato|Noritoshi|N|;Ishimoto|Takuji|T|;Kato|Sawako|S|;Kosugi|Tomoki|T|;Tsuboi|Naotake|N|;Mizuno|Masashi|M|;Ito|Yasuhiko|Y|;Maruyama|Shoichi|S|",
"chemical_list": "D009173:Mycophenolic Acid",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-018-1590-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "22(6)",
"journal": "Clinical and experimental nephrology",
"keywords": "Lupus nephritis; Mycophenolate mofetil; Systemic lupus erythematosus; Therapeutic drug monitoring",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "1341-1350",
"pmc": null,
"pmid": "29796823",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "9324032;22087680;17167111;11380817;20833738;18596121;15732286;19369404;24811231;20531457;22851469;16306519;12752309;20506558;25018937;10579476;17908276;14747370;22556106;24262502;15848556;3511372",
"title": "Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis.",
"title_normalized": "investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of japanese patients with lupus nephritis"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-04108",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "BACKGROUND\nIntravenous lipid emulsion (ILE) has gained favor as a rescue treatment for cardiovascular collapse due to intravenous local anesthetic overdose, however, goals of ILE therapy are still being defined. We describe a case of a girl given 66 mL/kg of 20% lipid emulsion (ILE) in the treatment of presumed mepivacaine toxicity.\n\n\nMETHODS\nAn 11-year-old girl weighing 55.6 kg developed pallor, rolling back of the eyes, and rhythmic muscle twitching after receiving a mandibular nerve block injection with a 1.8 mL ampule of 3% mepivacaine. With concern for persistent seizures she was given three 1 mL/kg boluses of ILE, followed by an infusion of 0.25 mL/kg/min. The total dose ultimately administered was 3670 mL (66 mL/kg) over 7 h. A serum triglyceride concentration, drawn 2 h after cessation of ILE infusion, was estimated to be 16,583 mg/dL (429 mmol/L) after several dilutions; her blood was grossly lipemic. Notable signs included hypersomnolence, tachypnea, and tachycardia. Other complications included apparent metabolic acidosis (serum bicarbonate of 5 mmol/L) with hyperlactatemia (lactate 7.0 mmol/L), difficulty with serum laboratory interpretation, and a non-contrast brain magnetic resonance imaging showing high signal in the dural venous sinuses. The lipemia cleared over three days and the patient recovered uneventfully. Case discussion: This case demonstrates a unique neurologic and metabolic toxicity associated with ILE given as an antidote in a high total dose, and highlights the need for cautious antidotal application of lipid emulsion infusions. Until more data is available, clinicians are advised to take great care if considering a dose in excess of 12.5 mL/kg/day, the maximum daily dosage recommended by the U.S. Food and Drug Administration for nutritional supplementation. Careful monitoring of total doses administered across institutions and hospital wards during transfers is paramount to avoid inadvertent overdose of antidotes.",
"affiliations": "a Division of Emergency Medicine , The Children's Hospital of Philadelphia , Philadelphia , PA , USA.;b Department of Anesthesiology and Critical Care Medicine , The Children's Hospital of Philadelphia , Philadelphia , PA , USA.;c Division of Neurology , The Children's Hospital of Philadelphia , Philadelphia , PA , USA.;a Division of Emergency Medicine , The Children's Hospital of Philadelphia , Philadelphia , PA , USA.",
"authors": "Corwin|Daniel J|DJ|;Topjian|Alexis|A|;Banwell|Brenda L|BL|;Osterhoudt|Kevin|K|",
"chemical_list": "D000779:Anesthetics, Local; D000931:Antidotes; D005217:Fat Emulsions, Intravenous; D008619:Mepivacaine",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1294693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "55(6)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Anesthetics; antidotes; fat emulsions; hypertriglyceridemia; intravenous; local",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000779:Anesthetics, Local; D000931:Antidotes; D002648:Child; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D008619:Mepivacaine; D009407:Nerve Block; D012640:Seizures",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "603-607",
"pmc": null,
"pmid": "28489457",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adverse events associated with a large dose of intravenous lipid emulsion for suspected local anesthetic toxicity.",
"title_normalized": "adverse events associated with a large dose of intravenous lipid emulsion for suspected local anesthetic toxicity"
} | [
{
"companynumb": "US-DENTSPLY-2018SCDP000527",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEPIVACAINE\\MEPIVACAINE HYDROCHLORIDE"
},
"... |
{
"abstract": "Between 1982 and 1986, 326 evaluable patients with acute myeloid leukemia (AML) were randomized to receive cytarabine (Ara-C) at 200 mg/m2 (A200) or 100 mg/m2 (A100) for induction and maintenance therapy. Cycle 1 of induction therapy consisted of 7 days of continuous intravenous (IV) Ara-C and 3 days of i.v. daunorubicin (DNR); cycle 2, if needed, consisted of 5 days of Ara-C and 2 days of DNR. Complete responders (CR) then received monthly subcutaneous (SC) Ara-C at the respective doses (A100 or A200) with 6-thioquanine (6TG) at months 1 and 5, with vincristine (VCR) and prednisone at months 2, 4, 6, and 8, and with DNR at months 3 and 7. Complete response rates were 58% (A100) and 64% (A200) (P = .29). Median survival was 46 weeks (A100) and 38 weeks (A200) (P = .64); 5-year survival was 10% (A200) and 8% (A100). Median time to remission was 6.7 weeks (A200) and 8.1 weeks (A100) (P = .18). Median disease-free survival was 41 weeks (A200) and 44 weeks (A100) (P = .86). Deaths were attributed to therapy-related toxicities in 21% (A200) and 13% (A100) (P = .05). The 5-year survival was 15% for patients with performance status (PS) 0, 8% for PS 1 to 2, and 2% for PS 3 to 4, 18% for patients less than 40 years, 8% for ages 40 to 59, and 3% for age 60 or greater. Stratification of data by age and PS suggested that A200 may improve survival in patients less than 60 years with a good PS 0 (P = .05). This trial does not support the superiority of A200 over A100 in the treatment of AML.",
"affiliations": "University of California San Diego School of Medicine.",
"authors": "Dillman|R O|RO|;Davis|R B|RB|;Green|M R|MR|;Weiss|R B|RB|;Gottlieb|A J|AJ|;Caplan|S|S|;Kopel|S|S|;Preisler|H|H|;McIntyre|O R|OR|;Schiffer|C|C|",
"chemical_list": "D003561:Cytarabine; D014750:Vincristine; D013866:Thioguanine; D011241:Prednisone; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "78(10)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D003630:Daunorubicin; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012074:Remission Induction; D013866:Thioguanine; D013997:Time Factors; D014750:Vincristine",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2520-6",
"pmc": null,
"pmid": "1824249",
"pubdate": "1991-11-15",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B.",
"title_normalized": "a comparative study of two different doses of cytarabine for acute myeloid leukemia a phase iii trial of cancer and leukemia group b"
} | [
{
"companynumb": "US-PFIZER INC-2021594820",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo compare the retinal and choroidal microvasculature quantitatively via optical coherence angiography (OCTA) in children with attention deficit hyperactivity disorder (ADHD) who were under methylphenidate (MFD) treatment or newly diagnosed as ADHD and were not taking any medication.\n\n\nMETHODS\nThis was a cross-sectional, comparative, and observational study. The children who were between 6 and 17 years old and previously diagnosed as ADHD and were under MFD treatment or who were newly diagnosed as ADHD were included in the study. Optical coherence tomography angiography imaging was performed via OCT RT XR Avanti with AngioVue software (Optivue Inc, Freemont, CA). The main outcome measure of the study was OCTA parameters of the children with ADHD.\n\n\nRESULTS\nA total of 186 eyes of 186 patients were included in the study. There were 80 eyes in the control group (newly diagnosed) and 106 eyes in the treatment group (under MFD treatment). The mean duration of methylphenidate use in the treatment group was 33.9 ± 20.1 months (between 6 and 84 months). The choriocapillary flow area (p = 0.03), superficial parafoveal thickness (p = 0.01), and deep parafoveal thickness (p = 0.01) were statistically greater in the treatment group than the control group.\n\n\nCONCLUSIONS\nMost of the important OCTA parameters especially foveal avascular zone (FAZ) area and FAZ perimeter were similar in the two groups. There was a significant difference between the two groups in parafoveal thickness values which might point to a slight effect of MFD on retinal circulation.",
"affiliations": "Department of Ophthalmology, University of Health Sciences Bakirkoy Training and Research Hospital, Istanbul, Turkey.;Department of Child and Adolescent Psychiatry, University of Health Sciences Bakirkoy Training and Research Hospital, Istanbul, Turkey.;Department of Child and Adolescent Psychiatry, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey.;Department of Ophthalmology, University of Health Sciences Bakirkoy Training and Research Hospital, Istanbul, Turkey.;Department of Ophthalmology, University of Health Sciences Bakirkoy Training and Research Hospital, Istanbul, Turkey.;Department of Ophthalmology, Memorial Sisli Hospital, Okmeydani, Sisli, 34000, Istanbul, Turkey. abdozkaya@gmail.com.",
"authors": "Tarakcioglu|Hatice Nur|HN|;Yilmaz|Semra|S|;Kara|Tayfun|T|;Mavi Yildiz|Aysegul|A|;Yigit|Ulviye|U|;Ozkaya|Abdullah|A|http://orcid.org/0000-0002-1940-8669",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-019-01281-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "40(5)",
"journal": "International ophthalmology",
"keywords": "Angiography; Hyperactivity; Methylphenidate; Optical coherence tomography",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity; D002196:Capillaries; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D005451:Fluorescein Angiography; D005584:Fovea Centralis; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D012171:Retinal Vessels; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "1155-1162",
"pmc": null,
"pmid": "31912403",
"pubdate": "2020-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Foveal avascular zone and vessel density in children with attention deficit hyperactivity disorder.",
"title_normalized": "foveal avascular zone and vessel density in children with attention deficit hyperactivity disorder"
} | [
{
"companynumb": "TR-JNJFOC-20200523568",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Recent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis.\n\n\n\nPatients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24.\n\n\n\nNinety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was -4.76 (0.86) for romilkimab versus -2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of -2.31 (1.21) (-4.32 to -0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab.\n\n\n\nThis study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance.\n\n\n\nNCT02921971.",
"affiliations": "Rheumatology Department, Cochin Hospital, Paris Descartes University, Paris, France yannick.allanore@cch.aphp.fr.;Sanofi R&D, Bridgewater, New Jersey, USA.;Sanofi R&D, Chilly-Mazarin, France.;Sanofi R&D, Chilly-Mazarin, France.;Immunology and Inflammation, Sanofi R&D, Chilly-Mazarin, France.;Statistics and Programming, Sanofi, Chilly-Mazarin, France.;Global Safety, Sanofi R&D, Bridgewater, New Jersey, USA.;Rheumatology Clinic, University of Michigan, Ann Arbor, Michigan, USA.;Centre for Rheumatology and and Connective Tissue Diseases, University College London Division of Medicine, London, UK.",
"authors": "Allanore|Yannick|Y|0000-0002-6149-0002;Wung|Peter|P|;Soubrane|Christina|C|;Esperet|Corinne|C|;Marrache|Frederic|F|;Bejuit|Raphael|R|;Lahmar|Amel|A|;Khanna|Dinesh|D|0000-0003-1412-4453;Denton|Christopher P|CP|0000-0003-3975-8938;|||",
"chemical_list": "D018033:Antibodies, Bispecific; C578095:IL13 protein, human; C508598:IL4 protein, human; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D015847:Interleukin-4",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2020-218447",
"fulltext": "\n==== Front\nAnn Rheum Dis\nAnn Rheum Dis\nannrheumdis\nard\nAnnals of the Rheumatic Diseases\n0003-4967 1468-2060 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32963047\nannrheumdis-2020-218447\n10.1136/annrheumdis-2020-218447\nSystemic Sclerosis\n1506\n2311\n2506\nA randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis\nhttp://orcid.org/0000-0002-6149-0002Allanore Yannick 1 Wung Peter 2 Soubrane Christina 3 Esperet Corinne 3 Marrache Frederic 4 Bejuit Raphael 5 Lahmar Amel 6 http://orcid.org/0000-0003-1412-4453Khanna Dinesh 7 http://orcid.org/0000-0003-3975-8938Denton Christopher P 8 Investigators \n1 \nRheumatology Department, Cochin Hospital, Paris Descartes University, Paris, France\n\n\n2 \nSanofi R&D, Bridgewater, New Jersey, USA\n\n\n3 \nSanofi R&D, Chilly-Mazarin, France\n\n\n4 \nImmunology and Inflammation, Sanofi R&D, Chilly-Mazarin, France\n\n\n5 \nStatistics and Programming, Sanofi, Chilly-Mazarin, France\n\n\n6 \nGlobal Safety, Sanofi R&D, Bridgewater, New Jersey, USA\n\n\n7 \nRheumatology Clinic, University of Michigan, Ann Arbor, Michigan, USA\n\n\n8 \nCentre for Rheumatology and and Connective Tissue Diseases, University College London Division of Medicine, London, UK\n\nCorrespondence to Professor Yannick Allanore, Rheumatology A, Hospital Cochin Rheumatology Institute, Paris 75014, France; yannick.allanore@cch.aphp.frYA and PW are joint first authors.\n\n\n12 2020 \n22 9 2020 \n79 12 1600 1607\n26 6 2020 10 8 2020 11 8 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Objectives\nRecent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis.\n\nMethods\nPatients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24.\n\nResults\nNinety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was –4.76 (0.86) for romilkimab versus –2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of –2.31 (1.21) (–4.32 to –0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab.\n\nConclusion\nThis study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance.\n\nTrial registration number\n\nNCT02921971.\n\nsclerodermasystemictherapeuticschemokinesautoimmune diseasesSanofi R&D, Francespecial-featureunlocked\n==== Body\nKey messages\nWhat is already known about this subject?\nSystemic sclerosis (SSc) is an orphan disease with no current treatments that can prevent disease progression.\n\nThere is strong evidence from clinical studies and animal models that interleukin (IL)-4 and IL-13 are involved in the pathology of SSc, but no therapies directed against these cytokines have been developed for the treatment of this disease.\n\nWhat does this study add?\nRomilkimab is a novel humanised bispecific immunoglobulin-G4 antibody that binds and neutralises both IL-4 and IL-13.\n\nResults from this phase II proof-of-concept study showed that romilkimab achieved the primary endpoint (ie, a statistically significant reduction in modified Rodnan skin score at week 24) compared with placebo.\n\nRomilkimab was well tolerated compared with placebo with no cardiac safety signals.\n\nHow might this impact on clinical practice or future developments?\nThis is the first study to highlight the potential of romilkimab in patients with diffuse cutaneous SSc (dcSSc), and its use warrants further investigation.\n\nThe study also provides further validation of the role that IL-4 and IL-13 may play in dcSSc.\n\nIntroduction\nSystemic sclerosis (SSc) is characterised by immune dysregulation and microvascular obliteration in skin and internal organs.1 2 Overall prognosis remains poor, and diffuse cutaneous SSc (dcSSc) has a 10-year mortality rate of ~20%.3 4 Treatment choice is still debated. Nintedanib can reduce decline in forced vital capacity (FVC) in patients with SSc and lung fibrosis, and high-intensity regimens with autologous stem cell transplantation can favourably modify disease course in some patients.5–7\n\n\nHowever, recent advances have shown that SSc involves a T-helper type-2 (TH2)-oriented immune response with key roles for interleukin (IL)-4 and IL-13.1 8 9 This profibrotic activity of TH2 cytokines is associated with increased periostin, a matricellular protein important in fibrogenesis.10 11 Furthermore, administration of anti-IL-4 and anti-IL-13 antibodies prevents the development of dermal fibrosis in animal models.2 8 This pathway, therefore, represents an exciting new avenue for fibrosis treatment.\n\nRomilkimab (SAR156597) is an engineered humanised IgG4 antibody that binds and neutralises IL-4 and IL-13.12 13 Romilkimab reduced thymus and activation-regulated chemokine (TARC or chemokine (C-C motif) ligand 17) in patients with idiopathic pulmonary fibrosis (IPF); TARC is directly induced by IL-4 and IL-13 receptor activation, and a key serum marker used to assess target engagement.12 14 15 Romilkimab was well tolerated in healthy subjects who received single subcutaneous doses ranging from 10 to 300 mg. The safety profile was generally comparable between placebo, romilkimab 200 mg one time per week and once every 2 weeks in patients with IPF although serious adverse events (SAEs) were more common in the one time per week group (see online supplemental table S1 for safety outcomes).12 Romilkimab is a promising option given the pathology of SSc described.\n\n10.1136/annrheumdis-2020-218447.supp1Supplementary data \n\n\n\n This 24-week, proof-of-concept study evaluated the efficacy and safety of romilkimab versus placebo in early dcSSc.\n\nMethods\nDesign\nThis was a multinational, randomised, double-blind, placebo-controlled, proof-of-concept study that investigated romilkimab in patients with dcSSc. The study was conducted in 51 centres (39 randomised at least one patient) in 13 countries (Argentina, Belgium, Estonia, France, Germany, Italy, Mexico, Poland, Romania, Russian Federation, Ukraine, UK, USA). First patient was randomised on 21 December 2016 and last patient completed on 1 April 2019.\n\nPatients were randomised (1:1) to receive romilkimab 200 mg one time per week subcutaneously or placebo one time per week subcutaneously. The study consisted of 4 weeks of screening, 24 weeks of treatment and 11 weeks of follow-up with no treatment (see online supplemental figure S1 for schedule). There was one protocol amendment (online supplemental table S3) driven by the imbalance of serious IPF and cardiac events between groups in the romilkimab study in IPF (online supplemental table S1).12 This amendment was endorsed by the independent Data Monitoring Committee (DMC). All patients provided written informed consent prior to participation.\n\n10.1136/annrheumdis-2020-218447.supp2Supplementary data \n\n\n\n Participants\nPatients were eligible if they were aged ≥18 years and were classified as having SSc,16 with the diffuse subtype as defined by LeRoy et al\n17 criteria. Patients could enrol on stable background immunosuppressive therapies defined as: cyclophosphamide ≤1 mg/kg oral/day or ≤750 mg intravenously/month; azathioprine ≤100 mg/day; methotrexate ≤15 mg/week, and mycophenolate mofetil ≤2 g/day with or without low-dose corticosteroids (≤10 mg/day of oral prednisone or equivalent). See online supplemental file for exclusion criteria.\n\nRandomisation, masking and treatment\nEligible patients were randomised to treatment via a centralised randomisation system using interactive response technology. Patients, investigators and study centre personnel (except those who reconstituted romilkimab and prepared syringes for injection) were blinded to treatment (online supplemental file).\n\nEfficacy endpoints\nPrimary efficacy endpoint was change from baseline to week 24 in modified Rodnan skin score (mRSS; a validated measure of skin thickening18).\n\nSecondary efficacy endpoints included change from baseline to week 24 in the Health Assessment Questionnaire-Disability Index (HAQ-DI), a measure of physical/functional disability, assessed using the Scleroderma Health Assessment Questionnaire (SHAQ)19–21 and observed FVC/observed diffusing lung capacity for carbon monoxide (DLCO; corrected for haemoglobin).\n\nExploratory efficacy endpoints included change from baseline to week 24 in the Visual Analogue Scale (VAS) for overall disease severity, pain severity, gastrointestinal function, breathing function, vascular function and digital ulcer impact on activity (assessed via SHAQ); University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 total score22; tender joint count 28; digital ulcer count; and the European Quality of Life-5 Dimension-5 Level (EQ-5D-5L) index.23 Composite response index in diffuse cutaneous systemic sclerosis (CRISS) was measured at week 24 as defined in Khanna et al.24 Other exploratory endpoints included patients (%) with improvement in mRSS of at least 20%, 40% and 60% from baseline to week 24, mean change in mRSS in predefined subgroups (ie, more severe skin involvement at baseline (mRSS ≥15), disease duration <20 and ≥20 months, use of background medication (methotrexate, mycophenolate mofetil, azathioprine or cyclophosphamide), and medical history of SSc-interstitial lung disease (ILD) from baseline to week 24) and biomarkers of disease activity and the IL-4 and IL-13 pathway from baseline to week 24.\n\nPost hoc analyses were undertaken to determine time to progression (ie, first event defined as death, relative change of at least 10% in % predicted FVC or at least 15% in % predicted DLCO (corrected for haemoglobin), increase of at least 20% or +5 in mRSS, or other defined Step 1 CRISS events not covered above), and patients with minimally important difference (MID) on mRSS calculated using the patients (%) that achieved an improvement in mRSS of 3.2 points at week 24. This MID estimate was based on a published study in SSc that used this threshold to illustrate clinically improved patients (effect size 0.40) at week 24.25\n\n\nSafety endpoints\nAn independent DMC was responsible for reviewing safety data. Safety assessments consisted of recording adverse events (AEs), clinical laboratory evaluations, physical examinations, vital signs and ECGs. AEs were coded using Medical Dictionary for Regulatory Activities V.22.0. Potential for immunogenicity measured via antidrug antibody (ADA) response was also assessed.\n\nPharmacokinetics, immunogenicity and biomarker endpoints\nProtein biomarkers associated with disease activity (cartilage oligomeric matrix protein, chemokine C-C motif ligand 2) and the IL-4/IL-13 pathway (TARC, periostin and eotaxin-3) were measured. Plasma samples tested for romilkimab were analysed by Bertin Pharma (Saclay, France). ADA testing was performed using a validated bridging qualitative ELISA with electrochemiluminescence detection (DSAR OC, Montpellier, France).\n\nStatistical analyses\nIt was estimated that 94 patients (47 in each treatment group) would yield 80% power to detect a difference between romilkimab and placebo of 3.6 in the mean change from baseline in mRSS at 24 weeks, assuming an SD of 7 and using a one-sided alpha of 5% (type I error) to maximise the power needed to detect a positive signal with the limited sample size. This estimate was based on published studies.25 26\n\n\nEfficacy endpoints were evaluated in the intent-to-treat population, defined as all randomised patients. Safety was reported in all randomised patients who received at least one dose or part dose of study treatment (safety population). Anti-romilkimab antibody analysis was performed in the safety population with at least one baseline and post-dose antibody sample. Efficacy endpoints were analysed using a mixed-effect model with repeated measures (MMRM) approach. Missing data were accounted for by the MMRM, which relied on the missing-at-random assumption. The model included interactions for fixed treatment effect, randomisation strata, timepoint and fixed baseline mRSS. The model provided baseline-adjusted least square (LS) means, SE and 95% CI. CRISS outcomes were compared between groups using van Elteren’s test stratified by randomisation strata.\n\nPost hoc time to progression analysis was performed using a Cox model with mRSS at baseline, randomisation strata and treatment groups as explanatory variables. Post hoc analyses used two-sided tests. Romilkimab concentrations at selected timepoints after the last dose were reported using descriptive statistics. Pharmacokinetic parameters were estimated using the population pharmacokinetic approach at the lowest drug concentration before the next dose was administered (Ctrough). Analyses for safety and immunogenicity endpoints were descriptive.\n\nStatistical analyses were performed using SAS (SAS Institute).\n\nPatient involvement\nPatients provided written informed consent at screening and attended scheduled clinic visits. Patients provided feedback regarding their condition throughout the study via the patient-reported outcome questionnaires.\n\nResults\nParticipants\nA total of 143 patients were screened, and 97 were randomised to treatment with romilkimab (n=48) or placebo (n=49). The main reason for screening failure in 46 patients was abnormal QuantiFERON-TB Gold results.\n\nEighty-seven (90%) randomised patients completed the 24-week treatment period and 10 (10%) patients permanently discontinued study treatment due to lack of efficacy (four, 4%), AEs (three, 3%) or other reasons (three, 3%) (online supplemental figure S2). Baseline demographic and clinical characteristics were generally comparable between treatment groups (table 1). Critical or major protocol deviations were reported in 9 (19%) patients from the romilkimab group and 19 (39%) patients from the placebo group. The higher rate of deviations in the placebo group was mainly related to randomisation procedures as shown in online supplemental table S4.\n\n10.1136/annrheumdis-2020-218447.supp3Supplementary data \n\n\n\n Table 1 Patient demographic and clinical characteristics at baseline\n\n\tPlacebo\nQW\n(n=49)\tRomilkimab\n200 mg QW\n(n=48)\tAll patients\n(N=97)\t\nAge (years)\t\n Mean (SD)\t47.2 (12.1)\t52.3 (10.8)\t49.7 (11.7)\t\n Median (range)\t45.0 (27–72)\t53.0 (20–78)\t51.0 (20–78)\t\nSex, n (%)\t\n Male\t11 (22)\t9 (19)\t20 (21)\t\n Female\t38 (78)\t39 (81)\t77 (79)\t\nRace, n (%)\t\n American Indian or Alaska Native\t0\t1 (2)\t1 (1)\t\n Asian\t1 (2)\t0\t1 (1)\t\n Black or African American\t2 (4)\t2 (4)\t4 (4)\t\n Native Hawaiian or other Pacific Islander\t1 (2)\t0\t1 (1)\t\n White\t45 (92)\t45 (94)\t90 (93)\t\nEthnicity, n (%)\t\n Hispanic or Latino\t12 (25)\t10 (21)\t22 (23)\t\n Not Hispanic or Latino\t37 (76)\t38 (79)\t75 (77)\t\nBMI (kg/m2)\t\t\t\t\n Mean (SD)\t24.9 (5.3)\t24.3 (4.4)\t24.6 (4.9)\t\n Median (range)\t23.2 (18–41)\t24.4 (16–33)\t23.9 (16–41)\t\nWeight (kg)\t\n Mean (SD)\t68.1 (18.0)\t67.1 (15.3)\t67.6 (16.6)\t\n Median (range)\t61.5 (46–118)\t64.5 (36–105)\t62.4 (36–118)\t\nDisease duration from the time of first non-Raynaud’s phenomenon manifestation (months)\t\n Mean (SD)\t21.8 (10.7)\t19.3 (9.2)\t20.6 (10.0)\t\n Median (range)\t25.4 (5–36)\t19.4 (6–36)\t20.0 (5–36)\t\nBaseline mRSS\t\n Mean (SD)\t20.6 (7.0)\t20.5 (6.1)\t20.6 (6.5)\t\n Median (range)\t18.0 (10–35)\t19.5 (11–35)\t19.0 (10–35)\t\nBaseline FVC (% predicted)\t\t\t\t\n Mean (SD)\t89.5 (15.8)\t96.1 (17.4)\t92.8 (16.9)\t\n Median (range)\t91.9 (48–127)\t97.3 (54–127)\t93.0 (48–127)\t\nBaseline DLCO (% haemoglobin corrected)\t\n Mean (SD)\t66.5 (14.6)\t72.4 (14.2)\t69.4 (14.7)\t\n Median (range)\t67.3 (38–102)\t72.7 (39–102)\t70.0 (38–102)\t\nMedical history of SSc-ILD, n (%)\t\n Yes\t18 (37)\t18 (38)\t36 (37)\t\n No\t31 (63)\t30 (63)\t61 (63)\t\nBackground medication of interest, n (%)\t\n Methotrexate\t21 (43)\t12 (25)\t33 (34)\t\n Mycophenolate mofetil\t7 (14)\t10 (21)\t17 (18)\t\n Azathioprine\t1 (2)\t4 (8)\t5 (5)\t\nDemographic and baseline characteristics were comparable between groups based on descriptive analysis.\n\nBMI, body mass index; DLCO, diffusing lung capacity for carbon monoxide; FVC, forced vital capacity; ILD, interstitial lung disease; mRSS, modified Rodnan skin score; QW, one time per week; SSc, systemic sclerosis.\n\nPrimary efficacy endpoint\nRomilkimab resulted in a statistically significant decrease in mRSS from baseline to week 24 versus placebo; the LS mean (SE) change was –4.76 (0.86) versus –2.45 (0.85), yielding a mean (SE) difference (90% CI) of –2.31 (1.21) (–4.32 to –0.31; p=0.0291, one-sided) (figure 1A). The observed mean (SD) mRSS at week 24 was 15.43 (7.12) for romilkimab (n=47) and 18.25 (8.62) for placebo (n=48).\n\nFigure 1 Mean change from baseline to week 24 in (A) mRSS (primary endpoint), (B) mRSS in more symptomatic patients at baseline (mRSS ≥15) and (C) mRSS responder rates (20%, 40% and 60% improvements in mRSS) in the ITT population treated with romilkimab versus placebo. ITT, intent-to-treat; LS, least squares; mRSS, modified Rodnan skin score; QW, one time per week.\n\nSecondary efficacy endpoints\nThe LS mean (SE) change in FVC was –10 (40) mL for romilkimab versus –80 (40) mL for placebo at week 24 resulting in a non-significant mean (SE) difference (95% CI) of 70 (60) mL (–40 to 190; p=0.10) favouring romilkimab (figure 2A). The LS mean (SE) change for DLCO (haemoglobin corrected) was –0.12 (0.10) with romilkimab versus –0.27 (0.10) with placebo at week 24 yielding a non-significant difference of 0.15 (0.14) (–0.12 to 0.42; p=0.14) (figure 2B). The mean HAQ-DI score decreased slightly (ie, improved) in both groups (figure 2C). The LS mean (SE) change was –0.09 (0.08) for romilkimab versus –0.12 (0.08) for placebo at week 24; the LS mean (SE) difference (95% CI) was 0.03 (0.11) (–0.19 to 0.24; p=0.40).\n\nFigure 2 Mean change from baseline to week 24 in (A) FVC (mL), (B) DLCO and (C) HAQ-DI in the ITT population treated with romilkimab versus placebo. DLCO, diffusing lung capacity for carbon monoxide; FVC, forced vital capacity; HAQ-DI, Health Assessment Questionnaire-Disability Index; ITT, intent-to-treat; LS, least squares; QW, one time per week.\n\nExploratory efficacy endpoints\nRomilkimab resulted in a statistically significant improvement in the EQ-5D-5L index compared with placebo; the LS mean (SE) change from baseline to week 24 was 0.07 (0.03) for romilkimab versus 0.00 (0.03) for placebo resulting in a mean (SE) difference (95% CI) of 0.07 (0.04) (–0.01 to 0.15; p=0.0363) (table 2). Additional exploratory efficacy endpoints are summarised in online supplemental table S5.\n\nTable 2 Mean change from baseline to week 24 in exploratory patient-reported outcomes in the ITT population treated with romilkimab versus placebo\n\n\tPlacebo\nQW\n(n=49)\tRomilkimab\n200 mg QW\n(n=48)\t\nSHAQ—VAS for overall disease severity\t\n Baseline mean (SD)\t54.00 (27.62)\t42.71 (30.95)\t\n LS mean (SE) change from baseline\t–7.30 (3.12) (n=48)\t–12.72 (3.16) (n=47)\t\n LS mean (SE) difference (95% CI), p value\t–5.42 (4.48) (–14.32 to 3.48), 0.11\t\nSHAQ—VAS for pain severity\t\n Baseline mean (SD)\t36.82 (26.72)\t28.65 (28.28)\t\n LS mean (SE) change from baseline\t1.18 (3.44) (n=48)\t–6.94 (3.46) (n=47)\t\n LS mean (SE) difference (95% CI), p value\t–8.12 (4.91) (–17.87 to 1.63), 0.0507\t\nSHAQ—VAS for gastrointestinal function\t\n Baseline mean (SD)\t15.39 (22.25)\t7.54 (17.84)\t\n LS mean (SE) change from baseline\t5.40 (3.06) (n=48)\t3.21 (3.08) (n=47)\t\n LS mean (SE) difference (95% CI), p value\t–2.20 (4.38) (–10.90 to 6.51), 0.31\t\nSHAQ—VAS for breathing function\t\n Baseline mean (SD)\t18.80 (23.96)\t10.38 (18.13)\t\n LS mean (SE) change from baseline\t2.32 (2.63) (n=48)\t0.14 (2.66) (n=47)\t\n LS mean (SE) difference (95% CI), p value\t–2.18 (3.78) (–9.70 to 5.33), 0.28\t\nSHAQ—VAS for vascular function (Raynaud’s phenomenon)\t\n Baseline mean (SD)\t39.90 (28.82)\t29.98 (32.07)\t\n LS mean (SE) change from baseline\t–4.26 (3.24) (n=48)\t–8.46 (3.27) (n=47)\t\n LS mean (SE) difference (95% CI), p value\t–4.20 (4.64) (–13.43 to 5.02), 0.18\t\nSHAQ—VAS for digital ulcer impact on activity\t\n Baseline mean (SD)\t23.44 (32.78) (n=48)\t15.00 (29.25) (n=47)\t\n LS mean (SE) change from baseline\t0.08 (3.38) (n=48)\t–6.10 (3.41) (n=46)\t\n LS mean (SE) difference (95% CI), p value\t–6.18 (4.81) (–15.74 to 3.38), 0.10\t\nEQ-5D-5L\t\n Baseline mean (SD)\t0.58 (0.24)\t0.64 (0.18)\t\n LS mean (SE) change from baseline\t0.00 (0.03) (n=48)\t0.07 (0.03) (n=47)\t\n LS mean (SE) difference (95% CI), p value\t0.07 (0.04) (–0.01 to 0.15), 0.0363\t\nDecline in SHAQ=improvement; increase in EQ-5D-5L=improvement.\n\nEQ-5D-5L, European Quality of Life-5 Dimension-5 Level; ITT, intent-to-treat; LS, least squares; QW, one time per week; SHAQ, Scleroderma Health Assessment Questionnaire; VAS, Visual Analogue Scale.\n\nPrespecified subgroup analyses\nThe LS mean (SE) difference (95% CI) in mRSS was statistically significantly in favour of romilkimab versus placebo in patients with more severely affected skin (ie, baseline mRSS ≥15; –3.42 (1.40) (–6.21 to –0.64; p=0.0083)) (figure 1B). Responder rate analysis indicated that 20%, 40% and 60% improvements in mRSS from baseline to week 24 was higher for romilkimab than placebo; the between-group difference for 40% improvement in mRSS was statistically significant (p=0.0194) (figure 1C). The LS mean difference in mRSS was numerically in favour of romilkimab versus placebo at week 24, regardless of the baseline disease duration (<20 and ≥20 months), use of background therapy or medical history of SSc-ILD (online supplemental table S6).\n\nPost hoc analyses\nThere was a trend of benefit for romilkimab in time to an event reflecting disease progression compared with placebo: 9 (19%) versus 15 (31%) (HR 0.47 (95% CI 0.20 to 1.11); p=0.09, two-sided), respectively (online supplemental figure S3 and table S7). Regarding skin thickness, we showed that a larger proportion of patients achieved an MID threshold of 3.2 units on mRSS change from baseline in the romilkimab than placebo group (54% vs 43% (90% CI 0.82 to 3.28)), respectively.\n\n10.1136/annrheumdis-2020-218447.supp4Supplementary data \n\n\n\n Safety endpoints\nAlthough the overall incidence of treatment-emergent AEs (TEAEs) was high (>80% in both groups, n=41 for placebo and n=40 for romilkimab), most were mild or moderate in intensity (n=19 (40%) mild, n=20 (42%) moderate and n=1 (2%) severe for romilkimab; and n=23 (47%) mild, n=14 (29%) moderate and n=4 (8%) severe for placebo), and the incidence of TEAEs leading to permanent treatment discontinuation was low (three overall) (table 3). There were two deaths (one scleroderma renal crisis on romilkimab and one cardiomyopathy on placebo), but neither were considered treatment related by the investigator. There were no clinically meaningful changes in laboratory parameters, vital signs or ECGs over the course of the study.\n\nTable 3 Summary of patients experiencing AEs over the 24-week study\n\nSafety population, n (%)\tPlacebo\nQW\n(n=49)\tRomilkimab\n200 mg QW\n(n=48)\t\nAny TEAE\t41 (84)\t40 (80)\t\nAny treatment-emergent SAE*\t5 (10)\t4 (8)\t\n Acute pyelonephritis\t1 (2)\t0\t\n Cardiac failure†\t1 (2)\t0\t\n Cardiomyopathy†\t1 (2)\t0\t\n Dyspnoea\t1 (2)\t0\t\n Intestinal pseudo-obstruction\t1 (2)\t0\t\n Abnormal echocardiogram\t1 (2)\t0\t\n Bacterial pneumonia\t0\t1 (2)\t\n Pneumonia\t0\t1 (2)\t\n Bronchiolitis\t0\t1 (2)\t\n Acute cholecystitis\t0\t1 (2)\t\n Scleroderma renal crisis\t0\t1 (2)\t\n Chest pain\t0\t1 (2)\t\nTEAEs occurring in ≥5% of patients in either treatment group*\t\n Skin ulcer\t15 (31)\t8 (17)\t\n Nasopharyngitis\t6 (12)\t6 (13)\t\n Diarrhoea\t4 (8)\t7 (15)\t\n Upper respiratory tract infection\t2 (4)\t5 (10)\t\n Cystitis\t2 (4)\t3 (6)\t\n Pruritus\t1 (2)\t3 (6)\t\n Arthralgia\t1 (2)\t4 (8)\t\n Headache\t1 (2)\t4 (8)\t\n Oral herpes\t1 (2)\t5 (10)\t\n Pharyngitis\t0\t3 (6)\t\n Cough\t0\t5 (10)\t\n Gastro-oesophageal reflux disease\t0\t3 (6)\t\nAny TEAE leading to permanent treatment discontinuation\t1 (2)\t2 (4)\t\n Cardiomyopathy\t1 (2)\t0\t\n Oesophageal stenosis\t0\t1 (2)\t\n Scleroderma renal crisis\t0\t1 (2)\t\nAny TEAE leading to death‡\n\t1 (2)\t1 (2)\t\n Scleroderma renal crisis\t0\t1 (2)\t\n Cardiomyopathy\t1 (2)\t0\t\n*Preferred terms.\n\n†These were two different patients.\n\n‡No death event was considered treatment-related by the investigator.\n\nAE, adverse event; QW, one time per week; SAE, serious adverse event; TEAE, treatment-emergent adverse event.\n\nPharmacokinetics, immunogenicity and biomarker endpoints\nPharmacokinetic analysis showed that steady state for romilkimab was reached by week 4. Arithmetic mean (SD) Ctrough was 38.23 (17.96) μg/mL at week 4 and 47.45 (30.23) μg/mL at week 24. Immunogenicity testing showed that three patients in the romilkimab group and zero in the placebo group developed positive ADAs by week 24; all were considered low titre (30). None were associated with TEAEs.\n\nRomilkimab was associated with a statistically significant reduction in TARC versus placebo, indicating a positive effect on this pathway; the LS mean difference (95% CI) at week 24 was –115.56 ng/L (–216.87 to –14.26; p=0.0258) (figure 3A). Periostin also showed a strong trend for greater decline with romilkimab versus placebo (figure 3B). Additional biomarkers were not significantly different between romilkimab and placebo (online supplemental table S8).\n\nFigure 3 Mean change from baseline to week 24 for (A) TARC and (B) periostin in patients treated with romilkimab versus placebo. LS, least squares; QW, one time per week; TARC, thymus and activation-regulated chemokine.\n\nDiscussion\nThis is the first study to evaluate the efficacy and safety of romilkimab in patients with early dcSSc. Importantly, this phase II proof-of-concept study showed that romilkimab was associated with a statistically significant reduction in skin fibrosis versus placebo. Predefined subgroup analysis indicated that the efficacy of romilkimab on mRSS extended to patients with the most severe disease at baseline (mRSS ≥15), and it was effective in patients at the earliest disease stages of less than 20 months.\n\nAlthough MID estimates for mRSS are not available at week 24 in other recently completed studies,27 28 a previous analysis from the D-penicillamine study suggested an estimate of 3.2 units at week 24.25 Applying this estimate to our study resulted in a larger proportion of patients achieving MID with romilkimab versus placebo although not reaching statistical significance. Altogether, these data are consistent with a meaningful benefit of romilkimab on skin involvement but should be interpreted with caution in a phase II study. Therefore, future studies should incorporate appropriate anchors to calculate the MID estimates at the 24-week period with background standard of care therapy.\n\nComparisons with other studies are favourable. FaSScinate was a phase II, 48-week study of tocilizumab in SSc.28 In this study, tocilizumab was associated with a numerically greater improvement in mRSS than placebo at 24 weeks; the LS mean change was ‒3.92 versus ‒1.22 (p=0.09).28 In our study, there was a statistically significant change in patients that would have been eligible for faSScinate (ie, those with higher baseline mRSS of ≥15). It is important to note, however, that background therapy was allowed in both groups in our study but was not allowed in faSScinate, and this may have contributed to the greater mRSS change in the placebo group. There was also indication of a possible additive effect of romilkimab in patients receiving background immunosuppressive therapy (56%; n=54/97) as shown by the change in mRSS at week 24 compared with patients without background medication (‒5.81 vs ‒3.64, respectively). Herein, there was an initial improvement of mRSS up to week 12 in both groups, followed by slight worsening of mRSS up to week 24 in the placebo group, which may reflect the initial impact of background therapy. However, the study was not designed to examine prior medication use in detail. Nevertheless, allowing background immunosuppressant in a study looking primarily at skin outcomes was novel. Our compelling results together with those of the SENSCIS lung study5 should establish a new standard for SSc studies by allowing background immunosuppressants. Another randomised study (ASSET) showed that abatacept was associated with a numerically greater improvement in adjusted mRSS (primary endpoint) than placebo at 12 months (mean (SE): ‒6.24 (1.14) vs ‒4.49 (1.14); p=0.28), but this study failed to reach statistical significance.29 It is not possible to determine if different mechanism of action between agents accounted for the variable results, but it must be noted that the primary analyses in our study were based on prespecified one-sided compared with two-sided alpha testing in faSScinate and ASSET. Despite several recent studies of potential therapies not meeting the mRSS endpoint, skin score assessment remains clinically relevant, alongside organ-specific or patient-reported outcomes in defining clinical benefit in SSc studies. Future studies may use combined composite endpoints to more robustly evaluate efficacy in SSc.\n\nIn the current study, romilkimab had a non-significant but favourable effect on lung outcomes, which warrants further evaluation. The loss of 80 mL for FVC between baseline and week 24 for patients treated with placebo supports previous findings that patients with early dcSSc may develop significant lung disease.30 Additionally, this highlights an overlap between the immunopathology of dcSSc and IPF, but there may be mechanistic differences between these two fibrotic conditions.\n\nSafety results were generally similar to those previously reported for patients who received romilkimab for the treatment of IPF.12 However, no serious or severe cardiac or respiratory TEAEs were reported in this study for those treated with romilkimab. Oral herpes has been reported with other IL-4/IL-13 blocking agents. Herein, oral herpes was more common in romilkimab-treated patients, but no herpes zoster or disseminated herpes infection was observed.\n\nThis study is limited by a relatively short treatment duration, which may not have permitted the detection of significant differences in other non-skin outcomes; however, this was consistent with previous phase II studies, and was chosen based on rapid response in skin outcomes, seen in other studies.28\n\n\nIn conclusion, this is the first study of romilkimab in patients with early dcSSc, and our findings provide strong justification for further studies. The impact on skin met the prespecified endpoint, which is the first time that this has been achieved in a phase II study in dcSSc.\n\nWriting assistance was provided by Sam Phillips, PhD, Parexel, Uxbridge, UK, and was funded by Sanofi. DMC members included Christian Pagnoux, MD, MSc, MPH (Chairman); Ami Shah, MD, MHS; and Lucy Shneyer, MA. The authors would also like to thank the patients who participated in this study, and their families, as well as the investigators, study coordinators, study teams and nurses. Centre details are listed in online supplemental table S9.\n\nHandling editor: Josef S Smolen\n\nCollaborators:\nYannick Allanore, Hugo Ascencio, Shervin Assassi, Hilario Avila Armengol, Jerome Avouac, Andra Balanescu, Guillermo Gerardo Bartel, Doreen Belz, Lorenzo Beretta, Horacio Berman, Francesco Boin, Mihai Bojinca, Violeta Bojinca, Martin Brom, Justyna Cal-Kocikowska, Maria Gabriela Cardozo, Renato Carignola, Emmanuel Chatelus, Soumya Chatterjee, Dorota Cieslak, Maurizio Cutolo, Maria Dall’Era, Behrus Darvishan, Ellen De Langhe, Nicoletta Del Papa, Christopher Denton, Oxana Desinova, Villafañe Nicolas Javier Destefani, Katrin Elsharkawi-Welt, Jorge A Esquivel-Valerio, Gulshat Fatkhullina, Dmytro Fedkov, Eugen Feist, Renaud Felten, Rosanna Ferreira Lopez, Alvarado Diana Elsa Flores, Rene A Flores-Franco, Ignacio Garcia-De La Torre, Maria Victoria Garcia, Ignacio Garcia Valladares, Olena Garmisch, Ana Gheorghiu, Andrey Gnilorybov, Bello Yelitza Concepción González, Maria Groseanu, Walter Hermann, Pawel Hrycaj, Oleg Iaremenko, Janusz Jaworski, Christian Jorgensen, Rimma Kamalova, Alina Kamynina, Claudia Kedor, Natalie Kelp, Elsa Khazeeva, Piotr Klepacki, Aleksandra Kolczewska, Ramona König, Volodymyr Kovalenko, Thomas Krieg, Marina Letaeva, Pavlo Logoida, Natalia Loschits, Lukasz Lubinski, Wanda Maglione, Olga Malyshenko, Elena-Laura Margarint, Ciprian M Marinescu, Alejandro Martelli, Maureen Mayes, Diana Mazilu, Valeriia Melokhina, Karin Melsens, Christopher Meneses Lopez, Maria Mirza, Maria Misterska-Skora, Pia Moinzadeh, Erika Montabone, Ulf Müller-Ladner, Edgardo Munoz-Esteves, Ene Ojassalu, Daniela Opris, Cesar Tena Pacheco, Hugo Parra Ruiz, Lorena Perez Barbosa, Yves-Marie Pers, Ana Petcu, Liubov Petelytska, Christiane Pfeiffer, Yves Piette, Oksana Pirogova, Horatiu V Popoviciu, Kaitlin Quinn, Tatiana Raskina, Eve-Kai Raussi, Simona Rednic, Greta Reyes, Janett Riega, Roberto Jesus Gallegos Rivero, Mariano Rivero, Andrii Romanovskyi, Ewa Rzeszewska, Mirtha Sabelli, Mikhail Sandin, Maria Lida Santiago, Mikk Saretok, Ioana Saulescu, Lena Schriever, Agata Sebastian, Adriana Severino, Anca Sindrilaru, Cassandra Skinner, Vanessa Smith, Christelle Sordet, Tatiana Sotnikova, Jorge Alberto Spindler, Javier Walter Spindler, Marina Stanislav, Gerald Stapfer, Mayya Starovoytova, Virginia Steen, Simona Szasz, Guillermo Tate, Patricio Tate, Piia Tuvik, Adelfia Quezada Urenda, Lyalya Valishina, Amber Vanhaecke, Brenda Vázquez, Ildiko Vicsi, Barbara Vigone, Oana Vutcanu, René Westhovens, Victoria Zimina, Anna Zubrzycka-Sienkiewicz. Primary investigators are highlighted in bold.\n\nContributors: YA and CPD contributed to the study concept and design, and data collection, analysis and interpretation. PW contributed to the study concept and design, data analysis and interpretation. DK, CE, FM and AL contributed to data analysis and interpretation. CS contributed to the study concept and design and data interpretation. RB designed the study analyses and contributed to data interpretation. All authors contributed to manuscript preparation and approved the final version.\n\nFunding: The study was funded by Sanofi R&D, France.\n\nCompeting interests: YA reports personal fees from Actelion, Bayer, BMS and Curzion, and grants and personal fees from Inventiva, Roche and Sanofi. CPD reports personal fees from Actelion, Bayer, Boehringer Ingelheim, Corbus, Roche, Sanofi, and grants and personal fees from CSL Behring, GlaxoSmithKline and Inventiva. DK reports personal fees from Acceleron, Actelion, Blade Therapeutics, Eicos Sciences, Inc, Galapagos, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme and UCB Pharma, and grants and personal fees from Bayer, Bristol Myers Squibb and Genentech/Roche; he is funded by the NIH/NIAMS K24 AR063120. PW, CS, CE, FM, RB and AL are employees of Sanofi. CS is a shareholder in Sanofi.\n\nPatient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.\n\nPatient consent for publication: Obtained.\n\nEthics approval: The study was conducted in accordance with Declaration of Helsinki and International Conference of Harmonisation guidelines for Good Clinical Practice. Each participating site’s institutional review board or ethics committee approved the protocol and amendment(s) (online supplemental table S2).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: Data are available upon reasonable request. Qualified researchers may request access to patient level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Patient level data will be anonymised, and study documents will be redacted to protect the privacy of study participants. Further details on Sanofi’s data sharing criteria, eligible studies and process for requesting access can be found at: https://www.clinicalstudydatarequest.com.\n==== Refs\nReferences\n1 \nAllanore Y , Simms R , Distler O , et al \nSystemic sclerosis\n. Nat Rev Dis Primers \n2015 ;1 :15002 . 10.1038/nrdp.2015.2 \n27189141 \n2 \nMcGaha T , Saito S , Phelps RG , et al \nLack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the Interleukin-4Rα and transforming growth factor-β genes\n. J Invest Dermatol \n2001 ;116 :136 –43\n. 10.1046/j.1523-1747.2001.00217.x \n11168809 \n3 \nRubio-Rivas M , Corbella X , Guillén-Del-Castillo A , et al \nSpanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: derivation and internal validation\n. Autoimmun Rev \n2020 ;19 :102507. 10.1016/j.autrev.2020.102507 \n32194200 \n4 \nSobanski V , Giovannelli J , Allanore Y , et al \nPhenotypes determined by cluster analysis and their survival in the prospective European Scleroderma Trials and Research cohort of patients with systemic sclerosis\n. Arthritis Rheumatol \n2019 ;71 :1553 –70\n. 10.1002/art.40906 \n30969034 \n5 \nDistler O , Highland KB , Gahlemann M , et al \nNintedanib for systemic sclerosis-associated interstitial lung disease\n. N Engl J Med \n2019 ;380 :2518 –28\n. 10.1056/NEJMoa1903076 \n31112379 \n6 \nSullivan KM , Goldmuntz EA , Keyes-Elstein L , et al \nMyeloablative autologous stem-cell transplantation for severe scleroderma\n. N Engl J Med \n2018 ;378 :35 –47\n. 10.1056/NEJMoa1703327 \n29298160 \n7 \nvan Laar JM , Farge D , Sont JK , et al \nAutologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial\n. JAMA \n2014 ;311 :2490 –8\n. 10.1001/jama.2014.6368 \n25058083 \n8 \nHuang X-L , Wang Y-J , Yan J-W , et al \nRole of anti-inflammatory cytokines IL-4 and IL-13 in systemic sclerosis\n. Inflamm Res \n2015 ;64 :151 –9\n. 10.1007/s00011-015-0806-0 \n25725697 \n9 \nGieseck RL , Wilson MS , Wynn TA \nType 2 immunity in tissue repair and fibrosis\n. Nat Rev Immunol \n2018 ;18 :62 –76\n. 10.1038/nri.2017.90 \n28853443 \n10 \nJakubzick C , Choi ES , Joshi BH , et al \nTherapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells\n. J Immunol \n2003 ;171 :2684 –93\n. 10.4049/jimmunol.171.5.2684 \n12928422 \n11 \nOkamoto M , Izuhara K , Ohta S , et al \nAbility of periostin as a new biomarker of idiopathic pulmonary fibrosis\n. Adv Exp Med Biol \n2019 ;1132 :79 –87\n. 10.1007/978-981-13-6657-4_9 \n31037627 \n12 \nRaghu G , Richeldi L , Crestani B , et al \nSAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772)\n. Eur Respir J \n2018 ;52 :1801130 \n10.1183/13993003.01130-2018 \n30337444 \n13 \nAllanore Y , Denton C , Khanna D , et al \nEfficacy and safety of romilkimab in diffuse cutaneous systemic sclerosis (dcSSc): a randomized, double-blind, placebo-controlled, 24-week, proof of concept study\n. Arthritis Rheumatol \n2019 ;71(abstract 1653) .\n14 \nFaffe DS , Whitehead T , Moore PE , et al \nIL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype\n. Am J Physiol Lung Cell Mol Physiol \n2003 ;285 :L907 –14\n. 10.1152/ajplung.00120.2003 \n12871855 \n15 \nSoubrane C , Lin Y , Delfolie A \nEvaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of ascending repeated doses of SAR156597 in patients with idiopathic pulmonary fibrosis (IPF): a randomized, double-blind, placebo-controlled study\n. 18th International Colloquium on Lung And Airway Fibrosis (ICLAF) ; 20-24 September 2014 , Quebec, Canada , 2014 .\n16 \nvan den Hoogen F , Khanna D , Fransen J , et al \n2013 classification criteria for systemic sclerosis: an American College of rheumatology/European League against rheumatism collaborative initiative\n. Ann Rheum Dis \n2013 ;72 :1747 –55\n. 10.1136/annrheumdis-2013-204424 \n24092682 \n17 \nLeRoy EC , Black C , Fleischmajer R , et al \nScleroderma (systemic sclerosis): classification, subsets and pathogenesis\n. J Rheumatol \n1988 ;15 :202 –5\n.\n3361530 \n18 \nKhanna D , Furst DE , Clements PJ , et al \nStandardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis\n. J Scleroderma Relat Disord \n2017 ;2 :11 –18\n. 10.5301/jsrd.5000231 \n28516167 \n19 \nPeytrignet S , Denton CP , Lunt M , et al \nDisability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study\n. Rheumatology \n2018 ;57 :370 –81\n. 10.1093/rheumatology/kex410 \n29207002 \n20 \nHudson M , Thombs BD , Steele R , et al \nQuality of life in patients with systemic sclerosis compared to the general population and patients with other chronic conditions\n. J Rheumatol \n2009 ;36 :768 –72\n. 10.3899/jrheum.080281 \n19228662 \n21 \nSteen VD , Medsger TA \nThe value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time\n. Arthritis Rheum \n1997 ;40 :1984 –91\n. 10.1002/art.1780401110 \n9365087 \n22 \nKhanna D , Hays RD , Maranian P , et al \nReliability and validity of the University of California, Los Angeles scleroderma clinical trial Consortium gastrointestinal tract instrument\n. Arthritis Rheum \n2009 ;61 :1257 –63\n. 10.1002/art.24730 \n19714600 \n23 \nHerdman M , Gudex C , Lloyd A , et al \nDevelopment and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)\n. Qual Life Res \n2011 ;20 :1727 –36\n. 10.1007/s11136-011-9903-x \n21479777 \n24 \nKhanna D , Berrocal VJ , Giannini EH , et al \nThe American College of rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis\n. Arthritis Care Res \n2016 ;68 :167 –78\n. 10.1002/acr.22804 \n\n25 \nKhanna D , Furst DE , Hays RD , et al \nMinimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study\n. Ann Rheum Dis \n2006 ;65 :1325 –9\n. 10.1136/ard.2005.050187 \n16540546 \n26 \nAmjadi S , Maranian P , Furst DE , et al \nCourse of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: analysis of three large multicenter, double-blind, randomized controlled trials\n. Arthritis Rheum \n2009 ;60 :2490 –8\n. 10.1002/art.24681 \n19644851 \n27 \nKhanna D , Clements PJ , Volkmann ER , et al \nMinimal clinically important differences for the modified Rodnan skin score: results from the Scleroderma Lung Studies (SLS-I and SLS-II)\n. Arthritis Res Ther \n2019 ;21 :23 . 10.1186/s13075-019-1809-y \n30651141 \n28 \nKhanna D , Denton CP , Jahreis A , et al \nSafety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial\n. Lancet \n2016 ;387 :2630 –40\n. 10.1016/S0140-6736(16)00232-4 \n27156934 \n29 \nKhanna D , Spino C , Johnson S , et al \nAbatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial\n. Arthritis Rheumatol \n2020 ;72 :125 –36\n. 10.1002/art.41055 \n31342624 \n30 \nKhanna D , CJF L , Kuwana M , et al \nEfficacy and safety of tocilizumab for the treatment of systemic sclerosis: results from a phase 3 randomized controlled trial\n. Arthritis Rheumatol \n2018 ;70(abstract 898) .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0003-4967",
"issue": "79(12)",
"journal": "Annals of the rheumatic diseases",
"keywords": "autoimmune diseases; chemokines; scleroderma; systemic; therapeutics",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D015847:Interleukin-4; D008297:Male; D008875:Middle Aged; D000075082:Proof of Concept Study; D045743:Scleroderma, Diffuse; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1600-1607",
"pmc": null,
"pmid": "32963047",
"pubdate": "2020-12",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "9365087;25058083;27189141;19714600;30337444;11168809;29207002;19644851;24092682;27156934;12928422;29298160;12871855;3361530;25725697;30969034;21479777;26806474;31037627;28853443;28516167;32194200;31112379;16540546;31342624;30651141;19228662",
"title": "A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis.",
"title_normalized": "a randomised double blind placebo controlled 24 week phase ii proof of concept study of romilkimab sar156597 in early diffuse cutaneous systemic sclerosis"
} | [
{
"companynumb": "FR-ROCHE-2724998",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSynovial sarcomas are uncommon malignancies that mainly affect adolescents and young adults. Most arise from the deep soft tissues of the extremities, but they can occur in other parts of the body such as the lung. Synovial sarcomas after radiation therapy are rare, in contrast with other sarcomas, with only six reported cases. Secondary malignancies after radioactive iodine (RAI) therapy are also uncommon, with the most consistent evidence for hematologic malignancies.\n\n\nMETHODS\nWe present what we believe to be the first report of a synovial sarcoma of the lung with an SS18/SSX1 translocation after RAI therapy. At age 20, the patient developed papillary thyroid cancer and later had two surgically confirmed recurrences. Over the course of her care, she received a total of about 220 mCi of RAI. At age 34, as part of an evaluation for another suspected recurrence, she had a position emission spectroscopy-computed tomography scan, and a pulmonary mass was detected.\n\n\nCONCLUSIONS\nAlthough not previously reported, this case suggests that synovial sarcomas may be a secondary malignancy after RAI therapy. The latency in this case is reasonable, the dose to the lungs was small, but in the range where radiation-related malignancy may occur, and the somatic chromosomal rearrangement could be a radiation effect.",
"affiliations": "Section of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.",
"authors": "Vora|Avni|A|;Schneider|Arthur B|AB|",
"chemical_list": "D007457:Iodine Radioisotopes",
"country": "United States",
"delete": false,
"doi": "10.1089/thy.2012.0472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-7256",
"issue": "23(3)",
"journal": "Thyroid : official journal of the American Thyroid Association",
"keywords": null,
"medline_ta": "Thyroid",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008168:Lung; D008175:Lung Neoplasms; D009381:Neoplasms, Radiation-Induced; D049268:Positron-Emission Tomography; D012008:Recurrence; D013584:Sarcoma, Synovial; D013964:Thyroid Neoplasms",
"nlm_unique_id": "9104317",
"other_id": null,
"pages": "371-5",
"pmc": null,
"pmid": "23205908",
"pubdate": "2013-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Synovial sarcoma of the lung in a patient who received radioactive iodine therapy for thyroid cancer.",
"title_normalized": "synovial sarcoma of the lung in a patient who received radioactive iodine therapy for thyroid cancer"
} | [
{
"companynumb": "US-MALLINCKRODT-T201501922",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "SODIUM IODIDE I-131"
},
"drugadditional": nu... |
{
"abstract": "The combination of lenalidomide (Revlimid® , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46-83]) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.",
"affiliations": "Medical Oncology and Haematology, Kantonsspital Graubünden, Chur, Switzerland.;Haematology/Oncology, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany.;Department of Oncology, Kantonsspital Baden, Baden, Switzerland.;Department of Oncology, Kantonsspital Baden, Baden, Switzerland.;Gemeinschaftspraxis Hämatologie/Onkologie, Leipzig, Germany.;Onkologie Ravensburg, Ravensburg, Germany.;Haemato-Onkologische Praxis Moers, Moers, Germany.;Fachinternistische Gemeinschaftspraxis und Therapiezentrum, Witten, Germany.;Oncology/Haematology, Kantonsspital Muensterlingen, Muensterlingen, Switzerland.;Department of Medical Oncology and Haematology, Stadtspital Triemli, Zuerich, Switzerland.;Haematology, Oncology and Tumourimmunology, Helios Clinic Berlin-Buch, Berlin, Germany.;Onkozentrum Dresden, Dresden, Germany.;Kantonsspital Winterthur, Winterthur, Switzerland.;Department of Haematology, Kantonsspital Luzern, Luzern, Switzerland.;Haemato-Onkologische Schwerpunktpraxis Troisdorf, Troisdorf, Germany.;Onkologische Gemeinschaftspraxis Frankfurt, Frankfurt, Germany.;Medical Oncology and Haematology, Kantonsspital Graubünden, Chur, Switzerland.;Medical Oncology and Haematology, Kantonsspital Graubünden, Chur, Switzerland.;Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.;Clinical Trials Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland.;Clinical Trials Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland.;Division of Haematology and Transfusion Medicine, Kantonsspital Aarau, Aarau, Switzerland.;Division of Haematology and Transfusion Medicine, Kantonsspital Aarau, Aarau, Switzerland.;Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.",
"authors": "Mey|Ulrich J M|UJ|;Brugger|Wolfram|W|;Schwarb|Heike|H|;Pederiva|Stefanie|S|;Schwarzer|Andreas|A|;Dechow|Tobias|T|;Jehner|Paul|P|;Rauh|Jacqueline|J|;Taverna|Christian J|CJ|;Schmid|Mathias|M|;Schmidt-Hieber|Martin|M|;Doerfel|Steffen|S|;Fischer|Natalie|N|;Ruefer|Axel|A|;Ziske|Carsten|C|;Knauf|Wolfgang|W|;Cathomas|Richard|R|;von Moos|Roger|R|;Hitz|Felicitas|F|;Sauter|Rafael|R|;Hiendlmeyer|Elke|E|;Cantoni|Nathan|N|;Bargetzi|Mario|M|;Driessen|Christoph|C|",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; D000069461:Bendamustine Hydrochloride; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14481",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "176(5)",
"journal": "British journal of haematology",
"keywords": "bendamustine; lenalidomide; multiple myeloma; phase II; second-line",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D003907:Dexamethasone; D006801:Humans; D000077269:Lenalidomide; D008875:Middle Aged; D009101:Multiple Myeloma; D009503:Neutropenia; D012074:Remission Induction; D016879:Salvage Therapy; D013792:Thalidomide; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "770-782",
"pmc": null,
"pmid": "27983764",
"pubdate": "2017-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial.",
"title_normalized": "bendamustine lenalidomide and dexamethasone brd has high activity as 2nd line therapy for relapsed and refractory multiple myeloma a phase ii trial"
} | [
{
"companynumb": "CH-CELGENEUS-151-21880-14072993",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
},
"drugadditional": "3",... |
{
"abstract": "We reported a case of a 6-month-old baby girl who was hospitalized in the pediatric emergency for central nervous system disorders then coma. Toxicology analysis showed the presence of amitriptyline (AMI) and its metabolite nortriptyline (NOR) in blood and urine of the baby. Additional investigations suggested a shaken baby syndrome. Given the family context, a judge ordered hair tests for both the child and his parents to document drug exposure. A liquid chromatography tandem mass spectrometric (LC-MS/MS) method was then developed to quantify AMI and NOR in hair. After decontamination and segmentation, 20 mg of hair was incubated overnight at 55 °C in methanol (MeOH). The LC-MS/MS method used an online solid phase extraction and the analysis was performed using two transitions per compound. The LOQ and LOD for the two compounds were estimated at 0.0075 ng/mg and 0.005 ng/mg respectively. All hair segments tested for both parents were negative. For the baby two strands of hair were collected one day after the acute intoxication for the first and 5 weeks later for the second. The first strand was not decontaminated before analysis to avoid losing specimen. The high and relatively homogenous concentrations of AMI (with a range of value from 6.65 to 9.69 ng/mg) and NOR (with a range of value from 7.12 to 8.96 ng/mg) measured suggested that contamination could have occurred. The analysis of the second strand after decontamination allowed to detect AMI and NOR in all hair segments. The obtained values varied between 0.54 and 1.41 ng/mg for AMI and between 1.26 and 4.00 ng/mg for NOR. These results supported the hypothesis of a chronic exposure during several months before hair collection with regular increase. However a single overdose could not be totally excluded. The interpretation of results must take into account the pharmacological and physiological parameters of hair of the children.",
"affiliations": "Université Grenoble Alpes, F-38041 Grenoble, France. Electronic address: nathalie.allibe@ujf-grenoble.fr.;Université Grenoble Alpes, F-38041 Grenoble, France; CHU, F-38043 Grenoble, France.;X-Pertise Consulting, 84 route de Saverne, 62705 Oberhausbergen, France.;CHU, F-38043 Grenoble, France.;CHU, F-38043 Grenoble, France.;Université Grenoble Alpes, F-38041 Grenoble, France.;Université Grenoble Alpes, F-38041 Grenoble, France; CHU, F-38043 Grenoble, France.;Université Grenoble Alpes, F-38041 Grenoble, France; CHU, F-38043 Grenoble, France; INSERM U1042, HP2, F-38041 Grenoble, France.",
"authors": "Allibe|Nathalie|N|;Eysseric-Guerin|Hélène|H|;Kintz|Pascal|P|;Bartoli|Mireille|M|;Bost-Bru|Cécile|C|;Grenier|Florian|F|;Scolan|Virginie|V|;Stanke-Labesque|Françoise|F|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "249()",
"journal": "Forensic science international",
"keywords": "Amitriptyline; Children's hair; LC–MS/MS; Nortriptyline",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000639:Amitriptyline; D000929:Antidepressive Agents, Tricyclic; D002649:Child Abuse; D002853:Chromatography, Liquid; D062787:Drug Overdose; D005260:Female; D053593:Forensic Toxicology; D006197:Hair; D006801:Humans; D007223:Infant; D015203:Reproducibility of Results; D038642:Shaken Baby Syndrome; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "53-8",
"pmc": null,
"pmid": "25676714",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amitriptyline poisoning of a baby: how informative can hair analysis be?",
"title_normalized": "amitriptyline poisoning of a baby how informative can hair analysis be"
} | [
{
"companynumb": "FR-MYLANLABS-2016M1017149",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Ergotism is a toxic condition resulting from overexposure to the ergot compounds produced by various fungi of the genus Claviceps. Traditionally, such exposure was due to ingestion of infected grains, but long-term or excessive use of medications containing ergot derivatives or drug-drug interactions between these medications can result in ergotism. Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4). Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism. A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997 (most recently reviewed by Frohlich et al).",
"affiliations": "HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.;HIV-NAT Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.;Chulalongkorn University, Bangkok, Thailand.;Khon Kaen University, Khon Kaen, Thailand.;Chonburi Hospital, Chonburi, Thailand.;Taksin Hospital, Bangkok, Thailand.;Chiang Rai Hospital, Chiang Rai, Thailand.;Chonburi Hospital, Chonburi, Thailand.;e HIV-NAT Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.;Chulalongkorn University, Bangkok, Thailand.;HIV-NAT Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.;Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.",
"authors": "Avihingsanon|Anchalee|A|;Ramautarsing|Reshmie A|RA|;Suwanpimolkul|Gompol|G|;Chetchotisakd|Ploenchan|P|;Bowonwatanuwong|Chureeratana|C|;Jirajariyavej|Supunnee|S|;Kantipong|Patcharee|P|;Tantipong|Hutsaya|H|;Ohata|June Pirapon|JP|;Suankratay|Chusana|C|;Ruxrungtham|Kiat|K|;Burger|David M|DM|",
"chemical_list": "D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D004878:Ergotamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2161-5853",
"issue": "21(5)",
"journal": "Topics in antiviral medicine",
"keywords": null,
"medline_ta": "Top Antivir Med",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D004347:Drug Interactions; D004878:Ergotamine; D004881:Ergotism; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D007866:Leg; D008297:Male; D008875:Middle Aged; D013785:Thailand",
"nlm_unique_id": "101560274",
"other_id": null,
"pages": "165-8",
"pmc": null,
"pmid": "24531557",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20048008;20738185;9009470",
"title": "Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning.",
"title_normalized": "ergotism in thailand caused by increased access to antiretroviral drugs a global warning"
} | [
{
"companynumb": "TH-WATSON-2014-20621",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INDINAVIR\\RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "We herein report the case of a patient with human immunodeficiency virus infection and acquired immune deficiency syndrome who was diagnosed with drug-induced pure red cell aplasia consequent to lamivudine treatment. The patient was admitted to our hospital for treatment of increasing shortness of breath following physical effort. Upon admission, routine blood tests revealed a hemoglobin level of 7.6 g/dL and a hematocrit proportion of 21.2%, with normal leukocyte and platelet counts. After stopping the lamivudine treatment, the patient's hemoglobin concentration and hematocrit level returned to normal. A bone marrow examination showed an exclusive reduction in erythrocyte formation. This case indicates that lamivudine can induce severe anemia without the influence of zidovudine.",
"affiliations": "Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases, Faculty of Medicine, University of the Ryukyus, Japan.",
"authors": "Nakamura|Kiwamu|K|;Tateyama|Masao|M|;Tasato|Daisuke|D|;Haranaga|Shusaku|S|;Tamayose|Maki|M|;Yara|Satomi|S|;Higa|Futoshi|F|;Fujita|Jiro|J|",
"chemical_list": "D019380:Anti-HIV Agents; D019259:Lamivudine; D015215:Zidovudine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.53.2460",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "53(15)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D019380:Anti-HIV Agents; D001707:Biopsy, Needle; D001853:Bone Marrow; D003937:Diagnosis, Differential; D015658:HIV Infections; D006801:Humans; D019259:Lamivudine; D008297:Male; D010976:Platelet Count; D012010:Red-Cell Aplasia, Pure; D055815:Young Adult; D015215:Zidovudine",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1705-8",
"pmc": null,
"pmid": "25088890",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pure red cell aplasia induced by lamivudine without the influence of zidovudine in a patient infected with human immunodeficiency virus.",
"title_normalized": "pure red cell aplasia induced by lamivudine without the influence of zidovudine in a patient infected with human immunodeficiency virus"
} | [
{
"companynumb": "JP-VIIV HEALTHCARE LIMITED-B0551326A",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ABACAVIR SULFATE"
},
"drugaddition... |
{
"abstract": "Coronavirus Disease 2019 (COVID-19) has become a pandemic since March 2020. We describe here 2 cases of COVID-19 infection in a posttransplant setting. First one is a 59-year-old renal transplant recipient; the second is a 51-year-old allogeneic bone marrow transplant recipient. Both patients were on immunosuppressant therapy and had stable graft function before COVID-19 infection. After the diagnosis of COVID-19, immunosuppressive agents were discontinued and methylprednisolone with prophylactic antibiotics were initiated, however, the lung injury progressed. The T cells were extremely low in both patients after infection. Both patients died despite the maximal mechanical ventilatory support. Therefore, the prognosis of COVID-19 pneumonia following transplantation is not optimistic and remains guarded. Lower T cell count may be a surrogate for poor outcome.",
"affiliations": "Department of Liver Research Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Department of Oncology, Fuzhou Pulmonary Hospital, Fuzhou, China.;Department of Liver Research Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Department of Tuberculosis, the Third People's Hospital of Yichang City, Yichang, China.;Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.;Department of Respiratory, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Department of Liver Research Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China.",
"authors": "Huang|Jiaofeng|J|;Lin|Heng|H|;Wu|Yinlian|Y|;Fang|Yingying|Y|;Kumar|Rahul|R|;Chen|Gongping|G|;Lin|Su|S|https://orcid.org/0000-0001-7517-9859",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15896",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "COVID-19; Coronavirus; transplantation",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D016026:Bone Marrow Transplantation; D000086382:COVID-19; D002681:China; D018352:Coronavirus Infections; D003428:Cross Infection; D017809:Fatal Outcome; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D011183:Postoperative Complications; D011379:Prognosis; D012121:Respiration, Artificial; D013601:T-Lymphocytes; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1879-1881",
"pmc": null,
"pmid": "32243697",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "COVID-19 in posttransplant patients-report of 2 cases.",
"title_normalized": "covid 19 in posttransplant patients report of 2 cases"
} | [
{
"companynumb": "CN-TEVA-2020-CN-1812473",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "The development of Angular Cheilitis and the reactivation of Herpes Simplex Virus, could be related to a decrease in the resistance of the immune system in the infected host, being common in cancer patients receiving antineoplastic chemotherapy. The objective of the present manuscript is to report Antimicrobial Photodynamic Therapy as a treatment of infected oral lesions of patients submitted to chemotherapy.",
"affiliations": "Santa Casa de Montes Claros Hospital - Minas Gerais, Brazil.;Santa Casa de Montes Claros Hospital - Minas Gerais, Brazil.;Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo (SP), 05508-000 São Paulo, SP, Brazil. Electronic address: lysimoes@usp.br.",
"authors": "Rocha|Breno Amaral|BA|;Melo Filho|Mário Rodrigues|MR|;Simões|Alyne|A|",
"chemical_list": "D000970:Antineoplastic Agents; D017319:Photosensitizing Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.pdpdt.2015.07.172",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1572-1000",
"issue": "13()",
"journal": "Photodiagnosis and photodynamic therapy",
"keywords": "Angular Cheilitis; Antimicrobial Photodynamic Therapy; Cancer patients; Chemotherapy; Herpes Simplex Virus Type 1; Oral lesions",
"medline_ta": "Photodiagnosis Photodyn Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D002613:Cheilitis; D005260:Female; D006561:Herpes Simplex; D006801:Humans; D008297:Male; D008875:Middle Aged; D009059:Mouth Diseases; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D016896:Treatment Outcome",
"nlm_unique_id": "101226123",
"other_id": null,
"pages": "350-352",
"pmc": null,
"pmid": "26222604",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antimicrobial Photodynamic Therapy to treat chemotherapy-induced oral lesions: Report of three cases.",
"title_normalized": "antimicrobial photodynamic therapy to treat chemotherapy induced oral lesions report of three cases"
} | [
{
"companynumb": "BR-FRESENIUS KABI-FK201603257",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": n... |
{
"abstract": "Although levetiracetam is the antiepileptic of choice in patients after hepatic transplantation and patients with hepatic dysfunction, we report a patient in whom levetiracetam was the most probable cause of hepatic dysfunction. Treatment of this hepatic dysfunction is to have a high degree of suspicion and withdraw the drug at the earliest to prevent morbidity and rarely mortality. Though rare, this is an important unwanted side effect of this highly useful medication.",
"affiliations": "Department of Neuroanesthesia and Neuro Intensive Care, Sagar Hospitals, Kumaraswamy Layout, Banashankari, Bengaluru, Karnataka, India.;Department of Neurosurgery, Sagar Hospitals, Kumaraswamy Layout, Banashankari, Bengaluru, Karnataka, India.;Department of Neurosurgery, Sagar Hospitals, Kumaraswamy Layout, Banashankari, Bengaluru, Karnataka, India.",
"authors": "Gayatri|Parthasarathi|P|;Selvam|Murali Mohan|MM|;Sreeharsha|S V|SV|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.293452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "68(4)",
"journal": "Neurology India",
"keywords": "Drug-induced liver injury; hepatic dysfunction; levetiracetam; side effect",
"medline_ta": "Neurol India",
"mesh_terms": "D000927:Anticonvulsants; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "910-912",
"pmc": null,
"pmid": "32859841",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Levetiracetam-Induced Hepatic Dysfunction.",
"title_normalized": "levetiracetam induced hepatic dysfunction"
} | [
{
"companynumb": "IN-CIPLA LTD.-2020IN06674",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
... |
{
"abstract": "Despite the development of new treatment options based on the molecular characterization of colorectal cancer, 20% of patients present de novo metastatic disease, whereas 30-40% of patients who receive curative treatment relapse during follow up. Herein, we report 2 cases with rectal cancer that developed uncommon sites of metastasis; the first patient had an isolated breast metastasis, while the second patient developed bone marrow infiltration with synchronous brain metastases. In order to evaluate the uncommon metastatic pattern of rectal cancer, we detected and enumerated circulating tumor cells (CTCs) using both immunofluorescence and real-time reverse transcriptase polymerase chain reaction in these patients' peripheral blood. The procedure revealed the presence of CTCs, positive for CEACAM5 but negative for epithelial phenotype (EpCAM-), that might explain the patients' metastatic potential and survival.",
"affiliations": "Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos).;Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos).;Laboratory of Translational Oncology, Faculty of Medicine, University of Crete (Ippokratis Messaritakis).;Department of Pathology, University Hospital of Heraklion, Crete (Maria Tzardi, Eleni Lagoudaki, Anastasios Koutsopoulos).;Department of Pathology, University Hospital of Heraklion, Crete (Maria Tzardi, Eleni Lagoudaki, Anastasios Koutsopoulos).;Department of Pathology, University Hospital of Heraklion, Crete (Maria Tzardi, Eleni Lagoudaki, Anastasios Koutsopoulos).;Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos).;Hematopathology Department, Evangelismos Hospital, Athens (George Kanellis), Greece.;Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos).;Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos).;Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos).",
"authors": "Thomopoulou|Konstantina|K|;Manolakou|Stavroula|S|;Messaritakis|Ippokratis|I|;Tzardi|Maria|M|;Lagoudaki|Eleni|E|;Koutsopoulos|Anastasios|A|;Koulouris|Andreas|A|;Kanellis|George|G|;Kalbakis|Konstantinos|K|;Mavroudis|Dimitris|D|;Souglakos|Ioannis|I|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.20524/aog.2019.0423",
"fulltext": "\n==== Front\nAnn GastroenterolAnn GastroenterolAnnals of Gastroenterology1108-74711792-7463Hellenic Society of Gastroenterology Greece AnnGastroenterol-33-9510.20524/aog.2019.0423Case ReportBrain and bone marrow metastases from rectal cancer Thomopoulou Konstantina a*Manolakou Stavroula a*Messaritakis Ippokratis bTzardi Maria cLagoudaki Eleni cKoutsopoulos Anastasios cKoulouris Andreas aKanellis George dKalbakis Konstantinos aMavroudis Dimitris aSouglakos Ioannis aa Medical Oncology Department, University Hospital of Heraklion, Crete (Konstantina Thomopoulou, Stavroula Manolakou, Andreas Koulouris, Konstantinos Kalbakis, Dimitris Mavroudis, Ioannis Souglakos)b Laboratory of Translational Oncology, Faculty of Medicine, University of Crete (Ippokratis Messaritakis)c Department of Pathology, University Hospital of Heraklion, Crete (Maria Tzardi, Eleni Lagoudaki, Anastasios Koutsopoulos)d Hematopathology Department, Evangelismos Hospital, Athens (George Kanellis), GreeceCorrespondence to: Ioannis Souglakos, PAGNI Hospital, 71110 Voutes, Heraklion, Crete, Greece, e-mail: johnsougl@gmail.com* Equal contribution\n\nJan-Feb 2020 08 10 2019 33 1 95 97 25 7 2019 06 9 2019 Copyright: © Hellenic Society of Gastroenterology2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Despite the development of new treatment options based on the molecular characterization of colorectal cancer, 20% of patients present de novo metastatic disease, whereas 30-40% of patients who receive curative treatment relapse during follow up. Herein, we report 2 cases with rectal cancer that developed uncommon sites of metastasis; the first patient had an isolated breast metastasis, while the second patient developed bone marrow infiltration with synchronous brain metastases. In order to evaluate the uncommon metastatic pattern of rectal cancer, we detected and enumerated circulating tumor cells (CTCs) using both immunofluorescence and real-time reverse transcriptase polymerase chain reaction in these patients’ peripheral blood. The procedure revealed the presence of CTCs, positive for CEACAM5 but negative for epithelial phenotype (EpCAM-), that might explain the patients’ metastatic potential and survival.\n\nRectal cancerrare metastasescirculating tumor cells\n==== Body\nIntroduction\nDespite developments in the management of colorectal cancer (CRC), eventually 20% of patients present de novo metastatic disease, whereas 30-40% of patients relapse after curative colectomy. The median overall survival of patients with metastatic CRC (mCRC) has increased significantly over the past decade and reaches almost 3 years [1]. The most common metastatic sites of relapse are the lung and the liver [2].\n\nHerein, we report 2 rectal cancer cases with extremely uncommon sites of metastasis: in one patient isolated breast metastasis and in the other bone marrow (BM) infiltration with synchronous brain metastasis.\n\nCase 1\nA 58-year-old female, with a medical history of hyperthyroidism and dilated cardiomyopathy and a family history of a first-degree relative with CRC at an early age, underwent a wide local excision of a rectal mass due to a pT1 low-grade adenocarcinoma, initially found on screening endoscopy. The patient had 3-monthly clinical examination and carcinoembryonic antigen (CEA) testing, and 6-monthly computed tomography (CT) scans of thorax and abdomen. At 30 months of follow up, a rising CEA level was detected and the CT showed 3 pulmonary nodules, histologically confirmed as mCRC. Detection of circulating tumor cells (CTCs) using immunofluorescence and real-time reverse transcriptase polymerase chain reaction revealed the presence of CEACAM5+/EpCAM-CTCs. The tumor harbored a KRAS G13D mutation and had a proficient mismatch repair system. The patient received oxaliplatin-based chemotherapy and after 4 cycles she presented a partial response (reduction in lung nodules >50%) and no other metastatic sites were detected by positron emission tomography or CT. The patient underwent a wide excision of all lung metastases. Five years later, she noticed a lump in her right breast (Fig. 1). Core biopsy revealed a breast metastasis of primary rectal cancer and she underwent right mastectomy with axillary node dissection. Histology was consistent with rectal metastasis with spread to 1 of 13 lymph nodes. She is on follow up with no evidence of occurrence.\n\nFigure 1 Mammography showing a breast mass measuring 11×10 cm\n\nCase 2\nAn 80-year-old female with a history of arterial hypertension presented with a T3bN2M0 rectal carcinoma with a positive circumferential margin on magnetic resonance imaging (MRI). The patient received neoadjuvant oxaliplatin-based chemotherapy in the context of a phase II clinical trial and after 6 cycles of chemotherapy she underwent low anterior resection. Histology showed a T3N1c undifferentiated rectal adenocarcinoma, with poor response to neoadjuvant chemotherapy. CTC detection revealed the presence of CEACAM5+/EpCAM-CTCs. The patient received 5 cycles of 5-fluorouracil/leucovorin postoperatively because of neurotoxicity. Six months later, the she presented with acute blurred vision and left hemiparesis. Brain MRI revealed one parieto-occipital lesion with malignant features (Fig. 2). Surgical excision of the mass was performed, and the histology revealed mCRC with invasion of excised meninx (Fig. 3A-D). After the operation, she developed persistent grade 3 thrombocytopenia and grade 2 anemia and she underwent BM aspiration and biopsy. Histology showed massive BM infiltration from mCRC (Fig. 4A-D). The patient died 3 months later as a result of sepsis from resistant urinary tract infection.\n\nFigure 2 Magnetic resonance imaging of the brain (T2-FLAIR sequence) revealed one parieto-occipital lesion with malignant features\n\nFigure 3 (A-D) Tissue sections from brain metastasis stained for (A) H&E, (B) CK20, (C) CDX-2 and (D) CK7. E-H: Representative sections (H&E, E) from surgical specimen of mastectomy showed histopathologic characteristics of a moderately differentiated adenocarcinoma with the following immunophenotype: (F) CK20+, (G) CDX-2+ and (H) CK7. The immunophenotype of both cases was consistent with metastatic colorectal carcinoma (magnification ×200)\n\nFigure 4 (A-D) Extended infiltration of bone marrow by an adenocarcinoma with almost complete effacement of hematopoietic lineages. Cell morphology consists of large cells with abundant cytoplasm, which form solid nests (B) and in some areas present with atypical glandular differentiation (C & D)\n\nDiscussion\nWe present 2 rectal cancer cases with rare metastatic sites. The first case, originally diagnosed with a stage I, low-grade adenocarcinoma, developed a single breast metastasis many years later, while the second patient, originally diagnosed as stage III, high-grade rectal cancer, relapsed rapidly with BM infiltration and a single brain metastatic lesion. In the literature, rectal cancer with breast and BM metastases signifies a highly aggressive nature of malignancy associated with a poor prognosis, given that the 1-year survival is <20% [3]. The different T status and histopathologic characteristics and the secondary BM tumor infiltration may explain the difference in their outcomes. A Swiss retrospective study demonstrated that bone marrow micrometastasis in stage I-III colon cancer was a negative prognostic factor for relapse and survival [2]. Moreover, in a retrospective study with 17,811 rectal cancer patients, the outcome depended on the mucinous or signet ring characteristics and T and N status at diagnosis [4]. The presence of CEACAM5+/EpCAM-CTCs in both patients may also explain the increase metastatic potential and their survival. In fact, as reported previously by our group, the detection of CTCs was a factor of poor prognosis, correlated with a poor outcome and metastatic spread [5]. It is also well recognized that CTCs undergo epithelial-to-mesenchymal transition during their hematogenous dissemination, as a prerequisite for invasion and metastasis, and thus fail to express epithelial surface antigens, such as EpCAM40 [6]. The fact that both patients presented CTCs with a loss of epithelial phenotype highlights their clinical relevance in representing the biological behavior of the tumor more appropriately.\n\nCentral nervous system metastases have been assessed as uncommon (<5%), while metastatic BM infiltration and breast metastases (incidence 0.5-2%) have been recorded only as case reports. For this reason, the differential diagnosis of primary neurological and hematological malignancies or a primary breast cancer may be challenging and the diagnostic workup should be also include the probability of metastasis for rectal cancer [7].\n\nNotably, there is no evidence concerning the treatment management of rectal patients with rare metastatic localizations and it has not yet been proved that metastasectomies confer a survival benefit. Indeed, it has been reported that both BM and breast metastases from rectal cancer are a sign of disseminated disease and chemotherapy alone may have a crucial role [8]. Moreover, several case reports of brain metastasis from colorectal cancer with a curative intent approach showed that a combination of local therapy—i.e., metastasectomy and/or whole brain radiotherapy or stereotactic radiosurgery—with systemic chemotherapy may have a role [9]. As far as breast metastasis treatment is concerned, there are only limited reports describing controversial strategies. Mammary metastasectomy is described as a possible treatment option, although Barthelmes et al argued that surgery should not be performed in view of the short overall survival and the complication of seeding [6]. Furthermore, it remains controversial whether sentinel lymph node biopsy is essential [10].\n\nIn conclusion, we have described 2 rectal cancer patients with unusual metastatic sites. Early recognition and diagnosis of rare metastases from rectal cancer is necessary to evaluate the disease’s aggressiveness and biological behavior, as well as to form an optimal individualizing treatment plan. However, questions still remain about the surgical and oncological management of these rare conditions and the therapeutic plan should be driven by multidisciplinary cancer teams.\n\nConflict of Interest: None\n\nUniversity Hospital of Heraklion, Crete; University of Crete; Evangelismos Hospital, Athens, Greece\n==== Refs\nReferences\n1 Stintzing S Miller-Phillips L Fischer von Weikersthal L Per protocol analysis and final OS update of the FIRE-3 (AIO KRK-0306) study comparing FOLFIRI plus cetuximab vs. FOLFIRI plus bevacizumab J Clin Oncol 2018 36 Suppl 3508 3508 \n2 Disibio G French SW Metastatic patterns of cancers:results from a large autopsy study Arch Pathol Lab Med 2008 132 931 939 18517275 \n3 Viehl CT Weixler B Guller U Presence of bone marrow micro-metastases in stage I-III colon cancer patients is associated with worse disease-free and overall survival Cancer Med 2017 6 918 927 28401701 \n4 Riihimäki M Hemminki A Sundquist J Hemminki K Patterns of metastasis in colon and rectal cancer Sci Rep 2016 6 29765 27416752 \n5 Messaritakis I Sfakianaki M Papadaki C Prognostic significance of CEACAM5mRNA-positive circulating tumor cells in patients with metastatic colorectal cancer Cancer Chemother Pharmacol 2018 82 767 775 30094617 \n6 Polyak K Weinberg RA Transitions between epithelial and mesenchymal states:acquisition of malignant and stem cell traits Nat Rev Cancer 2009 9 265 273 19262571 \n7 Williams SA Ehlers RA 2nd Hunt KK Metastases to the breast from nonbreast solid neoplasms:presentation and determinants of survival Cancer 2007 110 731 737 17582626 \n8 Barthelmes L Simpson JS Douglas-Jones AG Sweetland HM Metastasis of primary colon cancer to the breast - leave well alone. Breast care Breast Care (Basel) 2010 5 23 25 22619637 \n9 Kim DY Ryu CG Jung EJ Paik JH Hwang D Brain metastasis from colorectal cancer:a single center experience Ann Surg Treat Res 2018 94 13 18 29333421 \n10 Perin T Canzonieri V Memeo L Massarut S Breast metastasis of primary colon cancer with micrometastasis in the axillary sentinel node:a metastasis that metastasized? Diagn Pathol 2011 6 45 21619688\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7471",
"issue": "33(1)",
"journal": "Annals of gastroenterology",
"keywords": "Rectal cancer; circulating tumor cells; rare metastases",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "95-97",
"pmc": null,
"pmid": "31892804",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "30094617;18517275;27416752;22619637;28401701;17582626;19262571;21619688;29333421",
"title": "Brain and bone marrow metastases from rectal cancer.",
"title_normalized": "brain and bone marrow metastases from rectal cancer"
} | [
{
"companynumb": "GR-SA-2020SA004387",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL\\LEUCOVORIN"
},
"drugadditional": "3",
... |
{
"abstract": "To evaluate postpartum blood loss in women with treated intrahepatic cholestasis of pregnancy.\n\n\n\nIn a retrospective case-control study, 15,083 deliveries including 348 women with intrahepatic cholestasis of pregnancy (2.3%) were analyzed from 2004 to 2014. To adjust for differences in baseline characteristics, a propensity analysis was performed and women in the control group were matched to the women in the intrahepatic cholestasis of pregnancy group in a 5:1 ratio. Blood loss was analyzed by estimated blood loss and Δ hemoglobin (Hb, difference between prepartum and postpartum Hb). A subgroup analysis regarding severity of intrahepatic cholestasis of pregnancy based on maximum bile acid level (mild [less than 40 micromoles/L], moderate [40-99 micromoles/L], and severe intrahepatic cholestasis of pregnancy [100 micromoles/L or greater]) was performed. Differences in estimated blood loss, ΔHb, and meconium staining between subgroups were analyzed. A Spearman rank correlation was performed to evaluate the association of bile acid levels and blood loss within subgroups.\n\n\n\nEstimated blood loss (median 400 [300-600] mL compared with 400 [300-600] mL, P=.22), ΔHb (14.0 [5.0-22.0] compared with 12.0 [4.0-21.0] g/L, P=.09), meconium staining (14.5% compared with 11.4%, P=.12), and number of stillbirths after 26 weeks of gestation (0.6% compared with 1.8%, P=.10) were not significantly different in the study compared with the control group. In moderate and severe intrahepatic cholestasis of pregnancy, meconium staining was observed significantly more often compared with that in a control group (23.0% and 32.3% compared with 11.4%, P<.01). There was no correlation between estimated blood loss or ΔHb and severity of intrahepatic cholestasis of pregnancy.\n\n\n\nIn our cohort of women with intrahepatic cholestasis of pregnancy who are treated with ursodeoxycholic acid and have planned delivery (induction of labor or planned cesarean delivery) at 38 weeks of gestation, no differences in postpartum blood loss were seen.",
"affiliations": "Division of Obstetrics, University Hospital of Zürich, and the University of Zürich, and the Division of Obstetrics, Kantonsspital Baden, Baden, Switzerland.",
"authors": "Furrer|Romana|R|;Winter|Katharina|K|;Schäffer|Leonhard|L|;Zimmermann|Roland|R|;Burkhardt|Tilo|T|;Haslinger|Christian|C|",
"chemical_list": "D002352:Carrier Proteins; D006454:Hemoglobins; D008562:Membrane Glycoproteins; C037643:bile acid binding proteins; D014580:Ursodeoxycholic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000001693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "128(5)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D002352:Carrier Proteins; D002780:Cholestasis, Intrahepatic; D005260:Female; D006454:Hemoglobins; D006801:Humans; D008562:Membrane Glycoproteins; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D057216:Propensity Score; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "1048-1052",
"pmc": null,
"pmid": "27741180",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postpartum Blood Loss in Women Treated for Intrahepatic Cholestasis of Pregnancy.",
"title_normalized": "postpartum blood loss in women treated for intrahepatic cholestasis of pregnancy"
} | [
{
"companynumb": "CH-ALLERGAN-1813252US",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "The transdermal fentanyl patch (TDF) can be used when switching from other opioids; therefore, little is known about the efficacy and safety of TDF patches applied for opioid initiation. However, TDF patches have been applied for opioid initiation in gastrointestinal cancer patients with gastrointestinal obstruction. In this study, we retrospectively investigated 12 gastrointestinal cancer patients to evaluate the efficacy and frequency of adverse effects of TDF patches compared to oral oxycodone (OXY) for opioid initiation. The frequency of adverse effects such as nausea, somnolence, and constipation in the TDF patch group was 25%, 41.7%, and 8.3%, respectively. No severe adverse effects were observed, and there was no significant difference between the TDF patch and OXY groups. Moreover, according to the numerical pain rating scale(ranging from 0 [no pain] to 10 [worst possible pain]), the pain intensity in the TDF patch group decreased from 5.42 on the first day to 3.33 after 3 days (p=0.0377), and 2.67 after 7 days (p=0.0089), with no significant difference between groups. Our study results suggest that TDF patches applied for opioid initiation may be useful for gastrointestinal cancer patients with gastrointestinal obstruction.",
"affiliations": "Dept. of Pharmacy, National Hospital Organization Kyushu Medical Center.",
"authors": "Miyoshi|Takanori|T|;Yamauchi|Hiroko|H|;Misumi|Nobuhiro|N|;Goto|Takashi|T|;Kai|Saisei|S|;Yoshida|Eiko|E|;Nishino|Takashi|T|;Hasuo|Yasuyuki|Y|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(11)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D005260:Female; D005283:Fentanyl; D017219:Gastric Outlet Obstruction; D006801:Humans; D007415:Intestinal Obstruction; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D057968:Transdermal Patch",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1401-5",
"pmc": null,
"pmid": "25434443",
"pubdate": "2014-11",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of transdermal fentanyl patches for opioid initiation in patients with gastrointestinal obstruction.",
"title_normalized": "efficacy and safety of transdermal fentanyl patches for opioid initiation in patients with gastrointestinal obstruction"
} | [
{
"companynumb": "JP-JNJFOC-20141207756",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nPaclitaxel (Taxol) is an antineoplastic agent approved in the United States for the treatment of lung, breast, cervical, pancreatic cancers and Kaposi sarcoma. Paclitaxel does not cross the blood brain barrier, so central nervous system adverse effects are uncommon.\n\n\nMETHODS\nWe describe a 60-year-old woman with Stage IIIa squamous cell carcinoma of the left lung, who developed a generalized tonic-clonic seizure during her first infusion of paclitaxel.\n\n\nCONCLUSIONS\nSeizure related to a hypersensitivity reaction from paclitaxel infusion are rare but could be life-threatening and require immediate recognition, treatment and exclusion of other possible aetiologies.",
"affiliations": "John H Stroger Jr. Hospital of Cook County, Chicago, IL, USA.;John H Stroger Jr. Hospital of Cook County, Chicago, IL, USA.;John H Stroger Jr. Hospital of Cook County, Chicago, IL, USA.;John H Stroger Jr. Hospital of Cook County, Chicago, IL, USA.;John H Stroger Jr. Hospital of Cook County, Chicago, IL, USA.",
"authors": "Ajiboye|Oyintayo|O|https://orcid.org/0000-0002-6115-7568;Renu|Nair|N|;Ezegwu|Olisa|O|;Vohra|Ishaan|I|;Ayub|Muhammed Talha|MT|",
"chemical_list": "D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "44(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "chemotherapy; cremophor EL; hypersensitivity reaction; paclitaxel; seizures",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D001812:Blood-Brain Barrier; D002490:Central Nervous System; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D012640:Seizures",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "974-976",
"pmc": null,
"pmid": "31423611",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A rare case of generalized tonic-clonic seizure related to paclitaxel infusion.",
"title_normalized": "a rare case of generalized tonic clonic seizure related to paclitaxel infusion"
} | [
{
"companynumb": "US-PFIZER INC-2019384209",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"d... |
{
"abstract": "BACKGROUND\nAmphetamines have been reported to cause myocardial infarct, cerebral hemorrhage, aortic dissection, hypertension, vasculitis, aneurysms, and, occasionally, death from direct toxicity. To date, there have been no reports of coronary intimal hyperplasia in an amphetamine user.\n\n\nMETHODS\nA 29-year-old male was found collapsed after jogging. He had been taking amphetamines for 11 years for attention deficit/hyperactivity disorder. Past medical history was positive for mild hypertension and migraine headaches. He underwent a complete autopsy and drug screen.\n\n\nRESULTS\nAt gross autopsy his left anterior descending (LAD) coronary artery was occluded and he had an old myocardial infarct in the anterior wall of the left ventricle. Microscopic findings included occlusive intimal hyperplasia (positive for smooth muscle actin) in the LAD and an old left ventricular anterior wall infarct surrounded by acute infarct.\n\n\nCONCLUSIONS\nIn addition to other reported adverse effects, amphetamines can also cause occlusive intimal hyperplasia of the coronary arteries.",
"affiliations": "Department of Pathology and Laboratory Medicine, Spectrum Health Blodgett Campus, Grand Rapids, MI 49506, USA. sdcohle@comcast.net",
"authors": "Cohle|Stephen D|SD|",
"chemical_list": "C090411:Adderall; D000662:Amphetamines; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1054-8807",
"issue": "22(3)",
"journal": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology",
"keywords": null,
"medline_ta": "Cardiovasc Pathol",
"mesh_terms": "D000328:Adult; D000662:Amphetamines; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity; D003324:Coronary Artery Disease; D017809:Fatal Outcome; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008774:Methylphenidate; D009203:Myocardial Infarction; D011437:Propylamines; D017539:Tunica Intima",
"nlm_unique_id": "9212060",
"other_id": null,
"pages": "e1-4",
"pmc": null,
"pmid": "22981087",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal coronary artery intimal hyperplasia due to amphetamine use.",
"title_normalized": "fatal coronary artery intimal hyperplasia due to amphetamine use"
} | [
{
"companynumb": "US-RANBAXY-2013US-70032",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": null,
... |
{
"abstract": "Gitelman syndrome is an autosomal recessive genetic disease caused by pathogenic variants in SLC12A3 resulting in the loss of function of the Na-Cl co-transporter (NCC) in the distal tubules. Hypokalemia and diuretic effects can cause secondary type 2 diabetes and renal function decline. Here, we present the case of a 49-year-old male patient with chronic persistent treatment-resistant hypokalemia for the past 13 years who had been receiving treatment for type 2 diabetes mellitus for 6 years. He was referred to our department due to the presence of urinary protein, impaired renal function, high renin activity, and hyperaldosteronism. Laboratory test results showed hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Using next-generation and Sanger sequencing, we identified a novel stop-gain variant (NM_000339.3:c.137del [p.His47fs]) and a missense variant (NM_000339.3:c.2927C > T [p.Ser976Phe]) in the SLC12A3 gene. This novel pathogenic variant was located at the intracellular N-terminus of the NCC. Based on these findings, the patient was diagnosed with Gitelman syndrome. The use of next-generation sequencing facilitated the exclusion of diseases with similar clinical symptoms.",
"affiliations": "Department of Nephrology, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan. iioken16@outlook.com.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.;Department of Nephrology, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan.;Department of Nephrology, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan.;Department of Nephrology, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan.;Department of Nephrology, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan.;Department of Endocrinology and Metabolism, Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.;Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan.",
"authors": "Iio|Kenichiro|K|http://orcid.org/0000-0002-3885-1279;Mori|Takayasu|T|;Bessho|Saki|S|;Imai|Yosuke|Y|;Hatanaka|Masaki|M|;Omori|Hiroki|H|;Kouhara|Haruhiko|H|;Chiga|Motoko|M|;Sohara|Eisei|E|;Uchida|Shinichi|S|;Kaimori|Jun-Ya|JY|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-021-00652-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": null,
"journal": "CEN case reports",
"keywords": "Chronic kidney disease; Gitelman syndrome; Hypokalemia; SLC12A3; Type 2 diabetes mellitus",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34617250",
"pubdate": "2021-10-06",
"publication_types": "D016428:Journal Article",
"references": "26787741",
"title": "Gitelman syndrome with a novel frameshift variant in SLC12A3 gene accompanied by chronic kidney disease and type 2 diabetes mellitus.",
"title_normalized": "gitelman syndrome with a novel frameshift variant in slc12a3 gene accompanied by chronic kidney disease and type 2 diabetes mellitus"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-07953",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
},
"drugad... |
{
"abstract": "The authors report a case of intraoperative sinus arrest in an otherwise healthy patient undergoing craniotomy for aneurysm clipping after mild subarachnoid hemorrhage. The sinus arrest was precipitated by a rapid infusion of 1500 mg phenytoin and was successfully treated with standard resuscitative measures. The differential diagnosis of intraoperative cardiac arrest and the mechanisms of action of phenytoin are discussed. The authors emphasize the role of phenytoin in cerebral protection.",
"affiliations": "Department of Anesthesiology, University of Texas-Houston Health Science Center, USA.",
"authors": "Berry|J M|JM|;Kowalski|A|A|;Fletcher|S A|SA|",
"chemical_list": "D000927:Anticonvulsants; D018696:Neuroprotective Agents; D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1097/00008506-199901000-00008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0898-4921",
"issue": "11(1)",
"journal": "Journal of neurosurgical anesthesiology",
"keywords": null,
"medline_ta": "J Neurosurg Anesthesiol",
"mesh_terms": "D000927:Anticonvulsants; D003399:Craniotomy; D003937:Diagnosis, Differential; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007262:Infusions, Intravenous; D002532:Intracranial Aneurysm; D007431:Intraoperative Complications; D008875:Middle Aged; D018696:Neuroprotective Agents; D010672:Phenytoin; D012151:Resuscitation; D013345:Subarachnoid Hemorrhage",
"nlm_unique_id": "8910749",
"other_id": null,
"pages": "42-5",
"pmc": null,
"pmid": "9890385",
"pubdate": "1999-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sudden asystole during craniotomy: unrecognized phenytoin toxicity.",
"title_normalized": "sudden asystole during craniotomy unrecognized phenytoin toxicity"
} | [
{
"companynumb": "US-PFIZER INC-001-0073-990073",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEPERIDINE"
},
"drugadditional": null,
... |
{
"abstract": "We report the case of metformin-associated lactic acidosis (MALA) exacerbated by acute kidney injury (AKI) in a 65-year-old Asian American woman who was an overseas traveler. She had vomiting and diarrhea before arriving in Osaka, Japan, from the Philippines. She suffered from worsening respiratory distress, consciousness loss and anuria the day after coming to Japan. When she arrived at our emergency room via ambulance, she appeared to be in a state shock. Arterial blood gas analysis revealed severe lactic acidosis (pH 6.681, PO2 302 Torr under O2 supplementation, PCO2 15 Torr, HCO3-1.7 mmol/L, and lactate 17.00 mmol/L). She also had renal failure (BUN 108 mg/dL and serum creatinine 8.68 mg/dL) with hyperkalemia (6.1 mEq/L). We collected medical information from family members, and found her prescription medicines including metformin, diuretics and angiotensin-converting enzyme inhibitor (ACEI). We diagnosed her with MALA due to an unintended overdose of metformin resulting from acute kidney injury that can be induced by ACEI and diuretics in the volume-depleted condition. We immediately started hemodialysis therapy. Although she had a temporary cardiopulmonary arrest at the beginning of the treatment, her physical status was gradually improved and the severe acidemia resolved. On hospital day 4, she had urine and no longer needed hemodialysis therapy. On day 14, she was discharged and returned to the United States without noticeable sequelae. This is a case report of an overseas traveler who was successfully rescued through the collection of accurate medical information and understanding of the pathological condition.",
"affiliations": "Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Center for Diabetes and Endocrinology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan. tsukamoto5017@gmail.com.",
"authors": "Hayashi|Ayano|A|;Ishimura|Takuya|T|;Sugimoto|Hisashi|H|;Suzuki|Hiroyuki|H|;Hamasaki|Akihiro|A|;Tsukamoto|Tatsuo|T|http://orcid.org/0000-0003-2896-5595",
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"fulltext": "\n==== Front\nCEN Case Rep\nCEN Case Rep\nCEN Case Reports\n2192-4449\nSpringer Nature Singapore Singapore\n\n34837633\n665\n10.1007/s13730-021-00665-z\nCase Report\nMetformin-associated lactic acidosis exacerbated by acute kidney injury in an overseas traveler\nHayashi Ayano 12\nIshimura Takuya 12\nSugimoto Hisashi 12\nSuzuki Hiroyuki 13\nHamasaki Akihiro 4\nhttp://orcid.org/0000-0003-2896-5595\nTsukamoto Tatsuo tsukamoto5017@gmail.com\n\n1\n1 grid.415392.8 0000 0004 0378 7849 Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480 Japan\n2 grid.258799.8 0000 0004 0372 2033 Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan\n3 grid.415816.f 0000 0004 0377 3017 Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura-city, Kanagawa 247-8533 Japan\n4 grid.415392.8 0000 0004 0378 7849 Center for Diabetes and Endocrinology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480 Japan\n27 11 2021\n27 11 2021\n5 2022\n11 2 278282\n11 9 2021\n10 11 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/.\nWe report the case of metformin-associated lactic acidosis (MALA) exacerbated by acute kidney injury (AKI) in a 65-year-old Asian American woman who was an overseas traveler. She had vomiting and diarrhea before arriving in Osaka, Japan, from the Philippines. She suffered from worsening respiratory distress, consciousness loss and anuria the day after coming to Japan. When she arrived at our emergency room via ambulance, she appeared to be in a state shock. Arterial blood gas analysis revealed severe lactic acidosis (pH 6.681, PO2 302 Torr under O2 supplementation, PCO2 15 Torr, HCO3−1.7 mmol/L, and lactate 17.00 mmol/L). She also had renal failure (BUN 108 mg/dL and serum creatinine 8.68 mg/dL) with hyperkalemia (6.1 mEq/L). We collected medical information from family members, and found her prescription medicines including metformin, diuretics and angiotensin-converting enzyme inhibitor (ACEI). We diagnosed her with MALA due to an unintended overdose of metformin resulting from acute kidney injury that can be induced by ACEI and diuretics in the volume-depleted condition. We immediately started hemodialysis therapy. Although she had a temporary cardiopulmonary arrest at the beginning of the treatment, her physical status was gradually improved and the severe acidemia resolved. On hospital day 4, she had urine and no longer needed hemodialysis therapy. On day 14, she was discharged and returned to the United States without noticeable sequelae. This is a case report of an overseas traveler who was successfully rescued through the collection of accurate medical information and understanding of the pathological condition.\n\nKeywords\n\nMetformin\nLactic acidosis\nAngiotensin-converting enzyme\nAcute kidney injury\nCase report\nissue-copyright-statement© The Author(s) under exclusive licence to The Japan Society of Nephrology 2022\n==== Body\npmcIntroduction\n\nMetformin is a worldwide first-line agent for type 2 diabetes mellitus (DM). In the United States, the first-line use of metformin increased after 2005 according to Centricity Electronic Medical Records [1]. Metformin is a relatively safe drug for diabetic patients with normal renal function, but if patients have renal impairment, dose reduction or discontinuation is required. One of the severe adverse effects is metformin-associated lactic acidosis (MALA), which has an annual incidence of less than 10/100,000 patients [2]. MALA is thought to be less frequent in Japan. Since the MALA-associated mortality rate is 30 to 50%, rapid and appropriate treatment including blood purification is required [3].\n\nAngiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) are representative drugs used to treat hypertensive DM patients who have micro- or macro-proteinuria [4]. The combination of ACEI or ARB with diuretics is a common treatment for diabetic kidney disease patients who tend to have fluid overload, however, this prescription can cause acute kidney injury (AKI) under volume depletion [5]. In particular, ACEI accumulates in the body when renal function declines. Since inhibition of the rein-angiotensin-aldosterone system in the volume-depleted condition leads to severe hypotension, ACEI may be an exacerbating factor for AKI.\n\nHere, we report a case of MALA in an overseas traveler that was successfully rescued by rapid diagnosis and appropriate treatment. It is very important to collect medical information, especially in regard to therapeutic agents, in the case of overseas travelers with sudden illness. This case was instructive in the following three points: (1) the importance of collecting medical information, (2) the difference in metformin dose between Japan and the United States, and (3) the background conditions for the onset of MALA.\n\nCase report\n\nA 65-year-old Asian American woman with type 2 diabetes mellitus (DM) visited Osaka, Japan via the Philippines for sightseeing. She had diarrhea, poor appetite, and vomiting the day before her arrival in Japan. She also had hypoglycemia because of her poor appetite, and took glucose several times at her hotel. She suffered from worsening respiratory distress, loss of consciousness, and anuria upon arrival in Japan. When she visited our emergency room via ambulance, she was in a shock state. We obtained her medical history of type 2 DM, diabetic retinopathy and nephropathy, and ischemic heart disease from her family. We were unable to determine the details of her daily use medications at this time. Her height was 151.5 cm and her estimated body weight was 50.0 kg. Her level of consciousness was at Glasgow Coma Scale E3V4M5. Her blood pressure was 67/42 mmHg and pulse rate was 156 beats per minute. Her respiratory rate was 29 breaths per minute. Although her body temperature was normal at 36.0 °C, her extremities were cold and cyanotic. Laboratory examination revealed severe renal failure: blood urea nitrogen (BUN) 108.7 mg/dL serum creatinine (Cr) 8.68 mg/dL and hyperkalemia (6.1 mEq/L). Arterial blood gas analysis indicated severe acidemia: pH 6.68, PO2 302 Torr, PaCO2 15 Torr, bicarbonate (HCO3−) 1.7 mmol/L, and lactate 17 mmol/L, indicating severe lactic acidosis (Table 1).Table 1 Laboratory examination results on admission\n\nBiochemistry\tComplete blood count\tBlood gas (O2 10L/min mask)\t\nAST\t51 U/L\tWBC\t13,000 /µL\tpH\t6.681\t\nALT\t41 U/L\tNeutro\t81.0%\tPaCO2\t15 Torr\t\nLDH\t278 U/L\tLympho\t9.7%\tPaO2\t302 Torr\t\nALP\t162 U/L\tRBC\t319 × 104/µL\tHCO3−\t1.7 mmol/L\t\nγ-GTP\t23 U/L\tMCV\t110.0 fL\tAG\t37.8 mmol/L\t\nTP\t6.5 g/dL\tHb\t10.2 g/dL\tLactate\t17.0 mmol/L\t\nALB\t3.9 g/dL\tPlt\t30.8 × 104/µL\t\t\t\nCK\t166 U/L\t\t\t\t\t\nCK-MB\t58 IU/L\t\t\t\t\t\nGlu\t164 mg/dL\tCoagulation test\t\t\t\nT-CHO\t164 mg/dL\tPT-INR\t1.39\t\t\t\nBUN\t108.7 mg/dL\tAPTT\t33.6 s\t\t\t\nUA\t13.8 mg/dL\tD-dimer\t3.6 μg/dL\t\t\t\nCre\t8.68 mg/dL\t\t\t\t\t\nNa\t138 mEq/L\t\t\t\t\t\nK\t6.1 mEq/L\t\t\t\t\t\nCl\t93 mEq/L\t\t\t\t\t\nCa\t9.5 mg/dL\t\t\t\t\t\nP\t19.9 mg/dL\t\t\t\t\t\nCRP\t0.8 mg/dL\t\t\t\t\t\n\nAfter examining her cardiac function by electrocardiogram and echocardiography, we started fluid resuscitation and catecholamine administration. We used 1500 mL saline together with bicarbonate for three hours until blood pressure rose above 100/mmHg to correct volume depletion and metabolic acidosis. Despite the rapid fluid administration, her blood pressure did not go up, so we started the intravenous administration of noradrenalin. She had a cardiopulmonary arrest (CPA) at the beginning of the treatment, but we were able to get her ROSC (return of spontaneous circulation) quickly by standard cardiopulmonary resuscitation. Simultaneously, we collected medical information from family members, and found that her daily medications including metformin (2000 mg/day), glimepiride (8 mg/day), hydrochlorothiazide (25 mg/day), lisinopril (unknown dosage), amlodipine (unknown dosage), aspirin (unknown dosage) and rosuvastatin (5 mg/day). We diagnosed her with MALA due to an unintended overdose of metformin resulting from AKI that can be induced by ACEI and diuretics under volume depletion. We decided to start continuous renal replacement therapy (CRRT) to correct her highly impaired acid–base balance in our intensive care unit. After the initiation of CRRT, the severe acidemia and lactate levels were resolved quickly. Her vital signs, including blood pressure and respiratory status, also gradually recovered. On hospital day 2, her lactate levels decreased to 9.47 mmol/L and pH levels returned to 7.354 and she regained consciousness. We switched CRRT to intermittent renal replacement therapy (IRRT). Noradrenalin administration was also tapered. We did not determine her dry weight during blood purification therapy. The fluid removal on each dialysis session was set by referring to chest X-rays, edema, and the amount of infusion volume. When she got out of bed before returning to the US, her body weight was 50.4 kg. We stopped hemodialysis therapy on hospital day 4 after normalization of her metabolic state (Fig. 1).Fig. 1 Clinical course. Changes in arterial blood pH, HCO3−, and lactate levels over time are plotted along the clinical course. The patient regained consciousness on hospital day 3 and her kidney function recovered on hospital day 6 following multidisciplinary treatment, including blood purification therapy\n\nHer activities of daily livings were restored by rehabilitation without any neurological sequelae after CPA. Diarrhea, vomiting and other gastrointestinal symptoms that caused her sick day were spontaneously recovered without any special treatment. On hospital day 14, her serum creatinine levels decreased to 1.55 mg/dL. She returned to the US with her family. Her attending physician in Los Angeles, CA, subsequently informed us that her baseline creatinine level was 1.3 mg/dL before coming to Japan.\n\nDiscussion\n\nWe report a case of MALA in an overseas traveler successfully rescued by the rapid collection of medical information and appropriate hemodialysis therapy. This case was very instructive because details related to medical information and underlying diseases are limited when overseas travelers suddenly become severely ill. This case provided three important lessons.\n\nThe first lesson related to the importance of obtaining the patient’s medical history. In this case, we were initially unable to determine the patient’s medical history because of her severe loss of consciousness. We were also unable to obtain sufficient information from her family. As such, we had to infer her disease status by examining the prescribed medications she had with her (the prescription dose was unknown). As she went into CPA in our emergency room, we did not have time to interview her family. We assumed that she might have developed shock with severe lactic acidosis as a result of excess metformin intake.\n\nAlthough metformin poisoning can cause severe toxicity, but there is no specific antidote to reverse the toxic effects. One treatment option for MALA is sodium bicarbonate infusion. An intravenous administration of 1 to 2 mEq/kg BW sodium bicarbonate and a repeat administration at the same dosage after 30 to 60 min if the pH level remains below 7.1 is recommended [6]. Sodium bicarbonate did not extend patient life expectancy [6]. The other treatment option for MALA is hemodialysis therapy. The criteria for extracorporeal treatment (ECTR) were proposed by the Poisoning Workgroup [7]. When lactate level is > 20 mmol/L, pH is ≦ 7.0 and standard therapy (supportive measures, bicarbonate, etc.) fails, ECTR is recommended. On the other hand, when lactate level is 15 to 20 mmol/L, pH is 7.0 to 7.1, and there is impaired kidney function, shock, decreased level of consciousness, and liver failure, ECTR is suggested. ECTR discontinuation is indicated when the lactate level is < 3 mmol/L and pH is > 7.35. In our case, the pH alone met the recommended criteria for ECTR, and the other symptoms met the suggested criteria for ECTR. Given the cession criteria for ECTR, the lactate level was resolved to 1.9 mmol/L and the pH level was resolved to 7.53 on hospital day 2. We continued dialysis therapy until hospital day 5 because of her anuric condition (Fig. 1).\n\nThe prognosis of MALA can change depending on the modality of blood purification. Previously, 41 of 253 cases were reported to die and the mortality was 16.2% [8]. There were no differences in metformin dose, age, or modality of ECTR between the surviving and deceased groups, and the lactate levels and creatinine levels at the first arrival were higher in the deceased groups. This report indicated that lactate levels above 20 mmol/L may be associated with the mortality. In our case, we chose CRRT to treat severe lactic acidosis and shock with catecholamine support following the ROSC, which likely would have made it difficult to perform IRRT. Although her lactate level at the time first arrival was 17 mmol/L when she presented to the emergency room, this could have increased when we started CRRT.\n\nSecond, the regular and maximum dose of metformin in the US and England is much more than that in Japan (Table 2). In Japan, a daily dose of metformin is 750 to 1500 mg, and a maximum daily dose is 2250 mg. The use of metformin is contraindicated if eGFR is less than 30 mL/min/1.73m2 and it can be given carefully if eGFR is 30 to 45 mL/min/1.73m2 according to the “Recommendation for the proper use of metformin” of the Japan Diabetes Society [9]. Dose reduction is also required depending on renal functions. The maximum daily dose is 750 mg if eGFR is 30 to 45 mL/min/1.73m2, and it is 1500 mg if eGFR is 45 to 60 mL/min/1.73m2. On the other hand, metformin use is not recommended to start in renal impairment (eGFR 30 to 45 mL/min1.73m2) in the US, the maximal dose in the US and England is 1000 mg/day. Indeed, the efficacy of metformin use in patients with renal impairment has been reported. A retrospective cohort study of US veterans receiving care within the national Veterans Health Administration showed that in type 2 DM patients with renal impairment, metformin-alone therapy has a lower risk of major adverse cardiovascular events (MACEs) than sulfonylurea (SU) therapy; the use of metformin in encouraged in patients with mild to moderate renal impairment [10]. Another cohort study in the Geisinger Health System that considered the association between metformin use across all ranges of eGFR considering the aging changes and hospitalization due to lactic acidosis has suggested that metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73m2 [11]. In our case, the baseline renal function (eGFR) was between 30 and 45 mL/min/1.73m2. The maximum daily dose of metformin was 750 mg/day in our case in Japan, but she was actually prescribed at 2000 mg/day. Although the patient was American, she weighed 50 kg, and that dose of metformin would have been excessive. It should be noted that larger doses of metformin are prescribed outside of Japan. It is necessary to consider the possibility of overdose in cases of small body size, as in this case.Table 2 Difference in daily maximal dose of metformin in a patient with impaired kidney function among Japan, the United States, and England\n\nKidney function\tJapan\tUnited States\tEngland\t\n60 ≤ eGFR < 90\t2250\t3000\t3000\t\n45 ≤ eGFR < 60\t1500\t2000\t2000\t\n30 ≤ eGFR < 45\t750\t1000/Not recommended to start\t1000\t\n < 30\tContraindicated\tContraindicated\tContraindicated\t\n\nThird, the safety of metformin should be considered in a case with rapidly declining renal function. The patient had diarrhea, poor appetite, and vomiting the day before her arrival at Japan, leading to volume depletion. She took ACEI (lisinopril) and diuretics (hydrochlorothiazide) in addition to metformin. MALA is more likely to occur in patients who developed AKI by dehydration, vomiting or diarrhea, surgery, etc. [12]. Volume depletion can cause AKI and reduce metformin clearance, resulting in increased plasma metformin levels [13]. It is known that the combination of ACEI/ARB and non-steroidal anti-inflammatory drugs (NSAIDs) or diuretics is also likely to cause AKI [14]. Indeed, metformin, ACEI/ARB, and diuretics are commonly used in patients with diabetic nephropathy. Therefore, when prescribing a combination of these drugs, it is important to instruct patients not to take them when they are ill, especially when they are in a volume-depleted condition.\n\nConclusion\n\nHere, we report a case of MALA in an overseas traveler who was successfully rescued by rapid diagnosis and appropriate blood purification. When a foreigner with DM suddenly becomes ill, clinicians must investigate the difference in metformin dose between Japan and other countries, and the background conditions leading to the onset of MALA.\n\nAbbreviations\n\nCRRT Continuous renal replacement therapy\n\nIRRT Intermittent renal replacement therapy\n\nAcknowledgements\n\nWe thank clinical engineers in Kitano Hospital for their emergency response.\n\nAuthor contributions\n\nAH wrote the manuscript under the support of TT. AH and TI treated the patient during hospitalization. HI presented this case at the 49th Western Regional Meeting of the Japanese Society of Nephrology. HS performed blood purification therapy for this case. AH managed the diabetes care of this case. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was obtained for this case report.\n\nDeclarations\n\nConflict of interest\n\nThe authors have declared that no conflict of interest exists.\n\nEthical approval\n\nThe ethical committee of Kitano Hospital approved this case report.\n\nInformed consent\n\nInformed consent was obtained from the patient in this case report.\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. Montvida O Shaw J Atherton JJ Stringer F Paul SK Long-term trends in antidiabetes drug usage in the U.S.: real-world evidence in patients newly diagnosed with type 2 diabetes Diabetes Care 2018 41 1 69 78 10.2337/dc17-1414 29109299\n2. Kajbaf F Lalau JD The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis BMC Pharmacol Toxicol 2013 14 22 10.1186/2050-6511-14-22 23587368\n3. Eppenga WL Lalmohamed A Geerts AF Derijks HJ Wensing M Egberts A Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study Diabetes Care 2014 37 8 2218 2224 10.2337/dc13-3023 24842984\n4. Brenner BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving HH Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy N Engl J Med 2001 345 12 861 869 10.1056/NEJMoa011161 11565518\n5. Whiting P Morden A Tomlinson LA Caskey F Blakeman T Tomson C What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A systematic review and meta-analysis BMJ Open 2017 7 4 e012674 10.1136/bmjopen-2016-012674\n6. Jaber S Paugam C Futier E Lefrant JY Lasocki S Lescot T Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial Lancet 2018 392 10141 31 40 10.1016/S0140-6736(18)31080-8 29910040\n7. Calello DP Liu KD Wiegand TJ Roberts DM Lavergne V Gosselin S Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the extracorporeal treatments in poisoning workgroup Crit Care Med 2015 43 8 1716 1730 10.1097/CCM.0000000000001002 25860205\n8. Yeh HC Ting IW Tsai CW Wu JY Kuo CC Serum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series BMC Nephrol 2017 18 1 229 10.1186/s12882-017-0640-4 28693440\n9. Sciety TJD. Recommendation on proper use of metformin. 2020. http://www.jds.or.jp/modules/important/index.php?content_id=20. Accessed 27 Nov 2021.\n10. Roumie CL Chipman J Min JY Hackstadt AJ Hung AM Greevy RA Jr Association of treatment with metformin vs sulfonylurea with major adverse cardiovascular events among patients with diabetes and reduced kidney function JAMA 2019 322 12 1167 1177 10.1001/jama.2019.13206 31536102\n11. Lazarus B Wu A Shin JI Sang Y Alexander GC Secora A Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study JAMA Intern Med 2018 178 7 903 910 10.1001/jamainternmed.2018.0292 29868840\n12. DeFronzo R Fleming GA Chen K Bicsak TA Metformin-associated lactic acidosis: current perspectives on causes and risk Metabolism 2016 65 2 20 29 10.1016/j.metabol.2015.10.014 26773926\n13. Almirall J Briculle M Gonzalez-Clemente JM Metformin-associated lactic acidosis in type 2 diabetes mellitus: incidence and presentation in common clinical practice Nephrol Dial Transplant 2008 23 7 2436 2438 10.1093/ndt/gfn152 18388117\n14. Dreischulte T Morales DR Bell S Guthrie B Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury Kidney Int 2015 88 2 396 403 10.1038/ki.2015.101 25874600\n\n",
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"title": "Transformed lymphoma: what should I do now?",
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"abstract": "The increasing use of 3,4-methylenedioxymethamphetamine (MDMA, \"ecstasy\") and tendency of users to combine MDMA with pharmaceutical agents (especially serotonergic medication) warrants a thorough understanding of MDMA's toxicity profile and potential for drug interactions. This study examined the involvement of MDMA and concurrently administered pharmaceutical drugs in cases reported to the Victorian State Coroner. The National Coroners Information System was used to conduct a comprehensive search and examination of all closed cases between 2002 and 2008 where MDMA was detected. Pathology, toxicology, and Coroners' findings were considered in all cases. In all, 106 fatalities were identified, of which 43 (41%) cases involved the concomitant use of MDMA with other drugs, including pharmaceuticals that were likely to result in an adverse drug reaction or varying risks (4 high-risk cases involved moclobemide and MDMA, in addition to 10 moderate-risk cases, and 5 minor-risk cases). These findings highlight the importance of recognizing and publicizing potential drug interactions between MDMA and pharmaceutical preparations that may result in lethal toxicity, in particular serotonin toxicity.",
"affiliations": "Department of Forensic Medicine, Monash University, 57-83 Kavanagh Street, Southbank 3006, Victoria, Australia. jenniferp@vifm.org",
"authors": "Pilgrim|J L|JL|;Gerostamoulos|D|D|;Drummer|Olaf H|OH|",
"chemical_list": "D018490:Serotonin Agents; D018817:N-Methyl-3,4-methylenedioxyamphetamine",
"country": "England",
"delete": false,
"doi": "10.1093/anatox/35.4.219",
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"issue": "35(4)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018490:Serotonin Agents; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D014739:Victoria; D055815:Young Adult",
"nlm_unique_id": "7705085",
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"pages": "219-26",
"pmc": null,
"pmid": "21513615",
"pubdate": "2011-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Deaths involving MDMA and the concomitant use of pharmaceutical drugs.",
"title_normalized": "deaths involving mdma and the concomitant use of pharmaceutical drugs"
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"abstract": "A 49-year-old female with biopsy proven primary vitreoretinal lymphoma and primary central nervous system lymphoma (PCNSL) presented with asymmetric involvement of both eyes. Right eye had primarily retinal and optic nerve involvement with no light perception while the left eye had purely vitreal form of the disease with visual acuity of 6/18. She was treated with recommended DeAngelis protocol for PCNSL and achieved complete remission of CNS disease and in the right eye and responded only partially to the systemic chemotherapy in the left eye. She received multiple intravitreal methotrexate injections (400 μg/0.1 ml) for persisting disease in the left eye. However, she developed resistance to the same after repeated injections for which therapeutic vitrectomy was performed. She achieved final visual acuity of 6/12 in the right eye and 6/18 in the left eye and did not relapse until last follow-up of 2 years.",
"affiliations": "Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi, India.",
"authors": "Venkatesh|Pradeep|P|;Gogia|Varun|V|;Khanduja|Sumeet|S|;Gupta|Shikha|S|;Kumar|Lalit|L|;Garg|Satpal|S|",
"chemical_list": "D008727:Methotrexate",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.140824",
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"issn_linking": "1998-4138",
"issue": "11(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D064090:Intraocular Lymphoma; D058449:Intravitreal Injections; D008727:Methotrexate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016896:Treatment Outcome; D014821:Vitrectomy",
"nlm_unique_id": "101249598",
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"pmid": "26458712",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Therapeutic vitrectomy for vitreal recurrence of intraocular lymphoma resistant to intravitreal methotrexate post systemic chemotherapy.",
"title_normalized": "therapeutic vitrectomy for vitreal recurrence of intraocular lymphoma resistant to intravitreal methotrexate post systemic chemotherapy"
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"abstract": "Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care.",
"affiliations": "Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Hematology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, University of Ioannina, Ioannina, Greece.",
"authors": "Mavroeidis|Leonidas|L|;Vassou|Amalia|A|;Zarkavelis|George|G|;Papadaki|Alexandra|A|;Mouzaki|Ioanna|I|;Ntellas|Panagiotis|P|;Gkoura|Stefania|S|;Gazouli|Ioanna|I|;Pentheroudakis|George|G|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504338",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 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\n10.1159/000504338\ncro-0013-0001\nCase Report\nAcquired Hemophilia in an Elderly Patient with Carcinoma of the Ampulla of Vater\nMavroeidis Leonidas ab* Vassou Amalia c Zarkavelis George ab Papadaki Alexandra ab Mouzaki Ioanna a Ntellas Panagiotis ab Gkoura Stefania ab Gazouli Ioanna ab Pentheroudakis George ab aDepartment of Medical Oncology, University of Ioannina, Ioannina, Greece\nbSociety for the Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece\ncDepartment of Hematology, University of Ioannina, Ioannina, Greece\n*Prof. Leonidas Mavroeidis, Department of Medical Oncology, University of Ioannina, Niarxou Avenue, GR–45500 Ioannina (Greece), E-Mail leo.mavroidis@gmail.com\nJan-Apr 2020 \n13 1 2020 \n13 1 2020 \n13 1 1 6\n18 10 2019 22 10 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.Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care.\n\nKeywords\nAcquired hemophiliaCarcinoma of the ampulla of VaterParaneoplastic acquired hemophilia\n==== Body\nIntroduction\nAcquired hemophilia is a rare autoimmune bleeding disorder. In contrast to congenital hemophilia, which is caused by a deficiency in either clotting factor VIII or clotting factor IX, acquired hemophilia develops due to production of autoantibodies, known as inhibitors, most commonly against clotting factor VIII. Its incidence is 1–4 per million per year, and it usually presents in the elderly. Most cases are idiopathic (almost 50%), but other conditions may be related as well, such as pregnancy, malignancy, autoimmune disease, and certain medications [1].\n\nAcquired hemophilia usually manifests as soft tissue hematoma [2]. Bleeding in other sites may occur, such as in the gastrointestinal and genitourinary tract, while bleeding during invasive procedures may also take place. Unlike in congenital hemophilia, hemarthroses are rare. The laboratory hallmark is prolongation of the activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. Other causes of aPTT prolongation should be excluded, such as antiphospholipid syndrome and heparin use [3]. Screening for inhibitors is the next step in establishing the diagnosis. aPTT is measured after mixing the patient's plasma with pooled normal plasma. Correction of aPTT indicates a factor deficiency or von Willebrand disease, whereas consistent prolongation suggests the presence of an inhibitor. In case the aPTT is corrected with the addition of phospholipids, a diagnosis of antiphospholipid syndrome is established. If the aPTT is not corrected, the next step is the Bethesda assay to confirm and quantify the titer of the inhibitor of factor VIII.\n\nTreatment of acquired hemophilia consists of two axes [4]. Firstly, management of bleeding by administering a clotting factor with bypassing activity, and secondly, clearance of the inhibitor by using immunomodulatory agents. The most common agents are prednisolone and cyclophosphamide alone or in combination, while rituximab and immunoglobulin are also options.\n\nHere, we present the case of an elderly man with carcinoma of the ampulla of Vater who presented with soft tissue hematoma and a prolonged aPTT.\n\nCase Presentation\nAn 81-year-old man presented due to presyncope to the emergency department. The past medical history included blood hypertension and Whipple's operation for carcinoma of the ampulla of Vater that had been staged as pT2N1M0 two months earlier. He had not received adjuvant chemotherapy but was on prophylactic low-molecular-weight heparin treatment.\n\nThe clinical examination revealed ecchymosis and edema of the right shin and the right and left forearms (Fig. 1). A digital rectal examination was negative for bleeding. The laboratory workup demonstrated normocytic normochromic anemia, slightly elevated lactate dehydrogenase, a prolonged aPTT with a normal prothrombin time, and fibrinogen with absence of schistocytes on a blood film. An ultrasound was performed due to enlargement of the right shin, which excluded thrombosis and confirmed the presence of hematoma. Differential diagnoses included an adverse reaction due to heparin use, antiphospholipid syndrome, and bleeding disorder due to the presence of an acquired inhibitor in the clotting cascade.\n\nHeparin was discontinued and mixing studies were performed. Mixing with normal plasma did not correct the aPTT and the lupus anticoagulant test was negative. The presence of an acquired inhibitor of factor VIII was then suspected. Unfortunately, it was not possible to perform a Bethesda assay at the hematology laboratory of our hospital at that time due to lack of reagent. An investigation with immunological studies excluded other autoimmune diseases. A computed tomography scan of the abdomen was performed, exhibiting two peritoneal nodules compatible with metastasis. Therefore, his clinical condition was indirectly attributed to tumor recurrence.\n\nUpon establishing a diagnosis of acquired hemophilia, immunosuppressive treatment was initiated (Fig. 2). The patient received prednisone IV (1 mg/kg per day), cyclophosphamide (100 mg p.o.), and immunoglobulin G IV (400 mg/kg for 5 days). Due to the association of this condition with carcinoma of the ampulla of Vater, the patient also received a cycle of chemotherapy with gemcitabine (1,000 mg/m2 IV) combined with oxaliplatin (100 mg/m2 IV) on day 14 of hospitalization. The patient continued treatment with prednisone (1 mg/kg per day) combined with cyclophosphamide (100 mg per day p.o.) until signs of response were evident.\n\nThe patient had a prolonged hospitalization of 6 weeks. During his care, he complained of dysphagia, and laryngoscopy revealed a retropharyngeal hematoma (Fig. 1). This complication was managed with temporary discontinuation of alimentation and initiation of parenteral nutrition. Furthermore, care was complicated by nosocomial fever, which was effectively managed with piperacillin/tazobactam and vancomycin, while the patient later exhibited chemotherapy-induced neutropenia, managed with filgrastim. The aPTT decreased 2-fold (Fig. 2), while the levels of factor VIII remained undetectable during the entire course of hospitalization. The patient showed signs of clinical stability and was successfully discharged for further outpatient care.\n\nDiscussion and Conclusion\nHere, we presented a case of an elderly patient with acquired hemophilia, managed at the Department of Medical Oncology of the University of Ioannina, Greece. The patient's condition was attributed to tumor relapse. To the best of our knowledge, this is the first report of paraneoplastic hemophilia related to carcinoma of the ampulla of Vater [5].\n\nAcquired hemophilia is an extremely rare manifestation of cancer, and neoplasia is one of the less frequent causes. Several malignancies have been reported to be associated with this condition [5]. The most common causes are lung cancer, prostate cancer, and lymphoproliferative diseases, while cases of gastrointestinal tumor as well as breast and bladder cancer have also been reported. Establishing a diagnosis is challenging without clinical suspicion. Sometimes the clinical presentation of the disease may precede cancer detection. One of the clinical hallmarks that prompt investigation is soft tissue hematoma in the presence of an abnormal aPTT [6].\n\nThe pathogenesis of acquired hemophilia is related to the development of autoantibodies against clotting factor VIII, which is an essential component of the intrinsic system of coagulation. These antibodies are polyclonal antibodies that bind to the A2, A3, or C2 domains of factor VIII, thus inhibiting its action and interfering with the activation of factor X, the initial step of the common pathway of coagulation [7]. The end result is aPTT prolongation not corrected after mixing with normal plasma, due to neutralization of factor VIII from the inhibitors. Regarding autoantibody production, this may be linked with the immune response in the tumor microenvironment [1]. Tumor cells release damage signals that trigger inflammation and phagocytosis. An antigen presentation process then leads to activation of an adaptive immune response against tumor neoantigens with shared epitopes with the antigens of the host.\n\nManagement of acquired hemophilia is based on three principles [4]. The first priority is treatment of bleeding. The second objective is elimination of the inhibitor, while the final goal is treatment of the underlying cause. Treatment of life-threatening hemorrhage is managed by administration of bypassing agents such as recombinant factor VIIa and activated prothrombin complex concentrate. Human factor VIII replacement therapy is only effective in patients with low titers of inhibitor (<5 BU). Invasive procedures should be avoided; otherwise, replacement therapy should be given before and after the procedure.\n\nImmunosuppression is the mainstay of inhibitor elimination [8]. Effective regimens include prednisolone (1 mg/kg) monotherapy, combination of prednisolone (1 mg/kg) with cyclophosphamide (1–2 mg/kg p.o.), and rituximab administration with or without corticosteroids. The retrospective UKHCDO trial showed no statistically significant difference between corticosteroid monotherapy and combinational treatment [9], while a prospective study suggested that all patients should initially receive corticosteroids for 3 weeks and cyclophosphamide should be added if steroid resistance is noted [10]. However, we opted to treat this patient with a combination of corticosteroid and cyclophosphamide based on the results of the EACH2 registry, which demonstrated higher remission rates and a shorter time to remission with this regimen [11]. Although there is no proven added clinical benefit from retrospective studies, we also administered intravenous immunoglobulin as an adjunct based on results from case reports [12].\n\nIn addition to immunosuppression, treatment efficacy in cancer patients with acquired hemophilia is related to eradication of the tumor. In a systematic review, it was demonstrated that the best results regarding inhibitor elimination were achieved in patients who received effective treatment either by surgery or by chemotherapy or radiotherapy. By contrast, if cancer treatment was not successful, eradication of the inhibitor was not attained [5]. Our patient received a cycle of combinational chemotherapy with gemcitabine and oxaliplatin. We did not manage to administer more cycles during his hospitalization due to nosocomial infection and neutropenia. The patient was discharged after 6 weeks of hospitalization and was maintained on prednisolone (1 mg/kg) and cyclophosphamide (100 mg p.o.) with the aim to continue treatment for the underlying malignancy in the outpatient clinic. Although the patient was clinically stable, he was frail and never showed up at his appointment.\n\nStatement of Ethics\nWritten consent was obtained from the relatives of the deceased patient for publication of this case report.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors did not receive any funding.\n\nAuthor Contributions\nL.M. drafted the manuscript; L.M., A.V., and G.P. revised the manuscript; all authors were substantially involved in the conception and design of the case report, as well as in the acquisition, analysis and interpretation of the data; all authors approved the final version.\n\nFig. 1 Hematoma and ecchymosis. a Right forearm and arm. b Left forearm and arm. c Right shin. d Retropharyngeal hematoma.\n\nFig. 2 Activated partial thromboplastin time (aPTT) value during the course of the treatment. Treatment was initiated with prednisone, cyclophosphamide, and immunoglobulin G. Then, a cycle of gemcitabine/oxaliplatin chemotherapy was performed on day 14, after which there was a temporary discontinuation of cyclophosphamide due to fever and neutropenia.\n==== Refs\nReferences\n1 Sakurai Y Takeda T Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder J Immunol Res 2014 2014 320674 24741588 \n2 Collins P Baudo F Huth-Kühne A Ingerslev J Kessler CM Castellano ME Consensus recommendations for the diagnosis and treatment of acquired hemophilia A BMC Res Notes 2010 3 161 20529258 \n3 Tiede A Werwitzke S Scharf RE Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges Semin Thromb Hemost 2014 40 (7) 803 11 25299927 \n4 Kruse-Jarres R Kempton CL Baudo F Collins PW Knoebl P Leissinger CA Acquired hemophilia A: updated review of evidence and treatment guidance Am J Hematol 2017 92 (7) 695 705 28470674 \n5 Napolitano M Siragusa S Mancuso S Kessler CM Acquired haemophilia in cancer: a systematic and critical literature review Haemophilia 2018 24 (1) 43 56 28960809 \n6 Shetty S Bhave M Ghosh K Acquired hemophilia A: diagnosis, aetiology, clinical spectrum and treatment options Autoimmun Rev 2011 10 (6) 311 6 21115138 \n7 Ma AD Carrizosa D Acquired factor VIII inhibitors: pathophysiology and treatment Hematology Am Soc Hematol Educ Program 2006 432 7 17124095 \n8 Charlebois J Rivard GE St-Louis J Management of acquired hemophilia A: review of current evidence Transfus Apher Sci 2018 57 (6) 717 20 30396835 \n9 Collins PW Hirsch S Baglin TP Dolan G Hanley J Makris M Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation Blood 2007 109 (5) 1870 7 17047148 \n10 Green D Rademaker AW Briët E A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies Thromb Haemost 1993 70 (5) 753 7 8128430 \n11 Collins P Baudo F Knoebl P Lévesque H Nemes L Pellegrini F Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2) Blood 2012 120 (1) 47 55 22517903 \n12 Lafferty TE Smith JB Schuster SJ DeHoratius RJ Treatment of acquired factor VIII inhibitor using intravenous immunoglobulin in two patients with systemic lupus erythematosus Arthritis Rheum 1997 40 (4) 775 8 9125263\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Acquired hemophilia; Carcinoma of the ampulla of Vater; Paraneoplastic acquired hemophilia",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "32110212",
"pubdate": "2020",
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"title": "Acquired Hemophilia in an Elderly Patient with Carcinoma of the Ampulla of Vater.",
"title_normalized": "acquired hemophilia in an elderly patient with carcinoma of the ampulla of vater"
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"abstract": "This is a preliminary, multicenter, retrospective cohort study, including 272 consecutive patients with COVID-19 admitted to hospitals in Buenos Aires Province, between May 15th and July 1st, 2020, included in an expanded access program to convalescent plasma. Our objectives were to analyze mortality and its independent risk factors, and to assess the occurrence of a favorable evolution, defined as hospital discharge, or stay at the ward, or transfer from ICU to ward. Patients were stratified int o 4 subgroups: admission to the ward with pneumonia and/or oxygen requirement (WARD; n = 100); ICU admission (ICU; n = 87); ICU admission with requirement of mechanical ventilation (ICU-MV; n = 56), and ICU-MV plus septic shock (ICU-MV-SS; N = 29). Mortality at 28 days was 26.1% for the entire group, 14.0% for WARD group, 18.4% for ICU, 44.6% for ICU-MV, and 55.2% for ICU-MV-SS. Mean survival time (days) was 25.6 ± 0.6 (WARD); 25.3 ± 0.7 (ICU); 20.8 ± 1.2 (ICU-MV) and 18.2 ± 1.8 (ICU-MV-SS). Independent predictors of mortality were MV, septic shock and weight. A favorable evolution occurred in 81.4% of WARD patients; in 70.9% of ICU; in 39.6% of ICU-MV and in 27.6% of ICU-MV-SS patients. Severity of illness on admission, age, weight and heart rate were independently associated with evolution. No major adverse effects were recorded. The lack of a control group precluded the estimation of efficacy. However, our 26% mortality rate was higher than that of the treatment arm of clinical trials comparing plasma with usual treatment, which might be ascribed to higher proportion of patients with MV and septic shock in our cohort.",
"affiliations": "Ministerio de Salud de la Provincia de Buenos Aires, Argentina. E-mail: sole.estrella.gonzalez@gmail.com.;Servicio de Inmunología, Hospital Interzonal de Agudos Especializado en Pediatría Sor María Ludovica, La Plata, Argentina.;Instituto de Hemoterapia, Ministerio de Salud de la Provincia de Buenos Aires, Argentina.;Dirección de Investigación y Cooperación Técnica, Ministerio de Salud de la Provincia de Buenos Aires, Argentina.;Servicio de Docencia e Investigación, Hospital Interzonal de Agudos San Martín, La Plata, Argentina.;Terapia Intensiva, Hospital Interzonal de Agudos San Martín, La Plata, Argentina.",
"authors": "González|Soledad E|SE|;Regairaz|Lorena|L|;Ferrando|Noelia S|NS|;González Martínez|Veronica V|VV|;Salazar|Martín R|MR|;Estenssoro|Elisa|E|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D001118:Argentina; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
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"title": "Convalescent plasma therapy in COVID-19 patients, in the Province of Buenos Aires.",
"title_normalized": "convalescent plasma therapy in covid 19 patients in the province of buenos aires"
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"abstract": "Multidrug-resistant tuberculosis (MDR-TB) is a global public health problem affecting women of childbearing age. Little is known, however, about the safety of the drugs used to treat MDR-TB during pregnancy. We describe 7 patients who were treated for MDR-TB during pregnancy. These patients had chronic tuberculosis that had caused extensive parenchymal damage and had high-grade resistance to antituberculous drugs. All patients received individualized antituberculous therapy prior to delivery of healthy term infants. Neither obstetrical complications nor perinatal transmission of MDB-TB was observed. One patient experienced treatment failure, and another abandoned therapy. The other 5 patients are currently cured or in treatment and have culture-negative status. In each of these 7 cases, excellent treatment outcomes were obtained for the women and their children. Under certain circumstances, MDR-TB can be successfully treated during pregnancy.",
"affiliations": "Program in Infectious Disease and Social Change, Department of Social Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. sshin@partners.org",
"authors": "Shin|Sonya|S|;Guerra|Dalia|D|;Rich|Michael|M|;Seung|Kwonjune J|KJ|;Mukherjee|Joia|J|;Joseph|Keith|K|;Hurtado|Rocio|R|;Alcantara|Felix|F|;Bayona|Jaime|J|;Bonilla|Cesar|C|;Farmer|Paul|P|;Furin|Jennifer|J|",
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"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D016896:Treatment Outcome; D014376:Tuberculosis",
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"title": "Treatment of multidrug-resistant tuberculosis during pregnancy: a report of 7 cases.",
"title_normalized": "treatment of multidrug resistant tuberculosis during pregnancy a report of 7 cases"
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{
"companynumb": "PHBS2004US13757",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOFAZIMINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Saccharomyces cerevisiae is an emerging pathogen within the immunocompromised. We present a 4-year-old boy with acute lymphoblastic leukemia presenting with polymerase chain reaction-confirmed hepatosplenic S. cerevisiae infection and significant immune reconstitution symptoms. We explore the challenges of monitoring treatment efficacy using C-Reactive protein, β-D-glucan, and imaging and the administration of chemotherapy alongside antifungals and steroids for control of immune reconstitution syndrome.",
"affiliations": "Department of Clinical Virology, Manchester University Foundation Trust.;Departments of Paediatric Blood and Marrow.;Paediatric Radiology, Royal Manchester Children's Hospital, Manchester, United Kingdom.;Departments of Paediatric Blood and Marrow.",
"authors": "Davies|Emma|E|;Shipp|Adam|A|;Hawkes|Rob|R|;Wynn|Robert F|RF|",
"chemical_list": "D000935:Antifungal Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000935:Antifungal Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D016867:Immunocompromised Host; D008107:Liver Diseases; D008297:Male; D009181:Mycoses; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012441:Saccharomyces cerevisiae; D013158:Splenic Diseases",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e117-e120",
"pmc": null,
"pmid": "30629004",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Management of Hepatosplenic Infection Due to Saccharomyces cerevisiae in a Child With Acute Lymphoblastic Leukemia.",
"title_normalized": "successful management of hepatosplenic infection due to saccharomyces cerevisiae in a child with acute lymphoblastic leukemia"
} | [
{
"companynumb": "GB-TEVA-2020-GB-1220047",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 64-year-old woman who complained of abdominal pain underwent right radical nephrectomy under the clinical diagnosis of renal cell carcinoma in January, 2006. The pathological diagnosis was leiomyosarcoma originating from the kidney. Follow-up computed tomography revealed 2 small nodules in the left lung 15 months after nephrectomy. A lung nodule resected with video-assisted thoracic surgery (VATS) was identified as metastatic leiomyosarcoma. Since the pulmonary metastases progressed after VATS, systemic chemotherapy with gemcitabine and docetaxel (GD therapy) was started. The lung metastases responded well, and a durable partial response was achieved for 29 months. Subsequently, the patient developed new pulmonary metastases and pancreatic metastasis. Despite this disease progression, we elected to continue GD therapy, since the patient's performance status and quality of life were favorable during the treatment. So far, the GD therapy has been continued for another 23 months, for a total of 41 treatment cycles, with few adverse events. Although multiple metastases have slowly progressed, the patient has maintained good performance status in the outpatient clinic. In the present case, GD therapy seems to have been beneficial for survival, as metastatic renal leiomyosarcoma is considered to have an extremely poor prognosis.",
"affiliations": "The Department of Urology, University of Tsukuba, Japan.",
"authors": "Nagumo|Yoshiyuki|Y|;Kimura|Tomokazu|T|;Ichioka|Daishi|D|;Uchida|Masahiro|M|;Oikawa|Takehiro|T|;Suetomi|Takahiro|T|;Miyazaki|Jun|J|;Kawai|Koji|K|;Nagata|Chigusa|C|;Nishiyama|Hiroyuki|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "59(8)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D007890:Leiomyosarcoma; D008175:Lung Neoplasms; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D043823:Taxoids",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "497-501",
"pmc": null,
"pmid": "23995525",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-term survival with gemcitabine and docetaxel for renal leiomyosarcoma : a case report.",
"title_normalized": "long term survival with gemcitabine and docetaxel for renal leiomyosarcoma a case report"
} | [
{
"companynumb": "JP-CIPLA LTD.-2018JP10148",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Hypoparathyroidism is a rare endocrine disease with insufficient parathyroid hormone levels. Replacing the missing hormone is not yet a standard therapy. The objective of this retrospective cohort study was to evaluate if the usual therapy regimens of postsurgical hypoparathyroidism with calcitriol have a negative effect on renal function. We performed a chart analysis of patients who were seen in a tertiary care hospital in Brussels, Belgium. A total of 101 subjects were identified as patients with permanent post-surgical hypoparathyroidism, based on the hospital records of patients who underwent a total thyroidectomy between 1996 and 2016, while still being treated with calcitriol. Patients with pre-existing renal insufficiency and/or active malignancy were excluded. The cohort was predominantly female of Caucasian origin. Renal function was evaluated before and after surgery (with a maximum follow-up of 12 years), using the CKD-EPI equation. A multivariate linear regression model was used to correlate renal function decline with the duration of calcitriol therapy, while correcting for the mean calcium phosphate product and age. We found a statistically significant (p=0.027) relationship between the duration of calcitriol treatment and renal function decline at a rate of 1.06 ml/min/1.73 m2 per year of calcitriol therapy. Our study, although being retrospective, is the first one to demonstrate a relationship between the cumulative use of calcitriol therapy and renal function decline.",
"affiliations": "Department of Endocrinology, UZ Brussel, Vrije Universiteit Brussel (VUB), Jette, Belgium.;Department of Nephrology, Erasmus Ziekenhuis, Université Libre de Bruxelles (ULB), Bruxelles, Belgium.;Department of Endocrinology, UZ Brussel, Vrije Universiteit Brussel (VUB), Jette, Belgium.;Department of Statistics, Vrije Universiteit Brussel (VUB), Jette, Belgium.;Department of Endocrinology, UZ Brussel, Vrije Universiteit Brussel (VUB), Jette, Belgium.",
"authors": "Coudenys|Elien|E|;Van Meerhaeghe|Tess|T|;Unuane|David|D|;Buyl|Ronald|R|;Bravenboer|Bert|B|",
"chemical_list": "D002120:Calcium Channel Agonists; D002117:Calcitriol",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-0902-8476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5043",
"issue": "51(6)",
"journal": "Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme",
"keywords": null,
"medline_ta": "Horm Metab Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002117:Calcitriol; D002120:Calcium Channel Agonists; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007011:Hypoparathyroidism; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D051437:Renal Insufficiency; D012189:Retrospective Studies; D013965:Thyroidectomy; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "0177722",
"other_id": null,
"pages": "362-366",
"pmc": null,
"pmid": "31207657",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-Term Treatment with Calcitriol in Postsurgical Hypoparathyroidism Leads to Renal Function Decline.",
"title_normalized": "long term treatment with calcitriol in postsurgical hypoparathyroidism leads to renal function decline"
} | [
{
"companynumb": "BE-VALIDUS PHARMACEUTICALS LLC-BE-2019VAL000875",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCITRIOL"
},
"drugadd... |
{
"abstract": "Riluzole is a glutamate-modulating agent with neuroprotective properties approved for use in amyotrophic lateral sclerosis. The efficacy and safety of riluzole vs placebo as an adjunct to antidepressant medication in outpatients with major depressive disorder (MDD) was examined in a 3-site, 8-week, randomized, double-blind, placebo-controlled, fixed-dose trial using a sequential parallel comparison design comprised of two phases of 4 weeks. Patients with MDD in a current major depressive episode (N=104) with an inadequate response to either a prospective or a historical trial of an antidepressant medication were randomized in a 2 : 3 : 3 ratio to the treatment sequences of riluzole/riluzole, placebo/placebo, and placebo/riluzole, respectively. The primary outcome was change in depression severity, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary efficacy outcomes included the response rate, defined as at least a 50% improvement in MADRS, Clinical Global Impressions severity and improvement subscales, and patient-reported measures of depression and cognitive function. Eighty-five patients completed the randomized treatment phases. Treatment groups did not differ in mean change in MADRS scores, response rate, or in any secondary efficacy outcomes. Riluzole was generally well tolerated, with a side effect profile consistent with its clinical use. In conclusion, a fixed dose of riluzole (100 mg/day) did not show adjunctive antidepressant efficacy compared to placebo. The trial was adequately powered to detect a moderate riluzole effect, and the risk for exaggerated placebo responses was mitigated. The lack of efficacy suggests that mechanisms underlying riluzole's neuroprotective effects are insufficient for clinical response in treatment-resistant depression.",
"affiliations": "Mental Health Care Line, Michael E. DeBakey VA Medical Center, Houston, TX, USA.;Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.;Departments of Emergency Medicine and Anesthesiology, Yale University School of Medicine, New Haven, CT, USA.;Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.;Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.",
"authors": "Mathew|Sanjay J|SJ|;Gueorguieva|Ralitza|R|;Brandt|Cynthia|C|;Fava|Maurizio|M|;Sanacora|Gerard|G|",
"chemical_list": "D000928:Antidepressive Agents; D018696:Neuroprotective Agents; D019782:Riluzole",
"country": "England",
"delete": false,
"doi": "10.1038/npp.2017.106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-133X",
"issue": "42(13)",
"journal": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
"keywords": null,
"medline_ta": "Neuropsychopharmacology",
"mesh_terms": "D000328:Adult; D000553:Ambulatory Care; D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D061218:Depressive Disorder, Treatment-Resistant; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D011569:Psychiatric Status Rating Scales; D019782:Riluzole; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "8904907",
"other_id": null,
"pages": "2567-2574",
"pmc": null,
"pmid": "28553836",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "27021815;16330605;26937618;25629040;3774930;25073688;17848492;19218827;14702270;26997505;17141740;15705360;444788;18825147;26800392;22193671;15049516;8959995;25139008;19769599;8733206;22739126;17635670;19956089;26423481;26395901;19288975;16936714;26148812;21779782;25890643;22298121;26869247;18698875;12707478",
"title": "A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder.",
"title_normalized": "a randomized double blind placebo controlled sequential parallel comparison design trial of adjunctive riluzole for treatment resistant major depressive disorder"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US23107",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We present the case of a 12-year-old-girl who developed lichenoid dermatitis approximately 1 year after starting leflunomide for juvenile idiopathic arthritis. The eruption resolved promptly with discontinuation of the suspected culprit agent, supportive of a lichenoid drug eruption, but she subsequently developed markedly dystrophic nails with lichen planus-like features. A biopsy of her cutaneous findings at the time of initial presentation demonstrated lichenoid dermatitis, and a nail matrix biopsy was deferred given clinical correlation. Prominent nail changes in lichenoid drug eruptions, particularly in children, are rare but should be considered in children with new-onset nail dystrophy.",
"affiliations": "Division of Dermatology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington.;Division of Dermatology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington.;Division of Dermatology, Department of Pediatrics, School of Medicine, Seattle Children's Hospital, University of Washington, Seattle, Washington.;Department of Pathology, Seattle Children's Hospital, Seattle, Washington.;Division of Dermatology, Department of Pediatrics, School of Medicine, Seattle Children's Hospital, University of Washington, Seattle, Washington.",
"authors": "May|Caitlin|C|http://orcid.org/0000-0003-0082-7203;Fleckman|Philip|P|;Brandling-Bennett|Heather A|HA|;Cole|Bonnie|B|;Sidbury|Robert|R|",
"chemical_list": "D018501:Antirheumatic Agents; D007555:Isoxazoles; D000077339:Leflunomide",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13168",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "34(4)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D018501:Antirheumatic Agents; D002648:Child; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007555:Isoxazoles; D000077339:Leflunomide; D017512:Lichenoid Eruptions; D009260:Nail Diseases; D009262:Nails; D012867:Skin",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e225-e226",
"pmc": null,
"pmid": "28543792",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lichenoid Drug Eruption with Prominent Nail Changes Due to Leflunomide in a 12-Year-Old Child.",
"title_normalized": "lichenoid drug eruption with prominent nail changes due to leflunomide in a 12 year old child"
} | [
{
"companynumb": "PHHY2017US110901",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Fluoroquinolones are a class of popular outpatient antimicrobial agents with a wide spectrum of therapeutic indications for respiratory and genitourinary infections. Though the most common side effects are gastrointestinal, fluoroquinolones have been increasingly associated with neurotoxicity including peripheral neuropathy and seizures. We present here a case of a 43-year-old woman with previously resolved type I complex regional pain syndrome (CRPS) who presented with symptoms of CRPS and neurotoxicity in the setting of levofloxacin administration. Our aim is to advocate for increased caution in prescribing to patients with a history of neuropathology including CRPS.",
"affiliations": "From the Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.",
"authors": "Hao|David|D|;Kiss|Geza|G|;Grubb|William|W|;Cohen|Shaul|S|;Levin|Danielle|D|;Sakr|Ashraf|A|",
"chemical_list": "D064704:Levofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000769",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "11(6)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D001340:Autonomic Nerve Block; D005260:Female; D006801:Humans; D064704:Levofloxacin; D012019:Reflex Sympathetic Dystrophy; D062187:Spinal Cord Stimulation; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "158-159",
"pmc": null,
"pmid": "29621012",
"pubdate": "2018-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spinal Cord Neuromodulation Therapy for Levofloxacin-Reinduced Complex Regional Pain Syndrome and Neurotoxicity: A Case Report.",
"title_normalized": "spinal cord neuromodulation therapy for levofloxacin reinduced complex regional pain syndrome and neurotoxicity a case report"
} | [
{
"companynumb": "US-PFIZER INC-2017478885",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Adverse drug events (ADEs) are a significant cause of emergency department (ED) visits, with a major impact on healthcare resource utilization. A multicentre observational study, aimed to describe frequency, seriousness and preventability of ADEs reported in four EDs, was performed in Sicily (Italy) over a 1-year period.\n\n\n\nTwo trained monitors for each ED supported clinicians in identifying ADEs of patients admitted to EDs between June 1st, 2013 and May 31st, 2014 through a systematic interview of patients or their caregivers and with an additional record review. A research team analyzed each case of suspected ADE, to make a causality assessment applying the Naranjo algorithm and a preventability assessment using Schumock and Thornton criteria. Absolute and percentage frequencies with 95% confidence interval (CI) and medians with interquartile ranges (IQR) were estimated. Logistic regression models were used to evaluate independent predictors of serious and certainly preventable ADEs.\n\n\n\nOut of 16,963 ED visits, 575 (3.4%) were associated to ADEs, of which 15.1% resulted in hospitalization. ADEs were classified as probable in 45.9%, possible in 51.7% and definite in 2.4% of the cases. Moreover, ADEs were considered certainly preventable in 12.3%, probably preventable in 58.4%, and not preventable in 29.2% of the cases. Polytherapy influenced the risk to experience a serious, as well as a certainly preventable ADE. Whilst, older age resulted an independent predictor only of serious events. The most common implicated drug classes were antibiotics (34.4%) and anti-inflammatory drugs (22.6%). ADEs due to psycholeptics and antiepileptics resulted preventable in 62.7 and 54.5% of the cases, respectively. Allergic reactions (64%) were the most frequent cause of ADE-related ED visits, followed by neurological effects (10.2%) that resulted preventable in 1.9 and 37.3% of the cases, respectively.\n\n\n\nADEs are a frequent cause of ED visits. The commonly used antibiotics and anti-inflammatory drugs should be carefully managed, as they are widely involved in mild to severe ADEs. Polytherapy is associated with the occurrence of serious, as well as certainly preventable ADEs, while older age only with serious events. A greater sensitivity to drug monitoring programs among health professionals is needed.",
"affiliations": "Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.;Department of Emergency Medicine, University Hospital G. Martino, Via Consolare Valeria, 98125, Messina, Italy.;Department of Emergency Medicine, University Hospital V. Emanuele, Via S. Sofia, 95123, Catania, Italy.;Department of Emergency Medicine, General Hospital S. Elia, Via Luigi Russo, 93100, Caltanissetta, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125, Messina, Italy. vincenzo.arcoraci@unime.it.;Sicilian Regional Pharmacovigilance Center, Clinical Pharmacology Unit, University Hospital G. Martino, Via Consolare Valeria, 98125, Messina, Italy.",
"authors": "Lo Giudice|Ivan|I|;Mocciaro|Eleonora|E|;Giardina|Claudia|C|;Barbieri|Maria Antonietta|MA|;Cicala|Giuseppe|G|;Gioffrè-Florio|Maria|M|;Carpinteri|Giuseppe|G|;Di Grande|Aulo|A|;Spina|Edoardo|E|;Arcoraci|Vincenzo|V|0000-0003-0061-0477;Cutroneo|Paola Maria|PM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-019-0297-7",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 29710.1186/s40360-019-0297-7Research ArticleCharacterization and preventability of adverse drug events as cause of emergency department visits: a prospective 1-year observational study Lo Giudice Ivan 1Mocciaro Eleonora 1Giardina Claudia 1Barbieri Maria Antonietta 1Cicala Giuseppe 1Gioffrè-Florio Maria 2Carpinteri Giuseppe 3Di Grande Aulo 4Spina Edoardo 15http://orcid.org/0000-0003-0061-0477Arcoraci Vincenzo +390902213994vincenzo.arcoraci@unime.it 1Cutroneo Paola Maria 51 0000 0001 2178 8421grid.10438.3eDepartment of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy 2 0000 0004 1773 5724grid.412507.5Department of Emergency Medicine, University Hospital G. Martino, Via Consolare Valeria, 98125 Messina, Italy 3 grid.412844.fDepartment of Emergency Medicine, University Hospital V. Emanuele, Via S. Sofia, 95123 Catania, Italy 4 Department of Emergency Medicine, General Hospital S. Elia, Via Luigi Russo, 93100 Caltanissetta, Italy 5 0000 0004 1773 5724grid.412507.5Sicilian Regional Pharmacovigilance Center, Clinical Pharmacology Unit, University Hospital G. Martino, Via Consolare Valeria, 98125 Messina, Italy 27 4 2019 27 4 2019 2019 20 2111 7 2018 5 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAdverse drug events (ADEs) are a significant cause of emergency department (ED) visits, with a major impact on healthcare resource utilization. A multicentre observational study, aimed to describe frequency, seriousness and preventability of ADEs reported in four EDs, was performed in Sicily (Italy) over a 1-year period.\n\nMethods\nTwo trained monitors for each ED supported clinicians in identifying ADEs of patients admitted to EDs between June 1st, 2013 and May 31st, 2014 through a systematic interview of patients or their caregivers and with an additional record review. A research team analyzed each case of suspected ADE, to make a causality assessment applying the Naranjo algorithm and a preventability assessment using Schumock and Thornton criteria.\n\nAbsolute and percentage frequencies with 95% confidence interval (CI) and medians with interquartile ranges (IQR) were estimated. Logistic regression models were used to evaluate independent predictors of serious and certainly preventable ADEs.\n\nResults\nOut of 16,963 ED visits, 575 (3.4%) were associated to ADEs, of which 15.1% resulted in hospitalization. ADEs were classified as probable in 45.9%, possible in 51.7% and definite in 2.4% of the cases. Moreover, ADEs were considered certainly preventable in 12.3%, probably preventable in 58.4%, and not preventable in 29.2% of the cases. Polytherapy influenced the risk to experience a serious, as well as a certainly preventable ADE. Whilst, older age resulted an independent predictor only of serious events. The most common implicated drug classes were antibiotics (34.4%) and anti-inflammatory drugs (22.6%). ADEs due to psycholeptics and antiepileptics resulted preventable in 62.7 and 54.5% of the cases, respectively. Allergic reactions (64%) were the most frequent cause of ADE-related ED visits, followed by neurological effects (10.2%) that resulted preventable in 1.9 and 37.3% of the cases, respectively.\n\nConclusion\nADEs are a frequent cause of ED visits. The commonly used antibiotics and anti-inflammatory drugs should be carefully managed, as they are widely involved in mild to severe ADEs. Polytherapy is associated with the occurrence of serious, as well as certainly preventable ADEs, while older age only with serious events. A greater sensitivity to drug monitoring programs among health professionals is needed.\n\nKeywords\nEmergency departmentAdverse drug eventSeriousnessCausalityPreventabilityhttp://dx.doi.org/10.13039/501100002737Assessorato Regionale della Salute, Regione Sicilianaissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAdverse drug events (ADEs) have a considerable impact on public healthcare and are a significant burden on healthcare resources [1]. Emergency departments (EDs) constitute an essential part of the healthcare system and an important source of information regarding incidence and characteristics of ADEs, as they are an interface between hospitals and communities [2, 3]. Several studies have analysed ED visits potentially related to drug therapy [2, 4–10]. However, a wide range of ADE-related ED visits was reported and available evidence suggests that 0.6–12% of all visits are due to ADEs [5, 7, 10–12]. A recent study based on an active monitoring project regarding ADEs in EDs, carried out in the United States in 2013 and 2014 (NEISS-CADES, The National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance), estimated a rate of 4.0 ED visits per 1000 inhabitants year due to ADEs [9]. The wide range of reported ADE-related ED visits may reflect some methodological variances due to different types of hospital settings, study design, data source, variability in the definition of ADE, difficulty in diagnosis and determination of ADEs [6]. Indeed, many studies conducted in EDs have been limited to one hospital centre [13, 14], a specific population [15, 16], specific therapeutic classes or type of ADEs [17–20]. Other findings are attributable to retrospective study design [21, 22], short periods of observation [2, 5, 6, 23–25], or lack of information on preventability [7, 10, 26]. Moreover, some literature studies reported preventability assessment referred only to therapeutic classes [4, 27, 28]. Even though several studies were made in different European countries, few data are available especially in a South of Italy setting. Thus, more knowledge on occurrence, characteristics and preventability of ADEs is needed. In view of the above findings, the aims of this study were to determine the rate of ADEs leading to ED visits in four hospitals in Sicily (Italy) and to evaluate ADEs’ seriousness and preventability. Furthermore, the drug classes most frequently involved in ADEs, the characteristics of ADEs and their frequency were also evaluated, in terms of both severity and preventability.\n\nMethods\nData source and data collection\nAn active monitoring project of ADEs in four EDs in Sicily (Italy) was carried out in a one-year period. The University Hospitals of Messina and Catania and the General Hospitals S. Elia of Caltanissetta and Villa Sofia-Cervello of Palermo were selected for this study, as they serve widespread catchment areas of Sicily, which is a large Italian region that includes around 5 million inhabitants.\n\nAll patients aged ≥18 presenting to the four EDs between June 1st, 2013 and May 31st, 2014, were eligible for enrolment. For this study data concerning ADE-related ED visits were recorded in a dedicated database. ED records of involved hospitals were also reviewed. Two trained monitors (one pharmacist and one physician) with experience in pharmacovigilance were assigned to each hospital and they supported clinicians in identifying ADEs and gathering all available information through an accurate and systematic interview of patients (or their caregivers). Furthermore, an additional review of patients’ records was performed by monitors to detect other potential missed cases of ADEs that were included only if confirmed by ED physicians. A research group composed of clinical pharmacologists, operating in the Sicilian Pharmacovigilance Centre sited at University Hospital of Messina, ED physicians and monitors revised all detected cases of ADEs. In detail, the team analyzed every case of suspected ADE, to assess the correlation between drug administration and ADE onset using the Naranjo algorithm.\n\nIn particular, biological plausibility of symptoms and signs and characteristics of each suspected drug, plausible time relationship between drug intake and symptoms occurrence, potential alternative causes were considered. If a patient was in polytherapy, the association with ADE was evaluated for each drug taken. For each patient the following information were collected: demographic characteristics, clinical status at ED visit, medication use (prescription, over-the-counter, complementary and alternative medications), medical history, previous medication intolerance and allergies, as well as an accurate description of observed symptoms. All data were recorded in a dedicated database.\n\nCase definition and outcome measurement\nThe primary outcome of the study was to evaluate the rate of ADEs presenting in EDs. We included all cases of ADE diagnosed by ED physicians, due to prescription drugs, over-the counter medications, dietary supplements, or homeopathic products. An ADE was defined as “an injury resulting from medical intervention related to a drug”, a definition that was intended to encompass harm that arises from medication errors as well as typical adverse drug reactions [29]. Thus, ADEs include all events which derive from appropriate or inappropriate use of a medicinal product within as well as outside the terms of the marketing authorization.\n\nPatients were excluded from the study if (1) they left the ED before being seen by the ED physician; (2) they were seen directly by a consultant specialist physician rather than an ED physician; (3) data collection was not completed; (4) lack of diagnosis by the ED physician or (5) they were paediatric patients (age < 18). The causal relationship between the ADE and the suspected drug was assessed with the Naranjo algorithm, and each ADE case was categorized as: definite (score ≥ 9), probable (scores 5–8), possible (scores 1–4) or doubtful (score ≤ 0) [30]. Preventability of ADEs was also assessed, using the modified Schumock and Thornton criteria [31]. In our study all “certainly preventable” ADEs derived from one of the following suspected causes, according to European Pharmacovigilance guidelines [32]: drug abuse (intentional but excessive use of drug), misuse (intentional and inappropriate use for the patient’s clinical condition, age, weight, dose, route, or frequency of administration, or history of allergies or previous reactions), overdose, medication error.\n\nSerious ADEs were classified as all events resulting as fatal, life-threatening, leading to hospitalization, inducing serious/permanent disability [32]. Drugs involved in ADEs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system [33] and ADEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA®) [34]. Cases were classified by ED physician-developed primary diagnosis and grouped as previously published [9].\n\nStatistical analysis\nIn order to assess basal demographic characteristics and drug-related variables of patients with ADEs a descriptive statistical analysis was carried out. We calculated the rate of ADEs leading to ED visits as the ratio between the number of patients admitted to EDs who presented with an ADE and the total number of patients admitted to EDs during the study period. We estimated the rate of hospitalization for ADEs following ED visits by dividing the number of hospitalizations for ADEs by the total number of ADE-related ED visits in the same period. We used absolute and relative frequencies with 95% confidence interval (CI) for categorical variables, and medians with interquartile ranges (IQR) to estimate continuous variables. A non-parametric approach was performed as some of the numerical variables were not normally distributed after applying the Kolmogorov-Smirnov test. The Pearson’s chi-squared test and the Mann-Whitney U test were used to compare subjects’ characteristics, according to ADE seriousness. We applied a univariate logistic regression model to assess the possible influence of predictive factors of serious and certainly preventable ADEs, such as gender, age, number of reported comorbidities, comorbidities index values and number of administered drugs. Patients with not serious ADEs and patients with possibly preventable or not preventable ADEs were used as comparators, respectively. Furthermore, for each analysis the predictors gender, age and number of drugs taken were considered for a multivariate logistic regression model. The number of concomitant diseases and comorbidity index, that are inter-related to number of drugs assumed, were excluded from the analyses in the multivariate model in order to avoid multicollinearity. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each variable of interest in the univariate and in the multivariate models, respectively. P values ≤0.05 were chosen as the threshold of statistical significance. All the analyses were conducted with SPSS.20.0 (IBM Corp. SPSS Statistics).\n\nResults\nCharacteristics of study population\nDuring the one-year study period, a total of 18,646 patients were admitted to the EDs. Among these, 9.0% were not included (Fig. 1). An ADE was detected in 575 cases, with an overall prevalence rate of 3.4% (95%CI, 3.1–3.7). Among ADE-related visits, 170 (29.6%; 95%CI, 25.8–33.3) were associated with serious events and hospitalization was required in 87 patients (15.1%; 95%CI, 12.2–18.1). Demographic characteristics of patients with ADEs are reported in Table 1. Most patients with ADEs were females (63.1%; 95%CI, 59.2–67.1) and the median age was 52.0 years (IQR: 29.0). Patients with serious ADE were older than patients with not serious ADEs [62.0 years (IQR: 34.0) vs 49.0 years (IQR: 27.0); p < 0.001]. In particular, in patients affected by serious ADEs 46.8% were ≥ 65 years, compared to 19.9% without serious ADEs. The median number of drugs taken by patients who developed serious ADEs was higher than patients with not serious ADEs [3.0 (IQR: 4.0) vs 1.0 (IQR: 0.0); p < 0.001].Fig. 1 Study flow chart\n\nTable 1 Demographic characteristics of patients with adverse drug events (ADEs) leading to Emergency Departments (ED) visits\n\n\tADE-related ED visits\tSerious ADE-related\nED visits\tNot serious ADE-related\nED visits\t\nNo. of Cases (%)\t95% CI\tNo. of Cases (%)\t95% CI\tNo. of Cases (%)\t95% CI\t\nGender\t\naMales\t212 (36.9)\t32.9–40.8\t59 (34.7)\t27.5–41.9\t149 (37.2)\t32.4–41.9\t\nFemales\t363 (63.1)\t59.2–67.1\t111 (65.3)\t58.1–72.5\t252 (62.8)\t58.1–67.6\t\nPatient age group, years\t\nb18–34\t118 (20.5)\t17.2–23.8\t27 (15.6)\t10.2–21.0\t86 (22.2)\t18.1–26.3\t\nc35-49\t143 (24.1)\t20.6–27.5\t23 (13.3)\t8.2–18.4\t118 (28.3)\t24.0–32.6\t\n50–64\t150 (25.3)\t21.8–28.7\t39 (22.5)\t16.3–28.8\t111 (26.6)\t22.4–30.9\t\n65–79\t116 (19.5)\t16.3–22.7\t52 (30.1)\t23.2–36.9\t64 (15.3)\t11.9–18.8\t\n≥80\t48 (8.1)\t5.9–10.3\t29 (16.8)\t11.2–22.3\t19 (4.6)\t2.6–6.6\t\nNo. of medications by category\t\nd1\t380 (66.1)\t62.2–70.0\t57 (33.5)\t26.4–40.6\t319 (79.6)\t75.6–83.5\t\n≥2\t195 (33.9)\t30.0–37.8\t113 (66.5)\t59.4–73.6\t85 (20.4)\t16.5–24.4\t\nPreventability assessment\t\nCertainly preventable\t71 (12.3)\t9.7–15.0\t42 (24.7)\t18.2–31.2\t29 (7.2)\t4.7–9.8\t\nProbably preventablee\t336 (58.4)\t54.4–62.5\t101 (59.4)\t52.0–66.8\t232 (57.9)\t53.0–62.7\t\nNot-preventablef\t168 (29.2)\t25.5–32.9\t27 (15.9)\t10.4–21.4\t140 (34.9)\t30.2–39.6\t\n95% CI 95% confidence interval\n\na4 patients with unspecified ADE seriousness\n\nb2 patients with unspecified ADE seriousness\n\nc2 patients with unspecified ADE seriousness\n\nd4 patients with unspecified ADE seriousness\n\ne3 patients with unspecified ADE seriousness\n\nf1 patient with unspecified ADE seriousness\n\n\n\nUsing the Naranjo algorithm [31], all included ADEs were classified as probable in 45.9% (95%CI, 41.8–50), possible in 51.7% (95%CI, 47.6–55.7) and definite in 2.4% (95%CI, 1.2–3.7). With regard to preventability, 12.3% (95%CI, 9.7–15.0) of ADEs were considered certainly preventable, while 58.4% (95%CI, 54.4–62.5) were possibly preventable and only 29.2% (95%CI, 25.5–32.9) not preventable. In detail, among 71 cases classified as certainly preventable, 24 cases of ADEs were related to drug abuse, 20 cases to misuse, 17 cases derived from unintentional/intentional overdose and 10 from medication errors (Table 2). Finally, among possibly preventable ADEs, 20 cases related to drug-drug interactions and 1 off-label use occurred.Table 2 Suspected causes for a certainly preventable assessment and drugs involved\n\nSuspected causes (No. of cases)\tDrugs involved (No. of cases)a\t\nAbuse (24)\tLorazepam (6), quetiapine (3), clonazepam (2), haloperidol (2), bromazepam (2), paroxetine (2), lithium (2), methadone (2), triazolam (1), diazepam (1), chlorpromazine (1), telmisartan (1), alprazolam (1), tosylchloramide (1), clomipramine (1), citalopram (1), promazine (1), acetylsalicylic acid (1), oxazepam (1), venlafaxine (1), delorazepam (1), oxcarbazepine (1), brotizolam (1), valproic acid (1), pregabalin (1), tramadol (1)\t\nMisuse (20)\tDigoxin (2), acetylsalicylic acid (2), metformin (2), etoricoxib (2), ceftriaxone (1), promazine (1), clopidogrel (1), doxazosin (1), amoxicillin+clavulanic acid (1), ketoprofen (1), levofloxacin (1),\t\nOverdose (17)\tLorazepam (3), oxcarbazepine (2), carbamazepine (2), warfarin (2), olanzapine (2), acenocoumarol (2), olmesartan (2), morniflumate (1), oxcarbazepine (1), furosemide (1), acetylsalicylic acid (1), nimesulide (1), ketoprofen (1), paracetamol (1), bisoprolol (1), valproic acid (1), tosylchloramide (1), amoxicillin (1), oxycodone+naloxone (1)\t\nMedication error (10)\tWarfarin (2), human insulin (1), betamethasone (1), insulin aspart (1), metformin (1), prednisone (1), glicazide (1), paracetamol (1), clonazepam (1), furosemide (1), levothyroxine (1)\t\naThe sum of suspected drugs is higher than the total number of cases, since a single patient could have used multiple drugs\n\n\n\nAs assessed by the multivariate logistic regression models, gender did not influence the risk to experience a serious ADE (OR 1.20; 95% CI 0.78–1.85: p = 0.403), as well as a certainly preventable event (OR 1.18; 95% CI 0.70–2.01: p = 0.531). Conversely, age ≥ 65 years resulted an independent predictor of serious events (OR 2.66; 95% CI 1.72–4.11: p < 0.001), but not of certainly preventable events (OR 1.20; 95% CI 0.69–2.11: p = 0.516). Moreover, polytherapy influenced the risk to experience a serious (OR 6.45; 95% CI 4.26–9.76: p < 0.001), as well as a certainly preventable ADE (OR 1.87; 95% CI 1.11–3.17: p = 0.020).\n\nDrugs associated with adverse drug events\nThe drug classes most frequently involved in ADEs were antibiotics (34.4%), anti-inflammatory/antirheumatic drugs (22.6%) and antithrombotic agents (9.4%). Serious ADEs were shown in 18.7% (37/198) of ADEs due to antibacterials for systemic use and in 15.4% (20/130) of ADEs related to anti-inflammatory/antirheumatic drugs. ADEs due to diuretics, cardiac drugs (i.e. digital glycosides, antiarrhythmics, cardiac stimulants, vasodilators, other cardiac preparations) and agents acting on the renin-angiotensin system (RAS) were mainly serious (85.7% for diuretics, 84.2% for cardiac drugs, and 85.7% RAS-acting agents). ADEs due to psycholeptics and antiepileptics resulted preventable in 62.7% (32/51) and 54.5% (12/22) of the cases, respectively.\n\nThe most commonly involved drugs were amoxicillin/clavulanic acid (14.3%), ketoprofen (10.9%), ceftriaxone (6.6%), amoxicillin (4.9%), and acetylsalicylic acid (4.7%). All 6 cases of ADEs associated with digoxin and 6 out of 7 cases of ADEs related to furosemide and ramipril were classified as serious. ADEs due to lorazepam and warfarin were mainly preventable (9 out of 10 cases for lorazepam and 4 out of 8 cases for warfarin) (Table 3).Table 3 Most commonly implicated drugs in Emergency Department (ED) visits for adverse drug events (ADEs)\n\n\tADE-related\nED visitsa,b\tSerious ADE-related ED visitsa,b\tPreventable ADE-related ED visitsa,b\t\nATC 5th level\tDrug\tNo. of Cases (%)\tNo. of Cases (%)\tNo. of Cases (%)\t\nJ01CR02\tAmoxicillin/clavulanic acid\t82 (14.3)\t13 (7.6)\t1 (1.4)\t\nM01AE03\tKetoprofen\t62 (10.9)\t7 (4.1)\t2 (2.8)\t\nJ01DD04\tCeftriaxone\t38 (6.6)\t8 (4.7)\t1 (1.4)\t\nJ01CA04\tAmoxicillin\t28 (4.9)\t4 (2.4)\t1 (1.4)\t\nB01AC06\tAcetylsalicylic acid\t27 (4.7)\t9 (5.3)\t4 (5.6)\t\nJ01MA12\tLevofloxacin\t17 (3.0)\t5 (2.9)\t1 (1.4)\t\nM01AB05\tDiclofenac\t16 (2.9)\t1 (0.6)\t–\t\nM01AX17\tNimesulide\t13 (2.3)\t2 (1.2)\t1 (1.4)\t\nM01AE01\tIbuprofen\t15 (2.6)\t2 (1.2)\t–\t\nN05BA06\tLorazepam\t10 (1.7)\t7 (4.1)\t9 (12.7)\t\nM01AH05\tEtoricoxib\t10 (1.7)\t3 (1.8)\t2 (2.8)\t\nA10BA02\tMetformin\t9 (1.6)\t6 (3.5)\t3 (4.2)\t\nH02AB01\tBetamethasone\t9 (1.6)\t1 (0.6)\t1 (1.4)\t\nB01AA03\tWarfarin\t8 (1.4)\t5 (2.9)\t4 (5.6)\t\nJ01MA02\tCiprofloxacin\t8 (1.4)\t–\t–\t\nC03CA01\tFurosemide\t7 (1.2)\t6 (3.5)\t2 (2.8)\t\nC09AA05\tRamipril\t7 (1.2)\t6 (3.5)\t–\t\nN02BE01\tParacetamol\t6 (1.0)\t–\t2 (2.8)\t\nN02BE51\tParacetamol, combinations excl. Psycholeptics\t6 (1.0)\t–\t–\t\nN03AF01\tCarbamazepine\t6 (1.0)\t4 (2.4)\t2 (2.8)\t\nB01AA07\tAcenocoumarol\t6 (1.0)\t4 (2.4)\t2 (2.8)\t\nM03BX05\tThiocolchicoside\t6 (1.0)\t1 (0.6)\t–\t\nC01AA05\tDigoxin\t6 (1.0)\t6 (3.5)\t2 (2.8)\t\nN02BA51\tAcetylsalicylic acid, combinations excl. psycholeptics\t6 (1.0)\t–\t–\t\nATC (5th level), Anatomical Therapeutic Chemical classification (5th level)\n\naDrugs implicated in > 5 cases were considered\n\nbThe sum of suspected drugs is higher than the total number of cases, since a single patient could have used multiple drugs\n\n\n\nTypes of adverse drug events\nTypes of detected ADEs, along with most frequently involved drugs, are summarized in Table 4. The most of ADE related-ED visits were attributed to mild and moderate or severe allergic reactions (64%), certainly preventable in 1.9% (7/368) of the cases and mainly associated with antibiotics and anti-inflammatory/antirheumatic drug administration. Mild to severe neurological effects accounted for 59 ADEs, mainly due to antiepileptics, psycholeptics, and analgesics prescriptions, and 37.3% (22/59) were preventable. Gastrointestinal disturbances occurred in 27 cases, essentially related to anti-inflammatory/antirheumatic drugs, RAS-acting agents and antibiotics and 33.3% (9/27) were preventable.Table 4 Adverse drug events (ADEs) as cause of Emergency Department (ED) visits\n\nADEs a\tNo. of Cases (%)\tNo. of preventable Cases (%)\tMost frequent drug classes\n(No. of Cases)b\t\nMild allergic reactionc\t214 (37.2)\t1 (1.4)\tAntibiotics (116), anti-inflammatory/antirheumatic drugs (55)\t\nModerate to severe allergic reactiond\t154 (26.8)\t6 (8.5)\tAntibiotics (64), anti-inflammatory/antirheumatic drugs (52)\t\nModerate to severe neurological effecte\t30 (5.2)\t12 (16.9)\tPsycholeptics (12), antiepileptics (7)\t\nMild neurological effectf\t29 (5.0)\t10 (14.1)\tPsycholeptics (8), analgesics (6)\t\nGastrointestinal disturbanceg\t27 (4.7)\t9 (12.7)\tAnti-inflammatory/antirheumatic drugs (10), hRAS-acting agents (3), antibiotics (3), antineoplastic agents (3)\t\nHaemorrhage\t21 (3.7)\t4 (5.6)\t\t\n - Major haemorrhage (i.e. gastrointestinal or pulmonary haemorrhage)\t4 (0.7)\t1 (1.4)\tAntithrombotics (2), RAS-acting agents (1), antianemic preparations (1), beta-blocking agents (1), lipid modifying agents (1), anti-gout preparations (1)\t\n - Minor bleeding (e.g. epistaxis, gingival or conjunctival haemorrhage)\t17 (3.0)\t3 (4.2)\tAntithrombotics (15), lipid modifying agents (1), anti-inflammatory/antirheumatic drugs (1)\t\nRhythm disorder (e.g. bradycardia, tachycardia, palpitations, atrial fibrillation)\t16 (2.9)\t3 (4.2)\tCardiac therapy (8), RAS-acting agents (4)\t\nBlood pressure disorder (i.e. hypotension, hypertension)\t12 (2.1)\t3 (4.2)\tAntibiotics (3), cardiac therapy (3), psycholeptics (2), antihypertensives (2), beta blocking agents (2)\t\nSuicide attempt\t12 (2.1)\t12 (16.9)\tPsycholeptics (7), antiepileptics (3), psychoanaleptics (2)\t\nRespiratory distress (e.g. respiratory depression, dyspnoea, desaturation)\t7 (1.2)\t2 (2.8)\tPsycholeptics (4), antibiotics (2)\t\nHematologic disorder (e.g. anemia, leucopenia, thrombocytopenia)\t7 (1.2)\t–\tAntithrombotics (2), psychoanaleptics (2)\t\nHyperglycemia\t7 (1.2)\t3 (4.2)\tAnti-diabetes agents (3), corticosteroids for systemic use (2)\t\nAcute renal failure\t5 (0.9)\t–\tDiuretics (3), anti-diabetes agents (2)\t\nBehavioural psychiatric disorder (e.g. anxiety, stupor, aggression)\t4 (0.7)\t3 (4.2)\tAnti-inflammatory/antirheumatic drugs (1), analgesics (1), psycholeptics (1), anti-Parkinson (1)\t\nRhabdomyolysis\t4 (0.7)\t–\tAntiepileptics (2), RAS-acting agents (1), lipid modifying agents (1), psychoanaleptics (1)\t\nSubcutaneous abscess\t4 (0.7)\t–\tAntibiotics (4)\t\nPancreatitis\t3 (0.5)\t1 (1.4)\tAntiacid drugs (1), antibiotics (1), anti-inflammatory/antirheumatic drugs (1), calcium channel blockers (1), corticosteroids for systemic use (1), immunosuppressants (1), drugs for bone diseases (1)\t\nHypoglycaemia\t3 (0.5)\t2 (2.8)\tAnti-diabetes agents (3)\t\nOther effecti\t16 (2.9)\t–\tRAS-acting agents (4), psycholeptics (3), diuretics (2), anti-diabetes agents (2), psychoanaleptics (2)\t\naCases were classified by ED physician-developed primary diagnosis and grouped as published in NEISS-CADES analysis. Primary diagnoses are mutually exclusive. For example, an ED visit in which a patient experienced both erythema, dermatitis, pruritus would be categorized as mild allergic reactions; an ED visit in which a patient experienced both vomiting and abdominal pain would be categorized as gastrointestinal disturbance\n\nbWe have considered only the principal involved drug categories, for each primary diagnosis. In most cases more drug categories were simultaneously involved\n\ncErythema, urticaria, dermatitis, rash, localized or peripheral edema, flushing, pruritus, esanthema\n\ndAnaphylaxis, angioedema, facial edema, pharyngeal edema, laryngeal edema, labial edema, eyelid edema, orbital edema, vasculitis, hyperhidrosis, drug hypersensitivity, allergy-related respiratory compromise (dyspnoea, bronchospasm, throat tightness, tachypnea, hyperventilation)\n\neComa, panic attack, limbs paralysis, cranial traumatism, epilepsy, extrapyramidal disorder, loss of consciousness, headache, syncope, altered mental status\n\nfLethargy, fatigue, drowsiness, asthenia, hypoesthesia, paresthesia, tremor, vertigo\n\ngNausea, vomiting, abdominal pain, epigastric pain, ulcer, erosive gastropathy\n\nhRAS-acting agents, agents acting on the renin-angiotensin system\n\niLactic acidosis (2), limbs phlebitis (2), hypertransaminasemia (2), heart failure (2), dystonia (2), arthralgia (2), jaundice (1), venous sinus thrombosis (1), anemia and peripheral edema (1), conjunctival haemorrhage and epilepsy (1), conjunctival haemorrhage and hypertension (1)\n\n\n\nHospital admission due to ADEs was required in 87 patients and was mainly attributed to allergic reactions (23%). Moderate to severe neurological effects caused 10 hospitalizations. Mild neurological effects, rhythm disorders and haemorrhages accounted for 16.1% of the hospitalizations. Furthermore, 5 cases of acute renal failure, 3 of pancreatitis, and 3 of rhabdomyolysis caused patients’ admissions.\n\nDiscussion\nEDs represent a useful setting and a valuable data source to identify the occurrence of ADEs, because of easy access, 24-h availability, and the multidisciplinary nature of consultations [35, 36]. However, a significant heterogeneity among observational studies evaluating ADEs in EDs in terms of observed results and specifically in causality and preventability assessment was shown. The analysis carried out on the basis of real-world data could be essential to further provide additional information on the clinical impact of ED drug-related visits. We think that a focus on severe and preventable ADEs is interesting, in particular because drug classes that will need special monitoring result highlighted from our study. The evaluation of drug classes mainly involved in ADEs is also interesting because of the different results emerging from international and Italian studies. Even though several studies were made in different European countries, few data are available in Italy and especially in a South of Italy setting. In accordance with previous studies [5, 10–12] an overall prevalence rate of 3.3% of ADE-related ED visits was recorded. Our results are in accordance to those stated in a prospective observational study conducted in 22 Italian EDs (PSADE [ADE in Pronto Soccorso] study), reporting a 3.3% rate of patients affected by ADE [10]. The ADE-related hospitalization rate in our study was 15.1%. This result is in agreement with two different ED studies in Italy [5, 8]. Conversely, it differs from several international studies [9, 12, 37] in which higher hospitalization rates were observed, such as the NEISS-CADES study that reported 27.3% of hospitalizations caused by ADEs [9]. The inclusion of ED observation status or transfers to another facility for acute medical care might partially explain this difference.\n\nIt is very difficult to establish a clear cause-effect relationship between drug and adverse event, so clinical evaluations are necessary. We used a standardized causality assessment method, the Naranjo algorithm, to define the probability category for each ADE case. In our study, the frequency of probable ADEs was 45.9%. Various studies reported a wide range of probable ADE frequency: an Australian prospective study found 70.1% of probable ADEs and 24.1% possible, while another study identified 30.8% of probable events and 7.5% possible [15, 38]. This could be justified by differences in the assessment of causality criteria by subjective clinical judgments, usually based on limited clinical data.\n\nIn our investigation, ADEs identified in ED visits affected women more frequently, in accordance with the PSADE study [10]. Hormonal status, body constitution (body size, body fat), gender differences in drug metabolism and elimination, may influence the probability of experiencing ADEs. Moreover, women are more likely to use several classes of medications and this could explain the different chance of having ADEs between genders [39]. However, gender did not influence the risk to experience a serious, in accordance with a previous study [4]. On the contrary, in the PSADE study, male gender resulted associated with the occurrence of serious ADEs [10].\n\nIn our study, the higher rates of serious ADEs were observed in ≥65 years group (46.8%) and in patients treated with more than one drug (66.5%). Polytherapy influenced the risk to experience a serious, as well as a certainly preventable ADE, while age ≥ 65 resulted an independent predictor only of serious events, in accordance with previous studies [4, 8, 10]. It is acknowledged that older age is strongly associated with polytherapy, primarily because of comorbidities (e.g. cardiovascular or renal diseases, hypertension, diabetes) [40], both of which lead a high risk of serious ADEs [41–43]. Moreover, polytherapy could cause a higher risk to develop inappropriateness conditions, classified as certainly preventable events.\n\nThe appropriate use of drugs and population characteristics play a key role in the development of ADEs. However, many patients are inappropriately treated [44–53] and available evidence indicates that approximately 50% of ADEs are preventable [54, 55]. In our study, we found a high rate of avoidable ADEs. Overall, about 70% of ADEs were probably (58.4%) or certainly (12.3%) preventable. This finding is in agreement with previous studies [8, 28]. Two prospective, observational studies in EDs identified 70.4 and 68% preventable ADEs [12, 56]. Moreover, data from either retrospective and prospective studies indicate 70% of ED visits as preventable [57]. Similar to other studies [4, 12, 27], our investigation focused on certainly preventable ADEs derived from inappropriate drug use (misuse), abuse, overdose, medication errors. Drug-drug interactions and off-label use were reported among possibly preventable ADEs. A focus on severe and preventable ADEs is interesting because drug classes that will need special monitoring result highlighted from our study. In details, drugs that require constant monitoring due to the risk of acute toxicity (e.g. coumarin anticoagulants, digital glycosides, lithium salts) and central nervous system drugs (i.e. benzodiazepines, psycholeptics, antiepileptics, and psychoanaleptics) have been implicated in abuses, misuses, overdoses. Therefore, additional prevention strategies are needed to improve adherence to medication and the safety of drug prescribing. As previously reported, prevention of ADEs by identifying individuals at high risk is central to improve patient care and outcomes. In particular, additional monitoring and attention towards patients who are at high risk could reduce the impact of ADEs both in terms of cost and quality of care [58, 59].\n\nAntibiotics and anti-inflammatory/antirheumatic drugs, responsible for 57% of overall reports, were the therapeutic subgroups mainly involved in suspected ADEs in our study. This result partially disagrees with the NEISS-CADES study, where anticoagulants, antibiotics, diabetes agents, opioid analgesics, and antipsychotics were the most frequent drug classes related to ADE visits [9]. A review of retrospective and prospective observational studies reported that non-steroidal anti-inflammatory drugs, anticonvulsants, antidiabetic agents, antibiotics, respiratory drugs, hormones, central nervous system and cardiovascular drugs were most often implicated in ED visits [57]. However, several Italian studies [7, 10] confirm antibiotics and anti-inflammatory drugs as the therapeutic classes mainly involved in ADEs. These results might be partially explained by the wide use of anti-inflammatory drugs, most of them are available without medical prescription and then without accurate monitoring. Furthermore, in Italy, antibiotics are more widely prescribed among outpatients, often inappropriately, compared to Northern European countries [10, 60]. In accordance with another study, diuretics, cardiac drugs and RAS-acting agents were associated with higher rates of serious ADEs [10]. In fact, these drug groups require careful and constant monitoring for safe use. The most commonly involved drugs were amoxicillin/clavulanic acid, ketoprofen, ceftriaxone, amoxicillin and acetylsalicylic acid. These findings were similar to several studies conducted in outpatient settings [6, 8, 11]. Furthermore, in our study, warfarin was mainly related to certainly preventable ADEs, while digoxin, furosemide, and ramipril to serious events, because of their high toxicity, which requires close monitoring. ADEs frequently recorded in ED visits were mild and moderate to severe allergic reactions (37.2 and 26.8%, respectively), in line with previous data [2, 7, 8, 10]. These results might be partially explained because allergic reactions tend to be frequently recognized and reported by health professionals and, therefore, easily attributable to the previous drug administration. Furthermore, moderate to severe and mild neurological effects involved 5.2 and 5% of ED visits respectively, followed by gastrointestinal disturbances (4.7%). These data are in accordance with the NEISS-CADES study, where dermatologic, gastrointestinal and neurological events were the most frequent reported ADEs [11]. Allergic reactions and gastrointestinal disorders were mostly related to antibiotics and anti-inflammatory drugs, while neurological effects were related to psycholeptics, antiepileptics, and analgesics. Moreover, preventability assessment applied to primary diagnosis showed that 37.3% of neurological effects and 33.3% of gastrointestinal disturbances were certainly preventable. Few previous studies evaluated ADEs’ preventability in the context of ED [4, 28], but they only analysed the associated pharmacological categories, and not affected systems or associated diagnosis.\n\nIn the FORWARD study, antithrombotics, RAS-agents, NSAIDS, and diuretics were most frequently associated with hospitalizations [27]. Otherwise, in our study, hospitalizations were mainly due to moderate to severe allergic reactions and neurological effects, and the most associated therapeutic classes were antibiotics and psycholeptics and antiepileptics, respectively. Moreover, about 63% of ADEs attributed to psycholeptics and 54.5% related to antiepileptics were certainly preventable. The reduction of preventable ADE-related hospital admissions should be the target of intervention programmes aimed to improve prescriptive appropriateness in general practice. Careful monitoring of commonly used drugs, such as antibiotics, anti-inflammatories and nervous system drugs, could improve patient safety.\n\nThis study adds important information to the general knowledge about the impact of ADEs in ED visits. Thanks to ED physician-monitor collaboration, the identification of ADE cases at the time of the access to the ED or through patient record reviews was accurate. This study also has the advantage of ADE preventability assessment; indeed, about 12.3% of the cases resulted “certainly” preventable. However, preventability assessment using the modified Schumock and Thornton criteria has several potential limitations that need to be considered, especially related to missing anamnestic information in patient records. This could underestimate ADE identification and influence the causality assessment procedure. A recent study compared different methods for determining preventability ADEs in EDs claiming that a “best practice-based” preventability assessment was to be preferred by clinicians over an “algorithm-based” approach like the modified Schumock and Thornton criteria. The “best practice-based” approach required in any case a high level of clinical experience and expertise to assess an overall preventability ADEs [61]. Nevertheless, pharmacists or physicians were involved in our study, as monitors in EDs, to help ED physicians in obtaining medication histories, monitoring polypharmacy, and collecting additional information for causality and preventability assessment and to develop this critical component of patients’ interview.\n\nFurthermore, the number of analysed predictors of severity and preventability of ADEs is limited and more variables could influence the occurrence of events. Drug consumption in the general population also influences ADE occurrence; for example, the wide use of anti-inflammatory drugs in self-medication and the frequent overuse of antibiotics in Italy, could have influenced the higher rate of ADEs related to these drug categories.\n\nConclusion\nThe results from this study highlight the need to promote appropriate education strategies, aimed to improve awareness of pharmacovigilance. The first approach involves focusing on the analysis of the process of care, while the second method is through identification of patients who are ‘at-risk’, as elderly subjects, patients in polytherapy, and with comorbidities. Polytherapy is associated with the occurrence of serious, as well as certainly preventable ADEs, whilst older age only with serious events, providing a strong rationale to improve safety and to obtain greater sensitivity to drug monitoring programs among health professionals. The analysis carried out on the basis of real-world data could be essential to further develop interventions designed to measurably reduce preventable harm from medications. Most preventable ADEs involved two classes of drugs, psycholeptics and antiepileptics, widely used and sometimes inappropriately used. The heavy burden of preventable ADEs may translate into potentially significant cost savings if these education strategies can be implemented further.\n\nAbbreviations\nADEAdverse drug event\n\nADRAdverse drug reaction\n\nATCAnatomical therapeutic chemical\n\nCIConfidence interval\n\nEDEmergency department\n\nIQRInterquartile range\n\nMedDRAMedical dictionary for regulatory activities\n\nRASRenin-angiotensin system\n\nSPCSummary of product characteristics\n\nWe would like to thank all pharmacovigilance personnel of hospital structures involved into the project and all monitors participating to collect data for this study: Francesca Lo Monaco, Eugenia Aldisio, Gabriella Di Fresco, Mariolina Arnone, Maria Teresa Russo, Letizia Murabito, Francesca Di Prima, Alessio Comis, Anna Schillaci, Angela Mazzola, Dario Coppolino, Grazia Arcadipane, Manlio De Simone.\n\nEthical approval and consent to participate\nThe regional pharmacovigilance project “Adverse drug reactions (ADRs) as cause of Emergency Department visits” was approved by the Ethics Committee of Messina University Hospital (Coordinator Centre). For this type of study patient’s consent to participate is not requested. In accordance with specific activities of the emergency department, generally of urgent nature, the collection of informed consent is not compatible with the possibility of guaranteeing the conduct of normal clinical practice.\n\nFunding\nThis study was conducted as part of the regional pharmacovigilance project “Adverse drug reactions (ADRs) as cause of Emergency Department visits”, funded by Regional Healthcare Department of Sicily Region (Italy). The funder of the study had no role in the collection, analysis and interpretation of data, nor in the writing of the report, nor in the decision to submit the article for publication.\n\nAvailability of data and materials\nThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nILG, EM, ES, VA, PMC made substantial contributions to conception and design of the study. ILG, GC1, MGF, ADG made substantial contributions to acquisition of data. EM, ES, VA, PMC made substantial contributions to analysis and interpretation of data. EM, CG, MAB, GC2, ES, VA, PMC were involved in drafting the manuscript. All authors gave final approval of the version to be published. All authors revised and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Rodríguez-Monguió R Otero MJ Rovira J Assessing the economic impact of adverse drug effects Pharmacoeconomics. 2003 21 623 650 12807365 \n2. Budnitz DS Pollock DA Mendelsohn AB Weidenbach KN McDonald AK Annest JL Emergency department visits for outpatient adverse drug events: demonstration for a national surveillance system Ann Emerg Med 2005 45 197 206 15671977 \n3. Howard RL Avery AJ Howard PD Partridge M Investigation into the reasons for preventable drug related admissions to a medical admissions unit: observational study Qual Saf Heal Care 2003 12 280 285 \n4. 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Tangiisuran B Wright J Van der Cammen T Rajkumar C Adverse drug reactions in elderly: challenges in identification and improving preventative strategies Age Ageing 2009 38 358 359 19420141 \n60. Mazzaglia G Caputi AP Rossi A Bettoncelli G Stefanini G Ventriglia G Exploring patient- and doctor-related variables associated with antibiotic prescribing for respiratory infections in primary care Eur J Clin Pharmacol 2003 59 651 657 13680039 \n61. Woo SA Cragg A Wickham ME Peddie D Balka E Scheuermeyer F Methods for evaluating adverse drug event preventability in emergency department patients BMC Med Res Methodol 2018 18 160 30514232\n\n",
"fulltext_license": "CC BY",
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"issue": "20(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Adverse drug event; Causality; Emergency department; Preventability; Seriousness",
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D004636:Emergency Service, Hospital; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D019338:Polypharmacy; D011446:Prospective Studies; D012802:Sicily; D055815:Young Adult",
"nlm_unique_id": "101590449",
"other_id": null,
"pages": "21",
"pmc": null,
"pmid": "31029178",
"pubdate": "2019-04-27",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
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"title": "Characterization and preventability of adverse drug events as cause of emergency department visits: a prospective 1-year observational study.",
"title_normalized": "characterization and preventability of adverse drug events as cause of emergency department visits a prospective 1 year observational study"
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"abstract": "OBJECTIVE\nTo report the occurrence of fatal acute liver failure following addition of levothyroxine to a regimen of sunitinib and acetaminophen.\n\n\nMETHODS\nA 57-year-old woman who started sunitinib treatment for relapsed metastatic gastrointestinal stromal tumor after imatinib failure had disease stabilization and normal liver function through 8 cycles of sunitinib 50 mg/day for 4 weeks, followed by 2 weeks off treatment. Her continuing medications included acetaminophen approximately 4.5 g/wk, as well as standard medications for asthma. In cycle 8, she received oral levothyroxine 50-150 microg/day for approximately 30 days to control hypothyroidism before beginning cycle 9 of sunitinib. On day 4 of cycle 9, she was hospitalized with progressively rising circulating liver enzyme levels. She died 4 days postadmission despite discontinuation of sunitinib and initiation of intensive supportive treatment. At autopsy, her liver showed severe centrilobular necrosis with moderate-to-severe steatosis and minimal parenchymal invasion by the neoplasm. Viral stains were negative.\n\n\nCONCLUSIONS\nHepatic failure has been reported rarely in patients receiving sunitinib. Autopsy results excluded neoplastic disease progression and viral infection in the etiology of the event, and the patient may have died of the combined interaction of sunitinib, acetaminophen, and levothyroxine. Although sunitinib was not more than a possible hepatotoxin (Roussel Uclaf Causality Assessment Method) and may even have been hepatoprotective over a 48-week period against chronic intake of acetaminophen (probable hepatotoxin) by producing regional hypothyroidism within the liver, it is hypothesized that correction of the putative hepatic hypothyroidism with oral levothyroxine (possible hepatotoxin) and reinitiation of sunitinib treatment may have triggered hepatic necrosis.\n\n\nCONCLUSIONS\nAcetaminophen should be used with particular caution in patients receiving sunitinib. In sunitinib-treated patients who also require levothyroxine therapy, increased caution in restarting subsequent sunitinib treatment and discontinuation of acetaminophen, if possible, is advisable. Further evaluation of this potential interaction is warranted.",
"affiliations": "Department of Hematology/Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI 48201, USA. weise@kar-manos.org",
"authors": "Weise|Amy M|AM|;Liu|Chin Y|CY|;Shields|Anthony F|AF|",
"chemical_list": "D007211:Indoles; D011758:Pyrroles; D000082:Acetaminophen; D013974:Thyroxine; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1L528",
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"issn_linking": "1060-0280",
"issue": "43(4)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000082:Acetaminophen; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007211:Indoles; D017093:Liver Failure; D008875:Middle Aged; D011758:Pyrroles; D000077210:Sunitinib; D013974:Thyroxine",
"nlm_unique_id": "9203131",
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"pages": "761-6",
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"pubdate": "2009-04",
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"title": "Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine.",
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"abstract": "We evaluated the safety and efficacy of plerixafor, subsequent to disease-specific chemotherapy followed by granulocyte-colony stimulating factor (G-CSF), in 37 multiple myeloma (MM) or lymphoma patients, who were candidates for autologous stem cell transplantation (ASCT) predicted as poor mobilizers (PMs). Patients were identified as predicted PMs according to the history of a previously failed mobilization attempt or the presence of ≥1 factors predicting an unsuccessful harvest, such as advanced disease, prior extensive radiotherapy, or prolonged treatment, with stem cell poisons, advanced age, or extensive bone marrow involvement. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to 3 consecutive days while continuing G-CSF for 9 to 11 hours before the planned apheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a median 4-fold increase (range: 1.4-32) in the number of circulating CD34(+) cells following plerixafor compared with baseline CD34(+) cell concentration (from a median of 5 cells/μL, range: 1-32, to a median of 32 cells/μL, range: 6-201). Twenty-seven of the 37 patients (14 of 17 with MM and 13 of 20 with lymphoma) had ≥2×10(6) CD34(+) cells/kg collected in 1-3 apheretic procedures. Of the 27 patients rescued with plerixafor, 24 (13 MM, 11 lymphoma) have been transplanted with plerixafor-mobilized peripheral blood stem cells, showing a rapid and durable hematologic recovery. Our results suggest that the addition of plerixafor to G-CSF after disease-oriented chemotherapy is safe and allows for a satisfactory harvest in order to perform a safe ASCT, in a relevant proportion of lymphoma and MM patients considered to be PMs.",
"affiliations": "Divisione di Ematologia, Ospedale San Carlo, Via Potito Petrone 1, Potenza, Italy. imma.attolico@tin.it",
"authors": "Attolico|Immacolata|I|;Pavone|Vincenzo|V|;Ostuni|Angelo|A|;Rossini|Bernardo|B|;Musso|Maurizio|M|;Crescimanno|Alessandra|A|;Martino|Massimo|M|;Iacopino|Pasquale|P|;Milone|Giuseppe|G|;Tedeschi|Patrizia|P|;Coluzzi|Sabrina|S|;Nuccorini|Roberta|R|;Pascale|Sara|S|;Di Nardo|Elvira|E|;Olivieri|Attilio|A|",
"chemical_list": "D019380:Anti-HIV Agents; D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor",
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"title": "Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma.",
"title_normalized": "plerixafor added to chemotherapy plus g csf is safe and allows adequate pbsc collection in predicted poor mobilizer patients with multiple myeloma or lymphoma"
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"abstract": "Leishmaniasis is a protozoan disease caused by parasites of the genus Leishmania, transmitted to humans by sandflies. The diagnosis of leishmaniasis is often challenging as it mimics many other infectious or malignant diseases. The disease can present in three ways: cutaneous, mucocutaneous, or visceral leishmaniasis, which rarely occur together or consecutively.\n\n\n\nThe patient was a 52 years old immunosuppressed Belgian woman with a long history of severe rheumatoid arthritis. She underwent bone marrow biopsy to explore thrombocytopenia. Diagnosis of visceral leishmaniasis was made by identification of Leishman Donovan (LD) bodies in macrophages. Treatment with liposomal amphotericin B was successful. She later developed cutaneous leishmaniasis treated with amphotericin B lipid complex. She next presented with relapsing cutaneous lesions followed by rapidly progressing lymphadenopathies. Biopsy confirmed the diagnosis of leishmaniasis. Treatments by miltefosine, amphotericin B, N-methyl-glucamine antimoniate were subsequently initiated. She later presented a recurrent bone marrow involvement treated with intramuscular paromomycin and miltefosine. She died two years later from leukemia. At the time of death, she presented with a mucosal destruction of the nose. A Leishmania-specific PCR (Polymerase Chain Reaction) identified L. infantum as etiological agent.\n\n\n\nClinicians should be aware of the potential concomitant or sequential involvement of multiple anatomic localizations of Leishmania in immunosuppressed patients.",
"affiliations": "Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium. gdarcis@chu.ulg.ac.be.;Institute of Tropical Medicine, Antwerp, Belgium.;Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.;Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.;Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.;Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.;Institute of Tropical Medicine, Antwerp, Belgium.;Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.;Service of clinical Pathology, Lausanne University Hospital, Lausanne, Switzerland.;Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.",
"authors": "Darcis|Gilles|G|;Van der Auwera|Gert|G|;Giot|Jean-Baptiste|JB|;Hayette|Marie-Pierre|MP|;Tassin|Françoise|F|;Arrese Estrada|Jorge|J|;Cnops|Lieselotte|L|;Moutschen|Michel|M|;de Leval|Laurence|L|;Leonard|Philippe|P|",
"chemical_list": "D000981:Antiprotozoal Agents; C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D010303:Paromomycin; D000666:Amphotericin B",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 257110.1186/s12879-017-2571-xCase ReportRecurrence of visceral and muco-cutaneous leishmaniasis in a patient under immunosuppressive therapy Darcis Gilles gdarcis@chu.ulg.ac.be 1Van der Auwera Gert GVdAuwera@itg.be 2Giot Jean-Baptiste jbgiot@chu.ulg.ac.be 1Hayette Marie-Pierre mphayette@chu.ulg.ac.be 1Tassin Françoise francoise.tassin@chu.ulg.ac.be 1Arrese Estrada Jorge j.arrese@ulg.ac.be 1Cnops Lieselotte lcnops@itg.be 2Moutschen Michel michel.moutschen@ulg.ac.be 1de Leval Laurence Laurence.DeLeval@chuv.ch 3Leonard Philippe philippe.leonard@chu.ulg.ac.be 11 0000 0000 8607 6858grid.411374.4Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium 2 0000 0001 2153 5088grid.11505.30Institute of Tropical Medicine, Antwerp, Belgium 3 0000 0001 0423 4662grid.8515.9Service of clinical Pathology, Lausanne University Hospital, Lausanne, Switzerland 7 7 2017 7 7 2017 2017 17 4786 3 2017 27 6 2017 © The Author(s). 2017\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\nLeishmaniasis is a protozoan disease caused by parasites of the genus Leishmania, transmitted to humans by sandflies. The diagnosis of leishmaniasis is often challenging as it mimics many other infectious or malignant diseases. The disease can present in three ways: cutaneous, mucocutaneous, or visceral leishmaniasis, which rarely occur together or consecutively.\n\nCase presentation\nThe patient was a 52 years old immunosuppressed Belgian woman with a long history of severe rheumatoid arthritis. She underwent bone marrow biopsy to explore thrombocytopenia. Diagnosis of visceral leishmaniasis was made by identification of Leishman Donovan (LD) bodies in macrophages. Treatment with liposomal amphotericin B was successful. She later developed cutaneous leishmaniasis treated with amphotericin B lipid complex. She next presented with relapsing cutaneous lesions followed by rapidly progressing lymphadenopathies. Biopsy confirmed the diagnosis of leishmaniasis. Treatments by miltefosine, amphotericin B, N-methyl-glucamine antimoniate were subsequently initiated. She later presented a recurrent bone marrow involvement treated with intramuscular paromomycin and miltefosine. She died two years later from leukemia. At the time of death, she presented with a mucosal destruction of the nose. A Leishmania-specific PCR (Polymerase Chain Reaction) identified L. infantum as etiological agent.\n\nConclusions\nClinicians should be aware of the potential concomitant or sequential involvement of multiple anatomic localizations of Leishmania in immunosuppressed patients.\n\nKeywords\nCutaneous leishmaniasisMucosal leishmaniasisVisceral leishmaniasisImmunosuppressionParasitologyMicrobiologyhttp://dx.doi.org/10.13039/501100002661Fonds De La Recherche Scientifique - FNRSissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nLeishmaniasis is a protozoan disease caused by more than 20 species of the genus Leishmania and transmitted to humans by the bite of sandflies. The diagnosis of leishmaniasis is often challenging as it mimics many other infectious or malignant diseases.\n\nThree patterns of infection are described: cutaneous (CL), mucosal (ML) and visceral leishmaniasis (VL). CL usually presents as papules, plaques, ulcers or nodules and occurs mostly on exposed areas of the skin. ML is characterized by destructive lesions mainly affecting the nose and the mouth. VL, also known as kala-azar or black fever, is a potentially fatal disease. Symptoms include fever, weight loss, hepato- and splenomegaly. Anemia and thrombocytopenia occur when parasites accumulate in the bone marrow. VL widely predominates in poor rural and suburban areas of India, Bangladesh, Sudan, Ethiopia and Brazil while CL is more broadly distributed and occurs in the south and central American countries, the Mediterranean basin, and from the Middle East to Central Asia [1]. ML is mostly observed in Latin America.\n\n\nL. infantum is well recognized as the etiological agent of VL in southern Europe and is much less commonly reported as a cause of CL [2]. Mucosal forms of L. infantum infection are very rare [3–5]. Concomitant or consecutive cutaneous or mucosal with visceral clinical manifestations of leishmaniasis have been seldom described. Herein we report the first case of an immunosuppressed woman who presented the entire spectrum of the disease and we discuss its clinical significance.\n\nCase presentation\nThe patient was a Belgian woman born in 1956 with a long history of severe rheumatoid arthritis (RA) complicated by vasculitis and cryoglobulinemia, and treated with etanercept, ciclosporin and methylprednisolone. She had only travelled to Spain in 2004.\n\nIn 2006 she developed mild anemia, thrombocytopenia and splenomegaly which were interpreted as manifestations of Felty syndrome. Screening for infectious diseases including HIV was negative. In March 2007 she was diagnosed with stage IIB EBV-negative classical Hodgkin lymphoma, based on an inguinal lymph node biopsy. The patient was treated with four cycles of C-MOPP (cyclophosphamide, vincristine, procarbazine and prednisone) plus radiation therapy targeting the left inguinal region. While undergoing chemotherapy she had persistent neutropenia (neutrophils: 1390/mm3, norm: 2100–8000/mm3) thrombocytopenia (thrombocytes: 43,000/mm3, norm: 170,000–400,000/mm3) and increasing splenomegaly. The markedly enlarged spleen (850 g) was surgically removed and showed marked histiocytic infiltrate of the red pulp, hemophagocytosis, and reactive polytypic plasma cells. Since thrombocytopenia was still increasing, she underwent bone marrow biopsy and aspirate in 2008. Diagnosis of VL was made by identification of Leishman Donovan (LD) bodies in macrophages after Giemsa staining (Fig. 1a). Serum antibody tests (indirect immunofluorescence) were positive for L. braziliensis, L. infantum and L. tropica due to cross reactions between species. In retrospect, Leishmania was also detected in the splenic sections (Fig. 1b).Fig. 1 Visceral and cutaneous leishmaniasis. a. Bone marrow aspirate: May Grunwald Giemsa (original magnification: ×1000) showing two macrophages with abundant cytoplasm containing innumerable Leishmania amastigotes. b. Spleen histology: High power view of the splenic red pulp comprising a prominent infiltrate of histiocytes and plasma cells; the histiocytes show numerous cytoplasmic punctate bodies surrounded by a clear halo, suggestive of Leishman bodies (hematoxylin eosin staining; original magnification: ×400). c. Cutaneous histology: Diffuse infiltrate in the upper dermis consisting of predominantly large histiocytes, plasma cells and a few lymphocytes. Protozoan leishmania, visualized as multiple gray-blue bodies within the vacuolated cytoplasm of histiocytes (hematoxylin eosin staining)\n\n\n\n\nTreatment with liposomal amphotericin B (4 mg/kg for 10 days) was successful. Due to immunosuppression, secondary prophylaxis with monthly amphotericin B was given as proposed for patients with HIV coinfection [6], but stopped after only 2 doses because of medical costs issues.\n\nIn 2009, etanercept treatment was replaced by rituximab twice a year. She developed multiple cutaneous nodular lesions mainly located in the left elbow and the buttocks. Histopathology was performed. LD bodies were evident within macrophages (Fig. 1c). Amphotericin B lipid complex treatment (5 mg/kg for 10 days) allowed for complete healing of the lesions. Secondary prophylaxis with monthly amphotericin B was again given. In 2010, despite secondary prophylaxis, she presented with relapsing cutaneous lesions followed by rapidly progressing lymphadenopathies (cervical, subclavicular, sub- and sus-diaphragmatic) on PET/CT. Lymph node biopsy showed massive macrophagic infiltrate comprising LD bodies. Rituximab was stopped. Treatment by miltefosine (50 mg bd) was instituted but then stopped because of digestive intolerance. Amphotericin B was reintroduced but failed, probably because of resistance. N-methyl-glucamine antimoniate (20 mg/kg), more recently used with success by other groups when multiple failures or relapses occur after treatment with liposomal amphotericin B [7], was subsequently initiated and then stopped after the patient experienced torsade de pointes. Cutaneous lesions disappeared and PET/CT showed an almost full metabolic response with disappearance of adenopathy. However, she later presented thrombocytopenia due to recurrent bone marrow involvement which was successfully treated with intramuscular paromomycin (15 mg/kg) and miltefosine (50 mg bd) for 28 days.\n\nIn 2012, she presented few relapsing cutaneous lesions requiring topical treatment. Two years later she was diagnosed with chronic myelomonocytic leukemia and died in 2015 from blastic crisis. At the time of death, she presented with a mucosal destruction of the nose clearly visible on a CT scan performed a few days before she died (Fig. 2). Autopsy was performed to confirm the mucosal involvement by Leishmania. A real-time Leishmania-specific PCR [8] performed on the nasal biopsy was positive (cycle threshold value 23,87) and molecular HSP70-typing identified L. infantum as etiological agent [9].Fig. 2 Mucosal leishmaniasis. CT scan showing left maxillary sinusitis and centimetric perforation of the nasal septal cartilage\n\n\n\n\nDiscussion and conclusion\n\nL. infantum is the etiological agent of VL in Europe where it is endemic in the Mediterranean region. Dogs are considered the major reservoir and sandflies are the only proven vectors of this zoonotic protozoan disease [10]. The incidence of VL associated with the transmission of L. infantum has been declining in many foci where living standards have improved. Immunosuppression confers a higher risk of clinical disease due to L. infantum. While visceral and cutaneous manifestations of L. infantum are quite common, mucosal presentation is rare and has been only sporadically described. Association of cutaneous and visceral involvement has been reported in patients co-infected with HIV [11]. Simultaneous mucosal and visceral manifestations have been described in corticosteroid-treated patients [12]. Interestingly, Souza et al. very recently reported patients from an endemic area of leishmaniasis, treated for RA, who presented with recurrent CL or ML [13]. However, we believe that this case report is the first example of L. infantum infection with recurrent visceral, cutaneous and finally mucosal involvement. The development of all these clinical manifestations has been facilitated by immunosuppressive therapy required to control a severe RA.\n\nThis case also demonstrates that the diagnosis of leishmaniasis is often challenging as it mimics many other infectious or malignant diseases. The scarcity of leishamniasis in non-endemic settings like Belgium makes the diagnosis even more difficult and contributed to the delay before diagnosis. Thrombocytopenia was first thought related to hypersplenism. Following splenectomy, persistent thrombocytopenia could be caused by numerous conditions and manifestations of VL are often misinterpreted as symptoms of malignancies, other infectious or autoimmune diseases such as systemic lupus erythematosus [14]. Discussion of cutaneous lesions is also challenging since CL mimics other infectious conditions including mycobacteriosis or inflammatory diseases such as nummular dermatitis or psoriasis. Moreover, cutaneous lesions could have been considered as post-kala-azar dermal leishmaniasis. However, the recurrence of cutaneous lesions together with VL relapse as well as the localized nature of the cutaneous lesions rather suggests CL. Diagnosis of mucosal lesions located in the nose is complex since lesions often mimic neoplastic processes or necrotizing vasculitis [15].\n\nIn conclusion, this exceptional case highlights that clinicians should be aware of the potential concomitant or sequential involvement of multiple anatomic localizations of leishmaniasis in immunosuppressed patients. This observation is particularly relevant given the risk of emergence of leishmaniasis in Europe consequent to the increasing worldwide travelling of humans and domestic dogs, increasing flow of migrants from the Middle East to Europe and climatic changes [16]. Indeed, the occurrence of sandflies in Central Europe and in adjacent regions of Western-Europe is established and sandflies have been found in several parts of Germany and Belgium [17]. Thus local acquisition of leishmaniasis in Belgium is not totally excluded.\n\nAbbreviations\nCLCutaneous leishmaniasis\n\nC-MOPPCyclophosphamide, vincristine, procarbazine and prednisone\n\nLD bodiesLeishman Donovan bodies\n\nMLMucosal Leishmaniasis\n\nPCRPolymerase Chain Reaction\n\nVLVisceral leishmaniasis\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors declare no competing financial interests. This work was supported by the Belgian Fund for Scientific Research (FRS-FNRS, Belgium).\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nGD, JBG, MM and PL managed the patient. GVDA, MPH and LC performed and analyzed antibody testing and PCR. FT, LDL and JAE performed anatomo-pathological examination. All authors have been involved in drafting the manuscript as well as revising it critically for important intellectual content. All authors participated to literature search. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot Applicable.\n\nConsent for publication\nConsent to publish was obtained from a next-of-kin after the patient’s death.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Alvar J Velez ID Bern C Herrero M Desjeux P Cano J Leishmaniasis worldwide and global estimates of its incidence PLoS One 2012 7 e35671 10.1371/journal.pone.0035671 22693548 \n2. del Giudice P Marty P Lacour JP Perrin C Pratlong F Haas H Cutaneous leishmaniasis due to Leishmania infantum. Case reports and literature review Arch Dermatol 1998 134 193 198 10.1001/archderm.134.2.193 9487211 \n3. Ramos A Munez E Garcia-Dominguez J Martinez-Ruiz R Chicharro C Banos I Mucosal leishmaniasis mimicking squamous cell carcinoma in a liver transplant recipient Transpl Infect Dis 2015 17 488 492 10.1111/tid.12380 25816835 \n4. Jeziorski E Dereure J Mac Bullen G Blanchet C Ludwig C Costes V Mucosal relapse of visceral leishmaniasis in a child treated with anti-TNFalpha Int J Infect Dis 2015 33 135 136 10.1016/j.ijid.2014.12.036 25572168 \n5. Pampin Franco A Gamo Villegas R Caro-Gutierrez D Lopez-Estebaranz JL Pinedo F Mucosal leishmaniasis of the tongue caused by Leishmania infantum in an immunocompetent woman Int J Dermatol 2015 54 e39 e41 10.1111/ijd.12567 25312835 \n6. Lopez-Velez R Videla S Marquez M Boix V Jimenez-Mejias ME Gorgolas M Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of visceral leishmaniasis in HIV-infected patients J Antimicrob Chemother 2004 53 540 543 10.1093/jac/dkh084 14739148 \n7. Morizot G Jouffroy R Faye A Chabert P Belhouari K Calin R Antimony to cure visceral Leishmaniasis unresponsive to liposomal Amphotericin B PLoS Negl Trop Dis 2016 10 e0004304 10.1371/journal.pntd.0004304 26735920 \n8. Van Os L Cnops L Van Esbroeck M Dhubhghaill SN De Keizer RJ Asselman V Slowly progressive Keratouveitis in a patient with known systemic Leishmaniasis and HIV Ocul Immunol Inflamm 2015 23 248 251 10.3109/09273948.2013.876548 24432986 \n9. Van der Auwera G Maes I De Doncker S Ravel C Cnops L Van Esbroeck M Heat-shock protein 70 gene sequencing for Leishmania species typing in European tropical infectious disease clinics Euro Surveill 2013 18 20543 10.2807/1560-7917.ES2013.18.30.20543 23929181 \n10. Maia C Cardoso L Spread of Leishmania infantum in Europe with dog travelling Vet Parasitol 2015 213 2 11 10.1016/j.vetpar.2015.05.003 26021526 \n11. Postigo C Llamas R Zarco C Rubio R Pulido F Costa JR Cutaneous lesions in patients with visceral leishmaniasis and HIV infection J Inf Secur 1997 35 265 268 \n12. Pittalis S Nicastri E Spinazzola F Ghirga P De Marco M Paglia MG Leishmania infantum leishmaniasis in corticosteroid--treated patients BMC Infect Dis 2006 6 177 10.1186/1471-2334-6-177 17176478 \n13. Souza RM Andrade HFJ Duarte MI Braz LM Schubach AO Silva FC Reactivation of cutaneous and mucocutaneous tegumentary leishmaniasis in rheumatoid arthritis patients: an emerging problem? Rev Inst Med Trop Sao Paulo 2017 59 e6 28380117 \n14. Santana IU Dias B Nunes EA Rocha FA Silva FS Jr Santiago MB Visceral leishmaniasis mimicking systemic lupus erythematosus: case series and a systematic literature review Semin Arthritis Rheum 2015 44 658 665 10.1016/j.semarthrit.2014.12.004 25704907 \n15. Cobo F Rodriguez-Granger J Gomez-Camarasa C Sampedro A Aliaga-Martinez L Navarro JM Localized mucosal leishmaniasis caused by Leishmania infantum mimicking cancer in the rhinolaryngeal region Int J Infect Dis 2016 50 54 56 10.1016/j.ijid.2016.08.003 27515498 \n16. Ready PD Leishmaniasis emergence in Europe Euro Surveill 2010 15 19505 20403308 \n17. Aspock H Gerersdorfer T Formayer H Walochnik J Sandflies and sandfly-borne infections of humans in Central Europe in the light of climate change Wien Klin Wochenschr 2008 120 24 29 10.1007/s00508-008-1072-8 19066768\n\n",
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"journal": "BMC infectious diseases",
"keywords": "Cutaneous leishmaniasis; Immunosuppression; Microbiology; Mucosal leishmaniasis; Parasitology; Visceral leishmaniasis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000666:Amphotericin B; D000981:Antiprotozoal Agents; D001706:Biopsy; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007891:Leishmania; D016773:Leishmaniasis, Cutaneous; D007898:Leishmaniasis, Visceral; D008264:Macrophages; D008875:Middle Aged; D010303:Paromomycin; D010767:Phosphorylcholine; D016133:Polymerase Chain Reaction; D012008:Recurrence",
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"title": "Recurrence of visceral and muco-cutaneous leishmaniasis in a patient under immunosuppressive therapy.",
"title_normalized": "recurrence of visceral and muco cutaneous leishmaniasis in a patient under immunosuppressive therapy"
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"abstract": "BACKGROUND Vertical diplopia that follows local anesthesia is usually due to inferior rectus muscle fibrosis. Here, we report a rare case of acquired Brown syndrome following local anesthesia. CASE REPORT A 36-year-old woman underwent right inferior orbital fat decompression under local anesthesia. On the first postoperative day, she developed vertical diplopia. She had left hypertropia, which increased on left gaze, with limitation of elevation of the right eye on attempted adduction. Forced duction test of the right eye revealed resistance on elevation in adduction. Magnetic resonance imaging showed signal alteration, thickening, and irregularity involving the right superior oblique tendon and trochlea region. The diagnosis of iatrogenic Brown syndrome was made. Then, a single dose of 10 mg triamcinolone injection was given near the intratrochlear region. On follow-up, complete resolution of diplopia on primary gaze occurred 12 weeks after the incident. CONCLUSIONS The reported case highlights that local anesthesia carries a risk of Brown syndrome. We believe bupivacaine-induced superior oblique hypertrophy is the underlying mechanism. The patient showed excellent outcome after medical management, with no surgical intervention required after 3 months of follow-up.",
"affiliations": "Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.",
"authors": "Alsarhani|Waleed K|WK|;Almater|Abdullah I|AI|;Al-Ghamdi|Ismael S|IS|",
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"doi": "10.12659/AJCR.924678",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n10.12659/AJCR.924678\n924678\nArticles\nBrown Syndrome from Local Anesthesia for Inferior Orbital Fat Decompression\nAlsarhani Waleed K. EF Almater Abdullah I. EF Al-Ghamdi Ismael S. E Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia\nCorresponding Author: Waleed K. Alsarhani, e-mail: WAlsarhani@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n08 7 2020 \n21 e924678-1 e924678-4\n29 3 2020 05 5 2020 29 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 36-year-old\n\nFinal Diagnosis: Acquired Brown syndrome\n\nSymptoms: Diplopia • vertical diplopia\n\nMedication: —\n\nClinical Procedure: Local anesthesia • orbital fat decompression\n\nSpecialty: Ophthalmology\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nVertical diplopia that follows local anesthesia is usually due to inferior rectus muscle fibrosis. Here, we report a rare case of acquired Brown syndrome following local anesthesia.\n\nCase Report:\nA 36-year-old woman underwent right inferior orbital fat decompression under local anesthesia. On the first postoperative day, she developed vertical diplopia. She had left hypertropia, which increased on left gaze, with limitation of elevation of the right eye on attempted adduction. Forced duction test of the right eye revealed resistance on elevation in adduction. Magnetic resonance imaging showed signal alteration, thickening, and irregularity involving the right superior oblique tendon and trochlea region. The diagnosis of iatrogenic Brown syndrome was made. Then, a single dose of 10 mg triamcinolone injection was given near the intratrochlear region. On follow-up, complete resolution of diplopia on primary gaze occurred 12 weeks after the incident.\n\nConclusions:\nThe reported case highlights that local anesthesia carries a risk of Brown syndrome. We believe bupivacaine-induced superior oblique hypertrophy is the underlying mechanism. The patient showed excellent outcome after medical management, with no surgical intervention required after 3 months of follow-up.\n\nMeSH Keywords:\nBrown SyndromeDiplopiaOcular Motility DisordersStrabismus\n==== Body\nBackground\nAcquired Brown syndrome may be inflammatory, traumatic, or iatrogenic. Iatrogenic causes include scleral buckle, or glaucoma valve implants. However, Brown syndrome is not expected after local anesthesia. Vertical diplopia that follows local anesthesia is usually due to inferior rectus muscle fibrosis [1]. Here, we report a rare case of acquired Brown syndrome following local anesthesia.\n\nCase Report\nA 36-year-old woman, otherwise healthy, presented to the oculoplastics clinic with mild unilateral 2-mm proptosis of the right eye. Systemic work-up was negative, including thyroid function test and computerized tomography of the orbit. She underwent right inferior orbital fat decompression afterwards under local anesthesia and masked sedation. Local anesthesia was injected inferiorly and superonasally using a 25-gauge needle with 2% lidocaine, 1: 100 000 epinephrine, 0.5% bupivacaine, and 1500 IU of hyaluronidase. The aim of the superior-nasal injection was to block the infratrochlear nerve responsible for innervating the medial aspect of the lower lid. The inferior oblique muscle was clearly identified and was avoided during fat decompression. About 2.0 mL of inferior orbital fat was removed. Surprisingly, the patient developed vertical diplopia on the first postoperative day. Examination revealed a corrected distance visual acuity of 20/20 in both eyes. On inspection, she was using right head tilt position to relieve her diplopia. On primary gaze, she had left hypertropia of 6 and 12 prism diopters (PD) at near and distance, respectively. The hypertropia increased to 25–30 PD with limited elevation of the right eye on attempted adduction (Figure 1). Moreover, she had a mild degree of 8 PD of exotropia at primary position. In the outpatient clinic, under topical anesthesia, forced duction test of the right eye revealed resistance on elevation in adduction. The rest of the eye examination was unremarkable. She had not had strabismus surgery nor diplopia prior to the surgery.\n\nMagnetic resonance imaging (MRI) of the orbit without contrast showed signal alteration and thickening and irregularity involving the right superior oblique tendon and trochlea region (Figures 2, 3). The diagnosis of acquired Brown syndrome was made based on clinical presentation and MRI finding. Then, in the minor operation room under topical anesthesia, forced duction was repeated several times, and a single dose of 10-mg triamcinolone injection was given near the intratrochlear region. Furthermore, a topical nonsteroidal anti-inflammatory drug and Fresnel prisms were prescribed. Additionally, she was asked to perform elevation exercises at home, which were frequent adduction and elevation of the right eye 3 times per day. On serial follow-up, clinical improvement was noticed 2 weeks after the injection (Figure 4). Complete resolution of head tilt and diplopia on primary gaze occurred 12 weeks after the local anesthesia injection. However, there was residual left hypertropia of 18 PD on left gaze. The patient did not require any further surgical intervention.\n\nDiscussion\nStrabismus following peribulbar anesthesia is typically vertical and is usually a result of vertical rectus muscles dysfunction. In one report, vertical diplopia was seen in 0.64% of phacoemulsification under peribulbar anesthesia [2]. The reported cases were due to inferior rectus restriction caused by peribulbar anesthesia. In this case, we describe an unexpected case of Brown syndrome following local anesthesia. The reported case highlights that local superonasal anesthesia carries a risk of Brown syndrome.\n\nVertical diplopia following local anesthesia may be explained by different mechanisms. First, this could be attributed to the myotoxic effects of anesthesia. Carleson et al. reported that injection of local anesthesia into the extraocular muscles of monkeys caused muscle fibrosis [3]. Second, another reason could be scarring induced by the needle within the superior oblique tendon-trochlea complex. Another mechanism is hematoma from the ciliary artery causing muscle ischemia [4]. However, the latter 2 mechanisms are typically seen with deep local anesthesia, as in retrobulbar anesthesia. Since our patient’s diplopia started on the first postoperative day and then resolved without any surgical intervention, we think scarring of the tendon-trochlea complex is less likely to be the underlying mechanism. We believe the most likely mechanism in our case is muscle hypertrophy. This is supported by the MRI finding, which showed irregular thickening of the superior oblique tendon. A study by Miller et al. showed bupivacaine causes significant increase in extraocular muscle volume. Maximum muscle volume was noted 10 minutes after the injection and then decreased gradually over many months until it reached pre-injection muscle volume [5].\n\nOn review of the literature, we found only 4 cases of acquired superior oblique dysfunction following peribulbar anesthesia. Erie reported a case of acquired Brown syndrome following superonasal peribulbar anesthesia [6]. The anesthesia used was lidocaine 4%, bupivacaine hydrochloride 0.75%, and 1 mL of hyaluronidase. Erie stated the Brown syndrome was a result of scarring within the tendon or trochlea. Phillips et al. reported a case of superior oblique overaction following peribulbar anesthesia [7]. They described a case of Brown syndrome 7 weeks after phacoemulsification surgery under peribulbar anesthesia. The anesthesia agent used was a 50: 50 mixture of 2% lidocaine and 0.75% bupivacaine, with hyaluronidase injected inferotemporally and superonasally. Their patient eventually required superior oblique tenotomy and inferior rectus muscle recession. Hyaluronidase was part of the anesthesia mixture given in our case as well as in the cases reported by Erie and Phillips et al. [6,7]. There is controversy over the role of hyaluronidase in reducing the risk of postoperative diplopia.\n\nHamada et al. showed hyaluronidase reduced the risk of postoperative diplopia [8]. It is hypothesized that hyaluronidase causes diffusion of the anesthesia and reduces the adverse effects on the muscles. However, in a larger study on 17 531 eyes, Johnson reported no significant increase in postoperative diplopia during periods when hyaluronidase was not available [9].\n\nSuperior oblique hypoplasia is seen in congenital Brown syndrome but not in acquired causes [10]. MRI in our case showed asymmetric thickening of the superior oblique tendon. Lang et al. reported a similar MRI finding in 2 cases [11]. In our case, contrast could have shown better characterization of the superior oblique tendon, similar to that reported by Lang et al. [11]. Although spontaneous recovery has been previously reported in the literature [12], less invasive methods may be initially attempted to treat acquired Brown syndrome, such as local steroid injection or anti-inflammatory agents, as in our case [13,14]. Single intramuscular injection of betamethasone was shown to be effective in a case of inflammatory Brown syndrome [15]. Ravilla et al. reported a case series of 5 children with acquired Brown syndrome of idiopathic and presumed inflammatory etiology, which showed significant improvement following intratrochlear injection of 4 mg betamethasone [16]. In a recent study, intratrochlear injection of steroids was beneficial in the treatment of 11 cases of acquired Brown syndrome secondary to trochleitis [17]. However, there have been no reports on the role of local steroid injection in reversing the adverse effects of local anesthesia on extraocular muscles. We are not sure if peritrochlear steroid injection in our case had any impact, or if the resolution of the patient’s diplopia was part of the natural course of the disease. A larger study on the role of local steroid injection in such cases is needed to evaluate whether steroids are capable of accelerating recovery, but performing larger studies may be difficult due to the rarity of this complication.\n\nConclusions\nBrown syndrome is a rare but possible adverse effect of local anesthesia. We believe bupivacaine-induced superior oblique hypertrophy is the underlying mechanism. The patient showed excellent outcome after medical management, with no surgical intervention required after 3 months of follow-up.\n\nFigure 1. Nine-gaze image showing left hypertropia which increases on left gaze. There is limitation of elevation of the right eye on attempted adduction.\n\nFigure 2. MRI T1 showing thickening and irregularity involving the right superior oblique tendon-trochlea complex (arrow).\n\nFigure 3. MRI T2 showing thickening and irregularity involving of right superior oblique tendon-trochlea complex (arrow).\n\nFigure 4. Nine-gaze image showing improvement in vertical deviation in primary gaze 1 month after the incident.\n==== Refs\nReferences:\n1. Capó H Guyton DL Ipsilateral hypertropia after cataract surgery Ophthalmology 1996 103 5 721 30 8637680 \n2. Strouthidis NG Sivaprasad S Lanigan LP Hammond CJ Vertical diplopia following peribulbar anesthesia: The role of hyaluronidase J Pediatr Ophthalmol Strabismus 2004 41 25 30 14974831 \n3. Rainin EA Carlson BM Postoperative diplopia and ptosis: A clinical hypothesis based on the myotoxicity of local anesthetics Arch Ophthalmol 1985 103 9 1337 39 4038126 \n4. Hamed LM Mancuso A Inferior rectus muscle contracture syndrome after retrobulbar anesthesia Ophthalmology 1991 98 10 1506 12 1961635 \n5. Miller JM Scott AB Danh KK Bupivacaine injection remodels extra-ocular muscles and corrects comitant strabismus Ophthalmology 2013 120 12 2733 40 23916485 \n6. Erie J Acquired Brown’s syndrome after peribulbar anesthesia Am J Ophthalmol 1990 109 349 50 2309870 \n7. Phillips PH Guyton DL Hunter DG Superior oblique overaction from local anesthesia for cataract surgery J AAPOS 2001 2005 329 32 \n8. Hamada S Devys J-M Xuan TH Role of hyaluronidase in diplopia after peribulbar anesthesia for cataract surgery Ophthalmology 2005 112 5 879 82 15878070 \n9. Johnson DA Persistent vertical binocular diplopia after cataract surgery Am J Ophthalmol 2001 132 6 831 35 11730645 \n10. Suh S Le A Demer J Size of the oblique extraocular muscles and superior oblique muscle contractility in Brown syndrome Invest Ophthalmol Vis Sci 2015 56 10 6114 20 26397461 \n11. Lang M Faraji N Coffey M Badve C MRI of acquired Brown syndrome: A report of two cases Radiol Case Rep 2018 13 1 92 95 29487642 \n12. Wright K Brown’s syndrome: Diagnosis and management Trans Am Ophthalmol Soc 1999 97 1023 109 10703149 \n13. Lee J Management of Brown syndrome Semin Ophthalmol 2008 23 291 93 19085429 \n14. Somer D Budak K Corneal topography analysis in establishing the pathophysiologic mechanism of cyclic Brown’s syndrome strabismus. A case report Binocul Vis Strabolog Q Simms Romano 2013 28 238 43 24372418 \n15. Elnahry AG Elnahry GA Treatment of acquired Brown syndrome in a child with a single intramuscular systemic depot steroid injection J AAPOS 2019 23 5 292 93 31145990 \n16. Ravilla S Shetty S Perumalsa V Intratrochlear steroid injections in acquired Brown syndrome – a case series J AAPOS 2019 23 23.e1 e5 30611003 \n17. Giannaccare G Primavera L Maiolo C Steroid intra-trochlear injection for the treatment of acquired Brown syndrome secondary to trochleitis Graefes Arch Clin Exp Ophthalmol 2017 255 10 2045 50 28770346\n\n",
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"issue": "21()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000273:Adipose Tissue; D000328:Adult; D000772:Anesthesia, Local; D002045:Bupivacaine; D019299:Decompression, Surgical; D005260:Female; D006801:Humans; D013285:Strabismus",
"nlm_unique_id": "101489566",
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"pages": "e924678",
"pmc": null,
"pmid": "32687487",
"pubdate": "2020-07-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Brown Syndrome from Local Anesthesia for Inferior Orbital Fat Decompression.",
"title_normalized": "brown syndrome from local anesthesia for inferior orbital fat decompression"
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"abstract": "Methotrexate (MTX) is an effective but potentially toxic treatment for psoriasis. We describe a patient who administered 20 mg daily of MTX for 5 d and presented with ulcerated and necrotic lesions on the psoriatic plaques, mouth erosions and hair loss. However, his psoriatic plaques and ulcerations totally healed rapidly within two weeks and no recurrence has been observed for the 6 months of follow up.",
"affiliations": "Department of Dermatology, Dumlup|nar University, Kütahya Evliya C elebi Education and Research Hospital, Kütahya, Turkey. aslihanyy@yahoo.com",
"authors": "Koçak|Aslıhan Yonca|AY|;Koçak|Oğuzhan|O|;Aslan|Figen|F|;Tektaş|Mustafa|M|",
"chemical_list": "D005493:Folic Acid Antagonists; D008727:Methotrexate",
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"mesh_terms": "D000368:Aged; D005493:Folic Acid Antagonists; D006801:Humans; D008297:Male; D008727:Methotrexate; D011565:Psoriasis; D012867:Skin; D012883:Skin Ulcer",
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"title": "Methotrexate toxicity presenting as cutaneous ulcerations on psoriatic plaques.",
"title_normalized": "methotrexate toxicity presenting as cutaneous ulcerations on psoriatic plaques"
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"abstract": "BACKGROUND\nPeptic ulcer disease (PUD) is a rare condition in children. Perforated peptic ulcer (PPU), a complication of PUD has an estimated mortality between 1.3% and 20%. We evaluate incidence and outcomes of PPU in children using an administrative database, perform a review of the literature, and report our technique for laparoscopic omental patch repair for PPU in two pediatric patients.\n\n\nMETHODS\nKids' inpatient database (KID's) was analyzed for demographics, incidence, and outcomes. Incidence for each year was calculated based on the reported pediatric population in the United States for 2000, 2003, 2006, 2009, and 2012 by the U.S. Census Bureau. Additionally, we present two PPU cases, accompanied by a comprehensive review of the literature.\n\n\nRESULTS\nThe annual number of primary discharge diagnosis of PPU in the KID was 178 cases for 2000, 252 for 2003, 255 for 2006, 299 for 2009, and 266 for 2012. An increase trend over time was noted between 2000 and 2009; however, it was not statistically significant (0.05). PPU appears to be more common in Caucasian teenage boys. The mean length of stay was 8.02 days and with a statistically significant increase in healthcare charges ($33,187 versus $78,142, P = .002) when comparing year 2000-2012.\n\n\nCONCLUSIONS\nPPU is a rare cause of abdominal pain in children, but still a PUD complication that requires surgery. PPU should be included in the differential diagnosis in patients presenting with acute abdominal pain of uncertain etiology and pneumoperitoneum. Laparoscopy is both diagnostic and therapeutic. Laparoscopic omental patch repair is a safe and effective treatment for PPUs.",
"affiliations": "1 Division of Pediatric Surgery, Department of Surgery, Saint Louis University School of Medicine , Saint Louis, Missouri.;1 Division of Pediatric Surgery, Department of Surgery, Saint Louis University School of Medicine , Saint Louis, Missouri.;3 Saint Louis University School of Medicine , Saint Louis, Missouri.;3 Saint Louis University School of Medicine , Saint Louis, Missouri.;1 Division of Pediatric Surgery, Department of Surgery, Saint Louis University School of Medicine , Saint Louis, Missouri.;1 Division of Pediatric Surgery, Department of Surgery, Saint Louis University School of Medicine , Saint Louis, Missouri.;1 Division of Pediatric Surgery, Department of Surgery, Saint Louis University School of Medicine , Saint Louis, Missouri.",
"authors": "Munoz Abraham|Armando Salim|AS|;Osei|Hector|H|;Martino|Alice|A|;Kazmi|Sakina|S|;Saxena|Saurabh|S|;Fitzpatrick|Colleen M|CM|;Villalona|Gustavo A|GA|",
"chemical_list": null,
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"doi": "10.1089/lap.2018.0186",
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"issue": "29(2)",
"journal": "Journal of laparoendoscopic & advanced surgical techniques. Part A",
"keywords": "laparoscopic; omental patch; pediatric; peptic; perforation; ulcer",
"medline_ta": "J Laparoendosc Adv Surg Tech A",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D005260:Female; D017722:Hospital Charges; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D010535:Laparoscopy; D007902:Length of Stay; D008297:Male; D009852:Omentum; D010439:Peptic Ulcer Perforation; D012737:Sex Factors; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "9706293",
"other_id": null,
"pages": "248-255",
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"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Incidence and Outcomes of Perforated Peptic Ulcers in Children: Analysis of the Kid's Inpatient Database and Report of Two Cases Treated by Laparoscopic Omental Patch Repair.",
"title_normalized": "incidence and outcomes of perforated peptic ulcers in children analysis of the kid s inpatient database and report of two cases treated by laparoscopic omental patch repair"
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"abstract": "A 63-year-old man was admitted to our hospital for further investigation and management of brain metastases. The patient was initially presented with a 4-day history of confusion. On the day of admission, the patient was confused, agitated, disorientated in place and time, and had visual disturbances. His blood pressure was repeatedly recorded high, with levels of systolic blood pressure between 170-210 mm Hg. A brain magnetic resonance imaging showed areas of high signal on T2 and fluid-attenuated inversion recovery images, located bilaterally in the white matter of the occipital regions and unilateral in the left frontal lobe, suggestive of posterior reversible encephalopathy syndrome. Aggressive treatment of hypertension resulted in complete resolution of the clinical and radiologic features of the syndrome.",
"affiliations": "Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece.;Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece.;Radiology Department, Medical School, University Hospital of Ioannina, Ioannina, Greece.;Radiology Department, Medical School, University Hospital of Ioannina, Ioannina, Greece.;Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece. Electronic address: egepi@cc.uoi.gr.",
"authors": "Christopoulou|Foteini|F|;Rizos|Evangelos C|EC|;Kosta|Paraskevi|P|;Argyropoulou|Maria I|MI|;Elisaf|Moses|M|",
"chemical_list": "D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002227:Carbazoles; D011412:Propanolamines; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000077261:Carvedilol; D017311:Amlodipine; D013148:Spironolactone; D003404:Creatinine; D000077405:Irbesartan",
"country": "United States",
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"issue": "10(5)",
"journal": "Journal of the American Society of Hypertension : JASH",
"keywords": "Hypertension; PRES; confusion; encephalopathy",
"medline_ta": "J Am Soc Hypertens",
"mesh_terms": "D017311:Amlodipine; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D001921:Brain; D002227:Carbazoles; D000077261:Carvedilol; D000072226:Computed Tomography Angiography; D003221:Confusion; D003404:Creatinine; D004562:Electrocardiography; D005919:Glomerular Filtration Rate; D006212:Hallucinations; D006261:Headache; D006321:Heart; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D020343:Hypertensive Encephalopathy; D000077405:Irbesartan; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011412:Propanolamines; D012078:Renal Artery Obstruction; D013148:Spironolactone; D013777:Tetrazoles; D014463:Ultrasonography",
"nlm_unique_id": "101312518",
"other_id": null,
"pages": "399-403",
"pmc": null,
"pmid": "26896240",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Does this patient have hypertensive encephalopathy?",
"title_normalized": "does this patient have hypertensive encephalopathy"
} | [
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"companynumb": "GR-SA-2017SA241740",
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"occurcountry": "GR",
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"activesubstancename": "AMLODIPINE BESYLATE"
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... |
{
"abstract": "OBJECTIVE\nTreatment options for corticosteroid-refractory and/or high-grade checkpoint inhibitor (CPI)-induced cutaneous adverse events (CAEs) are limited; however, anecdotal reports of biologic therapies have been successful. We aim to characterize the appropriate treatment scenarios and safety and efficacy profiles of biologics used to treat patients with CPI-induced CAEs at a single institution.\n\n\nMETHODS\nThis is a retrospective case series of patients from January 1st, 2015 to October 20th, 2020, with CPI-induced CAEs who were treated with biologics at a single cancer center. Patients were identified using institutional electronic medical record who underwent CPI therapy with subsequent CAEs that necessitated biologic therapy. Diagnostic criteria utilized for CAEs were based on documentation by four board-certified dermatologists, in combination with detailed chart reviews and pathology findings. Primary study outcome measurements include CAE response, tumor response, and adverse events during biologics treatment.\n\n\nRESULTS\nWe identified 17 patients who fit study criteria. Sixteen patients experienced some degree of CAE improvement on biologics, with 10 of 10 patients reaching CAE resolution at 6 months post biologics. Eight patients needed new systemic treatment post biologics treatment, while 9 patients received no further treatment or stayed on the CPI. Thirteen patients tolerated biologics well with no significant adverse events or blood abnormalities, with only 2 patients experiencing biologic dose delays.\n\n\nCONCLUSIONS\nIn our cohort, biologics appear to be extremely efficacious in the treatment of severe-grade and/or steroid refractory CAEs. They also appeared to be well-tolerated without overtly negative effects on tumor response. In patients with limited cancer treatment options and good tumor response to CPIs, biologics should be considered for severe-grade and/or refractory CAEs.",
"affiliations": "Baylor College of Medicine, Houston, TX, USA.;Department of Dermatology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, TX, 77030-4009, USA.;Department of Dermatology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, TX, 77030-4009, USA.;Department of Dermatology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, TX, 77030-4009, USA.;Department of Dermatology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, TX, 77030-4009, USA. APatel11@mdanderson.org.",
"authors": "Lo|Jonathan J|JJ|;Heberton|Meghan M|MM|;Pacha|Omar|O|;Huen|Auris O|AO|;Patel|Anisha B|AB|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-021-06548-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": null,
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Drug reactions; Inflammatory skin diseases; Therapy and treatment",
"medline_ta": "Support Care Cancer",
"mesh_terms": null,
"nlm_unique_id": "9302957",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34519869",
"pubdate": "2021-09-14",
"publication_types": "D016428:Journal Article",
"references": "30931360;25840693;20525992;32226342;30996018;30025829;30399387;27981213;31754559;28355425;31200747;28514612;31216228",
"title": "Biologic therapies for checkpoint inhibitor-induced cutaneous toxicities: a single-institution study of 17 consecutively treated patients.",
"title_normalized": "biologic therapies for checkpoint inhibitor induced cutaneous toxicities a single institution study of 17 consecutively treated patients"
} | [
{
"companynumb": "US-009507513-2201USA005623",
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"occurcountry": "US",
"patient": {
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"activesubstancename": "PEMBROLIZUMAB"
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... |
{
"abstract": "BACKGROUND\nThe prognosis of refractory or relapsed pediatric solid tumors is very poor, and there is no standard treatment for this condition. The combination of irinotecan and temozolomide has proved useful in adults as a second-line treatment of different solid tumors. In pediatric patients, this combination has been effective in Ewing's sarcoma, neuroblastoma, and relapsed or refractory rhabdomyosarcoma.\n\n\nMETHODS\nA retrospective study was conducted on 32 pediatric patients with refractory or relapsed solid tumors, who were treated with irinotecan and temozolomide in the Oncology Department at Children's Hospital Niño Jesus from September 2005 to June 2012. The clinical characteristics, treatment performed, toxicity and outcome, were analyzed.\n\n\nRESULTS\nThirty-two patients received a total of 180 cycles. Of the 30 evaluable patients, 10 (33%) had a positive response (2 complete remission and 8 partial remission), and in 8 (27%) the disease remained stable. Almost all (94%) of the patients achieved a response in the first four cycles. Of the 180 cycles analyzed, only 50 (28%) had toxicity, and of these only 15 (8%) were grade iii-iv. The most common toxicity was diarrhea appearing in 18 patients. All patients received ambulatory treatment, except three of them who required hospitalization due to symptoms of their underlying disease.\n\n\nCONCLUSIONS\nThe combination of irinotecan and temozolomide is well tolerated and active against pediatric refractory or relapsed solid tumors.",
"affiliations": "Servicio de Hemato-Oncología Pediátrica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.",
"authors": "Hernández-Marqués|C|C|;Lassaletta-Atienza|A|A|;Ruiz Hernández|A|A|;Blumenfeld Olivares|J A|JA|;Arce Abaitua|B|B|;Cormenzana Carpio|M|M|;Madero Lopez|L|L|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1695-4033",
"issue": "79(2)",
"journal": "Anales de pediatria (Barcelona, Spain : 2003)",
"keywords": "Irinotecan; Irinotecán; Recaída; Refractarios; Refractory; Relapsed; Solid tumors; Temozolomida; Temozolomide; Tumores sólidos",
"medline_ta": "An Pediatr (Barc)",
"mesh_terms": "D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms; D012189:Retrospective Studies; D000077204:Temozolomide",
"nlm_unique_id": "101162596",
"other_id": null,
"pages": "68-74",
"pmc": null,
"pmid": "23332825",
"pubdate": "2013-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Irinotecan plus temozolomide in refractory or relapsed pediatric solid tumors.",
"title_normalized": "irinotecan plus temozolomide in refractory or relapsed pediatric solid tumors"
} | [
{
"companynumb": "ES-PFIZER INC-2014215312",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Bilateral thalamic infarcts are uncommon posterior circulation strokes. The artery of Percheron (AOP) is a rare anatomical variant involving a singular arterial supply to both thalami and occlusion leads to bilateral thalamic infarction.We report the case of a 71-year-old man who presented with decreased consciousness (fluctuating Glasgow Coma Scale score of 5-7). He had a background of atrial fibrillation and was anticoagulated with dabigatran, a novel oral anticoagulant. Computed tomography (CT) scan showed a mildly reduced attenuation in the region of the left thamalus.Subsequent diffusion-weighted magnetic resonance imaging (MRI) showed acute brainstem infarction, extending into the thalamus bilaterally, likely due to AOP occlusion. Bilateral thalamic infarcts due to AOP occlusion may not be recognised on initial CT scan and are more readily seen using diffusion-weighted MRI, which is the most beneficial imaging modality to aid in early diagnosis and treatment.",
"affiliations": "Ashford and St Peter's NHS Trust, Chertsey, UK.;Ashford and St Peter's NHS Trust, Chertsey, UK.;Ashford and St Peter's NHS Trust, Chertsey, UK.;Ashford and St Peter's NHS Trust, Chertsey, UK.",
"authors": "Berenson|Danielle|D|;Nuttall|Luke|L|;Hakim|Eluzai|E|;Abdel-Aziz|Khaled|K|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.7861/clinmedicine.18-2-183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2118",
"issue": "18(2)",
"journal": "Clinical medicine (London, England)",
"keywords": "Artery of Percheron; atrial fibrillation; bilateral thalamic infarcts; diffusion-weighted imaging; novel oral anticoagulants",
"medline_ta": "Clin Med (Lond)",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D001921:Brain; D017809:Fatal Outcome; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020521:Stroke",
"nlm_unique_id": "101092853",
"other_id": null,
"pages": "183-185",
"pmc": null,
"pmid": "29626028",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12933968;14625223;15466331;21293023",
"title": "Lesson of the month 2: A rare presentation of stroke: diagnosis made on magnetic resonance imaging.",
"title_normalized": "lesson of the month 2 a rare presentation of stroke diagnosis made on magnetic resonance imaging"
} | [
{
"companynumb": "GB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-019821",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Systemic amyloidosis is a clinical manifestation of the accumulation of amyloid fibrils in tissues because of persistent acute phase elevation and chronic inflammation. Its most common causes are inflammatory diseases and malignancies. Here, we present a 12-year-old girl diagnosed with systemic amyloidosis and Hodgkin lymphoma (HL) who was also previously diagnosed with familial Mediterranean fever (FMF). Despite colchicine treatment for FMF, the patient had a persistent elevation of acute phase reactants and AA-type amyloid deposits were observed in a kidney biopsy. Anakinra, an interleukin-1 antagonist, was added to the treatment. Shortly after the diagnosis of amyloidosis, mediastinal lymphadenopathy was recognized, and she was also diagnosed with HL. A chemotherapy protocol of doxorubicin, bleomycin, vinblastine, and dacarbazine was initiated. After 6 cycles of the chemotherapy and 8 months of the anakinra treatment, no recurrence or residual malignancy was observed and proteinuria was decreased. To the authors' knowledge, this is the first reported case of systemic amyloidosis in the literature associated with both FMF and HL.",
"affiliations": "Departments of Pediatric Rheumatology.;Pediatric Hematology and Oncology.;Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Departments of Pediatric Rheumatology.",
"authors": "Demir|Ferhat|F|;Bahadir|Ayşenur|A|;Mungan|Sevdegül|S|;Çobanoğlu|Ümit|Ü|;Kalyoncu|Mukaddes|M|",
"chemical_list": "D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D003078:Colchicine",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001504",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D018501:Antirheumatic Agents; D002648:Child; D003078:Colchicine; D010505:Familial Mediterranean Fever; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D053590:Interleukin 1 Receptor Antagonist Protein",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "234-237",
"pmc": null,
"pmid": "31094904",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic Amyloidosis in a Patient With Familial Mediterranean Fever and Hodgkin Lymphoma: A Case Report.",
"title_normalized": "systemic amyloidosis in a patient with familial mediterranean fever and hodgkin lymphoma a case report"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2019-04876",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"druga... |
{
"abstract": "A man, aged 61 years, with a history of hypogonadism and family history of cancer experienced persistent urinary difficulties with no visible prostate abnormalities. Laboratory testing and diagnostic imaging revealed a primary lesion in the prostate with lymph node involvement and multiple bone metastases. Treatment with androgen-deprivation therapy, 17,20-lyase inhibition, and bisphosphonates for 7 months was unsuccessful in preventing disease progression, but second-line chemotherapy and continued androgen-deprivation therapy improved prostate specific antigen levels. During the patient's second treatment regimen, his daughter received a diagnosis of breast cancer. The patient's daughter underwent genetic testing for oncogenic mutations, and it was discovered that she carried a mutation in RAD51C, a gene encoding a protein involved in DNA repair and genomic maintenance. Subsequent genetic testing of the patient revealed mutation in RAD51C as well. For patients with metastatic prostate cancer who are unresponsive to standard treatment and who have a positive family history of cancer, genetic testing may be warranted to develop alternative treatment regimens for the patient and guide family discussions regarding cancer risk. Targeted agents like poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors may be a consideration in prostate cancer patients with DNA repair mutations and with refractory disease.",
"affiliations": "Department of Internal Medicine, Marshfield Clinic, Marshfield, Wisconsin, USA.;Department of Hematology/Oncology, Marshfield Clinic, Weston, Wisconsin, USA.;Department of Hematology/Oncology, Marshfield Clinic, Weston, Wisconsin, USA onitilo.adedayo@marshfieldclinic.org.",
"authors": "Potugari|Bindu R|BR|;Engel|Jessica M|JM|;Onitilo|Adedayo A|AA|",
"chemical_list": "D004268:DNA-Binding Proteins; C448305:RAD51C protein, human",
"country": "United States",
"delete": false,
"doi": "10.3121/cmr.2018.1411",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-4182",
"issue": "16(3-4)",
"journal": "Clinical medicine & research",
"keywords": "Metastatic; Prostate cancer; RAD51C",
"medline_ta": "Clin Med Res",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D004260:DNA Repair; D004268:DNA-Binding Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms",
"nlm_unique_id": "101175887",
"other_id": null,
"pages": "69-72",
"pmc": null,
"pmid": "30587560",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27989354;21980511;2251225;21990120;24812039;22116601;21616938;24141787;25470109;20952512;25445424;22538716;23176254;20400964;22073129;9469824;17700570;28055103;26510020;27433846;26091339",
"title": "Metastatic Prostate Cancer in a RAD51C Mutation Carrier.",
"title_normalized": "metastatic prostate cancer in a rad51c mutation carrier"
} | [
{
"companynumb": "US-TEVA-2019-US-1074020",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEUPROLIDE"
},
"drugadditional": null,
... |
{
"abstract": "Osteonecrosis of the jaw may be caused by many different triggers. One of them is described to be the drug or medication related osteonecrosis of the jaw. Since many years bisphosphonates induced the dreaded diagnosis. Recently a drug named denosumab is reported to show similar effects on the jaw. In this case report we present a RANK-Ligand inhibitor associated osteonecrosis of the lower jaw and discuss the lights and shadows of this newly introduced drug.",
"affiliations": "Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Rashad|Ashkan|A|;Smeets|Ralf|R|;Heiland|Max|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.3205/iprs000037",
"fulltext": "\n==== Front\nGMS Interdiscip Plast Reconstr Surg DGPWGMS Interdiscip Plast Reconstr Surg DGPWGMS Interdiscip Plast Reconstr Surg DGPWGMS Interdisciplinary Plastic and Reconstructive Surgery DGPW2193-8091German Medical Science GMS Publishing House iprs00003710.3205/iprs000037Doc17urn:nbn:de:0183-iprs0000374ArticleRANK-Ligand inhibitor associated osteonecrosis of the jaw RANK-Ligand Inhibitor-assoziierte Osteonekrose des Kiefers Rashad Ashkan *1Smeets Ralf 1Heiland Max 11 Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany*To whom correspondence should be addressed: Ashkan Rashad, Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany, Tel.: +49-177/856-2393, Fax: +49-40/7410-55467, E-mail: a.rashad@uke.de19 11 2013 2013 2 Doc17Copyright © 2013 Rashad et al.2013This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/). You are free to copy, distribute and transmit the work, provided the original author and source are credited.This article is available from http://www.egms.de/en/journals/iprs/2013-2/iprs000037.shtmlOsteonecrosis of the jaw may be caused by many different triggers. One of them is described to be the drug or medication related osteonecrosis of the jaw. Since many years bisphosphonates induced the dreaded diagnosis. Recently a drug named denosumab is reported to show similar effects on the jaw. In this case report we present a RANK-Ligand inhibitor associated osteonecrosis of the lower jaw and discuss the lights and shadows of this newly introduced drug.\n\nZusammenfassung\nDie Osteonekrose des Kiefers kann durch verschiedene Auslöser verursacht sein. Einer dieser Auslöser wird als die Medikamenten-assoziierte Osteonekrose des Kiefers beschrieben. Seit mehreren Jahren induzieren Bisphosphonate die gefürchtete Diagnose. Kürzlich wurden ähnliche Auswirkungen durch Gabe des Arzneimittels Denosumab beobachtet. Anhand des Fallberichtes präsentieren wir eine RANK-Ligand Inhibitor assoziierte Osteonekrose des Unterkiefers und erörtern die Licht- und Schattenseiten des neuartigen Medikaments. \n\nRANK-Ligand inhibitordenosumabosteonecrosisjawbisphosphonates\n==== Body\nIntroduction\nMany patients suffer from bisphosphonate related osteonecrosis of the jaw (BRONJ). Bearing in mind increasing administration of bisphosphonates (BPs) worldwide, the peak is not yet reached [1]. BPs are drugs widely used in the treatment of various bone related disorders such as osteoporosis, multiple myeloma and bone metastases [2]. \n\nChemically, BPs are small molecular size stable analogues of natural inorganic pyrophosphates, with a carbon atom replacing the oxygen atom that connects the two phosphates [3]. They are classified as aminobisphosphonates or non-aminobisphosphonates and administered orally or intravenously. The mechanism of action concerns apoptosis of osteoclasts, decreased resorption activity and hence limited bone remodeling [4].\n\nRANK-Ligands (Receptor Activator of Nuclear Factor Kappa-B Ligand) are produced by osteoblasts and promote differentiation of osteoclasts by binding to RANK-receptors located on these. A new drug group, namely denosumab (Prolia®), acts by attaching to RANK-Ligands in order to prevent binding of the complex to RANK-receptors resulting in an impaired function of osteoclasts. While the pharmaceutical aim is the same as for BPs, the way of action differs [5]. In general, the area of indication is similar to widely distributed BPs [6], [7].\n\nDenosumab was approved by European Medicines Agency in May 2010 for the treatment of osteoporosis of women in postmenopause and osteoporosis in men caused by hormone therapy due to prostate cancer [8]. The US Food and Drug Administration followed that approval in June 2010 [9] and extended the therapeutic field for osteoporosis in men independent of hormone therapy in September 2012, which is still outstanding in European Union [10].\n\nCase description\nA 74-year-old edentulous woman with osteoporosis and fibromyalgia complained about growing pressure pain of the mandible following extraction of the lower anterior teeth and insertion of mucosa supported complete denture 6 months ago. Her medical history revealed 6 time administration of denosumab (Prolia® 60 mg) subcutaneously over the past 2.5 years. Fibromyalgia was treated with decortin. While intraorally no dehiscence was detected (Figure 1 (Fig. 1)), a panoramic view indicated irregular bone morphology especially in anterior mandible (Figure 2 (Fig. 2)) compared to preoperative imaging 10 months ago (Figure 3 (Fig. 3)). A CT scan illustrated the whole extent (Figure 4 (Fig. 4)). A RANK-Ligand inhibitor (denosumab) associated osteonecrosis of the mandible was diagnosed and reminded us of known BP effects on the jaw. Due to missing dehiscence she was treated conservatively with sultamicillin and prosthesis leave for 2 months with slight improvement of complaints. On the other hand with respect to the great extent of the osteonecrosis, we clarified the potential need of microvascular free flap for reconstruction. \n\nDiscussion and conclusion\nAbout 10 years after the first reported and published cases of BRONJ [11], [12], a new drug group seems to be associated with similar or even more serious impact. Denosumab is a human monoclonal antibody and inhibits osteoclast differentiation and proliferation. It has shown great clinical results with even better bone density values compared to BPs [13], [14]. However, the costs are many times higher than for BPs. But due to higher and improved bioavailability, administration of denosumab would be sufficient subcutaneously every 6 months. \n\nIn contrast to BPs, half-life is not supposed to be several years. Denosumab’s median half-life period amounts 26 days and could not be detected in more than half of probands after 6 months. This fact could be beneficial with respect to necessary dentoalveolar surgery. While that kind of treatment should be performed necessarily before BP uptake, denosumab could theoretically allow operation even after administration requiring absence of the drug for several months. \n\nNevertheless, above presented case suggests that the RANK-Ligand inhibitor is able to harm the jaw seriously in short period of time. Further studies have to investigate possible angiogenesis inhibition and soft tissue toxicity as reported for BPs [15], [16]. That is why we favor to treat conservatively if possible at the moment. Surgical procedures should be held limited and gentle to the periosteum as for BRONJ.\n\nNotes\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Intraoral illustration of lower jaw with absence of any dehiscence\nFigure 2 Panoramic view reveals edentulous site after extraction and disturbed presentation of mainly anterior part of the mandible\nFigure 3 Panoramic pre-extraction view with remaining anterior teeth 10 months ago\nFigure 4 Finally CT scan showed up whole extent of osteonecrosis\n==== Refs\n1 Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J Oral Maxillofac Surg 9 2003 61 9 1115 1117 12966493 \n2 Brumsen C Hamdy NA Papapoulos SE Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis Medicine (Baltimore) 7 1997 76 4 266 283 9279333 \n3 Russell RG Watts NB Ebetino FH Rogers MJ Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy Osteoporos Int 6 2008 19 6 733 759 10.1007/s00198-007-0540-8 Available from: http://dx.doi.org/10.1007/s00198-007-0540-8 18214569 \n4 Plotkin LI Manolagas SC Bellido T Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs Bone 9 2006 39 3 443 452 10.1016/j.bone.2006.02.060 Available from: http://dx.doi.org/10.1016/j.bone.2006.02.060 16627025 \n5 Baron R Ferrari S Russell RG Denosumab and bisphosphonates: different mechanisms of action and effects Bone 4 2011 48 4 677 692 10.1016/j.bone.2010.11.020 Available from: http://dx.doi.org/10.1016/j.bone.2010.11.020 21145999 \n6 Geusens P Emerging treatments for postmenopausal osteoporosis – focus on denosumab Clin Interv Aging 2009 4 241 250 19554095 \n7 Lewiecki EM Denosumab update Curr Opin Rheumatol 7 2009 21 4 369 373 10.1097/BOR.0b013e32832ca41c Available from: http://dx.doi.org/10.1097/BOR.0b013e32832ca41c 19424068 \n8 Prolia(R) (Denosumab) Granted Marketing Authorization in the European Union Amgen.com [Internet] 28 5 2010 Available from: http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1432232 \n9 FDA Approves Amgen’s Prolia(TM) (Denosumab) for Treatment of Postmenopausal Women With Osteoporosis at High Risk for Fracture [Internet] Amgen.com [Internet] 1 6 2010 Available from: http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1433162 \n10 FDA Approves New Indication For Prolia® (Denosumab) For The Treatment Of Bone Loss In Men With Osteoporosis At High Risk For Fracture Amgen.com [Internet] 20 9 2010 Available from: http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1737204 \n11 Ruggiero SL Guidelines for the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) Clin Cases Miner Bone Metab 1 2007 4 1 37 42 22460751 \n12 Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J Oral Maxillofac Surg 9 2003 61 9 1115 1117 12966493 \n13 Brown JP Prince RL Deal C Recker RR Kiel DP de Gregorio LH Hadji P Hofbauer LC Alvaro-Gracia JM Wang H Austin M Wagman RB Newmark R Libanati C San Martin J Bone HG Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial J Bone Miner Res 1 2009 24 1 153 161 10.1359/jbmr.080901 Available from: http://dx.doi.org/10.1359/jbmr.080901 18767928 \n14 Lipton A Steger GG Figueroa J Alvarado C Solal-Celigny P Body JJ de Boer R Berardi R Gascon P Tonkin KS Coleman R Paterson AH Peterson MC Fan M Kinsey A Jun S Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases J Clin Oncol 10 2007 25 28 4431 4437 10.1200/JCO.2007.11.8604 Available from: http://dx.doi.org/10.1200/JCO.2007.11.8604 17785705 \n15 Mortensen M Lawson W Montazem A Osteonecrosis of the jaw associated with bisphosphonate use: Presentation of seven cases and literature review Laryngoscope 1 2007 117 1 30 34 10.1097/01.mlg.0000240885.64568.9e Available from: http://dx.doi.org/10.1097/01.mlg.0000240885.64568.9e 17202926 \n16 Wood J Bonjean K Ruetz S Bellahcène A Devy L Foidart JM Castronovo V Green JR Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid J Pharmacol Exp Ther 9 2002 302 3 1055 1061 10.1124/jpet.102.035295 Available from: http://dx.doi.org/10.1124/jpet.102.035295 12183663\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2193-8091",
"issue": "2()",
"journal": "GMS Interdisciplinary plastic and reconstructive surgery DGPW",
"keywords": "RANK-Ligand inhibitor; bisphosphonates; denosumab; jaw; osteonecrosis",
"medline_ta": "GMS Interdiscip Plast Reconstr Surg DGPW",
"mesh_terms": null,
"nlm_unique_id": "101654993",
"other_id": null,
"pages": "Doc17",
"pmc": null,
"pmid": "26504708",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "18767928;17202926;22460751;9279333;18214569;12183663;19424068;17785705;19554095;21145999;16627025;12966493",
"title": "RANK-Ligand inhibitor associated osteonecrosis of the jaw.",
"title_normalized": "rank ligand inhibitor associated osteonecrosis of the jaw"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2015115937",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Secondary hyperparathyroidism (SHPT) occurs in patients with chronic renal failure complicated with renal bone disease and soft tissue/vascular calcification. In dialysis patients with severe SHPT, medical treatment may fail and parathyroidectomy (PTX) is indicated for definitive treatment. Severe hypocalcemia from hungry bone disease or postoperative hypoparathyroidism may occur during the postoperative period. We report here a case of severe SHPT in a hemodialysis patient treated with phosphate binders, calcitriol, and calcimimetics but who still required PTX. Severe hypocalcemia with muscle cramps occurred postoperatively. Around 1 year after PTX, anemia and features of SHPT have improved but the patient still has intermittent hypocalcemia with suspected postoperative hypoparathyroidism. Regular comprehensive assessment of calcium and phosphorus levels throughout all stages of chronic kidney disease is vital. The postoperative period of PTX in SHPT patients is critical, requiring monitoring to improve management.",
"affiliations": "Nephrology Center, First Central Hospital of Mongolia, Ulaanbaatar, Mongolia.",
"authors": "Adiya|Saruultuvshin|S|;Damdinsuren|Khurtsbayar|K|;Dorj|Chuluuntsetseg|C|",
"chemical_list": "D002117:Calcitriol",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000479616",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-5068",
"issue": "44 Suppl 1()",
"journal": "Blood purification",
"keywords": "Parathyroidectomy; Postoperative hypoparathyroidism; Renal bone disease; Secondary hyperparathyroidism",
"medline_ta": "Blood Purif",
"mesh_terms": "D000328:Adult; D002117:Calcitriol; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D006996:Hypocalcemia; D008297:Male; D008986:Mongolia; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic; D012720:Severity of Illness Index",
"nlm_unique_id": "8402040",
"other_id": null,
"pages": "35-40",
"pmc": null,
"pmid": "28869940",
"pubdate": "2017",
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"abstract": "Fanconi syndrome (FS) is a severe grade of drug-induced proximal tubule toxicity. There are numerous causes for acquired FS, and drug toxicity is one of the most common. FS is known to be associated with the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF). TDF is often used in combination with emtricitabine (FTC) for preexposure prophylaxis (PrEP) of human immunodeficiency virus (HIV) infection. TDF/FTC-induced FS has been observed as a dose-related phenomenon that is directly correlated to kidney function, high levels of absorption of the drug into the proximal tubule, and interactions with other medications. This case report describes a patient who acquired FS after starting TDF/FTC for PrEP in the setting of chronic kidney disease (CKD) with concomitant tacrolimus therapy, a known nephrotoxic agent.",
"affiliations": "University of Wyoming, Laramie, USA.;University of Wyoming, Laramie, USA.;University of Utah Health, Salt Lake City, USA.;Sheridan VA Medical Center, Sheridan, WY, USA.",
"authors": "Linn|Becky S|BS|0000-0001-9882-4275;Vandiver|Jeremy W|JW|;Ren|Dylan|D|;Shassetz|Joseph|J|",
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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\nSAGE Publications Sage CA: Los Angeles, CA\n\n34608820\n10.1177/23247096211050207\n10.1177_23247096211050207\nCase Report\nFanconi Syndrome Induced by Concomitant HIV PrEP and Tacrolimus\nhttps://orcid.org/0000-0001-9882-4275\nLinn Becky S. PharmD 1\nVandiver Jeremy W. PharmD 1\nRen Dylan PharmD 2\nShassetz Joseph PharmD 3\n1 University of Wyoming, Laramie, USA\n2 University of Utah Health, Salt Lake City, USA\n3 Sheridan VA Medical Center, Sheridan, WY, USA\nBecky S. Linn, PharmD, Associate Professor, Clinical, School of Pharmacy, University of Wyoming, 1000 E. University Ave., Laramie, WY 82071, USA. Email: blinn@uwyo.edu\n5 10 2021\nJan-Dec 2021\n9 2324709621105020714 6 2021\n31 8 2021\n12 9 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nFanconi syndrome (FS) is a severe grade of drug-induced proximal tubule toxicity. There are numerous causes for acquired FS, and drug toxicity is one of the most common. FS is known to be associated with the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF). TDF is often used in combination with emtricitabine (FTC) for preexposure prophylaxis (PrEP) of human immunodeficiency virus (HIV) infection. TDF/FTC-induced FS has been observed as a dose-related phenomenon that is directly correlated to kidney function, high levels of absorption of the drug into the proximal tubule, and interactions with other medications. This case report describes a patient who acquired FS after starting TDF/FTC for PrEP in the setting of chronic kidney disease (CKD) with concomitant tacrolimus therapy, a known nephrotoxic agent.\n\nFanconi\nPrEP\ntenofovir\ntoxicity\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nFanconi syndrome (FS) is one of the most severe grades of drug-induced proximal tubule toxicity. 1 There are numerous causes for acquired FS, but drug toxicity is one of the most common, with prior studies demonstrating the association that anti-viral medications have with this form of proximal tubule toxicity. 2 FS is associated with the anti-viral tenofovir (TDF), which works as a reverse transcriptase inhibitor and is used in combination with emtricitabine (FTC) for preexposure prophylaxis (PrEP) prevention of human immunodeficiency virus (HIV) infection in unaffected individuals who are in an ongoing relationship with a partner living with HIV. 3 TDF/FTC-induced FS has been observed as a dose-related phenomenon that is directly correlated to kidney function, high levels of absorption of the drug into the proximal tubule, as well as interactions with other medications. 1 Similarly, we report a case of a patient who acquired FS after starting TDF/FTC for PrEP in the setting of chronic kidney disease (CKD) with concomitant tacrolimus therapy, a known nephrotoxic agent. This scenario and interaction underscore the need to consider risk factors which may predispose patients to developing proximal tubule toxicity with TDF/FTC.\n\nCase Report\n\nA female in her early 60s presented to the emergency department (ED) with a chief complaint of sporadic and intractable nausea and vomiting that had been worsening over a 2-week period, acute kidney injury (AKI), hypokalemia, and elevated anion gap metabolic acidosis. Her history revealed numerous visits to the ED over the past year with the same complaint, presentation, and worsening serum creatinine. The diagnostic uncertainty and plan for further workup as an outpatient was discussed with the patient during these ED visits.\n\nThe patient’s pertinent past medical history to this case is significant for heart transplant due to dilated cardiomyopathy, chronic immunosuppression, stage III CKD diagnosed 5 years prior, and exposure to HIV from her partner. In addition, testing revealed she was negative for HIV, as well as hepatitis B virus (HBV). Her home medication of interest for this case included TDF/FTC 200/300 mg daily, which she was initiated 2 years prior and without dose adjustment for a baseline creatinine clearance (CrCl) of approximately 41 mL/min. The patient was also on tacrolimus and mycophenolate for the past 5 years. Other home medications include clonidine, quetiapine, potassium, pravastatin, oxymorphone, and lidocaine patch. The relevant laboratory results from a venous blood draw and a urinalysis, at baseline and presentation to the ED, are shown below in Table 1. At baseline, the patient had an elevated tacrolimus level, and was unsure if she followed through with the recommended dose reduction on a prior outpatient visit.\n\nTable 1. Baseline and ED Values.\n\nLab measurement\tValue at baseline\tED presentation\tReference\t\nSerum blood draw\t\n Bicarbonate (mEq/L)\t15-21\t8\t22-30\t\n Anion Gap\t18\t19\t4-15\t\n Potassium (mEq/L)\t3.0\t3.3\t3.5-5.1\t\n Magnesium (mg/dL)\tn/a\t1.2\t1.9-2.7\t\n Phosphorus (mg/dL)\tn/a\t1.1\t2.5-5.0\t\n Calcium (mg/dL)\t8\t8.6\t8.4-10.2\t\n Glucose (mg/dL)\t92\t109\t70-99\t\n Uric acid (mg/dL)\t2.0\tn/a\t2.5-6.2\t\n Tacrolimus (ng/mL)\t12.3-25\t14.1\t8-18\n5-10 heart transplant > 6 mos.\t\n Parathyroid hormone (PTH), (pg/mL)\tn/a\t136\t14.5-89.6\t\n Creatinine (mg/dL)\t1.4\t1.9\t0.52-1.04\t\n Blood urea nitrogen (BUN) (mg/dL)\t19\t14\t7-17\t\n Creatinine clearance (ml/min)\t41\t21\t>60\t\nUrine\t\n Protein (mg/dL)\t>500\t1,794\tNegative\t\n Glucose (mg/dL)\t>150\t>500\tNegative\t\nAbbreviation: ED, emergency department.\n\nThe patient was ultimately admitted and transferred to the medical floor where she received a normal saline infusion that improved her acute kidney injury to a creatinine of 1.5 mg/dL. On day 2, venous labs revealed ongoing acidosis, with the following values shown below in Table 2, and the patient was transferred to the intensive care unit (ICU) and nephrology consulted.\n\nTable 2. Day 2-6 Lab Values.\n\nLab measurement\tDay 2\tDay 3\tDay 4\tDay 5\tDay 6\tReference\t\nSerum blood draw\t\n Bicarbonate (mEq/L)\t8\t12\t15\t21\t19\t22-30\t\n Anion gap\t16\t14\t10\t13\t12\t4-15\t\n Potassium (mEq/L)\t3.1\t3.7\t3.6\t2.8\t4.3\t3.5-5.1\t\n Magnesium (mg/dL)\t2.9\t1.6\t1.5\t1.6\t1.7\t1.9-2.7\t\n Phosphorus (mg/dL)\t1.1\t4.5\t2.8\t3.3\t3.3\t2.5-5.0\t\n Calcium (mg/dL)\t8.0\t7.6\t7.0\t7.7\t7.8\t8.4-10.2\t\n Glucose (mg/dL)\t95\t92\t90\t85\t93\t70-99\t\n Uric acid (mg/dL)\tn/a\tn/a\tn/a\tn/a\tn/a\t2.5-6.2\t\n Tacrolimus (ng/mL)\tn/a\tn/a\t6.8\tn/a\tn/a\t8-18\n5-10 heart transplant >6 months\t\n Parathyroid hormone (PTH), (pg/mL)\tn/a\tn/a\tn/a\tn/a\tn/a\t14.5-89.6\t\n Creatinine (mg/dL)\t1.5\t1.3\t1.2\t1.10\t1.10\t0.52-1.04\t\n Blood urea nitrogen (BUN) (mg/dL)\t14\t6\t9\t9\t9\t7-17\t\n Creatinine clearance (ml/min)\t43\t50\t55\t>60\t>60\t>60\t\nUrine\t\n Protein (mg/dL)\tn/a\tn/a\tn/a\tn/a\tn/a\tNegative\t\n Glucose (mg/dL)\t500\tn/a\tn/a\tn/a\tn/a\tNegative\t\n\nArrangements were made with the transplant and infectious diseases (ID) team after the nephrologist requested tacrolimus and TDF/FTC be held due to a possible additive nephrotoxic effect. A sodium bicarbonate intravenous (IV) infusion at a rate of 150 milliequivalents (mEq) over 12 hours, until serum bicarbonate greater than 14, was initiated. The ICU electrolyte replacement protocol for calcium (1 gm IV), potassium (20 mEq), phosphorus (15 mmol), and magnesium (2 gm) was ordered every 2 to 6 hours as needed. The patient was transferred out of the ICU on day 3 and tacrolimus was restarted at a lower dose. Labs on the basic metabolic panel (BMP) were within normal limits by day 6 and the patient stated she was feeling back to baseline. Ultimately, the patient was determined to have TDF/FTC-induced FS based upon her clinical features of proteinuria, hypophosphatemia, normoglycemic glycosuria, metabolic acidosis, hypouricemia, and hypokalemia. 1\n\nUpon discharge from the hospital, TDF/FTC was not restarted for the patient, and tacrolimus was continued at the reduced dose. The patient also received prescriptions for oral magnesium oxide, potassium chloride, sodium bicarbonate, and potassium phosphate. At follow-up, ID recommended future treatment of PrEP with FTC/tenofovir alafenamide (TAF).\n\nDiscussion and Conclusions\n\nHaving a limited number of existing reports, FS is a relatively uncommon adverse event for anti-viral agents. This case report is of significance as FS occurred during PrEP therapy, confirmed via diagnosis by improvement in tubule function after withdrawal of the drug. 1 To support the findings from this case, another case report by Iwata et al described FS in a male who acquired HIV secondary to TDF/FTC therapy for standard antiretroviral therapy (ART). 4 This is again supported in a case report by Mugwanya et al, which thoroughly described the effect of TDF-based PrEP along with concomitant nephrotoxic medications to decrease proximal tubule function and induce FS. 5\n\nIn addition, we report the additive nephrotoxic effects, supratherapeutic levels, of tacrolimus in combination with TDF/FTC based PrEP contributed to the development of FS in this case. This interaction has not been reported before in the literature, and this case report is suspected to be the first identifying the risk of concomitant therapy of the 2 agents. Drug–drug interaction (DDI) databases as of now do not mention this interaction. 6 This has the potential for this DDI to be missed, as many electronic health record systems will not flag this interaction, leading to both potentially a failure in identifying this issue, as well as a delay in identifying it. While mycophenolate is also well-known to be nephrotoxic, it was not believed to be toxic in this patient and the known medication side effects are not consistent with many of the clinical features of FS.\n\nOverall, in the setting of FS, it is recommended that the offending medication be discontinued immediately and complications be addressed. 1 In this case report, ID and nephrology specialists were promptly consulted on day 2 of admission, facilitating a fairly rapid recognition of this drug-induced adverse event. TDF/FTC for PrEP was initiated in the face of risk factors for FS, including CKD, and proximal tubule complications could have been prevented with the following steps for early detection of renal decline and avoiding compounding or high-risk factors for renal toxicity:\n\nEstablish baseline kidney function prior to initiating TDF, and monitor every 4 weeks in the first year. 1\n\nUse caution with other nephrotoxic agents. 3\n\nDose reduce or avoid use when CrCl < 60 mL/min 3 .\n\nMonitor phosphate and vitamin D levels. 4\n\nMonitor for potential early symptoms of FS, including polyuria, bone pain, proximal muscle weakness, and fractures. 1\n\nThe patient in this case report developed FS after being initiated on TDF-based PrEP once daily with CKD and a CrCl of 41 mL/min. Due to the baseline kidney function, dosing every other day is recommended instead of the patient’s current regimen of a once daily dose. This was not addressed upon initiation and is likely a reason that this patient developed FS, further supporting the above recommended steps for identifying high risk factors of renal toxicity with TDF-based PrEP. When TDF-induced renal disease is recognized in a patient, TDF should generally be discontinued, and alternative therapies explored. In this patient case, the TDF was being used as HIV PrEP, where there are currently only 2 Food and Drug Administration (FDA)-approved medication options. The best alternative at this time would be transition patients to the combination of FTC/ TAF. TAF is a newer generation nucleoside analog that is a prodrug of tenofovir that results in up to 90% less systemic drug exposure than TDF. 7 There is emerging data to support its safety as an alternative in patients that develop renal complications on TDF. 8 However, there have been reports of TAF-induced FS have also been cited. 9 Due to the severity of FS, preventative monitoring and dosing strategies should be implemented as they are essential to mitigate risk of drug-induced kidney damage, which may have profound consequences for patients.\n\nAuthors’ Note: This case report has been previously presented as a poster in abstract form under the title, “Acute on chronic Fanconi syndrome induced by tenofovir compounded by tacrolimus toxicity,” at the American College of Clinical Pharmacy annual meeting in New York, New York, October 2019.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: This case report is exempt through our institution’s Institutional Review Board. Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Becky S. Linn https://orcid.org/0000-0001-9882-4275\n==== Refs\nReferences\n\n1 Hall AM Bass P Unwin RJ. Drug-induced renal Fanconi syndrome. QJM. 2014;107 (4 ):261-269.24368854\n2 Solomon MM Lama JR Glidden DV , et al . Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS. 2014;28 :851-859.24499951\n3 Centers for Disease Control and Prevention. US Public Health Service preexposure prophylaxis for the prevention of HIV infection in the United States–2017 update: a clinical practice guideline. Atlanta, GA: Centers for Disease Control and Prevention; 2014.\n4 Iwata K Nagata M Watanabe S Nishi S. Distal renal tubular acidosis without renal impairment after use of tenofovir: a case report. BMC Pharmacol Toxicol. 2016;17 (1 ):52.27866471\n5 Mugwanya K Baeten J Celum C , et al . Low risk of proximal tubular dysfunction associated with emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis in men and women. J Infect Dis. 2016;214 (7 ):1050-1057.27029778\n6 Tacrolimus. Lexi-drugs interactions. Hudson, OH: Lexicomp; 2015. http://online.lexi.com/. Accessed July 15, 2021.\n7 Sano T Kawaguhi T Ide T , et al . Tenofovir alafenamide rescues renal tubules in patients with chronic hepatitis B. Life. 2021;11 (3 ):1-8.\n8 Mothobi NZ Masters J Marriott DJ. Fanconi syndrome due to tenofovir disoproxil fumarate reversed by switching to tenofovir alafenamide fumarate in an HIV-infected patient. Ther Adv Infect Dis. 2018;5 (5 ):91-95.30224952\n9 Bahr NC Yarlagadda SG. Fanconi syndrome and tenofovir alafenamide: a case report. Annals of Internal Medicine. 2019;17011 :814-815.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Fanconi; PrEP; tenofovir; toxicity",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D019380:Anti-HIV Agents; D005198:Fanconi Syndrome; D015658:HIV Infections; D006801:Humans; D065129:Pre-Exposure Prophylaxis; D016559:Tacrolimus",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211050207",
"pmc": null,
"pmid": "34608820",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30690644;27029778;33806752;24499951;24368854;30224952;27866471",
"title": "Fanconi Syndrome Induced by Concomitant HIV PrEP and Tacrolimus.",
"title_normalized": "fanconi syndrome induced by concomitant hiv prep and tacrolimus"
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"abstract": "BACKGROUND\nSevere hypercalcemia is rare in newborns; even though often asymptomatic, it may have important sequelae. Hypophosphatemia can occur in infants experiencing intrauterine malnutrition, sepsis and early high-energy parenteral nutrition (PN) and can cause severe hypercalcemia through an unknown mechanism. Monitoring and supplementation of phosphate (PO4) and calcium (Ca) in the first week of life in preterm infants are still debated.\n\n\nMETHODS\nWe report on a female baby born at 29 weeks' gestation with intrauterine growth retardation (IUGR) experiencing sustained severe hypercalcemia (up to 24 mg/dl corrected Ca) due to hypophosphatemia while on phosphorus-free PN. Hypercalcemia did not improve after hyperhydration and furosemide but responded to infusion of PO4. Eventually, the infant experienced symptomatic hypocalcaemia (ionized Ca 3.4 mg/dl), likely exacerbated by contemporary infusion of albumin. Subsequently, a normalization of both parathyroid hormone (PTH) and alkaline phosphatase (ALP) was observed.\n\n\nCONCLUSIONS\nAlthough severe hypercalcemia is extremely rare in neonates, clinicians should be aware of the possible occurrence of this life-threatening condition in infants with or at risk to develop hypophosphatemia. Hypophosphatemic hypercalcemia can only be managed with infusion of PO4, with strict monitoring of Ca and PO4 concentrations.",
"affiliations": "Department of Translational Medical Sciences, Section of Pediatrics, Federico II University of Naples, Naples, Italy. nicolaimproda@gmail.com.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Baronissi, SA, Italy.;Department of Translational Medical Sciences, Section of Pediatrics, Federico II University of Naples, Naples, Italy.;Department of Ophthalmology, Umberto I Hospital, Nocera Inferiore, Italy.;Department of Public Health, Federico II University of Naples, Naples, Italy.;Neonatal Intensive Care Unit, Malzoni Medical Center, Avellino, Italy.",
"authors": "Improda|Nicola|N|http://orcid.org/0000-0003-4235-0917;Mazzeo|Francesca|F|;Rossi|Alessandro|A|;Rossi|Claudia|C|;Improda|Francesco Paolo|FP|;Izzo|Angelo|A|",
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"doi": "10.1186/s13052-021-01104-6",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288\nBioMed Central London\n\n1104\n10.1186/s13052-021-01104-6\nCase Report\nSevere hypercalcemia associated with hypophosphatemia in very premature infants: a case report\nhttp://orcid.org/0000-0003-4235-0917\nImproda Nicola nicolaimproda@gmail.com\n\n12\nMazzeo Francesca 3\nRossi Alessandro 1\nRossi Claudia 4\nImproda Francesco Paolo 5\nIzzo Angelo 6\n1 grid.4691.a 0000 0001 0790 385X Department of Translational Medical Sciences, Section of Pediatrics, Federico II University of Naples, Naples, Italy\n2 grid.4691.a 0000 0001 0790 385X Pediatric Endocrinology Unit, Department of Translational Medical Sciences, University of Naples “Federico II”, Via S. Pansini, 5, 80131 Naples, Italy\n3 grid.11780.3f 0000 0004 1937 0335 Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, SA Italy\n4 Department of Ophthalmology, Umberto I Hospital, Nocera Inferiore, Italy\n5 grid.4691.a 0000 0001 0790 385X Department of Public Health, Federico II University of Naples, Naples, Italy\n6 Neonatal Intensive Care Unit, Malzoni Medical Center, Avellino, Italy\n7 7 2021\n7 7 2021\n2021\n47 1555 11 2020\n6 6 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\nSevere hypercalcemia is rare in newborns; even though often asymptomatic, it may have important sequelae. Hypophosphatemia can occur in infants experiencing intrauterine malnutrition, sepsis and early high-energy parenteral nutrition (PN) and can cause severe hypercalcemia through an unknown mechanism. Monitoring and supplementation of phosphate (PO4) and calcium (Ca) in the first week of life in preterm infants are still debated.\n\nCase presentation\n\nWe report on a female baby born at 29 weeks’ gestation with intrauterine growth retardation (IUGR) experiencing sustained severe hypercalcemia (up to 24 mg/dl corrected Ca) due to hypophosphatemia while on phosphorus-free PN. Hypercalcemia did not improve after hyperhydration and furosemide but responded to infusion of PO4. Eventually, the infant experienced symptomatic hypocalcaemia (ionized Ca 3.4 mg/dl), likely exacerbated by contemporary infusion of albumin. Subsequently, a normalization of both parathyroid hormone (PTH) and alkaline phosphatase (ALP) was observed.\n\nConclusions\n\nAlthough severe hypercalcemia is extremely rare in neonates, clinicians should be aware of the possible occurrence of this life-threatening condition in infants with or at risk to develop hypophosphatemia. Hypophosphatemic hypercalcemia can only be managed with infusion of PO4, with strict monitoring of Ca and PO4 concentrations.\n\nKeywords\n\nHypercalcemia\nExtremely low birth weight\nHypophosphatemia\nSmall for gestational age\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nSevere hypercalcemia in newborns is a rare event and, even though generally well tolerated, it may be lethal or cause several complications, such as bradycardia, seizures, renal and brain calcifications [1–5]. Therefore, appropriate investigations and treatment strategies should be promptly established.\n\nExtremely (E-) or very (V-) low birth weight (LBW) neonates, especially if born small for gestational age (SGA) are more prone to develop hypophosphatemic hypercalcemia [1], due to a complex combination of factors, such as depleted phosphate (PO4) stores, renal immaturity, increased infection risk and early high-energy parenteral nutrition (PN) [2–4]. However, due to the rarity of the condition, the exact mechanism underlying the association between hypophosphatemia and severe hypercalcemia is still poorly understood.\n\nOptimal monitoring and nutritional strategies to prevent early hypophosphatemia in premature infants are still debated. Indeed, inadequate supply of PO4 in the first days of life represent a relevant issue [2, 4], particularly in countries like Italy, where the main PO4 source for PN (D-Fructose-1,6-diphosphate) is no longer available.\n\nWe report on a SGA ELBW neonate experiencing severe hypercalcemia due to hypophosphatemia with the aim of discussing pathogenesis, treatment and prevention of this rare condition.\n\nCase presentation\n\nA female baby was born at 29 weeks’ gestation by coesarian section because of placental vascular dysfunction and severe intrauterine growth restriction (IUGR), weighing 600 g (SGA). Her mother was receiving 2000 IU of vitamin D3 and 450 mg of magnesium per day and had no electrolytes abnormalities. Family history was negative for calcium (Ca) metabolism disorders. She developed respiratory distress necessitating mechanical ventilation for 2 days, followed by non-invasive ventilation. Spontaneous closure of ductus arteriosus was observed. C-reactive protein was raised at 12 h of life, but normalized 3 days after starting antibiotics. Blood culture was negative. She received PO4-free total PN for 2 days, containing amino acids up to 2.5 g/kg/day and Ca 0.5 mmol/kg/day. On day 3 of life, minimal enteral feeding was started using boluses of plain expressed breast milk (EBM), with gradual increase in the volume. Over the first 5 days of life, serum Ca concentrations were normal (between 7.8 mg/dl and 8.5 mg/dl).\n\nSince day 6, she became hypercalcemic and Ca concentrations rose progressively (Fig. 1). Despite decrease and eventual discontinuation of parenteral Ca and Vitamin D delivery, corrected Ca concentrations reached a peak of 24 mg/dl. Diagnostic work-up revealed PO4 1.4 mg/dl (nv 4.4–8), magnesium 2.2 mg/dl (nv 1.7–2.5), sodium 137 mmol/L, potassium 3.8 mmol/L, albumin 1.8 g/dl (nv 3.3–4.5), alkaline phosphatase (ALP) 377 IU/L (nv 77–375), creatinine 1.06 mg/dl, urea 0.75 g/l, urine Ca/creatinine ratio 2.8 mmol/mmol (nv 0.09–2.2), urine PO4/creatinine ratio 1 mmol/mmol (nv 1.2–19), calcitonin 27 pg/ml (nv 0.8–9.9), normal thyroid function and suppressed parathyroid hormone (PTH) 4.8 pg/ml (nv 7.5–53.5), suggesting PTH-independent hypercalcemia. The infant was asymptomatic, except for mild polyuria. Fig. 1 Onset and progress of hypercalcemia. Dotted lines indicate the normal range of serum corrected total calcium concentration for infants\n\nHypercalcemia did not improve after hyperhydration (220 ml/kg/day) and IV furosemide (1.5 mg/kg every 6 h) (Fig. 1). Given the rather small amount of EBM (16 ml/day), enteral nutrition was continued. Introduction of sodium glycerophosphate in the PN solution (PO4 80 mg/kg/day) resulted in a prompt decrease in Ca concentrations to 10 mg/dl within 24 h, with transient symptoms of hypocalcaemia (ionized Ca 3.4 mg/dl), which could be in part favored by contemporary infusion of albumin (Fig. 1). Therefore, the rate of infusion of sodium glycerophosphate was initially lowered and then a balanced infusion of Ca and PO4 was kept, in order to maintain normal Ca and PO4 concentrations. Four days after the introduction of PO4, PTH normalized (41.5 pg/ml, nv 7.5–53.5), while ALP was slightly raised at 788 IU/L, likely due to transient hypocalcemia. Within 3 weeks, her bone profile fully normalized (ALP 473 IU/L; PTH 39 pg/ml) and, due to good tolerance to formula milk feeds, Ca and PO4 supplements were discontinued. The baby had no evidence of renal or brain calcifications on repeated ultrasound scans nor bone lesions on x-ray.\n\nDiscussion and conclusions\n\nWe report on a SGA ELBW neonate experiencing sustained severe hypercalcemia since the first week of life, associated with hypophosphatemia while on PN. This case provides insights on the mechanisms of Ca dysregulation in hypophosphatemic infants, emphasizing appropriate investigations, prevention and treatment aspects of this rare condition.\n\nSevere hypercalcemia, defined as total serum Ca > 14 mg/dL [6], is uncommon in newborns. Although often asymptomatic, it may have important sequelae, such as brain calcifications and nephrocalcinosis possibly leading to distal tubular dysfunction, urinary stones, and renal failure [5]. Therefore, this condition requires prompt investigations and therapeutic interventions.\n\nNeonatal hypercalcemia recognizes mainly PTH-independent causes [7, 8], such as sepsis [7], iatrogenic (drugs, vitamin A intoxication or excess Ca intake), maternal [9] or neonatal Vitamin D excess (including subcutaneous fat necrosis, hypophosphatemia, excess intake, and granulomatous diseases), congenital syndromes (eg hypocalciuric hypercalcemia, hypophosphatasia, blue diaper syndrome, Williams syndrome, Jansen metaphyseal chondrodysplasia), severe dysthyroidism or idiopathic [8].\n\nIn our case, the late onset and the persistence of severe hypercalcemia despite no administration of Ca and Vitamin D, along with low PO4 concentrations indicate hypophosphatemia as a key pathogenic factor. The mechanisms by which hypophosphatemia can cause hypercalcemia are not completely understood. Inhibition of the secretion of FGF23, leading to increased activity of 1-alfa hydroxylase with production of 1,25(OH)2D [8] or alternatively excess release from bones of Ca along with PO4, aiming to compensate the hypophosphatemic state [10] have been proposed.\n\nData from our patient indirectly support the first theory. In fact, although Vitamin D metabolites were not measured, the infant initially exhibited biochemical signs of hypervitaminosis D, such as low renal phosphate excretion and ALP concentrations not elevated in spite of hypophosphatemia. Moreover, the prompt reduction in calcium concentrations, along with increase in PTH concentrations up to normal values following phosphate infusion may possibly result from reduced production of active vitamin-D metabolites.\n\nHypophosphatemic hypercalcemia is rare and may occur more frequently in preterm compared to infants at term [8], especially if IUGR/SGA [3, 11, 12], due to a complex combination of factors peculiar to this category of patients. During the third trimester of pregnancy babies exhibit the fastest bone mineralization with great requirements of Ca and PO4 and thus preterm infants have depleted stores of these electrolytes [13]. Moreover, hypophosphatemia in ELBW may be worsen by a sort of re-feeding syndrome [13], also known as Placental Incompletely Restored Feeding syndrome, occurring after introduction of early high-energy PN in babies experiencing intrauterine nutritional deprivation and characterized by intracellular redistribution and increased reprocessing of electrolytes stimulated by insulin [2, 3, 14, 15]. Finally, hypophosphatemia in neonates can be exacerbated by renal losses, sepsis [4] and use of breast milk (which contains relatively large content of Ca compared to PO4) [16]. Although as mentioned above sepsis may also cause hypercalcemia, likely via production of 1,25(OH)2D by extrarenal macrophages [17] or interleukine-induced bone resorption [18], our case suggests poor relevance of this mechanism, as Ca concentrations continued to rise despite the resolution of early-onset sepsis.\n\nBased on these considerations, monitoring and nutritional strategies for prevention of hypophosphatemia appear of paramount importance.\n\nEstablished monitoring protocols are currently lacking. It has been suggested that, evaluation of PO4 concentration and other biochemical features of re-feeding syndrome should be performed by the third day of life in infants at risk, including VLBW or ELBW neonates receiving PN and repeated every 2 or 3 days [4, 13] or even twice daily before stabilization [19], by using reference ranges appropriate to preterm neonates [20].\n\nAlthough PO4 supplementation is recommended from the third day of life [19], it has been shown that early introduction (even from the first day of life) in ELBW infants is safe [21–23] and results in lower incidence of Ca abnormalities and severe hypercalcemia, as well as in improved Ca retention [16, 24–26]. In addition, it might protect from negative effects exerted by hypophosphatemia on energy balance of several organs [4]. Nevertheless, there is a discrepancy between current recommendations on parenteral mineral supplementation. In fact, while guidelines by the American Academy of Pediatrics recommend PN supply of Ca and PO4 of 1.5–2 mmol/kg/day with Ca:PO4 ratio 1.1–1.3:1 [27], the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition recommend 0.8–2 mmol/kg/day of Ca, and 1–2 mmol/kg/day of PO4, with a Ca: PO4 ratio of 0.8–1:1 [19]. In this respect, several studies [2, 25, 26] indicate that equimolar Ca:PO4 ratio might be more appropriate to meet the great PO4 requirement in the early post-natal period in VLBW infants. Indeed, in the study by Christman et al. [26] hypophosphatemia was detected in up to 34% of babies, despite providing the maximum recommended doses of PO4 for preterm infants with a Ca:PO4 ratio of 1.56. Recently, concern has been raised in countries like Italy where D-Fructose-1,6-diphosphate, the most common PO4 source for PN, is no longer available, and its alternative sodium glycerophosphate has to be imported from abroad. Furthermore, a relationship between amino acid intake and the risk of hypophosphatemia has been noted in preterm infants [2]. Although this suggests that PO4 requirement calculation should also take into account amino acid supply, current evidence is limited to provide clear recommendations in these patients [28].\n\nAs far as it concerns treatment, consistent with previous reports [29, 30], our case highlights that hypophosphatemic hypercalcemia does not benefit from treatments commonly used for PTH-indipendent hypercalcemia (such as hyperhydration, furosemide, subcutaneous calcitonin, steroids), but improves dramatically after iv or even oral [29] administration of PO4. Although in theory a drop in ionized calcium may be observed during correction of hypophosphatemia, so far this has never been reported in neonatal hypophosphatemic hypercalcemia. Therefore, given that we used common therapeutic doses of PO4, we hypothesize that contemporary infusion of albumin might have favored symptomatic hypocalcemia. Finally, our case highlights the need for regular check of Ca and PO4 concentrations, even every 2 hours [4], during PO4 infusion.\n\nIn conclusion, clinicians should be aware of the possible occurrence of life-threatening severe hypercalcemia in infants with or at risk to develop hypophosphatemia. Our case provides additional information regarding the mechanisms of Ca dysregulation in hypophosphatemic infants and confirms that hypophosphatemic hypercalcemia can only be managed with infusion of PO4. Current strategies for monitoring of phosphatemia and for adequate PO4 supplementation of in the first weeks of life in premature infants need to be implemented.\n\nAbbreviations\n\nPN Parenteral nutrition\n\nPO4 Phosphate\n\nCa Calcium\n\nIUGR Intrauterine growth retardation\n\nPTH Parathyroid hormone\n\nALP Alkaline phosphatase\n\nELBW Extremely low birth weight\n\nVLBW Very low birth weight\n\nSGA Small for gestational age\n\nEBM Expressed breast milk\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nAll authors have made substantial contributions to the conception or design of the work and have equally participated in drafting of the manuscript and/or critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the parents of the patient for publication of this Case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Ehrenkranz RA Early nutritional support and outcomes in ELBW infants Early Hum Dev 2010 86 1 21 25 10.1016/j.earlhumdev.2010.01.014 20123153\n2. Bonsante F Iacobelli S Latorre G Rigo J De Felice C Robillard PY Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants: it is time to change the composition of the early parenteral nutrition PLoS One 2013 8 8 e72880 10.1371/journal.pone.0072880 23977367\n3. Ichikawa G Watabe Y Suzumura H Sairenchi T Muto T Arisaka O Hypophosphatemia in small for gestational age extremely low birth weight infants receiving parenteral nutrition in the first week after birth J Pediatr Endocrinol Metab 2012 25 3-4 317 321 10.1515/jpem-2011-0485 22768663\n4. Pająk A Królak-Olejnik B Szafrańska A Early hypophosphatemia in very low birth weight preterm infants Adv Clin Exp Med 2018 27 6 841 847 10.17219/acem/70081 29790700\n5. Rodd C Goodyer P Hypercalcemia of the newborn: etiology, evaluation, and management Pediatr Nephrol 1999 13 6 542 547 10.1007/s004670050654 10452286\n6. Bushinsky DA Monk RD Electrolyte quintet: calcium Lancet 1998 352 9124 306 311 10.1016/S0140-6736(97)12331-5 9690425\n7. McNeilly JD Boal R Shaikh MG Ahmed SF Frequency and aetiology of hypercalcaemia Arch Dis Child 2016 101 4 344 347 10.1136/archdischild-2015-309029 26903499\n8. Stokes VJ Nielsen MF Hannan FM Thakker RV Hypercalcemic disorders in children J Bone Miner Res 2017 32 11 2157 2170 10.1002/jbmr.3296 28914984\n9. Reynolds A O'Connell SM Kenny LC Dempsey E Transient neonatal hypercalcaemia secondary to excess maternal vitamin D intake: too much of a good thing BMJ Case Rep 2017 2017 bcr2016219043 10.1136/bcr-2016-219043\n10. Guellec I Gascoin G Beuchee A Boubred F Tourneux P Ramful D Zana-Taieb E Baud O Biological impact of recent guidelines on parenteral nutrition in preterm infants J Pediatr Gastroenterol Nutr 2015 61 6 605 609 10.1097/MPG.0000000000000898 26147627\n11. Brener Dik PH Galletti MF Fernández Jonusas SA Alonso G Mariani GL Fustiñana CA Early hypophosphatemia in preterm infants receiving aggressive parenteral nutrition J Perinatol 2015 35 9 712 715 10.1038/jp.2015.54 26067471\n12. Boubred F Herlenius E Bartocci M Jonsson B Vanpée M Extremely preterm infants who are small for gestational age have a high risk of early hypophosphatemia and hypokalemia Acta Paediatr 2015 104 11 1077 1083 10.1111/apa.13093 26100071\n13. Mizumoto H Mikami M Oda H Hata D Refeeding syndrome in a small-for-dates micro-preemie receiving early parenteral nutrition Pediatr Int 2012 54 5 715 717 10.1111/j.1442-200X.2012.03590.x 23005906\n14. Hearing SD Refeeding syndrome BMJ 2004 328 7445 908 909 10.1136/bmj.328.7445.908 15087326\n15. Marinella MA The refeeding syndrome and hypophosphatemia Nutr Rev 2003 61 9 320 323 10.1301/nr.2003.sept.320-323 14552069\n16. Hair AB Chetta KE Bruno AM Hawthorne KM Abrams SA Delayed introduction of parenteral phosphorus is associated with hypercalcemia in extremely preterm infants J Nutr 2016 146 6 1212 1216 10.3945/jn.115.228254 27146915\n17. Lietman SA Germain-Lee E Levine MA Hypercalcaemia in children and adolescents Curr Opin Pediatr 2010 22 4 508 515 10.1097/MOP.0b013e32833b7c23 20601885\n18. Davies JH Shaw NJ Investigation and management of hypercalcaemia in children Arch Dis Child 2012 97 6 533 538 10.1136/archdischild-2011-301284 22447996\n19. Mihatsch W Fewtrell M Goulet O Molgaard C Picaud JC Senterre T ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: calcium, phosphorus and magnesium Clin Nutr 2018 37 6 2360 2365 10.1016/j.clnu.2018.06.950 30097365\n20. Fenton TR Lyon AW Rose MS Cord blood calcium, phosphate, magnesium, and alkaline phosphatase gestational age-specific reference intervals for preterm infants BMC Pediatr 2011 11 1 76 10.1186/1471-2431-11-76 21884590\n21. Bolisetty S Pharande P Nirthanakumaran L Do TQ Osborn D Smyth J Improved nutrient intake following implementation of the consensus standardized parenteral nutrition formulations in preterm neonates before-after intervention study BMC Pediatr 2014 14 1 309 10.1186/s12887-014-0309-0 25514973\n22. Imel EA Econs MJ Approach to the hypophosphatemic patient J Clin Endocrinol Metab 2012 97 3 696 706 10.1210/jc.2011-1319 22392950\n23. Bustos Lozano G Soriano-Ramos M Pinilla Martín MT Chumillas Calzada S García Soria CE Pallás-Alonso CR Early hypophosphatemia in high-risk preterm infants: efficacy and safety of sodium Glycerophosphate from first day on parenteral nutrition J Parenter Enter Nutr 2019 43 3 419 425 10.1002/jpen.1426\n24. Senterre T Abu Zahirah I Pieltain C de Halleux V Rigo J Electrolyte and mineral homeostasis after optimizing early macronutrient intakes in VLBW infants on parenteral nutrition J Pediatr Gastroenterol Nutr 2015 61 4 491 498 10.1097/MPG.0000000000000854 25988555\n25. Mulla S Stirling S Cowey S Close R Pullan S Howe R Radbone L Clarke P Severe hypercalcaemia and hypophosphataemia with an optimised preterm parenteral nutrition formulation in two epochs of differing phosphate supplementation Arch Dis Child Fetal Neonatal Ed 2017 102 5 F451 F455 10.1136/archdischild-2016-311107 28456753\n26. Christmann V de Grauw AM Visser R Matthijsse RP van Goudoever JB van Heijst AF Early postnatal calcium and phosphorus metabolism in preterm infants J Pediatr Gastroenterol Nutr 2014 58 4 398 403 10.1097/MPG.0000000000000251 24253367\n27. American Academy of Pediatrics Committee on Nutrition Kleinman RE Nutritional needs of the preterm infant Pediatric Nutrition 2014 7 IL American Academy of Pediatrics 86 90\n28. National Institute for Health and Care Excellence Neonatal parenteral nutrition Ratio of phosphate to amino acids. NICE guideline NG154 2020\n29. Nesargi SV Bhat SR Rao PNS Iyengar A Hypercalcemia in extremely low birth weight neonates Indian J Pediatr 2012 79 1 124 126 10.1007/s12098-011-0511-0 21732019\n30. Lyon AJ McIntosh N Wheeler K Brooke OG Hypercalcaemia in extremely low birthweight infants Arch Dis Child 1984 59 12 1141 1144 10.1136/adc.59.12.1141 6441525\n\n",
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"keywords": "Case report; Extremely low birth weight; Hypercalcemia; Hypophosphatemia; Small for gestational age",
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"title": "Severe hypercalcemia associated with hypophosphatemia in very premature infants: a case report.",
"title_normalized": "severe hypercalcemia associated with hypophosphatemia in very premature infants a case report"
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"abstract": "Pseudoporphyria (PP) is used to describe a photodistributed bullous disorder with clinical and histologic features of porphyria cutanea tarda (PCT) but without accompanying biochemical porphyrin abnormalities. Medications, excessive sun and ultraviolet radiation exposure, have all been reported to develop PP. We report a case of PP in a 49-year-old man with CKD stage 3a, caused due to torsemide intake. This is probably the first reported case of PP developing in a dialysis naive patient CKD due to torsemide intake from India.",
"affiliations": "Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.;Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.;Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.",
"authors": "Quaiser|S|S|;Khan|R|R|;Khan|A S|AS|",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-25-30710.4103/0971-4065.160335Case ReportDrug induced pseudoporphyria in CKD: A case report Quaiser S. Khan R. Khan A. S. Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, IndiaAddress for correspondence: Dr. R. Khan, Department of Medicine, JNMC, AMU, Aligarh - 202 002, Uttar Pradesh, India. E-mail: drruhi5@gmail.comSep-Oct 2015 25 5 307 309 Copyright: © Indian Journal of Nephrology2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Pseudoporphyria (PP) is used to describe a photodistributed bullous disorder with clinical and histologic features of porphyria cutanea tarda (PCT) but without accompanying biochemical porphyrin abnormalities. Medications, excessive sun and ultraviolet radiation exposure, have all been reported to develop PP. We report a case of PP in a 49-year-old man with CKD stage 3a, caused due to torsemide intake. This is probably the first reported case of PP developing in a dialysis naive patient CKD due to torsemide intake from India.\n\nChronic kidney diseasepseudoporphyriatorsemide\n==== Body\nIntroduction\nPseudoporphyria (PP) is a rare, photodistributed bullous dermatosis that clinically, histopathologically, and immunologically resembles porphyria cutanea tarda (PCT)[12] but is not accompanied by porphyrin abnormalities in the serum, urine, or stool. It was initially described in patients with renal failure on dialysis as \"bullous dermatosis of hemodialysis.\"[3] Subsequently, PP has been associated with numerous photosensitizing medications, hormone replacement, and ultraviolet A (UVA) radiation in tanning beds, hepatitis C, sarcoidosis, Sjogren syndrome, hepatoma, HIV infection and lupus erythematosus. Drugs commonly associated with pseudoporphyria are naproxen, tetracycline, fluoroquinolones, voriconazole, furosemide, chlorthalidone, butamide, hydrochlorothiazide/triamterene, amiodarone, cyclosporine.[4]\n\nCase Report\nA 49-year-old hypertensive male presented with swelling over the body for the last 1-month. On detailed clinical and diagnostic workup, he was diagnosed as a case of chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate 51.6 ml/min/1.73 m2) of unknown etiology. He was prescribed torsemide, cilnidipine, calcium acetate, ferrous ascorbate, paricalcitol along with low salt and protein restricted diet. Three weeks later he came with complains of several erythematous lesions of the forearm and around the wrist. On clinical examination, several slightly pruritic, round, sharply demarcated, erythematous vesicular plaques were observed, symmetrically distributed over the anterior aspect of the forearm. No evidence of hypertrichosis, hyperpigmentation or sclerodermoid changes was seen [Figure 1].\n\nFigure 1 Erythematous vesicular plaques on anterior aspect of the forearm and palm\n\nDermatological opinion was suggestive of a blistering disorder either porphyria cutaneous tarda or PP. Histological examination undertaken of skin lesion showed hyperkeratosis and acanthosis of the epidermis. In the papillary dermis, we noted subepidermal cleft with preservation of papillae and no inflammatory infiltrate along with periodic acid stain positive, diastase negative, eosinophilic, donut-like rings around the capillaries as shown in Figures 2 and 3. Direct immunofluorescence showed microgranular deposition of the C3 around the papillary dermal vessels as shown in Figure 4. Levels of plasma porphyrins were normal (protoporphyrin <0.5 μg/L (normal <0.75 μg/L), coproporphyrin <0.01 μg/L (normal <0.01 μg/L); urinary levels were normal: Porphobilinogen 6 μmol/dl (normal <8 μmol/dl), uroporphyrin 21 nmol/dl (normal <28 nmol/dl); coproporphyrin I was normal at 12 nmol/dl (normal <35 nmol/dl); and coproporphyrin III was normal at 11 nmol/dl (normal <110 nmol/dl). Fecal total coproporphyrin was also normal at 25 nmol/g (normal 0–46 nmol/g), and fecal total porphyrin was 10 nmol/g (normal 0–50 nmol/g). Other laboratory investigations were as follows: Hemoglobin 9.6 g/dl (normal range 11.5–14.5 g/dl); serum iron 23 μmol/L (normal range 10–30 μmol/L); ferritin 207 μg/L (normal range 50–250 μg/L); alkaline phosphatase 102 U/L (normal range 40–120 U/L); alanine aminotransferase 15 U/L (normal range 10–55 U/L); and aspartate aminotransferase 19 U/L (normal range 10–40 U/L). Screening for hepatitis viruses and the human immunodeficiency virus were negative. Based on clinical and histological grounds, a diagnosis of PP was made. Torsemide was withdrawn, and the patient was treated for 4 weeks with antihistaminic with an only minimal improvement, which were then withdrawn. On 2 month follow-up, there was a significant improvement while in 4 months the lesions cleared completely with only residual post-inflammatory hyperpigmentation.\n\nFigure 2 Skin biopsy with hematoxylin and eosin stain showing subepidermal cleft with preservation of papillae with no inflammatory infiltrate (×40)\n\nFigure 3 Skin biopsy with Periodic acid Schiff (PAS) stain showing PAS-positive diastase negative hyaline material thickening the wall of dermal vessel and dermo-epidermal junction (×40)\n\nFigure 4 Direct Immunofluorescence - C3 deposits around dermal vessels and dermo-epidermal junction\n\nDiscussion\nIn 1964, Zelickson was first to describe this type of phototoxic reaction in patients after the use of nalidixic acid.[5] In a retrospective study of 20 cases, the mean age at diagnosis was 50 years.[6] Among patients with the end-stage renal disease, PP has been estimated to occur in 1.2–18% of those on hemodialysis and, less frequently, in those on peritoneal dialysis.[3]\n\nClinically, PP is characterized by bullae, developing on the photo-exposed skin, most commonly on the dorsum of the hands and feet, forearms, face, and neck. The lesions heal with scaring and milia formation. In contrast to PCT, hypertrichosis, hyperpigmentation, and sclerodermoid plaques only rarely occur.\n\nOf critical importance for the diagnosis of PP is the exclusion of true porphyria, especially PCT. By definition, in PP porphyrin profile is normal or near normal.[6] Individuals with CKD tend to have higher serum porphyrin levels than normal, with some levels determined to be within the lower end of the range commonly found in PCT patients with normal renal function. Furthermore, plasma uroporphyrin levels are generally higher in patients on hemodialysis compared with those on peritoneal dialysis, which may explain the lower incidence of PP in the latter group.\n\nIf the diagnosis of PP is suspected, biopsies for histologic evaluation with hematoxylin and eosin stains and direct immunofluorescence should be performed. Serum samples may also be obtained for indirect immunofluorescence evaluation to aid in the exclusion of bullous pemphigoid. The histologic features of PP are similar to those of PCT with subepidermal bullae and festooning of the dermal papillae and granular deposits of immunoglobulins, mostly IgG, and C3 at the basement membrane zone and in the perivascular region. Although direct immunofluorescence is not a useful tool in distinguishing PP from PCT, it is helpful in the evaluation of other entities in the differential diagnosis of PP, specifically epidermolysis bullosa acquisita. Epidermolysis bullosa acquisita can be ruled out by the lack of intense, linear immunoreactants at the dermal-epidermal junction. Neither PCT nor PP has circulating autoantibodies detected by indirect immunofluorescence study.\n\nThe thickness of the blood vessel wall may prove helpful in differentiating PP from PCT. In a comparative histologic study from biopsy samples of patients with PCT and PP, Maynard and Peters found thickened blood vessel walls in 11 of 13 patients with PCT. In contrast, similar findings in only 1 of 9 patients with PP were present.[7]\n\nThe exact pathophysiological mechanism of PP is unknown. Formation of phototoxic metabolites in genetically predisposed individuals may trigger the development of bullous lesions. In general, the action spectrum has been assumed to be in the range of UV radiation or possibly, visible light. There is evidence that some of the causally associated drugs also induce photosensitivity. Reactive oxygen species have been incriminated in the pathogenesis of dialysis-associated PP. These patients are at high-risk of oxidative stress due to deficiency of glutathione in the blood and erythrocytes, which may increase their susceptibility to the effects of UV exposure at even lower porphyrin levels. In addition, clearance of plasma-bound porphyrin precursors may lead to excessive porphyrin deposition in the skin. It could also be related to aluminum hydroxide, which is found in the dialysis solution and has been shown to produce a porphyria-like reaction to rats.\n\nIn cases of drug-induced PP, withdrawal of the suspected photosensitizing medication results in improvement usually within weeks to months (average 8 weeks) which were seen in our case. Strict UV rays protection, including a broad spectrum sunscreen, is crucial. In hemodialysis-associated PP, there are reports of complete resolution after treatment with N-acetylcysteine (800–1200 mg p.o. daily for 8 weeks), a glutathione precursor, but some authors noticed recurrence when the drug was discontinued.[8910] Chloroquine also has been tried with satisfactory results after 1-month.\n\nOur patient is probably the second reported case,[11] of PP developing in dialysis naive CKD patient, first from India. The question whether it is the disease CKD or the management (hemodialysis) which contributes most to the occurrence of PP remains to be answered. Dialysis in genetically predisposed patients may indeed contribute to PP development, either by the resulting in oxidative stress or by reflecting a more advanced stage of renal failure. Finally, but a thorough drug history should be ascertained in such cases, which might minimize the morbidity associated with this disorder.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Rapini RP Bolognia JL Jorizzo JL Dermatology: 2-Volume Set 2007 St. Louis Mosby \n2 James WD Berger TG Dirk Elston MD Andrews’ Diseases of the Skin: Clinical Dermatology 2006 United States Saunders Elsevier ISBN: 978-1-4377-0314-6 \n3 Green JJ Manders SM Pseudoporphyria J Am Acad Dermatol 2001 44 100 8 11148469 \n4 Suarez SM Cohen PR DeLeo VA Bullous photosensitivity to naproxen: “Pseudoporphyria” Arthritis Rheum 1990 33 903 8 2194465 \n5 Zelickson AS Phototoxic reaction with nalidixic acid JAMA 1964 190 556 7 14198018 \n6 Schanbacher CF Vanness ER Daoud MS Tefferi A Su WP Pseudoporphyria: A clinical and biochemical study of 20 patients Mayo Clin Proc 2001 76 488 92 11357795 \n7 Maynard B Peters MS Histologic and immunofluorescence study of cutaneous porphyrias J Cutan Pathol 1992 19 40 7 1556265 \n8 Guiotoku MM Pereira Fde P Miot HA Marques ME Pseudoporphyria induced by dialysis treated with oral N-acetylcysteine An Bras Dermatol 2011 86 383 5 21603831 \n9 Vadoud-Seyedi J De Dobbeleer G Simonart T Treatment of haemodialysis-associated pseudoporphyria with N-acetyleysteine: Report of two cases Br J Dermatol 2000 142 580 1 10777273 \n10 Tremblay JF Veilleux B Pseudoporphyria associated with hemodialysis treated with N-acetylcysteine J Am Acad Dermatol 2003 49 1189 90 14639417 \n11 Pérez-Bustillo A Sánchez-Sambucety P Suárez-Amor O Rodríiguez-Prieto MA Torsemide-induced pseudoporphyria Arch Dermatol 2008 144 812 3 18559783\n\n",
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"journal": "Indian journal of nephrology",
"keywords": "Chronic kidney disease; pseudoporphyria; torsemide",
"medline_ta": "Indian J Nephrol",
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"abstract": "Varenicline is a smoking cessation agent. Varenicline acts as a partial agonist of α4β2 neuronal nicotinic acetylcholine receptor and prevents nicotine binding to the same. It also causes dopamine (DA) stimulation that decreases craving and symptoms of dependence. A 40-year-old male diagnosed with alcohol and nicotine dependence syndrome was treated with 1 mg of varenicline for 3 days. Patient developed episodes of transient delirium within 15-30 min after administration of varenicline. Patient was disoriented and did not respond relevantly. Patient would have disorientation and would respond irrelevantly and was unable to recall the event completely. There were no features suggestive of seizures. The episodes resolved after the medication was stopped. Varenicline, with its partial agonistic effect on nicotinergic receptors, stimulates the release of multiple neurotransmitters including DA. DA dysregulation is probably responsible for the development of neuropsychiatric adverse reactions due to varenicline. This is the first case report to the best of our knowledge reporting varenicline induced dilirium. In this case, the adverse event was found in an alcohol and nicotine dependent patient undergoing treatment. It is essential to monitor uncommon adverse effects as this can cause significant morbidity.",
"affiliations": "Department of Pharmacy Practice, M.S. Ramaiah College of Pharmacy, Bengaluru, Karnataka, India.;Department of Psychiatry, M.S. Ramaiah Medical College, Bengaluru, Karnataka, India.;Department of Pharmacy Practice, M.S. Ramaiah College of Pharmacy, Bengaluru, Karnataka, India.;Department of Pharmacy Practice, M.S. Ramaiah College of Pharmacy, Bengaluru, Karnataka, India.;Department of Pharmacy Practice, M.S. Ramaiah College of Pharmacy, Bengaluru, Karnataka, India.;Department of Psychiatry, M.S. Ramaiah Medical College, Bengaluru, Karnataka, India.",
"authors": "Narayan|A Lakshmi|AL|;Virupaksha|H S|HS|;Thejaswi|G|G|;Saraswathy|G R|GR|;Madhavan|V|V|;Thyloth|Murali|M|",
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"fulltext": "\n==== Front\nIndian J Psychol MedIndian J Psychol MedIJPsyMIndian Journal of Psychological Medicine0253-71760975-1564Medknow Publications & Media Pvt Ltd India IJPsyM-37-35510.4103/0253-7176.162926Case ReportA Case Report on Varenicline Induced Delirium in an Alcohol and Nicotine Dependent Patient Narayan A. Lakshmi Virupaksha H. S. 1Thejaswi G. Saraswathy G. R. Madhavan V. Thyloth Murali 1Department of Pharmacy Practice, M.S. Ramaiah College of Pharmacy, Bengaluru, Karnataka, India1 Department of Psychiatry, M.S. Ramaiah Medical College, Bengaluru, Karnataka, IndiaAddress for correspondence: Dr. H. S. Virupaksha Department of Psychiatry, M.S. Ramaiah Medical College, MSRIT Post, MSR Nagar, Mathikere, Bengaluru, Karnataka, India. E-mail: virupaksha.hs@gmail.comJul-Sep 2015 37 3 355 357 Copyright: © Indian Journal of Psychological Medicine2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Varenicline is a smoking cessation agent. Varenicline acts as a partial agonist of α4β2 neuronal nicotinic acetylcholine receptor and prevents nicotine binding to the same. It also causes dopamine (DA) stimulation that decreases craving and symptoms of dependence. A 40-year-old male diagnosed with alcohol and nicotine dependence syndrome was treated with 1 mg of varenicline for 3 days. Patient developed episodes of transient delirium within 15-30 min after administration of varenicline. Patient was disoriented and did not respond relevantly. Patient would have disorientation and would respond irrelevantly and was unable to recall the event completely. There were no features suggestive of seizures. The episodes resolved after the medication was stopped. Varenicline, with its partial agonistic effect on nicotinergic receptors, stimulates the release of multiple neurotransmitters including DA. DA dysregulation is probably responsible for the development of neuropsychiatric adverse reactions due to varenicline. This is the first case report to the best of our knowledge reporting varenicline induced dilirium. In this case, the adverse event was found in an alcohol and nicotine dependent patient undergoing treatment. It is essential to monitor uncommon adverse effects as this can cause significant morbidity.\n\nDeliriumtobacco cessationvarenicline\n==== Body\nINTRODUCTION\nVarenicline is an anti-craving drug used for smoking cessation. The addiction toward smoking is mediated by nicotine, which stimulates α4β2 nicotinic acetylcholine receptors (nAChRs) in brain. Varenicline is a novel α4β2 nAChR partial agonist and has been found to be more effective than nicotine replacement therapy or bupropion in relieving craving and withdrawal symptoms after abstinence. It functions by preventing nicotine binding to the above mentioned receptors. It also provides low to moderate level of dopamine (DA) stimulation that helps to alleviate craving and symptoms of dependence.[1]\n\nIn tobacco smokers, a partial agonist would mostly work as an antagonist during smoking (i.e., high nicotine occupancy), but as an agonist during abstinence or withdrawal (i.e., low nicotine occupancy). Thus, the rewarding effects of smoking would decrease substantially, but not disappear completely, whereas withdrawal symptoms and craving episodes would occur less frequently during abstinence due to the release of a low-to-moderate level of DA produced by a partial agonist itself. Thus, varenicline has been recently Food and Drug Administration approved to be a first-line medication for smoking cessation in the United States and European countries. The most commonly reported adverse effects include nausea, insomnia, and headache. On the other hand, postmarketing data has linked varenicline to various neuropsychiatric symptoms such as seizures, suicidal attempts, depression, and psychosis. Other serious injuries potentially related to unconsciousness, dizziness or visual disturbances due to varenicline have also been reported.[2]\n\nCASE REPORT\nA 40-year-old male patient was admitted and treated for alcohol and nicotine dependence syndrome. After discharge, as he had significant craving for nicotine he was started on 0.5 mg tablet varenicline for 3 days, 0.5 mg twice daily for 4 days and then increased to 1 mg twice a day. Patient developed episodes of transient delirium 15-30 min after taking varenicline 1 mg twice a day. Patient was observed to be disoriented to time and place and at times, disoriented to person and would not respond relevantly. These episodes (total of three) were reported to last for around 30 min and resolved spontaneously after 30-40 min. Patient reported a sense of confusion and could not recall the event completely. There were no features suggestive of seizures. The episodes resolved after the medication was stopped. On general physical examination, there were no abnormalities and his investigations looking at electrolytes, liver function and renal function and were normal. Other parameters which could lead to delirium were absent. Patient did not have episodes of delirium after the reduction of the dose. There were no additional drugs prescribed during this period.\n\nDISCUSSION\nTo the best of our knowledge, this is the first report of varenicline induced delirium. There is one case report of varenicline withdrawal delirium.[3] In this case report, the symptoms were noted after abrupt stoppage of varenicline and clear association could not be determined.\n\nIn our case, there was temporal relationship between the increase of the dose and delirium, which resolved after reduction in the dose to 0.5 mg twice daily. The prime site of nicotine action in the brain is the mesolimbic system. Nicotine stimulates dopaminergic neurons located in the ventral tegmental area, increasing DA release in the nucleus accumbens. Nicotine interacts with nAChRs, which are pentameric ion channels located in the mesolimbic system. The highest-affinity nAChRs consist of two α4 subunits and three β2 subunits. Nicotine binds to and causes a conformational change in the α4β2 nAChR, increasing sodium (Na+) influx, resulting in release of DA. Varenicline causes partial stimulation and competitively inhibits nicotine binding. It helps chronic smokers to stop smoking by maintaining moderate levels of DA to counteract withdrawal symptoms of nicotine abstinence.[4] It mimics the action of nicotine and causes a moderate and sustained release of mesolimbic DA [Figure 1]. Because it is a partial agonist at these receptors, it elicits DA overflow, but not equivalent to the substantial increases evoked by nicotine.\n\nFigure 1 Mechanism of delirium by varenicline\n\nResponses mediated by the α4 subunit are thought to be responsible for sensitization to nicotinic effects, reinforcement, and tolerance, whereas involvement of the β2 subunit is thought to be associated with the development of dependence. Stimulation of DA release by nicotine also appears to be related to activation of glutamatergic and GABAergic neurons that contain nAChRs, which may mediate reinforcing behaviors in smokers.[5]\n\nNeural pathways that include prefrontal cortices, anterior and right thalamus, and right basilar mesial temporoparietal cortex, may be a final common pathway for delirium. This pathway may be responsible for symptoms such as disorientation, cognitive deficits, sleep-wake cycle disturbance, disorganized thinking, delusions, and affective lability. An imbalance in the cholinergic (acetylcholine [Ach] deficiency) and dopaminergic (DA excess) neurotransmitter systems appears to be critical in the final common pathway, which is commonly implicated in causing delirium. Varenicline, being a partial agonist of α4β2 nAChR receptors can explain the delirium symptoms and also it is consistent with the neuroanatomical pathways being implicated.[67]\n\nNicotine receptors within the brain bind Ach to modulate cognitive functioning, arousal, learning, and memory. Muscarinic Ach receptors, more widely distributed throughout the brain, may play a larger role in delirium. Anticholinergic compounds induce delirium through competitive antagonism of post synaptic muscarinic receptors. The cholinergic system is balanced by monoamine activity where dysfunction has also been associated with delirium. DA, NE, and 5HT have roles in arousal and the sleep-wake cycle, mediating physiological responses to stimuli. These responses are mediated by the cholinergic pathway. Thus, delirium development might involve interaction between the cholinergic pathway and these monoamines.\n\nVarenicline has been found to be a full agonist at the alpha 7-homomeric receptors. Several experimental studies have found that alpha 7-homomeric nicotinic receptors in the ventro tegmental area are involved in DA release in the nucleus accumbens.[4]\n\nDopamine excess may contribute to hyperactive delirium, linked to simultaneous Ach decreases. Thus, Ach and DA may be inversely related in delirium pathogenesis; pharmacological and neuroanatomical evidence support this model. Anatomically dopaminergic and cholinergic pathways overlap significantly in the brain. DA receptors impact Ach levels differently, which may explain the diverse clinical manifestations of delirium.[8]\n\nVarenicline binds with moderate affinity to the 5HT3 receptors it is possible that endogenous 5HT in stratum or nucleus accumbens acts as a local regulator of DA release acting via a transport-dependent mechanism.[6] A micro-analysis study in rats provided in vivo evidence of 5HT3 receptor agonist induced DA transporter mediated increase in DA release.[9] Moreover, stimulation of 5HT3 receptors inhibits Ach release.[10]\n\nReduced cholinergic function, excess release of DA, norepinephrine, glutamate, alterations in levels of serotonergic, gamma-aminobutyric acid activity may underlie the different symptoms and clinical presentations of delirium.[11]\n\nCONCLUSION\nVarenicline is associated with a higher risk of neuropsychiatric events. In this case, delirium was noted in an alcohol dependent patient undergoing treatment of the same. It is essential to monitor uncommon side effects especially delirium as this can cause significant morbidity and also possibility of mortality as a consequence.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Kasliwal R Wilton LV Shakir SA Safety and drug utilization profile of varenicline as used in general practice in England: Interim results from a prescription-event monitoring study Drug Saf 2009 32 499 507 19459717 \n2 Xi ZX Preclinical Pharmacology, Efficacy and Safety of Varenicline in Smoking Cessation and Clinical Utility in High Risk Patients Drug Healthc Patient Saf 2010 2010 39 48 \n3 May AC Rose D Varenicline withdrawal-induced delirium with psychosis Am J Psychiatry 2010 167 720 1 20516169 \n4 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 2012 4 CD006103 \n5 Garrison GD Dugan SE Varenicline: A first-line treatment option for smoking cessation Clin Ther 2009 31 463 91 19393839 \n6 Trzepacz PT Update on the neuropathogenesis of delirium Dement Geriatr Cogn Disord 1999 10 330 4 10473933 \n7 Trzepacz PT Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine Semin Clin Neuropsychiatry 2000 5 132 48 10837102 \n8 Hshieh TT Fong TG Marcantonio ER Inouye SK Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence J Gerontol A Biol Sci Med Sci 2008 63 764 72 18693233 \n9 Fink KB Göthert M 5-HT receptor regulation of neurotransmitter release Pharmacol Rev 2007 59 360 417 18160701 \n10 Bianchi C Siniscalchi A Beani L 5-HT1A agonists increase and 5-HT3 agonists decrease acetylcholine efflux from the cerebral cortex of freely-moving guinea-pigs Br J Pharmacol 1990 101 448 52 2147866 \n11 van der Mast RC Pathophysiology of delirium J Geriatr Psychiatry Neurol 1998 11 138 45 9894732\n\n",
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"abstract": "Symptoms of psychotic disorders can complicate efforts to accurately evaluate patients' medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders.\nThis was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs).\nFrom May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported.\nThe DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.",
"affiliations": "Global Clinical Development, CNS and Digital Medicine, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA.;Program Management, Otsuka Pharmaceutical Europe Ltd., Wexham, SL3 6PJ, UK.;Data Insights and Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA.;Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA.;Clinical Management, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA.;Institute of Psychiatry, Psychology and Neuroscience, King's College London and South London and Maudsley NHS Foundation Trust, London, SE5 8AF, UK.;Southern Health NHS Foundation Trust, Moorgreen Hospital, Clinical Trials Facility, Research Department, Southampton, SO30 3JB, UK.;Southern Health NHS Foundation Trust, Moorgreen Hospital, Clinical Trials Facility, Research Department, Southampton, SO30 3JB, UK.;Global Clinical Development, CNS and Digital Medicine, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA.",
"authors": "Fowler|J Corey|JC|;Cope|Nathan|N|;Knights|Jonathan|J|;Fang|Hui|H|;Skubiak|Taisa|T|;Shergill|Sukhi S|SS|;Phiri|Peter|P|;Rathod|Shanaya|S|;Peters-Strickland|Timothy|T|",
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"fulltext": "\n==== Front\nNeuropsychiatr Dis Treat\nNeuropsychiatr Dis Treat\nndt\nneurodist\nNeuropsychiatric Disease and Treatment\n1176-6328 1178-2021 Dove \n\n290793\n10.2147/NDT.S290793\nClinical Trial Report\nHummingbird Study: Results from an Exploratory Trial Assessing the Performance and Acceptance of a Digital Medicine System in Adults with Schizophrenia, Schizoaffective Disorder, or First-Episode Psychosis\nFowler et alFowler et alFowler J Corey 1 Cope Nathan 2 Knights Jonathan 3 Fang Hui 4 Skubiak Taisa 5 Shergill Sukhi S 6 Phiri Peter 7 Rathod Shanaya 7 Peters-Strickland Timothy 1 1 Global Clinical Development, CNS and Digital Medicine, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA\n2 Program Management, Otsuka Pharmaceutical Europe Ltd., Wexham, SL3 6PJ, UK\n3 Data Insights and Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA\n4 Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA\n5 Clinical Management, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA\n6 Institute of Psychiatry, Psychology and Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, London, SE5 8AF, UK\n7 Southern Health NHS Foundation Trust, Moorgreen Hospital, Clinical Trials Facility, Research Department, Southampton, SO30 3JB, UK\nCorrespondence: J Corey Fowler Otsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USATel +1 919 475 4823 Email corey.fowler@otsuka-us.com\n12 2 2021 \n2021 \n17 483 492\n06 11 2020 23 1 2021 © 2021 Fowler et al.2021Fowler et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nSymptoms of psychotic disorders can complicate efforts to accurately evaluate patients’ medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders.\n\nMethods\nThis was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT 03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs).\n\nResults\nFrom May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported.\n\nConclusion\nThe DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.\n\nKeywords\ndigital medicineantipsychoticdigital healthmedication adherenceOxford PharmaGenesis IncOtsuka Pharmaceutical Development & Commercialization, IncOtsuka Pharmaceutical Development & Commercialization, IncEditorial support for the development of this manuscript was provided by Michael Venditto, PharmD, and V. Ruvini Jayasinghe, PhD, of Oxford PharmaGenesis Inc, Newtown, PA, USA, which was funded by Otsuka Pharmaceutical Development & Commercialization, Inc. This study was funded and supported by the sponsor, Otsuka Pharmaceutical Development & Commercialization, Inc. Several authors are employees of Otsuka and therefore the study sponsor was involved in all aspects of this study and manuscript preparation.\n==== Body\nIntroduction\nSchizophrenia is a psychotic disorder that presents global health challenges and is among the leading causes of disability.1,2 The global prevalence of schizophrenia has increased from approximately 13 million people in 1990 to over 20 million in 2016.3 In Europe, the economic burden of psychotic disorders was estimated to be €93.9 billion in 2010.4 Schizophrenia, schizoaffective disorder, and first-episode psychosis are similarly presenting mental illnesses.5 Schizophrenia consists of psychosis, which can present as multiple symptoms, such as delusions, hallucinations, disorganized behavior, and a lack of awareness of disease.5 Schizoaffective disorder involves schizophrenia symptoms in the presence of major depressive episodes, with or without bipolar mania.5 First-episode psychosis refers to a period after an initial psychotic episode and recovery.5 The therapeutic goals for schizophrenia and other psychotic disorders include symptom control and relapse prevention.1,6 Antipsychotics, such as aripiprazole, olanzapine, quetiapine, and risperidone, are considered the first-line pharmacotherapy for these psychotic disorders.1,6\n\nAdherence to therapy is a major challenge in patients with psychotic disorders.7 An estimated 41–50% of patients with schizophrenia, and approximately 55% of patients with first-episode psychosis, are not fully adherent with their medication.7,8 Psychotic symptoms, such as unawareness of illness, poor memory, depression, paranoid delusions, and hallucinations, could underlie nonadherence in these patients.1,7 Poor adherence to antipsychotics has been associated with higher rates of violence, hospital admission, substance abuse, and an increased risk of mortality.9,10 Many tools are used to measure adherence, such as self-reporting, direct visualization, biomarkers and metabolites, pharmacy prescription data, and medication event-monitoring systems.10 Electronic adherence monitoring (EAM), which measures when medication is accessed, has been considered the gold standard of adherence measurement, and a recent meta-analysis found that EAM-measured adherence to oral antipsychotics was approximately 70%.11 These adherence tools, however, may be associated with disadvantages.12,13 For example, self-reporting and observational methods may be affected by patients reporting incorrect information or tampering with an adherence device (either purposefully or by accident), and measuring drug metabolism through assays can be expensive and intrusive.12,13\n\nThe digital medicine system (DMS) measures ingestion of a medication using an ingestible sensor that is either embedded within a tablet14,15 or embedded within an inert tablet and co-encapsulated with an oral medication tablet.16 After ingestion of the tablet, the sensor is activated by stomach fluid and sends a signal to a wearable sensor patch attached to the patient’s torso.16 A smartphone application collects these data from the patch via Bluetooth and transfers them to a secure digital health data server.16 The data can be accessed by patients through the smartphone application or by healthcare providers and caregivers through separate web portals.16 The DMS is intended to encourage greater self-management of mental illness by helping the patient and their healthcare provider track their medication-taking behaviors to support informed treatment discussions.16\n\nIncorporating smartphones in adherence management offers new opportunities and benefits—most patients with psychosis who own mobile phones use them daily, and smartphone ownership, while lower among those with psychosis than in the general population, is also growing.17–19 Although studies have shown that patients with schizophrenia may not have negative experiences with mobile devices,20 data collection could present a barrier for patients with paranoia or who are uncomfortable with this information being shared.17 Data collection also introduces numerous complex ethical issues regarding the privacy and security of patient information, which must be addressed to ensure patient and public trust in digital medicine.17 To protect patient privacy, the DMS is patient-centric, and allows specific authorization as to which healthcare providers, caregivers, and family members can access the information collected. The DMS uses industry-standard encryption protocols for data transmission from the patch to the mobile device, and from devices to the server; DMS data can be accessed only through the sponsor’s servers, which are also protected with industry-standard security features.\n\nIn previous Phase 2 clinical studies, the DMS was evaluated in the United States (US) in subjects with schizophrenia, bipolar I disorder, and major depressive disorder who were considered clinically stable and were receiving oral aripiprazole.21,22 The first DMS used aripiprazole paired with a sensor and was approved in the US as monotherapy for schizophrenia or bipolar 1 disorder, and as an adjunctive treatment for major depressive disorder.23 The DMS in this study used ingestible and wearable sensors certified by the British Standards Institute for use in Europe as class IIa medical devices (Conformité Européenne #559,373).24\n\nIn this phase 4 pragmatic study (the Hummingbird Study), we evaluated the clinical utility of the DMS in patients diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis potentially presenting with acute mental illness, who were receiving oral aripiprazole, olanzapine, quetiapine, or risperidone, and who also had a smartphone to use in the study. This study was performed using the National Health Service (NHS) Mental Health Trusts in the United Kingdom (UK), which presented an opportunity to evaluate the DMS in a different treatment system outside of the US.\n\nMethods\nStudy Design and Participants\nThis was an 8-week open-label, single-arm, multicenter, phase 4 pragmatic study performed at 5 NHS Foundation Trusts in the UK. The study was conducted in accordance with local laws, the International Conference on Harmonization Good Clinical Practice Consolidated Guideline, and the Declaration of Helsinki. The study protocol was approved by the London – City and East Research Ethics Committee and was registered with ClinicalTrials.gov (NCT 03568500) and with EudraCT (#2017-004602-17). All subjects provided written informed consent prior to participating in the study.\n\nSubjects for this study were identified using database searches conducted at each study site per provider discretion, from a range of clinical populations, including those being treated by acute-care teams or by community services. Key eligibility criteria included subjects being aged between 18 to 65 years; having a diagnosis of schizophrenia, schizoaffective disorder, or first-episode psychosis; and having a prescription for oral aripiprazole, olanzapine, quetiapine, or risperidone. Eligible subjects were able to complete onboarding and use the DMS by downloading and using the application on their personal smartphone with internet connectivity. Subjects were excluded from the study if they had an intellectual developmental delay or disorder, major neurocognitive disorder, or another condition that might impact the subject’s ability to participate in the trial or interact with the DMS, or if they were advised to not participate in the trial per their healthcare provider’s judgement. Full eligibility criteria and the study design have been previously published.16\n\nProcedures\nSubjects were screened for up to 1 week, followed by an 8-week assessment period while using the DMS (Appendix s-Figure-1). A safety follow-up telephone call was performed 2 weeks after the last visit. The DMS included a drug–device combination of the patient’s prescribed oral antipsychotic medication tablet co-encapsulated with an ingestible event marker (IEM) embedded in an inert tablet (Proteus Digital Health Inc., Redwood City, CA), a sensor patch (Disposable Wearable Sensor version 5 [DW-5], Proteus Digital Health Inc., Redwood City, CA) that was applied to the torso to detect ingestion of the antipsychotic, and a smartphone application for subjects with a web portal for healthcare providers (Otsuka Medical software version 2.1; Otsuka Pharmaceutical Development and Commercialization, Inc., Princeton, NJ). This study was conducted using both Android and iOS versions of the smartphone application. An integrated call center was available to answer any technical questions on the use of the DMS from the study subjects and participating investigators or site staff.\n\nOutcomes\nThe primary endpoint was the mean proportion of days with good patch coverage. Good patch coverage was defined as either having the patch worn with data collected for 80.0% or greater of the time or having an IEM detected within a given day of the assessment period. The primary endpoint was calculated per subject as days of good patch coverage divided by all assessment days (from first drug intake date until the last drug intake date for each subject). Each subject’s coverage value was then averaged to calculate a mean for each of the 3 diagnostic categories, as well as for the overall study population. The secondary endpoint of adherence metric was calculated as the mean proportion of each subject’s number of detected IEMs divided by the expected number of IEMs on assessment days of good patch coverage.\n\nExploratory endpoints related to device performance were the mean proportion of days that subjects wore the patch during the assessment period, and the mean number of IEMs registered on the digital health data server divided by the expected number of IEMs during the assessment period. Exploratory endpoints related to acceptance were responses to the Subject Usability and Satisfaction Scale on week 8. Other exploratory endpoints assessed included changes from baseline to week 8 in Patient Activation Measure-Mental Health (PAM-MH)25 and Clinical Global Impression-Severity of Illness Scale (CGI-S)26 scores as measured in subjects with baseline and postbaseline scores. The number of times per day that subjects used the application and the number of times per week that healthcare providers used the web portal were also captured.\n\nSafety was assessed as the incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), serious AEs, and reports of suicide or suicidal ideation. All AEs were classified using preferred terms of the standardized Medical Dictionary for Regulatory Activities version 22.0. TEAEs of medical device (patch) site irritation were graded by the healthcare provider using the Skin Irritation Scoring System (grades 0–7).27\n\nStatistical Analyses\nAs this was a feasibility study, no statistical comparisons or power calculations were performed. A sample size of 60 subjects was planned for this study with an anticipated discontinuation rate of 25.0%. Performance and acceptance analyses were assessed in the intent-to-treat population, which was defined as all subjects who entered the trial and used the DMS. Safety analyses were performed in the safety population, which was defined similarly to the intent-to-treat population. Descriptive statistics were used for all endpoints. Continuous variables were summarized by means, medians, or ranges, and relevant quartiles, standard deviations (SD), or standard errors of the mean. Categorical variables were summarized using frequency distributions. No imputation was performed for other missing data, unless specified otherwise.\n\nRole of the Funding Source\nAll aspects of the trial (design; data collection, analysis, and interpretation; writing the report; and decision to submit the paper for publication) were managed by the sponsor, including oversight of the contract research organization. The corresponding author (JCF) had full access to all data in the study and had final responsibility for the decision to submit for publication.\n\nResults\nSubjects\nFrom May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled in the trial, of whom 54.5% (24/44) completed the trial (Figure 1). One subject discontinued from the trial without ingesting any study medication. Most subjects had a diagnosis of schizophrenia (40.9%; 18/44), followed by first-episode psychosis (36.4%; 16/44), and schizoaffective disorder (22.7%; 10/44; Table 1). All but 1 of the subjects enrolled received antipsychotic medication (Table 1). Overall, subjects used the DMS for 1760 days (aripiprazole group: 711 days; olanzapine group: 865 days; quetiapine group: 184 days [no subjects enrolled used risperidone]). Of the 20 subjects who discontinued the trial early, 65.0% (13/20) used the Android version of the application, 15.0% (3/20) used the iOS version, and 20.0% (4/20) did not report the version. Further, of those who discontinued the trial early, 85.0% (17/20) contacted the call center (a total of 100 calls) for assistance with patch-related issues. Six subjects withdrew consent; of these, one felt uncomfortable wearing the patch and taking medication, and another found it difficult to cope with the technology, reporting that it made them feel “anxious.”Table 1 Subject Demographics and Baseline Characteristics\n\nCharacteristics\tEnrolled Subjects \n(n = 44)\t\nMean age, years (SD)\t34.4 (10.7)\t\nSex\t\t\n Female\t15 (34.1)\t\n Male\t29 (65.9)\t\nRace\t\t\n Black\t8 (18.2)\t\n White\t35 (79.5)\t\n Other\t1 (2.3)\t\nPsychiatric disease\t\t\n Schizophrenia\t18 (40.9)\t\n Schizoaffective disorder\t10 (22.7)\t\n First-episode psychosis\t16 (36.4)\t\nAntipsychotic taken\t\t\n Aripiprazole\t18 (40.9)\t\n Olanzapine\t19 (43.2)\t\n Quetiapine\t6 (13.6)\t\n Risperidone\t0\t\n None received\t1 (2.3)a\t\n≥ 1 Medications taken at baseline\t43 (100.0)b\t\nNotes: Data are presented as n (%), unless otherwise specified. aOne subject discontinued the study without receiving treatment. bBased on the 43 subjects who received the digital medicine system.\n\nAbbreviation: SD, standard deviation.\n\n\nFigure 1 Subject disposition. aOf the subjects enrolled, 43 received a treatment and were included in the intent-to-treat and safety sample analyses.\n\n\n\nPerformance\nFor the 8-week assessment period, the mean proportion of days with good patch coverage was 63.4% (SD: 26.6) for the overall population (Table 2). No noticeable difference was observed between psychiatric conditions with respect to the proportion of time with good patch coverage over the assessment period (Table 2). A decline in the proportion of time with good patch coverage from weeks 1–4, then followed by an increase from weeks 4–5, was observed in all groups over the assessment period, except for subjects with schizoaffective disorder. Subjects with schizoaffective disorder exhibited a decrease in time with good patch coverage during weeks 1–2, followed by a rebound during weeks 2–5 to a greater value than for the first week (Figure 2). A decline in time with good patch coverage was observed over weeks 5–8 in all groups regardless of psychiatric condition (Figure 2). For the overall population, the mean proportion of days over the 8-week assessment period that subjects wore the patch was 55.1% (SD: 27.8) (Table 2). No noticeable differences in the proportion of time that subjects wore the patch were observed between psychiatric conditions (Table 2).Table 2 Summary of Digital Medicine System Performance Endpoints Related to Patch Wear (Intent-to-Treat Population)\n\nEndpoint\tSchizophrenia (n = 18)\tSchizoaffective Disorder (n = 9)\tFirst-Episode Psychosis (n = 16)\tOverall (n = 43)\t\nProportion of days with good patch coverage (primary endpoint)\t\nMean (SD)\t64.3 (20.2)\t63.0 (37.7)\t62.5 (27.5)\t63.4 (26.6)\t\nMedian (Q1, Q3)\t62.0 (49.1, 85.7)\t76.8 (42.4, 98.2)\t67.3 (50.7, 74.6)\t66.7 (48.3, 85.7)\t\nRange\t26.7–92.9\t0.0–100.0\t7.3–100.0\t0.0–100.0\t\nProportion of days that subjects wore the patch\t\nMean (SD)\t59.0 (22.5)\t53.1 (37.6)\t51.9 (28.4)\t55.1 (27.8)\t\nMedian (Q1, Q3)\t62.4 (42.9, 84.2)\t43.0 (22.6, 87.8)\t56.5 (37.3, 65.2)\t58.3 (39.9, 84.2)\t\nRange\t22.4–86.7\t1.7–98.8\t2.7–99.2\t1.7–99.2\t\nNote: Data are presented as %.\n\nAbbreviations: Q, quartile; SD, standard deviation.\n\n\nFigure 2 Proportion of time with good patch coverage over the assessment period (intent-to-treat population). Data are means ± standard error.\n\nNote: Arrow represents scheduled provider visit during week 4. \n\n\n\nThe proportion of IEMs ingested and registered on the digital health data server over the 8-week assessment period was 56.4% (SD: 25.6) for the overall population (Table 3). For subjects with schizophrenia or with first-episode psychosis, the proportions of IEMs registered on the digital health data server were comparable (Table 3). Subjects with schizoaffective disorder had the lowest proportion of IEMs registered (Table 3). The mean adherence metric for the 8-week assessment period was 86.6% (SD: 14.5) for the overall population (Table 3). Subjects with schizophrenia and first-episode psychosis had relatively consistent adherence metrics over the assessment period (Figure 3). Subjects with schizoaffective disorder, however, had a lower mean and higher variability in adherence metrics compared with other psychiatric conditions over the assessment period (Table 3; Figure 3).Table 3 Summary of Digital Medicine System Endpoints Based on IEM Detection (Intent-to-Treat Population)\n\n\tSchizophrenia (n = 18)\tSchizoaffective Disorder (n = 9)\tFirst-Episode Psychosis (n = 16)\tOverall (n = 43)\t\nAdherence metric based on digital health dataa\t\nMean (SD)\t88.9 (8.1)\t72.3 (25.7)\t91.0 (7.4)\t86.6 (14.5)\t\nMedian (Q1, Q3)\t89.8 (84.3, 95.5)\t79.6 (66.7, 87.5)\t92.2 (87.3, 96.4)\t89.3 (83.3, 94.7)\t\nRange\t69.0–100.0\t14.3–96.4\t75.0–100.0\t14.3–100.0\t\nProportion of IEMs ingestedb\t\nMean (SD)\t58.4 (17.5)\t50.2 (37.4)\t57.6 (26.8)\t56.4 (25.6)\t\nMedian (Q1, Q3)\t58.0 (49.1, 72.2)\t66.7 (12.5, 69.6)\t60.9 (46.3, 65.2)\t60.0 (45.6, 69.6)\t\nRange\t24.1–88.5\t0.0–96.4\t5.5–100.0\t0.0–100.0\t\nNotes: Data are presented as %. aOne subject in the schizoaffective disorder group was excluded because they had 0 days of good patch coverage. bIngested IEMs were registered on the digital health data server.\n\nAbbreviations: IEM, ingestible event marker; Q, quartile; SD, standard deviation.\n\n\nFigure 3 Adherence metric over the assessment period (intent-to-treat population). aOne subject in the schizoaffective disorder group was excluded because they had 0 days of good patch coverage. Data are means ± standard error. Arrow represents scheduled provider visit during week 4.\n\n\n\nAcceptance\nWhen surveyed on their experience of the DMS, 53.5% (23/43) of subjects were somewhat satisfied, satisfied, or extremely satisfied with the DMS, and 51.2% (22/43) of subjects found the DMS somewhat helpful, helpful, or extremely helpful in managing their condition (Appendix s-Table 1). Proportions of subjects who reported it somewhat easy, easy, or extremely easy to use the DMS: 69.8% (30/43); to apply the patch, 67.4% (29/43); and to use the mobile application, 60.5% (26/43; Appendix s-Table 1).\n\nWhen asked about the patch, 60.5% (26/43) of subjects somewhat agreed, agreed, or strongly agreed with not minding the patch, and 58.1% (25/43) of subjects needed assistance in changing and pairing patches (Appendix s-Table 1). An insignificant decrease in mean PAM-MH scores from baseline (64.5) to week 8 or early termination (63.6) was observed. No change in the mean CGI-S score from baseline (2.6) to week 8 or early termination (2.6) was observed. Overall, subjects used the smartphone application 0.5 times per day (SD: 0.3), and healthcare providers accessed the web portal 1.8 times per week (SD: 0.8).\n\nData from the call center indicated that 11 subjects telephoned 34 times for patch-related issues, and 9 times for issues related to smartphone application usage. Further, research or clinical staff telephoned the call center 23 times for patch-related issues during onsite visits for subjects in need of assistance with the system.\n\nSafety\nOver the 8-week assessment period, AEs were reported in 9 subjects (Table 4). No deaths, serious AEs, or AEs related to suicide or suicidal ideation were reported during the study (Table 4). TEAEs were reported in 9 subjects, all of which were associated with medical device site irritation due to the adhesive patch (Table 4). Most of these TEAEs were considered mild in severity. One TEAE was considered of moderate intensity and resolved after discontinuation of the DMS. Four subjects discontinued the study due to a TEAE (Table 4). Most (88.9% [8/9]) patch-related skin irritation scores were from 0–2, which were not considered medically significant (Table 5).Table 4 Summary of Safety (Safety Population)\n\nParameter\tAripiprazole (n = 18)\tOlanzapine (n = 19)\tQuetiapine (n = 6)\tOverall (n = 43)\t\nSubjects with AEs\t4 (22.2)\t2 (10.5)\t3 (50.0)\t9 (20.9)\t\nSubjects with serious AEs\t0\t0\t0\t0\t\nDeaths\t0\t0\t0\t0\t\nSubjects with TEAEs\t4 (22.2)\t2 (10.5)\t3 (50.0)\t9 (20.9)\t\n Leading to study discontinuation\t1 (5.6)\t1 (5.3)\t2 (33.3)\t4 (9.3)\t\n Medical device site irritationa\t4 (22.2)\t2 (10.5)\t3 (50.0)\t9 (20.9)\t\nNotes: Data are presented as n (%). aMedical device site irritation due to the adhesive patch.\n\nAbbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.\n\n\nTable 5 Skin Irritation Scoring System for Patch-Related Skin TEAEs (Safety Population)\n\nScoring System\tOverall \n(n = 43)a\t\n0: No evidence of skin irritation\t3 (7.0)\t\n1: Minimal erythema, barely visible\t2 (4.7)\t\n2: Definite erythema, readily visible; minimal edema or minimal papular response\t3 (7.0)\t\n3: Erythema and papules\t1 (2.3)\t\n4: Definite edema\t0\t\n5: Erythema, edema, and papules\t0\t\n6: Vesicular eruption\t0\t\n7: Strong reaction spreading beyond the test site\t0\t\nNotes: Data are presented as n (%). a8 Subjects answered the skin irritation questionnaire; scores were limited to 1 per subject, except for 1 subject who reported 2 scores.\n\nAbbreviation: TEAE, treatment-emergent adverse event.\n\n\n\n\nDiscussion\nIn this phase 4 pragmatic study in subjects with schizophrenia, schizoaffective disorder, or first-episode psychosis who were receiving aripiprazole, olanzapine, or quetiapine, good patch coverage with the DMS was reported 63.4% of the time over the 8-week assessment period. Overall, the DMS generated an adherence metric of 80.0% or greater, reflecting the percentage of IEMs detected that would be expected when good patch coverage was reported. The DMS was generally well-tolerated in this study population and no new safety findings were reported. The incidence of TEAEs (20.9%), which were all associated with patch-related skin reactions, was consistent with reports from previous trials with the DMS (32.8%21 and 34.7%22). Together, these results support the use of the DMS in a broader population of patients and with different types of antipsychotics than seen in previous clinical trials.21,22 Specifically, this study included patients with schizoaffective disorder or first-episode psychosis and those who may have presented with acute illness. Moreover, these findings suggest that the DMS could be successfully used with aripiprazole and other oral antipsychotics, such as olanzapine and quetiapine.\n\nThe proportion of time that subjects had good patch coverage in this study (63.4%) was lower compared with a previous 8-week phase 2 trial with the DMS (80.1%).22 Moreover, a lower proportion of time spent wearing the patch was reported in this study (55.1%) compared with previous phase 2 trials with the DMS (70.7%21 and 77.9%22). Although the proportion of time with good patch coverage appeared to decline from baseline to week 8, an increase between weeks 4–5 was noticed in all subjects, regardless of psychiatric condition. This increase may have been due to the scheduled interaction with a healthcare provider at week 4, which suggests that healthcare providers could increase patient engagement during visits, possibly by reviewing ingestion data of their patients using the web portal. A possible explanation for why less patch wear was reported in this study compared with previous reports may be related to issues with pairing the patch and smartphone application, as indicated by the number of calls from subjects and healthcare providers to the call center.\n\nTo our knowledge, this was the first study to evaluate the DMS where subjects could use their own smartphone, which included the iOS and Android application platforms. Compatibility of the DMS with various smartphones across diverse subject demographics may have resulted in user error and affected subjects’ ability to successfully engage with the smartphone application and pair patches. Additionally, this study had fewer scheduled interactions or touchpoints with healthcare providers (3 interactions) compared with previous clinical trials with the DMS (4 to 5 interactions).21,22 This study also included subjects with acute mental illness, whereas previous trials recruited only subjects who were already on stable antipsychotic doses and did not have acute psychotic symptoms.21,22 These features of the study design provided a more real-world setting to evaluate performance and acceptance of the DMS. Issues with pairing patches with the smartphone application, the fewer number of touchpoints, and the inclusion of subjects with acute mental illness may have negatively influenced patch coverage metrics in this study.\n\nIn this study, the DMS showed good acceptance in the overall subject population, as evidenced by responses to the user-experience survey. Overall, subjects were satisfied with using the DMS and generally found its components easy to use. However, less than half of subjects found it easy to pair the patch with the smartphone application, and over half of subjects needed help with changing or pairing patches. This may indicate a lack of familiarity with pairing Bluetooth devices, or that compatibility issues between the patch and smartphone application were encountered. Acknowledging the limitations of cross-study comparisons, the proportion of subjects in this study who were satisfied with the DMS (53.5%) and found it helpful in managing their condition (51.2%) appeared to be lower compared with a previous phase 2 study in subjects with schizophrenia who were stable on medication (78.3% and 70.0%, respectively).21 These findings may be explained by similar factors that affected patch coverage. Specifically, having fewer scheduled interactions, the inclusion of subjects with acute mental illness, and issues related to pairing the patch to the smartphone application may explain why fewer subjects were satisfied with the DMS in this study compared with prior reports.\n\nThe proportion of IEMs detected (56.4%) and the adherence metric (86.6%) in this study were similar to findings in previous phase 2 trials with the DMS (59.4% and 73.9%–88.6%, respectively).21,22 These results, along with considerations that this study included different populations, acutely ill subjects, and the use of different types of smartphones suggest that the DMS could be a clinically useful tool to measure intake of medication in diverse populations with varying disease severity. This is beneficial, as accurate measurements of adherence can be particularly challenging in patients with severe mental illness.7\n\nA potential limitation of this study was the small sample size, especially in the group with schizoaffective disorder (n=10), which could have contributed to the wide variability in the proportion of time with good patch coverage and adherence metric observed in this group. Also, allowing subjects to use their own smartphone that was compatible with the application could have led to lower-than-planned enrollment. A limitation pertaining to patient comfort with data collection is that paranoid symptoms were not assessed, thus conclusions cannot be drawn on whether patients with paranoia could use the DMS successfully. Further, patients were excluded if they had a condition judged to impair their ability to engage with the DMS, which could have included patients who refused to comply with data collection policies. Of note, 2 patients withdrew consent due to discomfort with the DMS, although it is unclear if this was due to paranoia, discomfort with data collection, or another reason. Another limitation may be that information on the smartphone operating systems and reasons for which subjects and healthcare providers contacted the call center were not fully collected. Such data could have been useful to better understand the source of compatibility issues between the patch and smartphone application, which may have affected the performance and acceptance of the DMS. Moreover, to gain better insights to the real-world applicability of the DMS, future studies could benefit from enrolling more subjects per psychiatric condition and collecting more information on smartphones used in the study and related technical issues. These studies could also be enhanced by examining the impact of sharing the DMS’s data with patients, both on adherence metrics and the quality of their relationships with healthcare providers. Lastly, a more user-friendly design may be necessary to reach a broader population of patients who have serious mental illnesses and concerns with the process of data collection.\n\nConclusions\nOverall, the DMS observed good patch coverage and high treatment adherence metrics over the 8-week assessment period. Most subjects were satisfied with using the DMS and generally found its components easy to use. Moreover, the DMS was associated with a safety profile that was comparable to that of previous reports.21,22 Together, these findings suggest that the DMS could be a useful tool to measure intake of various antipsychotics, including olanzapine and quetiapine, in addition to aripiprazole. However, compared with previous studies,21,22 the lower values for patch-related endpoints and subject satisfaction21,22 suggest that regular clinical contact, more support and engagement from the care team, and better training may be required to reinforce performance and acceptance of the DMS in patients with psychotic disorders. This study reflects use of the DMS in a more real-world setting where patients would likely use their own smartphone. A goal for future studies is to better understand smartphone ownership in patient populations to help optimize testing processes of the DMS’s smartphone application. Further evaluation of the DMS in larger clinical trials including different types of antipsychotics and patients with various psychotic disorders may be necessary to establish its clinical utility and to determine its impact on improving treatment adherence in patients with serious mental illness.\n\nAcknowledgments\nThe authors thank the patients, patient advisers, and NHS staff from all 5 participating sites (Oxford Health NHS Foundation Trust, Northumberland, Tyne and Wear NHS Foundation Trust, Southern Health NHS Foundation Trust, South London and Maudsley NHS Foundation Trust, and Surrey and Borders Partnership NHS Foundation Trust) for their contributions to the study methodology. SS is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.\n\nData Sharing Statement\nData collected for this study will not be made available to others.\n\nEthics Approval and Informed Consent\nThis study protocol and informed consent forms were approved by the London – Central and East ethics committee.\n\nConsent for Publication\nNo patient data are identifiable, thus no consent is required.\n\nAuthor Contributions\nJCF, NC, JK, TS, SS, PP, SR, and TP-S contributed to study conception design and data collection. All authors contributed to data analysis and interpretation, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nJCF, NC, JK, HF, TS, and TP-S are employees of Otsuka Pharmaceutical. SR has received honoraria from Otsuka and Lundbeck LLC, Deerfield, IL for educational sessions. SS has received honoraria from Lundbeck for educational sessions. PP has received honoraria from Otsuka. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n1. National Collaborating Centre for Mental Health (UK) . Psychosis and Schizophrenia in Adults: Treatment and Management. National Clinical Guideline Number 178 . London, UK : National Institute for Health and Care ; 2014 \nAvailable from : https://www.nice.org.uk/guidance/cg178/evidence/full-guideline-490503565. Accessed 1 21 , 2021.\n2. World Health Organization. The Global Burden of Disease: 2004 Update . Geneva, Switzerland : World Health Organization ; 2008 \nAvailable from : https://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf. Accessed 1 21 , 2021.\n3. Charlson \nFJ , Ferrari \nAJ , Santomauro \nDF , et al. 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Patient Relat Outcome Meas . 2014 ;5 :43 –62\n. doi:10.2147/PROM.S42735 25061342 \n8. Schoeler \nT , Petros \nN , Di Forti \nM , et al. Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: a prospective analysis\n. Lancet Psychiatry . 2017 ;4 (8 ):627 –633\n. doi:10.1016/S2215-0366(17)30233-X 28705600 \n9. Cullen \nBA , McGinty \nEE , Zhang \nY , et al. Guideline-concordant antipsychotic use and mortality in schizophrenia\n. Schizophr Bull . 2013 ;39 (5 ):1159 –1168\n. doi:10.1093/schbul/sbs097 23112292 \n10. Steinkamp \nJM , Goldblatt \nN , Borodovsky \nJT , et al. Technological interventions for medication adherence in adult mental health and substance use disorders: a systematic review\n. JMIR Ment Health . 2019 ;6 (3 ):e12493 . doi:10.2196/12493 30860493 \n11. Yaegashi \nH , Kirino \nS , Remington \nG , Misawa \nF , Takeuchi \nH . Adherence to oral antipsychotics measured by electronic adherence monitoring in schizophrenia: a systematic review and meta-analysis\n. CNS Drugs . 2020 ;34 (6 ):579 –598\n. doi:10.1007/s40263-020-00713-9 32219681 \n12. Sajatovic \nM , Velligan \nDI , Weiden \nPJ , Valenstein \nMA , Ogedegbe \nG . Measurement of psychiatric treatment adherence\n. J Psychosom Res . 2010 ;69 (6 ):591 –599\n. doi:10.1016/j.jpsychores.2009.05.007 21109048 \n13. Lam \nWY , Fresco \nP . Medication adherence measures: an overview\n. Biomed Res Int . 2015 ;2015 :217047 . doi:10.1155/2015/217047 26539470 \n14. Kane \nJM , Perlis \nRH , DiCarlo \nLA , Au-Yeung \nK , Duong \nJ , Petrides \nG . First experience with a wireless system incorporating physiologic assessments and direct confirmation of digital tablet ingestions in ambulatory patients with schizophrenia or bipolar disorder\n. J Clin Psychiatry . 2013 ;74 (6 ):e533 –e540\n. doi:10.4088/JCP.12m08222 23842023 \n15. Knights \nJ , Heidary \nZ , Peters-Strickland \nT , Ramanathan \nM . Evaluating digital medicine ingestion data from seriously mentally ill patients with a Bayesian Hybrid Model\n. NPJ Digit Med . 2019 ;2 :20 . doi:10.1038/s41746-019-0095-z 31304367 \n16. Fowler \nJC , Cope \nN , Knights \nJ , et al. Hummingbird Study: a study protocol for a multicentre exploratory trial to assess the acceptance and performance of a digital medicine system in adults with schizophrenia, schizoaffective disorder or first-episode psychosis\n. BMJ Open . 2019 ;9 (6 ):e025952 . doi:10.1136/bmjopen-2018-025952 \n17. Firth \nJ , Cotter \nJ , Torous \nJ , Bucci \nS , Firth \nJA , Yung \nAR . Mobile phone ownership and endorsement of “mHealth” among people with psychosis: a meta-analysis of cross-sectional studies\n. Schizophr Bull . 2016 ;42 (2 ):448 –455\n. doi:10.1093/schbul/sbv132 26400871 \n18. Collins \nTR . Smartphone interventions benefit schizophrenia patients\n. Clinical Psychiatry News ; 2019 \nAvailable from : https://www.mdedge.com/psychiatry/article/199479/schizophrenia-other-psychotic-disorders/smartphone-interventions-benefit. Accessed 1 21 , 2021.\n19. Lee \nK , Bejerano \nIL , Han \nM , Choi \nHS . Willingness to use smartphone apps for lifestyle management among patients with schizophrenia\n. Arch Psychiatr Nurs . 2019 ;33 (4 ):329 –336\n. doi:10.1016/j.apnu.2019.01.002 31280776 \n20. Gay \nK , Torous \nJ , Joseph \nA , Pandya \nA , Duckworth \nK . Digital technology use among individuals with schizophrenia: results of an online survey\n. JMIR Ment Health . 2016 ;3 (2 ):e15 . doi:10.2196/mental.5379 27146094 \n21. Peters-Strickland \nT , Pestreich \nL , Hatch \nA , et al. Usability of a novel digital medicine system in adults with schizophrenia treated with sensor-embedded tablets of aripiprazole\n. Neuropsychiatr Dis Treat . 2016 ;12 :2587 –2594\n. doi:10.2147/NDT.S116029 27785036 \n22. Kopelowicz \nA , Baker \nRA , Zhao \nC , Brewer \nC , Lawson \nE , Peters-Strickland \nT . A multicenter, open-label, pilot study evaluating the functionality of an integrated call center for a digital medicine system to optimize monitoring of adherence to oral aripiprazole in adult patients with serious mental illness\n. Neuropsychiatr Dis Treat . 2017 ;13 :2641 –2651\n. doi:10.2147/NDT.S143091 29089771 \n23. Otsuka America Pharmaceutical, Inc. Abilify MyCite® (Aripiprazole Tablets with Sensor) [Package Insert] . Rockville, MD : Otsuka America Pharmaceutical, Inc. ; 2020 .\n24. European Medicines Agency. Qualification Opinion on Ingestible Sensor System for Medication Adherence as Biomarker for Measuring Patient Adherence to Medication in Clinical Trials . London, UK : European Medicines Agency ; 2016 \nAvailable from : https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/qualification-opinion-ingestible-sensor-system-medication-adherence-biomarker-measuring-patient_en.pdf. Accessed 1 21 , 2021.\n25. Green \nCA , Perrin \nNA , Polen \nMR , Leo \nMC , Hibbard \nJH , Tusler \nM . Development of the patient activation measure for mental health\n. Adm Policy Ment Health . 2010 ;37 (4 ):327 –333\n. doi:10.1007/s10488-009-0239-6 19728074 \n26. Busner \nJ , Targum \nSD . The clinical global impressions scale: applying a research tool in clinical practice\n. Psychiatry . 2007 ;4 (7 ):28 –37\n.\n27. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) . Guidance for Industry: assessing the irritation and sensitization potential of transdermal and topical delivery systems for ANDAs\n. 2018 \nAvailable from : https://www.fda.gov/media/117569/download. Accessed 1 21 , 2021.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "17()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "antipsychotic; digital health; digital medicine; medication adherence",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "483-492",
"pmc": null,
"pmid": "33603385",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016430:Clinical Trial",
"references": "30860493;31304367;23112292;28705600;23842023;20526405;21924589;32219681;21109048;27146094;26539470;25061342;31280776;29089771;19728074;27785036;31253613;26400871;29762765",
"title": "Hummingbird Study: Results from an Exploratory Trial Assessing the Performance and Acceptance of a Digital Medicine System in Adults with Schizophrenia, Schizoaffective Disorder, or First-Episode Psychosis.",
"title_normalized": "hummingbird study results from an exploratory trial assessing the performance and acceptance of a digital medicine system in adults with schizophrenia schizoaffective disorder or first episode psychosis"
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"companynumb": "US-OTSUKA-2021_010022",
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"occurcountry": "US",
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"activesubstancename": "ARIPIPRAZOLE"
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{
"abstract": "In burnt or skeletonized bodies dental hard tissue sometimes is the only remaining specimen available. Therefore, it could be used as an alternative matrix in post mortem toxicology. Additionally, analysis of dental tissues could provide a unique retrospective window of detection. For forensic interpretation, routes and rates of incorporation of different drugs as well as physicochemical differences between tooth root, tooth crown and carious material have to be taken into account. In a pilot study, one post mortem tooth each from three drug users was analyzed for medicinal and illicit drugs. The pulp was removed in two cases; in one case the tooth was root canal treated. The teeth were separated into root, crown and carious material and drugs were extracted from the powdered material with methanol under ultrasonication. The extracts were screened for drugs by LC-MS(n) (ToxTyper™) and quantitatively analyzed with LC-ESI-MS/MS in MRM mode. The findings were compared to the analytical results for cardiac blood, femoral blood, urine, stomach content and hair. In dental hard tissues, 11 drugs (amphetamine, MDMA, morphine, codeine, norcodeine, methadone, EDDP, fentanyl, tramadol, diazepam, nordazepam, and promethazine) could be detected and concentrations ranged from approximately 0.13pg/mg to 2,400pg/mg. The concentrations declined in the following order: carious material>root>crown. Only the root canal treated tooth showed higher concentrations in the crown than in the root. In post mortem toxicology, dental hard tissue could be a useful alternative matrix facilitating a more differentiated consideration of drug consumption patterns, as the window of detection seems to overlap those for body fluids and hair.",
"affiliations": "Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Albertstraße 9, 79104 Freiburg, Germany; Hermann Staudinger Graduate School, University of Freiburg, Hebelstraße 27, 79104 Freiburg, Germany.;Center for Dental Medicine, Department of Operative Dentistry and Periodontology, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Albertstraße 9, 79104 Freiburg, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Albertstraße 9, 79104 Freiburg, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Albertstraße 9, 79104 Freiburg, Germany. Electronic address: merja.neukamm@uniklinik-freiburg.de.",
"authors": "Klima|Miriam|M|;Altenburger|Markus J|MJ|;Kempf|Jürgen|J|;Auwärter|Volker|V|;Neukamm|Merja A|MA|",
"chemical_list": "D013287:Illicit Drugs",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "265()",
"journal": "Forensic science international",
"keywords": "Alternative matrices; Drugs of abuse; Forensic toxicology; Post mortem toxicology; Teeth",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D005260:Female; D049429:Forensic Pathology; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D014070:Tooth; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "166-71",
"pmc": null,
"pmid": "26930453",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Determination of medicinal and illicit drugs in post mortem dental hard tissues and comparison with analytical results for body fluids and hair samples.",
"title_normalized": "determination of medicinal and illicit drugs in post mortem dental hard tissues and comparison with analytical results for body fluids and hair samples"
} | [
{
"companynumb": "DE-WATSON-2016-08646",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIACETYLMORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "Our report describes the case of patient with hypersensitive reaction regularly arising early after initiation of haemodialysis. This characteristic reaction with pletoric face coloration, bronchospasm, increase of blood pressure, anxiety and decrease of blood oxygen saturation at the consequence and central cyanosis was regularly present without dependence on type of dialysis membrane, drug premedication or prophylactic flushing haemodialysis system by isotonic natrium chloride solution. Low platelet value and trouble-free haemodialysis realized without heparin showed real cause of patients problem. Resolution of this state was regional citrate anticoagulation during intermitent haemodialysis.",
"affiliations": null,
"authors": "Masopust|Jan|J|;Charvát|Jiří|J|;Mokrá|Dana|D|;Hloch|Ondřej|O|;Háša|Jan|J|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-773X",
"issue": "61(3)",
"journal": "Vnitrni lekarstvi",
"keywords": null,
"medline_ta": "Vnitr Lek",
"mesh_terms": "D000925:Anticoagulants; D006493:Heparin; D006801:Humans; D006435:Renal Dialysis; D051437:Renal Insufficiency; D013921:Thrombocytopenia",
"nlm_unique_id": "0413602",
"other_id": null,
"pages": "260-63",
"pmc": null,
"pmid": "25873123",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypersensitive reaction after application of heparin with activation heparin induced trombocytopenia in initiation of intermittent haemodialysis.",
"title_normalized": "hypersensitive reaction after application of heparin with activation heparin induced trombocytopenia in initiation of intermittent haemodialysis"
} | [
{
"companynumb": "PHHY2015CZ090696",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim⁻Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.",
"affiliations": "Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. s.pischke@uke.de.;Service d'hépato-gastroentérologie, Hôpital Purpan CHU Toulouse, Université Paul Sabatier III, 31000 Toulouse, France. peron.jm@chu-toulouse.fr.;Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. m.von-wulffen@uke.de.;Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. j.von-felden@uke.de.;Gastroenterology, Hannover Medical School, 30625 Hannover, Germany. HoenerzuSiederdissen.Christoph@mh-hannover.de.;Service d'hépato-gastroentérologie, Hôpital Purpan CHU Toulouse, Université Paul Sabatier III, 31000 Toulouse, France. fournier.s@chu-toulouse.fr.;German Centre for Infection Research (DZIF), Hamburg partner site, 20246 Hamburg, Germany. mluetgehetmann@uke.de.;Rheumatology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. c.iking-konert@uke.de.;Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. dominik.bettinger@uniklinik-freiburg.de.;Clinical Centre, First Department of Medicine, University of Pécs, H-7622 Pécs, Hungary. pargabriella@gmail.com.;Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. robert.thimme@uniklinik-freiburg.de.;Service d'hépato-gastroentérologie, Hôpital Purpan CHU Toulouse, Université Paul Sabatier III, 31000 Toulouse, France. cantagrel.a@chu-toulouse.fr.;Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. a.lohse@uke.de.;German Centre for Infection Research (DZIF), Hamburg partner site, 20246 Hamburg, Germany. Wedemeyer.Heiner@mh-hannover.de.;Gastroenterology and Hepatology, Erasmus MC Medical Center Rotterdam, 3062 PA Rotterdam, The Netherlands. r.deman@erasmusmc.nl.;Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Hepatology Service, Institut National de la Santé et de la Recherche Médicale unité 1223, Institut Pasteur, 75006 Paris, France. vincent.mallet@aphp.fr.",
"authors": "Pischke|Sven|S|;Peron|Jean-Marie|JM|;von Wulffen|Moritz|M|;von Felden|Johann|J|0000-0003-2839-5174;Höner Zu Siederdissen|Christoph|C|;Fournier|Sophie|S|;Lütgehetmann|Marc|M|;Iking-Konert|Christoph|C|0000-0002-8716-3894;Bettinger|Dominik|D|;Par|Gabriella|G|0000-0002-6943-6756;Thimme|Robert|R|;Cantagrel|Alain|A|;Lohse|Ansgar W|AW|;Wedemeyer|Heiner|H|;de Man|Robert|R|;Mallet|Vincent|V|0000-0003-2219-9201",
"chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral; D012254:Ribavirin; D008727:Methotrexate",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/v11020186",
"fulltext": "\n==== Front\nVirusesVirusesvirusesViruses1999-4915MDPI 10.3390/v11020186viruses-11-00186ArticleChronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study Pischke Sven 12†Peron Jean-Marie 3†von Wulffen Moritz 1https://orcid.org/0000-0003-2839-5174von Felden Johann 1Höner zu Siederdissen Christoph 4Fournier Sophie 3Lütgehetmann Marc 25https://orcid.org/0000-0002-8716-3894Iking-Konert Christoph 6Bettinger Dominik 78https://orcid.org/0000-0002-6943-6756Par Gabriella 9Thimme Robert 7Cantagrel Alain 3Lohse Ansgar W. 12Wedemeyer Heiner 24de Man Robert 10‡https://orcid.org/0000-0003-2219-9201Mallet Vincent 11*‡1 Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; s.pischke@uke.de (S.P.); m.von-wulffen@uke.de (M.v.W.); j.von-felden@uke.de (J.v.F.); a.lohse@uke.de (A.W.L.)2 German Centre for Infection Research (DZIF), Hamburg partner site, 20246 Hamburg, Germany; mluetgehetmann@uke.de (M.L.); Wedemeyer.Heiner@mh-hannover.de (H.W.)3 Service d’hépato-gastroentérologie, Hôpital Purpan CHU Toulouse, Université Paul Sabatier III, 31000 Toulouse, France; peron.jm@chu-toulouse.fr (J.-M.P.); fournier.s@chu-toulouse.fr (S.F.); cantagrel.a@chu-toulouse.fr (A.C.)4 Gastroenterology, Hannover Medical School, 30625 Hannover, Germany; HoenerzuSiederdissen.Christoph@mh-hannover.de5 Microbiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany6 Rheumatology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; c.iking-konert@uke.de7 Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; dominik.bettinger@uniklinik-freiburg.de (D.B.); robert.thimme@uniklinik-freiburg.de (R.T.)8 Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany9 Clinical Centre, First Department of Medicine, University of Pécs, H-7622 Pécs, Hungary; pargabriella@gmail.com10 Gastroenterology and Hepatology, Erasmus MC Medical Center Rotterdam, 3062 PA Rotterdam, The Netherlands; r.deman@erasmusmc.nl11 Université Paris Descartes, Assistance Publique—Hôpitaux de Paris (AP—HP), Hôpital Cochin, Hepatology Service, Institut National de la Santé et de la Recherche Médicale unité 1223, Institut Pasteur, 75006 Paris, France* Correspondence: vincent.mallet@aphp.fr† These authors share first authorship.\n\n‡ These authors share senior authorship.\n\n22 2 2019 2 2019 11 2 18616 1 2019 19 2 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim–Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.\n\nhepatitis Echronic hepatitis Edisease-modifying antirheumatic drugs (DMARDs)ribavirin\n==== Body\n1. Introduction\nHepatitis E virus (HEV), which is the causative agent of hepatitis E, is a non-enveloped RNA virus and a member of the genus Orthohepevirus within the Hepeviridae family. There are four major HEV genotypes (1, 2, 3, and 4) that can infect humans. The preferential mode of transmission of HEV is enteric via drinking water contaminated by HEV-1 or HEV-2 or via infected food contaminated by HEV-3 or HEV-4. HEV infection is a pandemic, including in high-income countries, where HEV-3 is the most prevalent genotype [1].\n\nIn general, HEV infection is self-limiting but can evolve to chronic hepatitis E in immunocompromised patients, including transplant recipients and HIV-infected patients [2,3]. In solid organ recipients, chronic HEV infection is defined as the persistence of viral replication beyond 3 months after infection [4]. In general, patients with chronic hepatitis E clear HEV infection when immunity is restored or a short course of ribavirin monotherapy is administered [5,6]. \n\nThe HEV infection course in internal medicine/rheumatology patients has been infrequently reported. Whether internal medicine/rheumatology patients, including patients treated with disease-modifying agents (DMARDs), are at risk of developing chronic hepatitis E remains controversial [7,8].\n\nWe analyzed the course of HEV infection in a retrospective cohort from seven internal medicine and rheumatology centers across Europe and show that internal medicine/rheumatology patients, including patients treated with DMARDs, are at risk of developing chronic hepatitis E.\n\n2. Patients and Methods\n2.1. Patients\nWe conducted a retrospective European case series study that included data from 7 rheumatology and internal medicine centers in Germany, Italy, the United Kingdom, the Netherlands and France. The data included all cases of HEV infection diagnosed between April 2014 and April 2016. An investigator from each center collected the patient data from the medical records. All authors vouch for the completeness and accuracy of the presented data. \n\nBecause of the retrospective and observational nature of the study and in accordance with German law, ethical approval for the study was waived. Some patients (n = 9) were previously included in two case series [7,8].\n\nThe decision to lower the patients’ immunosuppressive regimen or treat patients with ribavirin was made individually based on the physicians’ experience. The dosing and duration of the ribavirin treatment were not standardized.\n\n2.2. Virological Assessment\nIn all patients, HEV infection was confirmed by nucleic acid testing (NAT). In 18 patients polymerase chain reaction (PCR) positivity based on in-house PCR assays, while in 3 patients a commercial PCR assay was used (Altona Diagnostics, Hamburg, Germany). The majority of used PCR assays had a lower limit of detection (95% hit rate) of 143 IU/mL as determined by the first World Health Organization (WHO) standard for HEV RNA nucleic acid amplification testing-based assays. The proven duration of infection was determined prospectively or retrospectively based on stored frozen serum samples. A sustained virological response was defined as an undetectable level of HEV RNA in the serum 24 weeks after the completion of ribavirin therapy. \n\nTo confirm PCR results serological testing was performed in all patients. In the majority (n = 14) the Wantai anti HEV IgG assay (Wantai, Bejing, China) was used according to manufacturers instructions.\n\n3. Results\n3.1. Cohort Characteristics\nThe cohort comprised 21 patients (Table 1). The sex ratio was balanced (n = 11 [52%] males). The age of the patients ranged from 25 to 75 years (median 57 years). All patients presented with detectable anti HEV IgG at diagnosis ot within the further course. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim–Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). \n\nWe could not determine the exact ratio of HEV positive patients in the total cohort of internal medicine/rheumatology patients. In total, 3,800 patients are treated annually at the Rheumatological Department of the University Hospital Hamburg Eppendorf and the clinic at Bad Bramstedt. The total number (percent) of patients diagnosed with HEV in this subgroup was five (0.07%) during the observational study period. \n\nThe immunosuppressive treatments included methotrexate monotherapy (n = 4), anti-TNF (tumor necrosis factor) monotherapy (n = 4), methotrexate/anti-TNF combination therapy (n = 4), methotrexate/rituximab (n = 1), methotrexate/prednisolone (n = 1), sirolimus/prednisolone (n = 1), mycophenolate mofetil/prednisolone (n = 1), abatacept (n = 1), and cyclophosphamide (n = 1). \n\nAll but one of the HEV infections were locally acquired. HEV genotype 3c was identified in two patients, and HEV genotype 3f was identified in 2 patients. One case (genotype 1) was imported from Indonesia (patient #5, Table 1). This patient was a 65-year-old woman with rheumatoid arthritis. She cleared the infection without any relevant problems after the cessation of methotrexate. \n\nIn most patients, HEV genotyping was not performed.\n\nThe HEV viral load was determined in 10 patients and ranged from 216 IU/mL to 8,600,000 IU/mL (mean 1,123,183 IU/mL, standard deviation 2,653,320 IU/mL). \n\nThe peak values of ALT (Alnanine amino transferasis)ranged from 88 to 5231 U/L (median 610 U/L) during the HEV infection, while the ALT levels ranged from 15 to 35 U/L (median 22 U/L, missing: n = 11) before the HEV infection and ranged from 4–47 U/L (median 17 U/L, missing: n = 9) after the HEV infection (p < 0.001, p < 0.001, Figure 1).\n\n3.2. Course of Hepatitis E Virus (HEV) Infection\nHEV RNA was detected by NAT in all patients at the time of the diagnosis of HEV infection. The duration of the HEV infection ranged from 0 to 96 weeks (median 4 weeks). No liver-related complications, including cirrhosis and end-stage liver disease, were reported. No extrahepatic manifestation attributable to the HEV infection was observed [9]. Seven patients developed a course of HEV infection lasting longer than 3 months (Table 1, Figure 1). Three patients with chronic HEV infection had a hereditary impairment of their immune response (patients #3, 10, and 20; Table 1). One patient with chronic HEV infection had retroperitoneal fibrosis and was treated with sirolimus/prednisolone. One patient with chronic HEV infection (#18) had systemic granulomatosis and was treated with mycophenolate mofetil/prednisolone. The remaining two patients with chronic HEV infection had rheumatoid arthritis (#6 and #11) and were treated with either methotrexate or abatacept.\n\n3.3. Treatment of Chronic HEV Infection\nThe total cohort can be divided into the following 4 subgroups (Table 2): patients who spontaneously cleared the infection, patients who cleared the infection after a reduction of immunosuppression, patients who have been treated with ribavirin and patients who have been treated with a reduction of immunosuppression plus ribavirin. The duration of the HEV infection and the ALT peak levels did not significantly differ between these groups (p = ns) (Figure 1).\n\nRibavirin treatment (11–13.5 mg/kg body weight, median 12.8 mg/kg; duration 1–26 weeks, median 12 weeks) was initiated in 9 patients (7 ribavirin mono therapy), including 5 patients with chronic HEV infection (#6, #10, #18, #19, and #20; Table 1). Ribavirin dose reduction was only necessary in one patient. No serious adverse events resulting from the ribavirin treatment were reported. Immunosuppressive treatment was alleviated or differed in 8 (38%) patients, including two patients simultaneously treated with ribavirin. Abatacept therapy was stopped in 1 patient (#11) with chronic HEV infection. HEV infection did not lead to any treatment modification in 6 (29%) patients. All patients achieved a sustained virological response (one patient lost to follow up).\n\nOnly one of the patients (#10) relapsed after the ribavirin therapy. No patient relapsed in the group without ribavirin therapy. \n\nThe ALT peak and duration of viremia did not significantly differ among the patients without a change in immunosuppression, patients with reduced immunosuppression and patients treated with ribavirin (Figure 1, p = ns).\n\n3.4. Outcome of Selected Patients\nNo patients died from hepatic complications. One patient with chronic infection (#3) was lost to follow-up. The outcomes of the seven remaining patients with chronic infection are described below. The lymphocyte count was determined in 5 patients at the time of HEV infection and ranged from 560–1900 cells/mm3 (median: 1050 cells/mm3). The total IgG level was determined in 5 patients and ranged from 7.6–14.1 g/dL (median 11.3 g/dL).\n\nPatient #3 was a 51-year-old male with common variable immunodeficiency and chronic HEV infection lasting for more than 6 months. He was lost to follow-up.\n\nPatient #6 was a 75-year-old female under methotrexate treatment for rheumatoid arthritis with chronic hepatitis E lasting for more than 4 months. Her INR and total bilirubin peaked at 1.4 and 25.6 mg/dL (437 µmol/L), respectively. She experienced clearance of the HEV infection after 26 weeks of ribavirin treatment.\n\nPatient #10 was a woman aged 57 years with idiopathic CD4 T lymphocytopenia and a primary deficiency in IgG-1, -2, and -4 subclasses. Total lymphocyte count was 0.41 109 cells/L. The CD4 T-lymphocyte count was 0.22 109 cells/L. The CD8 T-lymphocyte count was 0.05 109 cells/L. The CD19 B-lymphocyte count was 0.03 109 cells/L. Chronic hepatitis E was diagnosed in December 2009. Ribavirin treatment 600 mg/d (12 mg/kg) was initiated for 12 weeks. The patient relapsed after treatment. Ribavirin was reintroduced without a virological response. Ribavirin was pursued at lower doses to maintain normal liver function tests. The patient died under ribavirin with metastatic epidermoidal cancer in 2018.\n\nPatient #11 was a 51-year-old female under abatacept treatment for rheumatoid arthritis with chronic HEV infection lasting for more than 16 weeks. She exhibited clearance of the HEV infection after withdrawal from abatacept.\n\nPatient #18 was a 29-year-old male under mycophenolate (1500 mg daily) and prednisolone (7.5 mg daily) treatment for systemic granulomatosis with chronic HEV infection lasting for more than 1 year. He exhibited clearance of the HEV infection after 5 months of ribavirin treatment.\n\nPatient #19 was a 34-year-old male under prednisolone (60 mg daily) and sirolimus (4 mg daily) treatment for retroperitoneal fibrosis with chronic HEV infection lasting for more than 2 years. He exhibited clearance of the HEV infection after 5 months of ribavirin treatment.\n\nPatient #20 was a 48-year-old female with an undefined CD4 cell deficiency and chronic HEV infection. She exhibited clearance of the HEV infection after 5 months of ribavirin treatment.\n\n4. Discussion\nIn a multicenter, international cohort of 21 internal medicine/rheumatology patients, HEV infection persisted for more than 12 weeks in 7 (33.3%) patients and more than 24 weeks in 5 (24%) patients (Table 1). Chronic hepatitis E was associated with methotrexate or abatacept treatment in two rheumatoid arthritis patients. All but one of the patients cleared HEV infection (one further patient was lost to follow-up), including 15 (71%) patients who cleared the infection after the discontinuation of treatment with immunosuppressants and/or ribavirin. The ALT peak levels and duration of HEV infection did not significantly differ among patients treated with various antiviral strategies, such as ribavirin or reduction of immunosuppression (Figure 1). Thus, the efficacy of these regimens could not be evaluated, and larger cohort studies are needed.\n\nOur findings demonstrate that the progression of HEV infection from acute to chronic is not limited to organ transplant recipients and HIV-infected patients with a low CD4 T cell count [10,11,12] and can occur in internal medicine/rheumatology patients, including patients undergoing treatment with DMARDs. Unexpectedly, we observed chronic HEV infection in a patient undergoing methotrexate treatment for rheumatoid arthritis without overt lymphopenia. In contrast to our findings, a previous French observational study did not report any case of chronic HEV infection among rheumatology patients, including rheumatoid arthritis patients [7]. However, both studies are retrospective analyses of small unstructured cohorts. Perhaps cessation of immunosuppression or initiation of ribavirin interfered with the clinical course of HEV infection. It is still completely unclear, how many patients might have developed chronic infection without any actions of the responsible physicians.\n\nOther case reports of chronic hepatitis E among patients with immunological/rheumatological diseases were limited to strongly immunosuppressed patients [13,14]. Chronic HEV infection has been associated with lymphopenia, a low CD4 T cell count and impaired HEV-specific T cell response [15]. The retrospective nature of our study did not allow us to identify the risk factors for chronic HEV infection among the internal medicine/rheumatology patients. Our clinical study does not warrant any insights into the underlying pathophysiology of chronic HEV infection in rheumatological patients. However, recently a study using a pig model revealed that active suppression of cell-mediated immune responses under immunocompromised conditions may facilitate the establishment of chronic HEV infection [16]. Further studies investigating the exact role of methotrexate or anti-TNF medications in this context are needed. \n\nOur study also highlights the relevance of HEV infection as a potential differential diagnosis in internal medicine/rheumatology patients with elevated transaminase levels. HEV is an endemic worldwide, including in industrialized countries [1]. In general, internal medicine/rheumatology patients are treated as outpatients, and the diagnosis of chronic hepatitis E can easily be overlooked; at least initially, patients may have no symptoms. Often, the only clues regarding the diagnosis are mild fluctuating abnormalities in liver function tests. These abnormalities are commonly and incorrectly attributed to drug-induced liver injury given the polypharmacy that many patients receive. In addition, serological screening in these types of patients often yields false-negative results [17]. The diagnosis requires the demonstration of the persistence of HEV RNA by NAT. \n\nHowever, while more than 1% (n = 4) of 287 liver transplant recipients at the University Hospital Hamburg Eppendorf presented with hepatitis E [18], only 0.07% of rheumatological patients at the same center were diagnosed with HEV infection in the present study. These data indicate that HEV infections in rheumatological patients rarely develop chronic courses.\n\nAll but one chronic hepatitis E patients cleared the HEV infection after ribavirin treatment with or without the discontinuation of immunosuppressive treatment. The high rate of sustained virological response is consistent with the results of previous studies in other populations of immunosuppressed patients [6]. Because of the uncontrolled nature of our study, we cannot exclude the possibility that some patients could have resolved the HEV infection after the discontinuation of immunosuppressive treatment without ribavirin treatment. We also cannot exclude the possibility that some patients could have cleared the HEV infection at a time beyond 12 to 24 weeks. In a previous study, no HEV clearance was observed in solid organ transplant patients between months 3 and 6 after infection [4]. The burden of chronic HEV infection, including cirrhosis and extrahepatic manifestations, has been reported in immunosuppressed patients [2,19]. Evidence supporting the guidelines for the treatment of immunosuppressed patients with chronic HEV infection, including the alleviation of immunosuppressive treatment and the provision of antiviral treatment, is increasing [20]. Fortunately, the European Association for the Study of the Liver (EASL) guidelines for hepatitis E have been released this year and provide some critical recommendations for HEV in transplant recipients. The current knowledge regarding HEV infections in immunosuppressed patients other than transplant recipients and HIV patients is still rudimentary. The present study largely contributes to this field. The EASL guidelines clearly suggest treating HEV infection in immunosuppressed patients lasting for more than 3 months either by decreasing immunosuppression or with ribavirin [21]. Our observations demonstrate that both the cessation of immunosuppression and ribavirin can be used safely in rheumatological patients. \n\nAs in rheumatological patients, knowledge regarding HEV is still limited in patients with hematological diseases and patients with inflammatory bowel diseases. Recently, two case reports on HEV infection in inflammatory bowel disease patients have been published. One case of spontaneously self-limited HEV infection in a patient with ulcerative colitis [22] and one uncommon case of chronic HEV genotype 1 infection in a patient with Crohn’s disease treated with mercaptopurine, adalimumab and prednisolone [23] have been reported. \n\nThe present study depicts a large cohort of a rare phenomenon. However, this retrospective analysis has several limitations, as follows: the viral load and the genotype of each patient were not determined. Some clinical data are missing due to the retrospective, unstandardized characteristics of the study, including a standardized assessment of hepatic and extrahepatic symptoms. Prospective, standardized multicentric cohort studies are needed to optimize our understanding of the relevance of HEV infections in rheumatological and internal medicine patients.\n\nIn conclusion, HEV should always be a part of the workup for internal medicine/rheumatology patients with abnormal liver function tests. Internal medicine/rheumatology patients, including patients under methotrexate treatment, are at risk of developing chronic HEV infection. The alleviation of immunosuppressive treatment with or without ribavirin treatment should be considered for internal medicine/rheumatology patients with chronic hepatitis E. Future studies are needed to describe the burden of chronic hepatitis E among IM/R patients.\n\nAuthor Contributions\nConception and design: S.P., J.-M.P., R.d.M., and V.M.; Analysis and interpretation of the data: S.P. and V.M.; Drafting of the manuscript: S.P., J.-M.P., R.d.M., and V.M.; Critical revision of the article for important intellectual content: S.P., V.M., J.-M.P., M.v.W., J.v.F., C.H.-z.-S., M.L., C.I.-K., D.B., G.P., R.T., A.W.L., H.W., and R.d.M.; Final approval of the manuscript: S.P., R.d.M., and V.M.; Provision of study materials or patients: S.P. and V.M.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 ALT peak levels (A) and duration of proven HEV viremia (B) in patients with spontaneous clearance, patients with reduction of immunosuppression, patients treated with ribavirin and patients treated with reduction of immunosuppression plus ribavirin.\n\nviruses-11-00186-t001_Table 1Table 1 Characteristics of internal medicine/rheumatology patients with hepatitis E virus (HEV) infection (chronic patients with more than 3 months of viremia: gray shading).\n\nPatient\tUnderlying Disease\tSex\tAge (yrs)\tPeak ALT (IU/mL)\tTreatment for Rheumatic Disease\tDuration of Viremia (weeks)\tIntervention\t\n#1\tRheumatoid arthritis\tM\t57\t1081\tMethotrexate, rituximab\t11\tNo intervention\t\n#2\tRheumatoid arthritis\tF\t69\t610\tMethotrexate, anti-TNF\t4\tNo intervention\t\n#3\t\nCVID\n\tM\t57\t2849\tNo immunosuppressive therapy\t> 24\tNo intervention, lost to follow-up\t\n#4\tSystemic lupus erythematosus\tF\t56\t543\tMethotrexate, anti-TNF\t4\tNo intervention\t\n#5\tRheumatoid arthritis\tF\t65\t469\tMethotrexate\t4\tDiscontinuation of immunosuppression\t\n#6\tRheumatoid arthritis\tF\t75\t1654\tMethotrexate\t18\tRibavirin treatment\t\n#7\tPsoriatic arthritis\tM\t67\t1201\tAnti-TNF biotherapy\t11\tRibavirin treatment\t\n#8\tErdheim–Chester disease\tM\t58\t2140\tMethotrexate, anti-TNF\t3\tDiscontinuation of immunosuppression\t\n#9\tGranulomatosis\tM\t59\t5231\tCyclophosphamide\t4\tNo intervention\t\n#10\tPrimary immune deficiency\tF\t57\t546\tNo immunosuppressive therapy\t53\tRibavirin treatment (relapse)\t\n#11\tRheumatoid arthritis\tF\t51\t1750\tAbatacept\t16\tDiscontinuation of immunosuppression\t\n#12\tJuvenile arthritis\tF\t30\t591\tMethotrexate, anti-TNF\t4\tRibavirin, discontinuation of IS\t\n#13\tPsoriatic arthritis\tF\t54\t121\tAnti-TNF\t4\tNo intervention\t\n#14\tPsoriatic arthritis\tM\t62\t1190\tMethotrexate\t7\tRibavirin, discontinuation of IS\t\n#15\tAxial spondyloarthritis\tF\t52\t142\tInfliximab\t3\tdiscontinuation of IS\t\n#16\tPsoriatic arthritis\tF\t25\t88\tMethotrexate, anti-TNF\t< 1\tDiscontinuation of immunosuppression\t\n#17\tUndetermined arthritis\tM\t70\t3170\tMethotrexate/Prednisolone\t6\tDiscontinuation of immunosuppression\t\n#18\tGranulomatosis\tM\t29\t216\tMycophenolate/prednisolone\t48\tRibavirin treatment\t\n#19\tRetroperitoneal fibrosis\tM\t34\t568\tSirolimus/prednisolone\t96\tRibavirin treatment\t\n#20\tUndefined CD4 disturbance\tM\t48\t282\tNo immunosuppressive therapy\t96\tRibavirin treatment\t\n#21\tPsoriatic arthritis\tM\t55\t1669\tAnti-TNF\t3\tDiscontinuation of immunosuppression\t\nviruses-11-00186-t002_Table 2Table 2 Comparison of patient cohorts.\n\n\n\tPatients without Antiviral Treatment (n = 6)\tPatients with Reduced Immunosuppression (n = 6)\tPatients Treated with Ribavirin (n = 7)\tPatients Treated with Reduced Immunosuppression Plus Ribavirin (n = 2)\t\nMale\t3 (50%)\t3 (50%)\t4 (57%)\t1 (50%)\t\nAge in years, mean (range, SD)\t59 (54–69, 5)\t54 (25–70, 16)\t52 (29–75, 17)\t46 (30–62)\t\nBilirubin peak, mean (range, SD), mg/dL\t4.1 (1.0–8.0, 2.9)\t1.3 (1.0–1.5, 0.4)\t3.5 (1.7–7.4, 2.5)\t1.0 (1.0–1.0, nd)\t\nALT peak in U/L\t1739 (121–5231, 1959)\t1548 (88–3170, 1125)\t658 (142–1654, 564)\t891 (591–1190, 424))\t\nDuration of proven HEV viremia in weeks (range, SD)\t9 (4–24, 8)\t5 (0–16, 6)\t45 (3–96, 40)\t6 (4–7, 2)\t\nUnderlying diseases\t-> 2 Rheumatoid a.\n-> 1 Psoriatic a. \n-> 1 Granulomatosis\n-> 1 CVID\n-> 1SLE\t-> 2 Rheumatoid a.\n-> 2 Psoriatic a. \n-> 1 Erdheim Chester\n-> 1 Undefined a.\t-> 1 Rheumatoid a.\n-> 1 Psoriatic a.\n-> Axial spondyloarthritis\n-> 1 Granulomatosis\n-> Primary immune deficiency\n-> Retroperitoneal fibrosis\n-> Undefined CD4 disturbance\t-> 1 Psoriatic a.\n-> Juvenile\n==== Refs\nReferences\n1. Mansuy J.M. Gallian P. Dimeglio C. Saune K. Arnaud C. Pelletier B. Morel P. Legrand D. Tiberghien P. Izopet J. A nationwide survey of hepatitis E viral infection in French blood donors Hepatology 2016 63 1145 1154 10.1002/hep.28436 27008201 \n2. Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. Cointault O. Esposito L. Abravanel F. Danjoux M. Hepatitis E virus and chronic hepatitis in organ-transplant recipients N. Engl. J. Med. 2008 358 811 817 10.1056/NEJMoa0706992 18287603 \n3. Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient N. Engl. J. Med. 2008 358 859 860 10.1056/NEJMc0708687 18287615 \n4. Kamar N. Rostaing L. Legrand-Abravanel F. Izopet J. How should hepatitis E virus infection be defined in organ-transplant recipients? Am. J. Transplant. 2013 13 1935 1936 10.1111/ajt.12253 23659713 \n5. Pischke S. Hardtke S. Bode U. Birkner S. Chatzikyrkou C. Kauffmann W. Bara C.L. Gottlieb J. Wenzel J. Manns M.P. Ribavirin treatment of acute and chronic hepatitis E: A single-centre experience Liver Int. 2013 33 722 726 10.1111/liv.12114 23489973 \n6. Kamar N. Izopet J. Tripon S. Bismuth M. Hillaire S. Dumortier J. Radenne Y. Coilly A. Garrique V. DÀlteroche L. Ribavirin for chronic hepatitis E virus infection in transplant recipients N. Engl. J. Med. 2014 370 1111 1120 10.1056/NEJMoa1215246 24645943 \n7. Bauer H. Luxembourger C. Gottenberg J.E. Fournier S. Abravanel F. Cantagrel A. Chatelus E. Claudepierre P. Hudry C. Izopet J. Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: A French retrospective multicenter study Medicine (Baltimore) 2015 94 e675 10.1097/MD.0000000000000675 25860212 \n8. Honer zu Siederdissen C. Pischke S. Schlue J. Deterding K. Hellms T. Schuler-Luttmann S. Schwarz A. Manns M.P. Cornberg M. Wedemeyer H. Chronic hepatitis E virus infection beyond transplantation or human immunodeficiency virus infection Hepatology 2014 60 1112 1113 10.1002/hep.26987 24375747 \n9. Pischke S. Hartl J. Pas S.D. Lohse A.W. Jacobs B.C. Van der Eijk A.A. Hepatitis E virus: Infection beyond the liver? J. Hepatol. 2017 66 1082 1095 10.1016/j.jhep.2016.11.016 27913223 \n10. Dalton H.R. Bendall R.P. Keane F.E. Tedder R.S. Ijaz S. Persistent carriage of hepatitis E virus in patients with HIV infection N. Engl. J. Med. 2009 361 1025 1027 10.1056/NEJMc0903778 19726781 \n11. Dalton H.R. Hunter J.G. Bendall R. Autochthonous hepatitis E in developed countries and HEV/HIV coinfection Semin. Liver Dis. 2013 33 50 61 23564389 \n12. Ingiliz P. Mayr C. Obermeier M. Herbst H. Polywka S. Pischke S. Persisting hepatitis E virus infection leading to liver cirrhosis despite recovery of the immune system in an HIV-infected patient Clin. Res. Hepatol. Gastroenterol. 2016 40 e23 e25 10.1016/j.clinre.2016.01.005 27055386 \n13. van Bijnen S.T. Ledeboer M. Martens H.A. Chronic hepatitis E in a patient with rheumatoid arthritis treated with adalimumab and methotrexate Rheumatology 2017 56 497 498 10.1093/rheumatology/kew388 27940593 \n14. Fraticelli P. Bagnarelli P. Tarantino G. Martino G.P. Benfaremo D. Nobili L. Mandolesi A. Barbisan F. Marinelli K. Mattioli M. Chronic hepatitis E in a patient treated with rituximab and mycophenolate mofetil for Sjogren’s syndrome Rheumatology 2016 55 2275 2277 10.1093/rheumatology/kew282 27498353 \n15. Suneetha P.V. Pischke S. Schlaphoff V. Grabowski J. Fytili P. Gronert A. Bremer B. Markova A. Jaroszewicz J. Bara C. Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection Hepatology 2012 55 695 708 10.1002/hep.24738 22006345 \n16. Cao D. Cao Q.M. Subramaniam S. Yugo D.M. Heffron C.L. Rogers A.J. Kennedy S.P. Tian D. Matzinger S.R. Overend C. Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity Proc. Natl. Acad. Sci. USA 2017 114 6914 6923 10.1073/pnas.1705446114 28630341 \n17. Pischke S. Suneetha P.V. Baechlein C. Barg-Hock H. Heim A. Kamar N. Schlue J. Strassburg C.P. Lehner F. Raupach R. Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients Liver Transplant. 2010 16 74 82 10.1002/lt.21958 \n18. Galante A. Pischke S. Polywka S. Luetgehethmann M. Suneetha P.V. Gisa A. Hiller J. Dienes H.P. Nashan B. Lohse A.W. Relevance of chronic hepatitis E in liver transplant recipients: A real-life setting Transpl. Infect. Dis. 2015 17 617 622 10.1111/tid.12411 26094550 \n19. Wedemeyer H. Pischke S. Manns M.P. Pathogenesis and treatment of hepatitis E virus infection Gastroenterology 2012 142 1388 1397.e1 10.1053/j.gastro.2012.02.014 22537448 \n20. Mallet V. van Bommel F. Doerig C. Pischke S. Hermine O. Locasciulli A. Cordonnier C. Berg T. Moradpour D. Wedemeyer H. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: Recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5) Lancet Infect. Dis. 2016 16 606 617 10.1016/S1473-3099(16)00118-3 27599653 \n21. European Association for the Study of the Liver EASL Clinical Practice Guidelines on hepatitis E virus infection J. Hepatol. 2018 68 1256 1271 10.1016/j.jhep.2018.03.005 29609832 \n22. Suzuki K. Kumagai I. Yoshida Y. Miyasaka A. Takikawa Y. Kamiya R. Kondo K. Kato A. Chiba T. Okamoto H. Asymptomatic acute hepatitis E in a female patient with ulcerative colitis Clin. J. Gastroenterol. 2017 10 255 260 10.1007/s12328-017-0730-7 28353200 \n23. Robins A.E.M. Bowden D.J. Gelson W.T.H. Chronic genotype 1 hepatitis E infection from immunosuppression for ileo-colonic Crohn’s disease Oxf. Med. Case Rep. 2018 2018 omy059 10.1093/omcr/omy059 30159153\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1999-4915",
"issue": "11(2)",
"journal": "Viruses",
"keywords": "chronic hepatitis E; disease-modifying antirheumatic drugs (DMARDs); hepatitis E; ribavirin",
"medline_ta": "Viruses",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D001168:Arthritis; D005060:Europe; D005260:Female; D016751:Hepatitis E; D006521:Hepatitis, Chronic; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007388:Internal Medicine; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012367:RNA, Viral; D012008:Recurrence; D012189:Retrospective Studies; D012219:Rheumatology; D012254:Ribavirin; D012307:Risk Factors",
"nlm_unique_id": "101509722",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30813268",
"pubdate": "2019-02-22",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "30159153;27599653;24645943;29609832;25860212;18287615;22537448;27913223;18287603;27940593;27008201;24375747;22006345;19726781;28353200;19866448;28630341;27055386;27498353;23489973;23564389;23659713;26094550",
"title": "Chronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study.",
"title_normalized": "chronic hepatitis e in rheumatology and internal medicine patients a retrospective multicenter european cohort study"
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"companynumb": "FR-TEVA-2019-FR-1052619",
"fulfillexpeditecriteria": "1",
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{
"abstract": "To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age.\n\n\n\nThis is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005.\n\n\n\nAs of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults.\n\n\n\nNewer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management.",
"affiliations": "From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City. Kristen.krysko@ucsf.edu.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.;From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children's Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children's Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City.",
"authors": "Krysko|Kristen M|KM|;Graves|Jennifer|J|;Rensel|Mary|M|;Weinstock-Guttman|Bianca|B|;Aaen|Gregory|G|;Benson|Leslie|L|;Chitnis|Tanuja|T|;Gorman|Mark|M|;Goyal|Manu|M|;Krupp|Lauren|L|;Lotze|Timothy|T|;Mar|Soe|S|;Rodriguez|Moses|M|;Rose|John|J|;Waltz|Michael|M|;Charles Casper|T|T|;Waubant|Emmanuelle|E|;|||",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000006471",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "91(19)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009103:Multiple Sclerosis; D010818:Practice Patterns, Physicians'; D014481:United States",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e1778-e1787",
"pmc": null,
"pmid": "30333163",
"pubdate": "2018-11-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19139299;24768216;17884679;23401129;26996405;21149803;26603152;11562627;20089952;15753430;11571702;19387545;17603763;12910434;23021975;27572865;18272891;22992073;26407848;23572237;17177154;29363396;16042224;26026897;25270659;16510744;23420110;28933245;17881262;19892770;25878006;22232346;28389054",
"title": "Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US.",
"title_normalized": "use of newer disease modifying therapies in pediatric multiple sclerosis in the us"
} | [
{
"companynumb": "PHHY2019US001191",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Cancers can develop the ability to evade immune recognition and destruction. Immune checkpoint inhibitors (ICIs) are drugs targeting these immune evasion mechanisms. ICIs have significantly improved outcomes in several cancers including metastatic melanoma. However, data on toxicities associated with allograft transplant recipients receiving ICI is limited. We describe a case of a 71-year-old woman who was diagnosed with metastatic melanoma 13 years after renal transplantation. She was commenced on the ICI nivolumab. She developed acute renal transplant rejection 15 days after administration of the first dose. She continues on haemodialysis but has demonstrated complete oncological response. This case demonstrates the risk of acute renal transplant rejection versus improved oncological outcomes. Patients and clinicians must consider this balance when initiating ICI therapy in allograft transplant recipients. Patients should be fully consented of the potential consequences of acute renal transplant rejection including lifelong dialysis.",
"affiliations": "Tayside Cancer Centre, Ninewells Hospital, Dundee, Dundee, UK brandonszemann.tan@nhs.scot.;Tayside Cancer Centre, Ninewells Hospital, Dundee, Dundee, UK.;Tayside Cancer Centre, Ninewells Hospital, Dundee, Dundee, UK.",
"authors": "Tan|Brandon|B|http://orcid.org/0000-0003-0347-8539;Baxter|Mark|M|;Casasola|Richard|R|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "cancer intervention; malignant disease and immunosuppression; skin cancer; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006084:Graft Rejection; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008545:Melanoma; D000077594:Nivolumab; D012535:Scalp; D012878:Skin Neoplasms; D013997:Time Factors; D014184:Transplantation, Homologous",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33558380",
"pubdate": "2021-02-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute renal transplant rejection following nivolumab therapy for metastatic melanoma.",
"title_normalized": "acute renal transplant rejection following nivolumab therapy for metastatic melanoma"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1902215",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1"... |
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