Rifampin-Related Acute Renal Failure, Thrombocytopenia, and Leukocytoclastic Vasculitis TOTHE EDITOR: Rifampin is a first-line drug in the treatment of Mycobacteriumkansasii. Acute renal failure and thrombocytopenia due to rifampinhave been reported sporadically.P and a case presenting witha skin lesion suggestiveof vasculitis has been described.'This is the first case in which rifampin administration was followedby these 3 adverse reactions concurrently in the same patient.withhistological confirmation of a vasculitic lesion.Case Report. A 76-year-oldman with a past historyof stableangina pectoris treated with aspirin was transferred to our hospitalwith a oneweek historyof fever,dry cough,dyspnea,oliguria.and bilateraledema in lowerextremities. 1\vo monthsearlierthe patienthad been diagnosed with M. kansasii pulmonary disease and was treated with a combined preparation of isoniazid 50 mg, rifampin 120mg, and pyrazinamide 300 mg (Rifater). He was taking 5 tablets daily (total daily dose: isoniazid 250 mg, rifampin 600 mg, pyrazinamide 1500mg). At that time,laboratory parameters included hemoglobin 15.3 g/dL, white blood cell (WBC) count 7540ljlL. platelets 232 x IDlljlL, serum creatinine 1.1 mg/elL, and urea56 mg/elL.On the patient'sadmission, laboratory data showedacute renalfailure (serum creatinine 9.6 mg/dL, urea 168 mg/dL) and thrombocytopenia (platelets85 x IDlljlL). Other results were WBC count 13,3oo/jlL,he-This is, to the bestof our knowledge,the first reportedcase of histologically confirmed rifampin-induced leukocytoclastic vasculitis. Iredale • et al. l reported on a patientwitha skinlesionsuggestive of vasculitis, but therewas no histological confirmation. Use of the Naranjoprobability scale indicated a probable relationship betweenrifampin and acute renalfailure,thrombocytopenia, and leukocytoclastic vasculitis.' This case has beenreported to the SpanishHealth Authorities (number 07-121).
using immunohistochemistry for p53 (p53 wild-type "p53wt" or p53 aberrant "p53abn" expression) and mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), considering MMR deficiency (MMRd) when a loss of MMR nuclear staining for at least one protein was identified. Identification of POLE mutations (POLE-EDM) was made by sequencing exons 9e14. Only pathogenic variants described in COSMIC database were considered for further analysis. Clinicopathological variables and survival ([RFS, relapse free survival; OS, overall survival]) correlations were assessed by the Kaplan Meier method and log rank.Results: A cohort of 54 patients fulfilled clinical and pathological criteria. Distribution by histological subtype was: endometrioid (46.3%), serous (33.3%), undifferentiated (11.1%), mixed (5.6%), and clear cell (3.7%). Molecular profile was fully evaluable in 49 samples: MMRd (26.5%), POLE-EDM (12.2%), p53wt (22.5%), p53abn (38.8%). Regardless of molecular subtype, 5 year relapse rate was: POLE 0%, MMRd 31.6%, p53wt 35.7%, p53abn 48.9% (p¼0.23), and 5 year OS rate was: POLE-EDM 100%, MMRd 76.2%, p53wt 48% and p53abn 38.5% (p¼0.18). Considering only endometrioid subtype, there was a statistically significant correlation of the molecular classification with 5 year OS (p¼0.02).Conclusions: To our knowledge, this is the first series that has evaluated the molecular classification focused on early-stage HG-EC, including all histologies. Patients with POLE-EDM have an excellent prognosis, with no relapses in this subgroup, whereas patients with p53abn have the worst prognosis. The application of molecular classification in daily practice could be useful in a better design of adjuvant therapy.Legal entity responsible for the study: The authors.
Results: 375 samples were profiled for HRD status and were divided into four tiers based on the weight of HRD-related mutation pattern. Cox model showed significant survival difference (p-value ¼ 0.001) proportional to the weight of HRD mutation pattern with higher weight being the longest survival and vice versa. 223 and 152 samples were categorized as HRD and non-HRD based on optimized threshold and survival difference remains significant (p-value ¼ 0.0017). Similar survival difference was observed (p-value¼0.0013) suggesting the validity of the method on targeted sequencing. Out of 124, 49 and 19 breast, ovarian and prostate cancer samples, 13, 11 and 4 of them were labeled as HRD positive based on known HRD causing variants. All but one HRD positive samples were consistently classified by our method.Conclusions: Our results showed that NMF method is able to faithfully detect HRD samples. The method can be applied to WES as well as targeted sequencing and achieve equally significant survival difference between samples with different HR status. Upon detecting HRD, this method can identify additional HRD patients and therefore make better patient stratification.
Background: PROs enable direct measurement of the experiences of pts with cancer related to an intervention. Regulators increasingly use PROs to inform the risks and benefits of new drug candidates, focusing on 3 core concepts: physical functioning (PF), disease-related symptoms (DRS), and symptomatic adverse events (AEs). Dostarlimab is an investigational antieprogrammed death-1 monoclonal antibody that has shown activity in pts with advanced dMMR EC (objective response rate, 42%; disease control rate, 58%) and an acceptable safety profile. Here, we report on PROs in pts treated with dostarlimab in the single-arm GARNET trial.Methods: Pts with recurrent or advanced dMMR/MSI-H EC that progressed on a platinum regimen received 500 mg Q3W*4 of dostarlimab, then 1000 mg Q6W until disease progression or discontinuation (DC). PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline (BL), each dose cycle, and after DC. For PF and DRS (pain and fatigue), we conducted multi-item descriptive analyses, including change from BL. For symptomatic AEs and tolerability (nausea, vomiting, constipation, diarrhea, tiredness/fatigue), we conducted item-level analyses to understand response distribution and change in response categories from BL: improved, stable, and 1-, 2-, or 3-category worsening.Results: PRO data were available for 66/104 pts who received 1 dose of dostarlimab. Questionnaire compliance was consistent across domains, ranging from 100% at BL to 45% at cycle 7. Pain, fatigue, and PF were maintained above BL starting at cycles 1, 3, and 4, respectively. Symptomatic AEs were experienced by a minority of pts, with <25% and <6% of pts having 1-or 2-category worsening, respectively. Improved scores were reported by 6% to 37% of pts.Conclusions: PROs from the GARNET trial showed that dostarlimab was generally well tolerated and disease-related symptoms were improved or maintained while on treatment. These data, along with the efficacy and safety profile of dostarlimab, support use of dostarlimab in pts with dMMR/MSI-H advanced EC.Clinical trial identification: NCT02715284.
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