Search

Immune checkpoint inhibitors (ICIs), aiming to foster cancer-targeted immune response, proved to be effective in several advanced malignancies at the price of immune-related adverse events affecting various organs, notably the kidneys. Herein, a retrospective descriptive analysis was performed on all biopsy-confirmed cases of ICI-induced nephropathy notified to the French Pharmacovigilance database to date. Data were gathered about patients' characteristics, acute kidney injuries and histopathological features. A total of 63 biopsy-proven cases were included for analysis. Immune-related nephropathy occurred after a mean of 105.5 ± 98.6 (standard deviation) days after the introduction of the ICI. Kidney Disease: Improving Global Outcomes acute kidney injury stage 3 occurred in 36.5% of patients, and the mean peak serum creatinine was 288 µmol/L. Histopathology suggested acute tubule-interstitial nephritis in 52 patients (83%), while signs of acute tubular necrosis were found in 18 (29%) and glomerular involvement in 5 of them (8%). Another immune-related adverse event was documented in 25 patients (39.7%). Patients were treated with corticosteroids in 88.9% of cases. All in all, 27.0% fully recovered, 54.0% partially recovered, 12.7% did not recover. Rechallenge was attempted in 19 patients and one patient relapsed. Three-quarters of patients received a medication known to cause acute tubule-interstitial nephritis. The major limits of this study are those inherent to pharmacovigilance studies, such as its retrospective nature and incomplete data. Although it cannot pretend drawing any pathophysiological conclusion, this study depicts the clinical and histopathological pictures of ICI-induced nephropathies in a large cohort of biopsied patients with all grades of severity.

Anemia associated with Immune checkpoint inhibitor (ICI) is usually hemolytic and regenerative. Cases of non-regenerative pure red cell aplasia are rare, and typically improve upon drug discontinuation and after corticotherapy. We herein report a case of nivolumab-related erythroblastopenia refractory to steroids in a melanoma patient that improved only after treatment with cyclosporin. Nivolumab had been well tolerated for 2 months after being introduced as an adjuvant treatment. Hemoglobin level then progressively decreased from 12.7 g/dl as baseline value to a nadir of 4.3 g/dL despite transfusion with a total of 29 packed red blood cells in 3 months. Extensive workup including repeated bone marrow examinations led to the diagnosis of pure red cell aplasia. Anemia persisted despite nivolumab discontinuation and over a month of corticotherapy, but improved dramatically 3 days after cyclosporin initiation and did not recur upon cyclosporin tapering. The patient remains cancer-free 9 months after nivolumab withdrawal. This case highlights the under-recognized risk of erythroblastopenia in patients treated with ICI and proves cyclosporin is a valid alternative for the treatment of steroid-refractory cases.

Background Studies have shown disparate results on the consequences of morphine use in ST-segment elevation myocardial infarction (STEMI). No study has evaluated alternative treatments that could be at least non-inferior to morphine without its potentially damaging consequences for myocardial function and platelet reactivity. The aim of this study was to evaluate whether nitrous oxide/oxygen plus intravenous acetaminophen (NOO-A) is non-inferior to morphine to control chest pain in STEMI patients. Methods This multicenter, open-label, cluster-randomized, controlled, non-inferiority study compared NOO-A with morphine in 684 prehospital patients with ongoing suspected STEMI of Results The median baseline pain score was 7.0 in both groups. The primary endpoint occurred in 51.7% of the NOO-A group and 73.6% of the morphine group (absolute risk difference − 21.7%; 95% confidence interval − 29.6 to − 13.8). At 30 days, the rate of serious adverse events was 16.0 and 18.8% in the NOO-A and morphine groups respectively (p = NS). The rate of death was 1.8% (NOO-A group) and 3.8% (morphine group) (p = NS). Conclusion Analgesia provided by NOO-A was inferior to morphine at 30 min in patients with acute STEMI in the prehospital setting. Rates of serious adverse events did not differ between groups. Trial registration ClinicalTrials.gov: NCT02198378.

BackgroundDespite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.MethodsPreviously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (NCT02799901). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.ResultsSeventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2–28.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-α and interferon-γ (IFN-γ) (1136 pg/mL vs 5558 pg/mL, pConclusionsOur findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy.