Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population

Predictive factors of functional remission in patients with early to mid-stage schizophrenia treated by long acting antipsychotics and the specific role of clinical remission

International audienceBackground: Functional remission has become a major therapeutic objective in schizophrenia, but the probability of such positive outcome has a large variability, ranging from 15% to 51%. Additionally, how clinical remission constitutes a prerequisite for functional remission also remains unclear.Methods: A prospective observational study was conducted in French schizophrenic patients who initiated treatment with a long-acting injectable (LAI) after an acute episode. Functional and clinical remissions were assessed using the FROGS and the Andreasen criteria, and the role of clinical remission and predictive factors of functional remission was evaluated.Results: Three hundred three patients with schizophrenia (DSM-IV criteria) were followed for 12 months. At 12 months, 45.1% of the patients reached functional remission while 55.1% obtained clinical remission. Clinical remission facilitated functional remission (OR = 14.74), especially in patients with psychosis for less than 5 years (OR = 23.73). Other predictive factors concerned the family environment, education level, employment status, baseline functioning levels and level of insight.Conclusions: About half of patients treated with LAI reached functional remission after one year of follow-up. Reduced clinical symptoms and reaching clinical remission largely favored functional remission. These results stress the importance of continuous and appropriate symptomatic treatment to reach functional remission and maximize recovery chances

The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks

1. Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I(KACh) by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the effect of tertiapin, a bee venom peptide blocking I(KACh), to evaluate the role of I(KACh) in Langendorff preparations challenged with ACh. 2. ACh (0.5 μM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). 3. Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P<0.01). 4. Tertiapin dose-dependently blunted the ACh-induced negative chronotropic response from an ACh-induced decrease in heart rate of 39±16% in control conditions to 3±3% after 300 nM tertiapin (P=0.01). These effects were not accompanied by any significant change in QT intervals. 5. Tertiapin blocked I(KACh) with an IC(50) of 30±4 nM with no significant effect on the major currents classically associated with cardiac repolarisation process (I(Kr), I(Ks), I(to1), I(sus), I(K1) or I(KATP)) or AV conduction (I(Na) and I(Ca(L))). 6. In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I(KACh)

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression