Comparison of clinical safety between standard versus extended interval dosing of immune checkpoint inhibitors: a real-world retrospective cohort study.

BACKGROUND: Extended interval dosing (ED) for inhibitors of programmed cell death protein 1 (anti-PD-1) (nivolumab, pembrolizumab) or its ligand (anti-PD-L1) (durvalumab) were recently approved based on pharmacokinetic model results that predicted a benefit-risk profile comparable with the standard dosing (SD) regimen. However, safety data in real-world condition of use are lacking. The objective was to compare the incidence and the risk factors of serious immune-related adverse events (irAEs) and any-grade irAEs between the SD and ED regimens in patients treated with anti-PD-1 or anti-PD-L1. MATERIALS AND METHODS: IrAEs were assessed from medical records in all new users of nivolumab, pembrolizumab, or durvalumab between 1 January 2019 and 31 December 2020 across two oncology centers in France. The incidence of irAEs was compared between both dosing regimens using Cox proportional hazards models adjusting for the main available confounders. RESULTS: Among 686 patients included, 63% were new users of an SD regimen, 14% of ED regimen, and 23% started with SD and switched to ED regimen during follow-up. Overall, 34.6% of patients experienced at least one irAE of any grade and 11.4% presented at least one serious grade ≥3 irAE. No statistical difference was found between the SD and ED regimen on the risk of grade ≥3 irAEs [adjusted hazard ratio (HR) 1.40, 95% confidence interval (CI) 0.71-2.76] but our results suggest an increased risk of any-grade irAEs with the ED regimen (adjusted HR 1.46, 95% CI 1.00-2.12, P = 0.048). IrAEs resolved without sequelae in 46.4% of cases, and they were fatal for three patients (0.4%). Autoimmune pre-existing condition was confirmed as a risk factor for grade ≥3 irAEs (HR 2.56, 95% CI 1.53-4.27) and for all-grade irAEs (HR 1.60, 95% CI 1.17-2.20). CONCLUSIONS: In a real-world setting, according to the regimen chosen by the oncologist based on clinical characteristics, we did not observe an increase in grade ≥3 irAE incidence between the SD and ED regimens.

[Management of immune-related toxicities associated with immune checkpoints inhibitors: Data from the multidisciplinary meeting « ToxImmun ¼ in Eastern Occitania]. / Gestion des toxicités induites par les inhibiteurs de checkpoint immunologique : données de la réunion de concertation pluridisciplinaire « ToxImmun ¼ en Occitanie Est.

Immune checkpoint inhibitors (ICIs) can cause numerous and complex immune-related adverse events whose management need a multidisciplinary approach. Herein, we investigated 114 requests, mostly concerning patients suffering from lung cancer, that were submitted to the « ToxImmun ¼ multidisciplinary meeting in Eastern Occitania between December the 17th 2018 and January the 20th 2020. The leading reasons for the request concerned the putative causal link between immunotherapy and immune-toxicity and its management, followed by possible retreatment after temporary withdrawn because of adverse event, and finally the possibility to initiate ICIs in patients with pre-existing autoimmunity. Colitis, hepatitis and myocarditis were the most frequent immune-related adverse events (IRAEs), both all grade and grade 3-4. Sicca syndrome (with or without Sjogren criteria) was also frequent (26% of cases) and seems to be associated with severe toxicity and multi-toxicity. The mean time to first IRAE was 3.8 months, a time shortened with the use of anti-PD-L1 agents or ICI combination. A majority of requests came from initial evaluation by the internist confirming the early and main role of this specialty in the management of immunotoxicity. Expansion of this regional multidisciplinary meeting, coordinated by internists and medical oncologists, could improve management of immune-related adverse events for the patients' benefits.

Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial. METHODS: A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia. RESULTS: A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39). CONCLUSION: There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

Dipeptidyl peptidase-4 inhibitors and the risk of community-acquired pneumonia in patients with type 2 diabetes.

AIMS: To determine whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with an increased risk of community-acquired pneumonia. METHODS: The UK Clinical Practice Research Datalink and the Hospital Episodes Statistics database were used to conduct a nested case-control analysis within a cohort of new users of antidiabetic drugs between 2007 and 2012. Incident cases of hospitalization for community-acquired pneumonia were matched with up to 20 controls on age, duration of treated diabetes, calendar year and duration of follow-up. Conditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for hospitalization for community-acquired pneumonia associated with current use of DPP-4 inhibitors compared with current use of two or more oral antidiabetic drugs. RESULTS: The cohort included 49,653 patients, of whom 562 were hospitalized for community-acquired pneumonia during follow-up (incidence rate 5.2/1000 person-years). Compared with current use of two or more oral antidiabetic drugs, current use of DPP-4 inhibitors was not associated with an increased risk of hospitalized community-acquired pneumonia overall (adjusted OR 0.80, 95% CI 0.50-1.29) or according to duration of use (p for trend = 0.57). CONCLUSIONS: The use of DPP-4 inhibitors was not associated with an increased risk of hospitalization for community-acquired pneumonia. Additional research is needed to assess the association between these drugs and other serious infections.

Evaluation of a laparoscopic training program with or without robotic assistance.

The aim of the present study was to evaluate the value of a box trainer simulator in laparoscopy training. A further aim was to determine if robotic-assisted approaches further improved the young residents' skills in laparoscopic surgery. The study was a prospective randomized study. Twelve residents in obstetrics & gynecology completed four laparoscopy-related procedures of varying complexity using a box trainer simulator. Participants were randomized into two groups; robotic-assisted laparoscopy (LRA) and traditional laparoscopy (TL). All subjects were assessed with a time and technical score, which are quantitative and qualitative approaches (respectively). All residents completed the training and a satisfaction questionnaire, which confirmed that the training was well regarded. Regardless of the workshop type, there was a clear time and technical improvement for the difficult tasks. The improvement of time score was most apparent for simple tasks in LRA and for more complex tasks in TL. After training, we did not find a significant difference for the technical score between Novices and Experts in TL and LRA. These findings suggest that training in laparoscopy surgery is useful, reproducible and well accepted by both novice and more advanced trainees. Furthermore, gynecological endoscopy center consider including robotic-assisted approaches in their surgical training program.

[Functional MRI by general radiologists in prediction of side-specific extracapsular extension after radical prostatectomy: what value in daily practice?]. / IRM fonctionnelle par des radiologues généralistes, dans la prédiction de l'extension extracapsulaire lobe spécifique après prostatectomie radicale : quelle valeur en pratique quotidienne ?

OBJECTIVE: To evaluate the performance of functional MRI (FMRI) performed by general radiologists (GR) in detection of side-specific extracapsular extension (SSECE) prostate cancer (PCa). METHODS: We retrospectively analyzed 79 patients who underwent FMRI with pelvic phased array coil before radical prostatectomy (RP) performed at University Hospital (UH) of Nîmes. Twelve GR (including three from UH) interpreted the images during their daily practice. FMRI results were dichotomized as positive or negative and confronted to pathological reports for SSECE and side-specific seminal vesicle invasion (SSSVI), with calculation of diagnostic values. The influence of interval between biopsy and FMRI, diffusion-weighted sequence (DWS) and intensity of FMRI, on the diagnostic performance were assessed by Fisher's exact test. RESULTS: A SSECE and a SSSVI were observed at FMRI and pathology respectively on 14 (8.8%) and 38 (24.1%) prostate lobes, and on six (3.8%) and seven (4.4%) prostate lobes. The sensitivity, specificity, positive and negative predictive values of FMRI for SSECE were respectively 24%, 96%, 64% and 80%; and for SSSVI were 14%, 97%, 17% and 96% respectively. The time between biopsy and FMRI, intensity of FMRI and DWS, did not influence the sensitivity and specificity of fMRI at Fisher test. CONCLUSION: This study found that preoperative prostate FMRI performed by GR has good specificity but poor sensitivity in predicting SSECE on pathological reports.

[Reliability of the pulse contour analysis for cardiac output measurement for assessing the fluid responsiveness]. / La mesure du débit cardiaque par analyse du contour de l'onde de pouls n'est pas fiable pour diagnostiquer une réponse au remplissage vasculaire.

BACKGROUND: The cardiac output (CO) is classically measured in intensive care unit patients. pulse contour (PC) method allows monitoring of CO. OBJECTIVE: The aim of the present study was to assess the ability of PC to assess the fluid responsiveness defined as an increase in CO more than or equal to 15% after 500 mL hydroxyethyl starch over 20 minutes. PATIENTS AND METHODS: In this observational prospective study, patients in shock in whom a PC method was inserted were included. CO was measure using the PC and thermodilution methods before and after a fluid challenge indicated by the physician. The correlation coefficient was measured, the diagram of Bland and Altman was built and the percentage of error (Critchley and Critchley method) was calculated. The ability of PC to diagnose fluid responsiveness was assessed using a receiver operating characteristics (ROC) curve. RESULTS: Sixty-two fluid challenges were performed in 37 included patients. After fluid challenge, r(2) was 0.05 (P<0.01), the bias between PC and thermodilution was 0.3 ± 1.2L/min and the percentage of error was 36%. The area of the ROC curve was 0.601 [0.468-0.723]. CONCLUSION: In ICU patients with shock, PC cannot replace thermodilution to diagnose fluid responsiveness.

[Influence of acute aggravations on the development of long-term handicap in relapsing remitting multiple sclerosis: a clinical study in 99 patients]. / Influence des poussées sur la survenue d'un handicap au long cours dans la sclérose en plaques de forme rémittente: étude observationnelle de 99 patients.

INTRODUCTION: Rate of relapse occurring during the first 5 years of MS-RR is a prognosis factor of occurrence of disability or secondary progressive (SP) phase. Progressive phase, related to chronic axonal loss, is mainly considered as the principal factor of disability progression. Influence of acute relapses during the relapsing-remitting phase on disability development is not known as a prognosis factor. OBJECTIVES: To determine the influence of the exacerbations among patients with RR-MS after the second clinical event on the disability occurrence. METHODS: Diagnosis of multiple sclerosis was established according to Poser's classification. Disability measurement was made with the use of the Expanded Disability Status Scale (EDSS). The patients included in the study were classified as clinically definite RR-MS, with an EDSS score500 m. The study began at the time of the second clinical event and ended when an EDSS score of 4.0 was reached or when a SP phase was beginning or at the last follow-up visit date if these two stages were not reached. The primary outcome measure was the comparison of the risk and the average time to reach an EDSS>or=4.0 or a SP form according to the annual exacerbation rate (AER) using Kaplan-Meier survival curve. RESULTS: Among the 238 ms patients of the database, 136 patients were classified as having a definite RR-MS. Among these 136 patients, 99 patients could be included in the study according to the inclusion criteria. The median follow up of the patients since the first clinical event was 9.8 years (range 4 to 44). The average EDSS score was 0.7 at the beginning of the study and 2.3 at the end. 20.2p.cent of patients (n=20) reached an EDSS score of 4.0 or a SP-MS. The median AER was 0.4 and the average 0.62 (range 0 to 6.1). The time to reach the primary end point for 25p.cent of the population was 17.8 years in group with an AER<0.4 (group A) and 6.9 years in group with an AER>0.4 (group B) (logrank; p<0.0001). The relative risk for patients of the group B compared to group A to reach an EDSS of 4.0 or a SP form was 8.01 (IC-95p.cent: 2.74-23.46; p=0.0001). CONCLUSIONS: In spite of a limited number of patients, this study gives evidence that a high rate of acute exacerbations in RR-MS patients after the second clinical event may be an independent predictive factor of long-term residual disability progression. High relapse rate leads to a more frequent and faster SP or EDSS>4.0 occurrence.

[In vitro fertilization and smoking: use of urinary cotinine and expired air carbon monoxide measurements]. / Fécondation in vitro et tabac: intérêt de la cotininurie et de l'analyseur de monoxyde de carbone expiré.

OBJECTIVE: To study the correlation between expired air carbon (EACO) and urinary cotinine, and to determine the impact of tobacco smoking on in vitro fertilization (IVF) results. PATIENTS AND METHODS: We studied prospectively 221 patients in our ART center from October 2002 to October 2004: 51 active smokers, 85 passive smokers, and 85 non-smokers. Patients were classified into active, passive smokers, or non-smokers, based on a questionnaire. We measured urinary cotinine and EACO on the embryo transfer day and we recorded the IVF parameters. RESULTS: Two hundred and twenty-one patients were included. We observed a 17.2% reduction of estradiolemy (P=0.05), a 1.5% reduction of pregnancies (NS), a 7.8% reduction of infants born alive (NS), a 28.5% reduction of twin pregnancies (P=0.06), as well as a 10% increase of miscarriages (NS) in the active smokers in comparison with non-smokers (the same trends were observed between active and passive smokers). EACO and urinary cotinine were well correlated. There was a negative correlation between estradiolemy and urinary cotinine (R=-0.15, P=0.02). DISCUSSION AND CONCLUSION: Tobacco smoking intensity may be dilatory on IVF results. There is a high correlation between EACO and urinary cotinine. Other larger studies would probably obtain results more statistically significant.