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Background The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). Objective The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. Design, setting, and participants CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. Intervention Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). Outcome measurements and statistical analysis Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. Results and limitations Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. Conclusions Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. Patient summary We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

Atezolizumab is an anti–PD-L1 immune checkpoint inhibitor recommended for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) after prior platinum-containing chemotherapy, regardless of PD-L1 status, among other treatment settings. We conducted a long-term follow-up to the exploratory analysis of overall survival (OS) and safety for the IMvigor211 intent-to-treat (ITT) population. Patients with mUC and disease progression during or following platinum-based chemotherapy were randomised 1:1 to receive atezolizumab 1200 mg or chemotherapy (vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or docetaxel 75 mg/m2 according to investigator choice) intravenously every 3 wk. Although the primary analysis did not demonstrate statistically significant longer OS for patients receiving atezolizumab versus chemotherapy, updated OS showed long-term durable remission. With a median of 33 mo of follow-up, the 24-mo OS rate was 23% with atezolizumab and 13% with chemotherapy. Safety findings were consistent with the primary analysis, with no new signals detected. Chemotherapy-treated patients experienced more grade 3/4 treatment-related adverse events (AEs; 43% vs 22%) and more AEs leading to treatment discontinuation (18% vs 9%). Atezolizumab-treated patients experienced more AEs of special interest (35% vs 20%), which tended to be grade 1–2. Our findings support the use of atezolizumab in platinum-treated patients with mUC regardless of PD-L1 status. Patient summary We report follow-up results from a study of an immunotherapy treatment, atezolizumab, in patients with bladder cancer who had already received platinum-containing chemotherapy. This analysis compared the effectiveness of atezolizumab with chemotherapy over 2.5 years after starting treatment. The results show that patients who received atezolizumab lived longer and had manageable side effects compared with patients who received chemotherapy. This trial is registered at ClinicalTrials.gov as NCT02302807.

Background Pazopanib is a tyrosine kinase inhibitor given at the approved dose of 800 mg orally once daily (OD), but often requiring individual dose adjustment due to toxicity. Limited data is available to guide prescription in older patients especially the unfit according to geriatric assessment. Patients and methods VOTRAGE is a 3 + 3 dose-escalation, open-label phase I trial of continuous OD oral administration of pazopanib to evaluate safety, PK and PD data in unfit older patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD). PK data were compared with those obtained in younger adult patients in a population PK analysis. Results Eighteen patients with a median age of 82.5 years (range 75–91) were included in three dosing cohorts (400, 600, and 800 mg daily). Three dose-limiting toxicities (DLT) were observed in five patients at 800 mg and one DLT at 600 mg in six evaluable patients. MTD was defined as level 2 dose (600 mg). Individual oral clearance was not correlated with age. A relationship was observed between the occurrence of DLT and pazopanib plasma exposure. Decreased oral bioavailability of pazopanib when given with proton-pump inhibitors was confirmed in this group of patients. Conclusion We recommend performing geriatric assessment in patients older than 75 and starting pazopanib at 600 mg per day in unfit older patients. Therapeutic drug monitoring appears very helpful in this population.

Immune checkpoint inhibitors have been approved as adjuvant therapy. Adverse immune events occurred during the administration of treatment, and delayed immune-related events have low incidence. A 66-year-old man was treated for hypopharynx cancer in 2012. In 2019, he was treated for a new oropharynx cancer. After undergoing surgery and complete response, the patient received nivolumab as adjuvant treatment. 5 months after the last dose of nivolumab, he presented with grade III diarrhea and abdominal pain for 3 weeks. Rectoscopy showed infiltration of mucous by lymphocytes. Corticosteroid was started resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.Lay abstract Immune checkpoint inhibitors have changed the outcomes of several cancers and have been approved after local treatment for melanoma or lung cancer. The toxicities of this treatment were immune-related adverse events and any organ can be involved. Usually, toxicity occurred during the administration of treatment and delayed immune-related events have low incidence. Here, we presented a case report of a patient treated with anti-programmed cell death protein 1 after loco-regional treatment for head and neck cancer and presented with severe diarrhea 5 months after the last dose of treatment. Corticosteroid was started, resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.

Background The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. Objective To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participants IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. Intervention Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysis The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitations Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. Conclusions The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summary Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

Objectives The objective of the study was to develop a classification of methods used to personalize participative interventions in randomized controlled trials (RCTs). Study Design and Setting We conducted a systematic review including protocols of RCTs assessing participative interventions in PubMed and ClinicalTrials.gov between June 2018 and May 2019. Data extraction was performed by two independent reviewers. We developed a precise classification of methods used to personalize interventions. Then, protocols were reviewed to determine whether personalization was sufficiently described to enable replication. Results We included 109 protocols. The classification used four components and 13 subcomponents accounting for decision points (when interventions were personalized), tailoring variables (on what interventions were personalized), decision rules (how and by whom interventions were personalized), and nature of the subsequent tailoring (what was personalized in the interventions). In 95% of protocols, at least one component or subcomponent of our classification was not adequately reported to enable the replication of the intervention. Components the least well described were tailoring variables (72% of protocols insufficiently described) and the nature of the subsequent tailoring (46% of protocols). Conclusion This study provides the first detailed classification of methods used to personalize interventions. This is required to transparently implement personalization and improve reporting in RCTs.

Aims To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD). Methods and results We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34–0.72] and 0.47 (95% CI 0.31–0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17–0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04–0.62). All other sensitivity analyses yielded similar results. Conclusion Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

Immune checkpoint inhibitors (ICIs) have radically changed the clinical outcome of several cancers with durable responses. CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death protein 1) or PDL-1 (programmed cell death ligand protein 1) represent ICIs that can be used as monotherapy or in combination with other agents. The toxicity p\rofiles of ICIs differ from the side effects of cytotoxic agents and come with new toxicities like immune-related adverse events. Typically, these toxicities occur in all organs. However, the main organs affected are the skin, digestive, hepatic, lungs, rheumatologic, and endocrine. Most of the immune toxicity that occurs is low grade but some more severe toxicities can occur that require a rapid diagnosis and appropriate treatment. The recognition of symptoms by physicians and patient is necessary to resolve them rapidly and adapt treatment to allow the toxicity to resolve.

Adjuvant treatment with VEGFR tyrosine kinase inhibitor in renal cell carcinoma after nephrectomy has been reported through four clinical trials: S-TRAC, ASSURE, PROTECT and ATLAS. Only S-TRAC has been significantly positive on primary endpoint DFS under sunitinib compared to placebo, whereas ASSURE, PROTECT and ATLAS did not show any gain under sunitinib, sorafenib, pazopanib or axitinib, respectively. Nevertheless, there are arguments for a trend for the impact of anti-angiogenic therapy on outcome of patients with high-risk renal cell carcinoma cancer following nephrectomy, allowing for a fair discussion with patients to decide for or against an adjuvant treatment.

Background Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Objective To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen. Design Randomized controlled trial. (ClinicalTrials.gov: NCT02433522). Setting 39 clinical centers in France. Patients 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy. Intervention Rituximab or placebo infusion every 6 months for 18 months (4 infusions). Measurements The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. Results From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group. Limitation Potential selection bias based on previous rituximab response and tolerance. Conclusion Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. Primary funding source French Ministry of Health and Hoffmann-La Roche.

OBJECTIVE To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC. PATIENTS AND METHODS SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naive patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. RESULTS Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. CONCLUSIONS The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

The safety profile characteristics of sunitinib were evaluated in patients who underwent nephrectomy for kidney cancer.In this literature review, safety data were evaluated from phase III trials investigating sunitinib following nephrectomy, either in the more recent adjuvant setting after nephrectomy or in the metastatic setting, with a focus on new data from the CARMENA and SURTIME trials. In particular, the aim was to determine the specificity of toxicity in the adjuvant setting.In the adjuvant setting, even if the toxicity profile of sunitinib does not differ significantly from that in the metastatic setting, the importance of the dose intensity and, thus, exposure has been emphasized. Consequently, as described mainly in the metastatic setting, management of the adverse effects of sunitinib remains critical.

Objective To evaluate patient-reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death-ligand 1 (PD-L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2-point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

The therapeutic landscape of renal cell cancer has evolved rapidly over the past 2 years with nivolumab and ipilimumab for patients with metastatic disease and an intermediate or poor prognosis, in the first line setting. More recently, data from trials combining antiangiogenic agents and immune checkpoint inhibitors demonstrated a major benefit of this treatment approach for all patients.One of three recent trials evaluated the combination of atezolizumab, an anti-programmed death ligand 1 antibody, with bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody. In this manuscript, we summarize the preclinical, clinical, and safety data on atezolizumab for treatment of renal cell carcinoma and describe ongoing trials.Atezolizumab was evaluated in combination with an antiangiogenic agent. These trials were designed based on the hypothesis that selecting patients according to the expression of programmed death ligand 1 would increase the benefit of the treatment combination. Despite positive effects on the primary endpoints progression-free survival and response rate in this selected population, overall survival in the global population did not meet the criteria for significance at the time of the intermediate analysis. The major information was a proposed tumor gene expression signature. The signature was predictive of the sensitivity to anti-angiogenic and/or immune checkpoint inhibitor therapy.

Background The management of patients with locally recurrent rectal cancer (LRRC) is often complex and requires multidisciplinary input whereas only few patients are referred to a specialist centre. The aim of this study was to design a regional referral pathway for LRRC, in Nouvelle Aquitaine (South-West, France). Methods In 2016, we conducted with a Study Steering Committee (SC) a three phase mixed-methods study including identification of key factors, identification of key stakeholders and Delphi voting consensus. During three rounds of Delphi voting, a consensus was defined as favorable, if at least 80% of participating experts rate the factor, below or equal to 3/10 using a Likert scale, or consider it as “useful” using a binary scale (third round only). Finally, the SC drafted guidelines. Results Among the 423 physicians involved in 29 regional digestive Multi-Disciplinary Team (MDT) meeting, 59 participants (from 26 MDT meeting) completed all three rounds of Delphi voting. Thirteen out of twenty initially selected factors reached a favorable consensus. All patients with a LRRC need to be included into a referral pathway. Patients with a central pelvic recurrence offered curative treatment in their local hospital and patients with unresectable metastatic disease were excluded of the referral. Key performance indicators were also agreed including the time to referral and completion of pelvic MRI-, CT-, PET-scan prior to MDT referral. Conclusion The development of this referral pathway represents an innovative health service, which will improve the management of patients with LRRC in France.

International audience; The etiologies of undifferentiated fever in pregnant women have not been studied thoroughly. Because of its non-specific presentation but severe prognosis, listeriosis is often suspected in this setting, but in most cases not confirmed. We studied the causes of undifferentiated fever in pregnant women who received preemptive listeriosis treatment. We conducted from November 1, 2011, to June 30, 2013, a prospective multicentric observational cohort study of pregnant women referred to obstetrical wards with undifferentiated fever and who received listeriosis preemptive treatment. Clinical and biological features, treatment, outcome, and final diagnosis were collected. We enrolled 103 febrile pregnant women. A cause was identified in 77/103 (75%): viral infection in 52/103 (50%, influenza in 21 (20%)), bacterial infection in 22 (21%, including 16 pyelonephritis (16%) and 3 pneumonias (3%)), and TORCH infection in 3 (3%, varicella, toxoplasmosis, and cytomegalovirus primo-infections, n=1, each). Viral infections collected during influenza outbreaks (December–March) accounted for 43/57 (75%) cases. Two fetal losses were reported in the context of febrile pneumonia. Final diagnoses required adapting medical care in 46/77 (60%) of cases, for bacterial, influenza, or TORCH infections. A large array of benign to potentially severe infections manifests as acute undifferentiated fever in pregnant women, requiring careful repeated evaluation.

Objective To provide a comprehensive overview of interventional clinical trials registered in international databases and planned and conducted within the last 10 years in patients with systemic sclerosis (SSc). Methods We searched the International Clinical Trials Registry Platform for all records on interventional clinical trials targeting patients with SSc performed since September 2007. Two reviewers selected studies according to the prespecified eligibility criteria. Information on start date, country of origin, funding sources, phase of development, study design, (planned) sample size, enrollment status, outcomes, disease complication, and treatments investigated were retrieved and summarized. Results Among the 198 eligible studies identified (122 randomized controlled trials [RCTs; 62%]), 87 (30%) were conducted in Europe, 165 (83%) in a single country, and 81 (41%) were industry-funded. The majority of trials investigated pharmacologic treatments (75%), mostly nonbiotherapies (57%). RCTs were mostly 2-arm (82%) placebo-controlled (71%) studies with a median number of patients enrolled or planned to be enrolled of 40 (interquartile range 25-77 [range 10-586]). Twenty-one RCTs (17%) planned to enroll or enrolled >100 patients. Time to assess the primary outcome was found to be adequate in 29% to 50% of RCTs retrieved. Patients age >65 years were excluded in 14% of studies. SSc complications more frequently investigated in overall studies were skin thickness (26%), Raynaud's phenomenon/digital ulcers (24%), and interstitial lung disease (14%). Conclusion The SSc research landscape is dominated by small, short, and mainly placebo-controlled trials, especially investigating pharmacologic treatments. Some patients' needs continue to be neglected.

The 2017 American College of Cardiology/American Heart Association hypertension guidelines lowered the thresholds for defining and treating hypertension. However, the SPRINT trial showed substantial heterogeneity in benefits and harms of intensive antihypertensive treatment depending on patients’ characteristics. We aimed at illustrating the potential gains of personalizing intensive antihypertensive treatment. Using the US National Health and Nutrition Examination Survey 2011 to 2014 (n=2067), and prediction models derived from the SPRINT trial, we computed expected benefits and harms of intensive antihypertensive treatment for individuals aged 50 or more. We compared 2 interventions: (1) intensive antihypertensive treatment for all individuals meeting the 2017 American College of Cardiology/American Heart Association thresholds and (2) a stratified medicine strategy excluding from intensive treatment individuals with predicted unfavorable benefit-risk. Outcome measures were model-predicted 5-year risk of cardiovascular events or death (myocardial infarction, acute coronary, stroke, acute decompensated heart failure, and cardiovascular-related death), and severe adverse events (hypotension, syncope, electrolyte abnormalities, bradycardia, and acute kidney injury). Per 2017 American College of Cardiology/American Heart Association guidelines, 40.1 million (39.2%) US individuals aged 50 or more should initiate or intensify antihypertensive treatment, thereby preventing cardiovascular events for 795 000 individuals and inducing severe adverse events for 848 000 over 5 years. A stratified treatment strategy could decrease the number of individuals treated by 21.2 million (52.9%) and reduce the number of individuals with severe adverse events by 38.3%, with 11.7% fewer individuals with cardiovascular events prevented. Personalizing antihypertensive treatment according to predicted benefits and harms could spare treatment for more than half individuals while reducing harms 3× more than benefits.

Background The peer review process has been questioned as it may fail to allow the publication of high-quality articles. This study aimed to evaluate the accuracy in identifying inadequate reporting in RCT reports by early career researchers (ECRs) using an online CONSORT-based peer-review tool (COBPeer) versus the usual peer-review process. Methods We performed a cross-sectional diagnostic study of 119 manuscripts, from BMC series medical journals, BMJ, BMJ Open, and Annals of Emergency Medicine reporting the results of two-arm parallel-group RCTs. One hundred and nineteen ECRs who had never reviewed an RCT manuscript were recruited from December 2017 to January 2018. Each ECR assessed one manuscript. To assess accuracy in identifying inadequate reporting, we used two tests: (1) ECRs assessing a manuscript using the COBPeer tool (after completing an online training module) and (2) the usual peer-review process. The reference standard was the assessment of the manuscript by two systematic reviewers. Inadequate reporting was defined as incomplete reporting or a switch in primary outcome and considered nine domains: the eight most important CONSORT domains and a switch in primary outcome(s). The primary outcome was the mean number of domains accurately classified (scale from 0 to 9). Results The mean (SD) number of domains (0 to 9) accurately classified per manuscript was 6.39 (1.49) for ECRs using COBPeer versus 5.03 (1.84) for the journal’s usual peer-review process, with a mean difference [95% CI] of 1.36 [0.88–1.84] (p Conclusions Trained ECRs using the COBPeer tool were more likely to detect inadequate reporting in RCTs than the usual peer review processes used by journals. Implementing a two-step peer-review process could help improve the quality of reporting. Trial registration Clinical.Trials.govNCT03119376 (Registered April, 18, 2017).

Digital medicine, digital research and artificial intelligence (AI) have the power to transform the field of diabetes with continuous and no-burden remote monitoring of patients’ symptoms, physiological data, behaviours, and social and environmental contexts through the use of wearables, sensors and smartphone technologies. Moreover, data generated online and by digital technologies – which the authors suggest be grouped under the term ‘digitosome’ – constitute, through the quantity and variety of information they represent, a powerful potential for identifying new digital markers and patterns of risk that, ultimately, when combined with clinical data, can improve diabetes management and quality of life, and also prevent diabetes-related complications. Moving from a world in which patients are characterized by only a few recent measurements of fasting glucose levels and glycated haemoglobin to a world where patients, healthcare professionals and research scientists can consider various key parameters at thousands of time points simultaneously will profoundly change the way diabetes is prevented, managed and characterized in patients living with diabetes, as well as how it is scientifically researched. Indeed, the present review looks at how the digitization of diabetes can impact all fields of diabetes – its prevention, management, technology and research – and how it can complement, but not replace, what is usually done in traditional clinical settings. Such a profound shift is a genuine game changer that should be embraced by all, as it can provide solid research results transferable to patients, improve general health literacy, and provide tools to facilitate the everyday decision-making process by both healthcare professionals and patients living with diabetes.

International audience; Brown and brown-like adipocytes (BBAs) control thermogenesis and are detected in adult humans. They express UCP1, which transforms energy into heat. They appear as promising cells to fight obesity. Deciphering the molecular mechanisms leading to the browning of human white adipocytes or the whitening of BBAs represents a goal to properly and safely control the pathways involved in these processes. Here, we analyzed how drugs endowed with therapeutic potential affect the differentiation of human adipose progenitor-cells into BBAs and/or their phenotype. We showed that HIV-protease inhibitors (PI) reduced UCP1 expression in BBAs modifying their metabolic profile and the mitochondria functionality. Lopinavir (LPV) was more potent than darunavir (DRV), a last PI generation. PPARγ and PGC-1α were decreased in a PI or cell-specific manner, thus altering UCP1's constitutive expression. In addition, LPV altered p38 MAPK phosphorylation, blunting then the β-adrenergic responses. In contrast, low doses of resveratrol stimulated the activatable expression of UCP1 in a p38 MAPK-dependent manner and counteracted the LPV induced loss of UCP1. This effect was independent of the resveratrol-induced sirtuin-1 expression. Altogether our results uncover how drugs impact crucial components of the networks regulating the expression of the thermogenic signature. They provide important information to control the relevant pathways involved in energy expenditure.

Introduction: Urothelial carcinoma (UC) has a poor prognosis, with the only standard first-line metastatic treatment being platinum-based chemotherapy. Until 2018, there was no Food and Drug Administration (FDA)-approved drug for second-line setting, and only vinflunine was approved by the European Medicines Agency (EMEA) in Europe. However, targeting the programmed cell-death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitor (ICI) agents has shown encouraging results. Avelumab is a human anti-PD-L1 antibody that is currently being investigated in several trials. Areas covered: In this review article, we summarise preclinical, clinical, and safety data on avelumab for UC, and describeongoing trials that are evaluating avelumab for local or advanced diseases. We also compare its place in the management of UC. Expert opinion: Avelumab has shown clinical efficacy for metastatic and advanced UC in phase I studies after the failure of platinum-based therapy with a well-tolerated safety profile. This anti-PD-L1 targeting agent has the capacity to induce antibody-dependant cellular cytotoxicity (ADCC)-mediated tumor cell lysis compared to other ICI. These results led to FDA approval of avelumab as a second-line treatment for locally advanced and metastatic UC. Avelumab is also investigated in phase II and in a randomized phase III trial as a maintenance therapy in UC as well for combination use with chemotherapy.

Objectives: New forms of research involving collective intelligence (CI) of diverse individuals mobilized through crowdsourcing is successfully emerging in various fields. This scoping review aimed to describe these methods across different fields and propose a framework for implementation. Study Design and Setting: We searched seven electronic databases for reports describing projects that had mobilized CI with crowdsourcing. We used content analysis to develop themes and categories of the methods. Results: We identified 145 reports. CI was mobilized to generate ideas, conduct evaluations, solve problems, and create intellectual outputs. Most projects (n=110, 76%) were open to the public without restrictions on participants’ expertise. Participants contributed to projects by independent contribution (i.e., no interaction with other participants) (n=50, 34%), collaboration (n=41, 28%), competitions (n=33, 23%), and playing games (n=16, 11%). In total, 61% of articles (n=89) reported methods to evaluate participants’ contribution and decision-making process: 43% used an independent panel of experts and 18% involved end users. We identified challenges in implementation and sustainability of CI and proposed solutions. Conclusion: New research methods based on CI through crowdsourcing could transform clinical research. This framework facilitates the implementation of these methods.

BackgroundThis study aimed to involve patients with chronic conditions in generating ideas for improving their care.MethodsWe performed a citizen science study. Participants were adult patients with chronic conditions recruited in Community of Patients for Research ‘ComPaRe,’ a French e-cohort of patients with chronic conditions. Participants generated ideas to improve their care in answer to the open-ended question, ‘If you had a magic wand, what would you change in your healthcare?’ Three researchers and two patients independently extracted ideas from open-ended answers by using thematic analysis. Ideas were grouped into areas for improvement at the consultation, hospital/clinic and health system levels. Findings were validated and enriched by a second sample of participants recruited in ComPaRe.ResultsBetween May 2017 and April 2018, a total of 1636 patients provided 3613 ideas to improve consultations (1701 ideas related to 58 areas for improvement), hospitals/clinics (928 ideas related to 41 areas for improvement) and the health system (984 ideas related to 48 areas for improvement). At the consultation level, most ideas were related to improving physician–patient discussions, informing patients about their own care, and adapting treatment to patient preferences and context. At the hospital/clinic level, most ideas aimed at improving the coordination and collaboration in care. At the health system level, most ideas were related to decreasing the administrative burden imposed on patients, improving access to care and reducing the costs of care.ConclusionPatients have many ideas to improve their care, from the content of consultations to the organisation of hospitals. Our study provides the proof of concept for a method to leverage patients’ practical knowledge of the care system to improve it.

Objectives We aimed to develop and evaluate an algorithm for automatically screening citations when updating living network meta-analysis (NMA). Study Design and Setting Our algorithm learns from the initial screening of citations conducted when creating an NMA to automatically identify eligible citations (i.e., needing full-text consideration) when updating the NMA. We evaluated our algorithm on four NMAs from different medical domains. For each NMA we constructed sets of initially screened citations and citations to screen during an update that took place 2 years after the conduct of the NMA. We encoded free text of citations (title and abstract) using word embeddings. On top of this vectorized representation, we fitted a logistic regression model to the set of initially screened citations to predict the eligibility of citations screened during an update. Results Our algorithm achieved 100% sensitivity on two NMAs (100% [95% confidence interval 93–100] and 100% [40–100] sensitivity), and 94% (81–99) and 97% (86–100) on the remaining two others. For all NMAs, our algorithm would have spared to manually screen 1,345 of 2,530 citations, decreasing the workload by 53% (51–55), while missing 3 of 124 eligible citations (2% [1–7]), none of which were finally included in the NMAs after full-text consideration. Conclusion For updating an NMA after 2 years, our algorithm considerably diminished the workload required for screening, and the number of missed eligible citations remained low.

This follow-up study of the CORIMUNO-TOCI-1 randomized clinical trial examines the association between survival and C-reactive protein levels in patients hospitalized with COVID-19 who were treated with tocilizumab.

ObjectivesRandomised controlled trials conducted using cohorts and routinely collected data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. A Consolidated Standards of Reporting Trials (CONSORT) statement extension for trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE) has been developed with the goal of improving reporting quality. This article describes the processes and methods used to develop the extension and decisions made to arrive at the final checklist.MethodsThe development process involved five stages: (1) identification of the need for a reporting guideline and project launch; (2) conduct of a scoping review to identify possible modifications to CONSORT 2010 checklist items and possible new extension items; (3) a three-round modified Delphi study involving key stakeholders to gather feedback on the checklist; (4) a consensus meeting to finalise items to be included in the extension, followed by stakeholder piloting of the checklist; and (5) publication, dissemination and implementation of the final checklist.Results27 items were initially developed and rated in Delphi round 1, 13 items were rated in round 2 and 11 items were rated in round 3. Response rates for the Delphi study were 92 of 125 (74%) invited participants in round 1, 77 of 92 (84%) round 1 completers in round 2 and 62 of 77 (81%) round 2 completers in round 3. Twenty-seven members of the project team representing a variety of stakeholder groups attended the in-person consensus meeting. The final checklist includes five new items and eight modified items. The extension Explanation & Elaboration document further clarifies aspects that are important to report.ConclusionUptake of CONSORT-ROUTINE and accompanying Explanation & Elaboration document will improve conduct of trials, as well as the transparency and completeness of reporting of trials conducted using cohorts and routinely collected data.

OBJECTIVE: To assess the effectiveness of corticosteroids on outcomes of patients with COVID-19 pneumonia requiring oxygen without mechanical ventilation. METHODS: We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) versus standard of care (no-CTC group) among adults 18 to 80 years old with confirmed COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death by day 28. In our main analysis, characteristics of patients at baseline (i.e., time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting. RESULTS: Among the 891 patients included in the analysis, 203 were assigned to the CTC group. Use of corticosteroids was not significantly associated with risk of intubation or death by day 28 (weighted hazard ratio [wHR] 0.92, 95% CI 0.61 to 1.39) or cumulative death rate (wHR 1.03, 95% CI 0.54 to 1.98). However, use of corticosteroids was associated with reduced risk of intubation or death by day 28 in the prespecified subgroups of patients requiring oxygen ≥ 3 L/min (wHR 0.50, 95% CI 0.30 to 0.85) or C-reactive protein level ≥ 100 mg/L (wHR 0.44, 95%CI 0.23 to 0.85). Number of hyperglycaemia events was higher for patients with than without corticosteroids, but number of infections was similar. CONCLUSIONS: We found no association between the use of corticosteroids and intubation or death in the broad population of patients 18 to 80 years old with COVID-19 hospitalized in non-intensive care unit settings. However, the treatment was associated with reduced risk of intubation or death for patients with ≥ 3 L/min oxygen or C-reactive protein level ≥ 100 mg/L at baseline. Further research need to confirm the right timing of corticosteroids for patients with COVID-19 requiring oxygen only.

Background: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. Objectives: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. Search methods: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. Selection criteria: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. Data collection and analysis: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. Main results: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo. a. Effectiveness of tocilizumab for patients with COVID-19. Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19. The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo. The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded. No data were available for other critical outcomes. Authors' conclusions: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

Background To develop and validate patient-reported instruments, based on patients’ lived experiences, for monitoring the symptoms and impact of long coronavirus disease (covid). Methods The long covid Symptom and Impact Tools (ST and IT) were constructed from the answers to a survey with open-ended questions to 492 patients with long COVID. Validation of the tools involved adult patients with suspected or confirmed coronavirus disease 2019 (COVID-19) and symptoms extending over 3 weeks after onset. Construct validity was assessed by examining the relations of the ST and IT scores with health-related quality of life (EQ-5D-5L), function (PCFS, post-COVID functional scale), and perceived health (MYMOP2, Measure yourself medical outcome profile 2). Reliability was determined by a test-retest. The “patient acceptable symptomatic state” (PASS) was determined by the percentile method. Results Validation involved 1022 participants (55% with confirmed COVID-19, 79% female, and 12.5% hospitalized for COVID-19). The long COVID ST and IT scores were strongly correlated with the EQ-5D-5L (rs = −0.45 and rs = −0.59, respectively), the PCFS (rs = −0.39 and rs = −0.55), and the MYMOP2 (rs = −0.40 and rs = −0.59). Reproducibility was excellent with an interclass correlation coefficient of 0.83 (95% confidence interval .80 to .86) for the ST score and 0.84 (.80 to .87) for the IT score. In total, 793 (77.5%) patients reported an unacceptable symptomatic state, thereby setting the PASS for the long covid IT score at 30 (28 to 33). Conclusions The long covid ST and IT tools, constructed from patients’ lived experiences, provide the first validated and reliable instruments for monitoring the symptoms and impact of long covid.

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.

International audience; Background: Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods: In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.Findings: Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).Interpretation: Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.Funding: The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

Background: Immune checkpoint inhibitors (ICIs) are approved for first-line (cisplatin unfit, PD-L1+) and platinum-refractory urothelial carcinoma (UC). Still, most patients experience progressive disease (PD) as the best response. Although higher response rates to subsequent systemic treatment (SST) have been described, post-PD outcome data are scarce. Objective: To examine the outcome of UC patients who received SST and no SST after progressing to ICIs. Design, setting, and participants: A retrospective analysis of UC patients progressing to frontline or later-line anti-PD-1/PD-L1 therapy in 10 European institutions was conducted between March 2013 and September 2017. Intervention: Post-PD management as per standard practice. Outcome measurements and statistical analysis: Overall survival (OS) was analyzed with a Kaplan-Meier model. Cox regression was used for multivariate analysis (MV). Impact of SST on OS was examined with a time-varying covariate model. Results and limitations: A total of 270 UC patients with PD to ICIs (69 frontline, 201 later line) were analyzed. Of the patients, 57% of frontline-ICI-PD and 34% of later-line-ICI-PD patients received SST, and SST had an impact on OS in MV (frontline: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.10-0.51, p< 0.001; later line: HR 0.22, 95% CI 0.13-0.36, p< 0.001). In the frontline-ICI-PD group, median OS with and without SST was 6.8 mo (95% CI 5.0-8.6) and 1.9 mo (95% CI 0.9-3.0), respectively. High disease burden (three or more metastatic sites: HR 2.49, p = 0.03; simultaneous liver/bone metastases: HR 3.93, p = 0.03) predicted worse survival. In later-line-ICI-PD group, response to ICIs (HR 0.37, p = 0.03), longer exposure to ICIs (HR 0.89, p = 0.002), and bonemetastasis (HR 2.42, p< 0.001) predicted survival. The retrospective nature of this study and a lack of certain parameters limit the interpretation of our analysis. Conclusions: Patients progressing to frontline ICIs are at risk of early death, excluding them from experiencing potential benefit from chemotherapy Patient summary: Our analysis suggests that outcomes after failing immunotherapy are poor, particularly in UC patients who received no prior chemotherapy. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

BackgroundThe Nutri-Score, a front-of-pack nutrition label, has been adopted in 2017 in France but its impact on low-income populations is unknown, and they are more at risk of having unhealthy diets. The present study assessed the effects of the Nutri-Score on the nutritional quality of purchasing intentions among low-income individuals, compared with the current French labelling situation: references intakes (RIs) and no label, using a three-arm parallel-group randomised controlled trial.MethodsLow-income active adults from the NutriNet-Santé cohort (household income below €1200/month) were asked to perform a shopping task in an experimental online supermarket after being randomised in one of the three conditions (Nutri-Score, RIs or no labelling). The main outcome was the overall nutritional quality of the virtual shopping cart, assessed with the French-modified Food Standards Agency Nutrient Profiling System (FSAm-NPS), and secondary outcomes were the nutrient content of the shopping carts. 524 subjects were randomised, and 336 included in the analyses.ResultsThe Nutri-Score resulted in the highest overall nutritional quality of the shopping cart, as reflected by a FSAm-NPS score (1.86 (SD 3.59) points) significantly lower (reflecting higher nutritional quality) than the RIs (3.21 (SD 4.14) points, p≤0.05) but not significantly lower than no label (2.60 (SD 3.09) points, p=0.3). The Nutri-Score also resulted into significantly lower contents in calories and saturated fatty acids in the shopping cart, compared with the RIs only (p≤0.05).ConclusionThe implementation of the front of pack nutrition label Nutri-Score, adopted in France and in different European countries, appears to have the potential to encourage purchasing intentions of foods from higher nutritional quality among low-income individuals, compared with the RIs label promoted by food manufacturers.Trial registration number:NCT02769455

Aim: To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting. Materials & methods: Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS). Results: In 609 patients, DFS was similar for baseline PLR Clinical Trials Registration: NCT00375674 ( ClinicalTrials.gov )

Adjuvant therapy with antiangiogenic agents in locoregional renal cell carcinoma did not translate into a sufficient benefit and highlight the crucial role of patient selection. Ongoing clinical trials with immune-targeted agents hold great promise for this unmet clinical need.

While many patients with non-metastatic renal cell carcinoma (RCC) can be cured with surgery alone, upward of 40% of patients recur in a short delay, raising the question of additional perioperative treatments. To address this clinical need, multiple trials have investigated the addition of systemic therapy after surgery in localized or locally advanced RCC. However, adjuvant systemic therapies in the past decades have provided disappointing results with only one positive study of antiangiogenic treatments. Debatable clinical benefit of adjuvant antiangiogenic tyrosine kinase inhibitors (TKIs) therapy at cost of high adverse event profiles have paved the way for development of alternative perioperative strategies, such as immune checkpoint inhibitors (ICIs). Further investigation into combination therapies with immunotherapy, neoadjuvant approaches and patient selection will be key to determining optimal adjuvant therapy regimens to improve outcomes and increase cure rates for patients with non-metastatic RCC. In this review, we extensively present the strong and weakness of the five adjuvant antiangiogenic TKI trials, highlight the main differences and discuss about the reasons of failure. We also expose the current ongoing clinical trials in the perioperative setting and provide new insights concerning the evolving landscape of the management of non-metastatic RCC.

Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1 + myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature. This work was funded by the British Heart Foundation (chair award CH/11/1/28798 and programme grant RG/08/003/25264 to PRR) and supported by the BHF Oxbridge Centre of Regenerative Medicine (RM/13/3/30159); a Wellcome Trust Doctoral Training Fellowship 106334/Z/14/Z to TJC; a Wellcome Trust Four year PhD Studentship 215103/Z/18/Z to KK; a BHF Intermediate Basic Science Research Fellowship FS/19/31/34158 to JMV; a British Israel Research and Academic Exchange Partnership (BIRAX) Grant 13BX14PRET; a Leducq Foundation Transatlantic Network of Excellence Program 14CVD04 and MRC Unit funding to DGJ. Sí

Randomised controlled trials are increasingly conducted as embedded, nested, or using cohorts or routinely collected data, including registries, electronic health records, and administrative databases, to assess if participants are eligible for the trial and to facilitate recruitment, to deliver an embedded intervention, to collect trial outcome data, or a combination of these purposes. This report presents the Consolidated Standards of Reporting Trials (CONSORT) extension for randomised controlled trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE). The extension was developed to look at the unique characteristics of trials conducted with these types of data with the goal of improving reporting quality in the long term by setting standards early in the process of uptake of these trial designs. The extension was developed with a sequential approach, including a Delphi survey, a consensus meeting, and piloting of the checklist. The checklist was informed by the CONSORT 2010 statement and two reporting guidelines for observational studies, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and the REporting of studies Conducted using Observational Routinely collected Data (RECORD) statement. The extension includes eight items modified from the CONSORT 2010 statement and five new items. Reporting items with explanations and examples are provided, including key aspects of trials conducted using cohorts or routinely collected data that require specific reporting considerations.

[Background] There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC)., [Objective] To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial., [Design, setting, and participants] ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy., [Intervention] Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC., [Outcome measurements and statistical analysis] Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed., [Results and limitations] Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available., [Conclusions] Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention., [Patient summary] Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly., Queen Mary University of London was the Sponsor of the study. Roche granted QMUL funding for the study. J. Bull and M. Jacobson also provided financial support for aspects of the biomarker analysis. We acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network, and La Roche-Hoffmann for funding.

Background The impact of social support on the long-term condition after a spinal cord injury (SCI) varies across studies mainly involving self-report questionnaires. Objective We aimed to establish the common factors associated with social support leading individuals with an SCI to the effective prevention of secondary complications, including via adherence to medical follow-up. Methods Inclusion criteria were a history of acquired SCI of any etiology, wheelchair use, and age ≥ 18 years at the time of the study. Participants should have completed their initial rehabilitation program in France ≥ 1 year earlier and were also enrolled according to 2 related study variables: routine medical follow-up (patients were or were not followed up) and the medically supervised reporting of a pressure ulcer after the initial rehabilitation session (0 or ≥ 1 pressure ulcers). We performed a preparatory quantitative and qualitative literature review to identify factors affecting long-term follow-up after SCI, then adopted a narrative design with semi-structured interviews, transcribed and analyzed progressively by using qualitative analysis software. Results We included 32 participants. We categorized our results based on the knowledge, attitudes, beliefs and practices of participants with respect to pressure ulcer prevention and long-term medical follow-up. Our narrative approach allowed us to identify 3 main domains relevant to social support: reciprocity, self-management and timing related to social support. Conclusions Our study showed social support as a dynamic process, a reciprocal phenomenon evolving in variations over time. These findings should be central to short- and long-term therapeutic education programs for patients and for people providing social support. Effective changes should also be implemented through the concept of the Learning Health System.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To provide a living mapping of registered randomized trials, and to assess and rank where appropriate the relative effects of interventions for the prevention and treatment of COVID-19. Our approach has been described in Boutron 2020 and Nguyen 2020. As part of the methodological process of living systematic reviews, we will continuously (i.e. every working day) collect and critically appraise results from all eligible RCTs addressing specific clinical outcomes related to COVID-19. We will synthesize the available study results using pairwise meta-analyses and when possible and appropriate, network meta-analyses (NMAs). The interventions and the research questions considered will evolve over time and will be guided by end-users’ needs. We will report our updated evidence synthesis every week, and will make all results available on a website: www.covid-nma.com. In addition, we will update this Cochrane Review at least once every six months, or as soon as the certainty of evidence (assessed with the GRADE methodology) changes. We will wait until the accumulating evidence changes one or more of the following aspects of the review, before incorporating it and re-publishing the Cochrane Review:. the findings of one or more critical outcomes; the credibility (e.g. GRADE rating) of one or more critical outcomes; new settings, population, interventions, comparisons or outcomes studied; or new serious adverse events. We will develop a steering committee of epidemiologists, methodologists, statisticians and clinicians with content expertise. This committee will meet regularly and discuss the conduct of the project, difficulties encountered and possible changes in the protocol according to new knowledge becoming available for the disease. Changes to the protocol could include, for example, changes in the search strategy, eligibility criteria (e.g. study design), research questions for the pairwise meta-analyses, or outcomes. The steering committee will systematically discuss and achieve consensus on the changes to the protocol. The process will also evolve over time according to new knowledge available regarding COVID-19.

International audience; These authors propose an “evidence ecosystem” for COVID-19–related studies that minimizes multiple low-quality reviews and helps connect evidence generation, synthesis, and decision making.

Aims Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. Methods This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment. Results Thirty-one patients received >= 1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56)vsthose with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22)vsthose with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. Conclusion Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.

Core outcome sets (COSs) are agreed-on standardized sets of outcomes that should be minimally measured in all trials of a given disease. To enhance the uptake of COSs in trials, their generalizability should be increased by a change in the number and diversity of stakeholders involved in their development. Also, their credibility should be improved by methods that allow the fair capture of participants' views. This article proposes three adjustments to the development of COSs. First, instead of a qualitative study with few participants, we propose to generate the outcome domains by mapping the expectations toward treatment of a large number of stakeholders, internationally, by using an online survey with open-ended questions. Second, we propose to separate preference elicitation from the decision-making process in the selection of core outcomes. Preference elicitation would rely on an international online ranking survey, whereas the decision-making process would involve a formalized discussion among all stakeholders. Third, we propose to involve a large number of participants, including patients, in an online survey to select outcome measurement instruments. Our propositions are low-cost and scalable and help with the involvement of more stakeholders in the development of COSs, thereby increasing their generalizability, credibility, and uptake in trials.

Background The current clinical research system relies on a “one-off” project-by-project model involving a costly and time-wasting permanent construction and deconstruction of the research infrastructure. We propose a new model of research relying on collaborative principles: the COllaborative Open Platform (COOP’) e-cohort. Development The COOP’ e-cohort aims at building a large community of patients willing to participate in research by contributing to the generation of a large database of patient-reported data, passively enriched, at the individual level, by linkage with routinely collected care and/or medico-administrative data. Approved teams can use the platform and benefit from already enrolled participants or collected data or add new online questionnaires to perform observational or interventional studies to answer a broad range of research questions. Application The Community of Patients for Research (ComPaRe) is a proof-of-concept COOP’ e-cohort in the field of chronic conditions that was launched in 2017. As of April 2020, 36,000 patients have joined the project and contributed to more than 4 million data points. Patient-reported data will be enriched by linkage with the French national health system databases and with hospital data for patients receiving care in the Paris region. Since 2017, 150 researchers have used the platform for research projects. Three clinical trials nested in ComPaRe have been funded. Conclusion By moving from myriad independent studies to a large collaborative infrastructure of research, COOP’ e-cohorts will accelerate the research process by avoiding the redundancy of many steps common to all research projects and by limiting waste of research.

The "one-off" approach of systematic reviews is no longer sustainable; we need to move toward producing "living" evidence syntheses (i.e., comprehensive, based on rigorous methods, and up-to-date). This implies rethinking the evidence synthesis ecosystem, its infrastructure, and management. The three distinct production systems-primary research, evidence synthesis, and guideline development-should work together to allow for continuous refreshing of synthesized evidence and guidelines. A new evidence ecosystem, not just focusing on synthesis, should allow for bridging the gaps between evidence synthesis communities, primary researchers, guideline developers, health technology assessment agencies, and health policy authorities. This network of evidence synthesis stakeholders should select relevant clinical questions considered a priority topic. For each question, a multidisciplinary community including researchers, health professionals, guideline developers, policymakers, patients, and methodologists needs to be established and commit to performing the initial evidence synthesis and keeping it up-to-date. Encouraging communities to work together continuously with bidirectional interactions requires greater incentives, rewards, and the involvement of health care policy authorities to optimize resources. A better evidence ecosystem with collaborations and interactions between each partner of the network of evidence synthesis stakeholders should permit living evidence syntheses to justify their status in evidence-informed decision-making.

To become user driven and more useful for decision-making, the current evidence synthesis ecosystem requires significant changes (Paper 1. Future of evidence ecosystem series). Reviewers have access to new sources of data (clinical trial registries, protocols, and clinical study reports from regulatory agencies or pharmaceutical companies) for more information on randomized control trials. With all these newly available data, the management of multiple and scattered trial reports is even more challenging. New types of data are also becoming available: individual patient data and routinely collected data. With the increasing number of diverse sources to be searched and the amount of data to be extracted, the process needs to be rethought. New approaches and tools, such as automation technologies and crowdsourcing, should help accelerate the process. The implementation of these new approaches and methods requires a substantial rethinking and redesign of the current evidence synthesis ecosystem. The concept of a "living" evidence synthesis enterprise, with living systematic review and living network meta-analysis, has recently emerged. Such an evidence synthesis ecosystem implies conceptualizing evidence synthesis as a continuous process built around a clinical question of interest and no longer as a small team independently answering a specific clinical question at a single point in time.