REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas.

BACKGROUND: Novel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single-arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs. PATIENTS AND METHODS: Adult patients with IDHm WHO grade 3-4 gliomas recurring after radiotherapy and ≥ 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24-week progression-free survival rate (24w-PFS) according to RANO criteria. RESULTS: From July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15-44.9%). Median PFS and OS were 1.84 (CI95% 1.81-5.89) and 14.7 months (CI95% 9.18-NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and non-responders. The safety profile of Nivolumab was consistent with prior studies. CONCLUSIONS: We report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors).

Interim FDG-PET improves treatment failure prediction in primary central nervous system Lymphoma: a LOC network prospective multicentric study.

PURPOSE: The purpose of our study was to assess the predictive and prognostic role of 2-18F-fluoro-2-deoxy-D-glucose (FDG) PET/MRI during high-dose methotrexate-based chemotherapy (HD-MBC) in de novo primary central nervous system lymphoma (PCNSL) patients aged 60 and above. METHODS: This prospective multicentric ancillary study included 65 immunocompetents patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post two cycles (PET/MRI2), and post-treatment (PET/MRI3). FDG-PET response was dichotomized, with "positive" indicating persistent tumor uptake higher than the contralateral mirroring brain region. Performances of FDG-PET and International PCNSL Collaborative Group criteria in predicting induction response, progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: Of 48 PET2 scans performed, nine were positive and aligned with a partial response (PR) on MRI2. Among these, eight (89%) progressed by the end of the induction phase. In contrast, 35/39 (90%) of PET2-negative patients achieved complete response (CR). Among the 18 discordant responses at interim (PETCR/MRIPR), 83% ultimately achieved CR. 87% of the PET2-negative patients were disease-free at 6 months versus 11% of the PET2-positive patients (p<0.001). The MRI2 response did not significantly differentiate patients based on their PFS, regardless of whether they were in CR or PR. Both PET2 and MRI2 independently predicted OS in multivariate analysis, with PET2 showing stronger association. CONCLUSION: Our study highlights the potential of interim FDG-PET for early management of PCNSL patients. Response-driven treatment based on PET2 may guide future clinical trials.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial.

PURPOSE: Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS: ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI >6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1-positive populations (alpha .025 for each population). RESULTS: Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1-positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1-positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION: ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1-positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.

FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial.

BACKGROUND: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. METHODS: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering-from day 1 to day 7-of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). RESULTS: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, - 1.9 [- 3.3; - 0.5] vs. - 0.8 [- 5.5; - 1.1] mL/kg; estimated effect - 0.8 [- 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). CONCLUSIONS: In this unique-dosing-regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020.

[18F]FDG PET-MRI provides survival biomarkers in primary central nervous system lymphoma in the elderly: an ancillary study from the BLOCAGE trial of the LOC network.

PURPOSE: Primary central nervous system lymphoma (PCNSL) incidence is rising among elderly patients, presenting challenges due to poor prognosis and treatment-related toxicity risks. This study explores the potential of combining [18F]fluorodeoxyglucose ([18F]FDG) PET scans and multimodal MRI for improving management in elderly patients with de novo PCNSL. METHODS: Immunocompetent patients over 60 years with de novo PCNSL were prospectively enrolled in a multicentric study between January 2016 and April 2021. Patients underwent brain [18F]FDG PET-MRI before receiving high-dose methotrexate-based chemotherapy. Relationships between extracted PET (metabolic tumor volume (MTV), sum of MTV for up to five lesions (sumMTV), metabolic imaging lymphoma aggressiveness score (MILAS)) and MRI parameters (tumor contrast-enhancement size, cerebral blood volume (CBV), cerebral blood flow (CBF), apparent diffusion coefficient (ADC)) and treatment response and outcomes were analyzed. RESULTS: Of 54 newly diagnosed diffuse large B-cell PCNSL patients, 52 had positive PET and MRI with highly [18F]FDG-avid and contrast-enhanced disease (SUVmax: 27.7 [22.8-36]). High [18F]FDG uptake and metabolic volume were significantly associated with low ADCmean values and high CBF at baseline. Among patients, 69% achieved an objective response at the end of induction therapy, while 17 were progressive. Higher cerebellar SUVmean and lower sumMTV at diagnosis were significant predictors of complete response: 6.4 [5.7-7.7] vs 5.4 [4.5-6.6] (p = 0.04) and 5.5 [2.1-13.3] vs 15.9 [4.2-19.5] (p = 0.01), respectively. Two-year overall survival (OS) was 71%, with a median progression-free survival (PFS) of 29.6 months and a median follow-up of 37 months. Larger tumor volumes on PET or enhanced T1-weighted MRI were significant predictors of poorer OS, while a high MILAS score at diagnosis was associated with early death (< 1 year). CONCLUSION: Baseline cerebellar metabolism and sumMTV may predict response to end of chemotherapy in PCNSL. Tumor volume and MILAS at baseline are strong prognostic factors.

Is vaccine response to SARS-CoV-2 preserved after switching to anti-CD20 therapies in patients with multiple sclerosis or related disorders?

BACKGROUND: Although vaccination against SARS-CoV-2 is recommended prior to introducing anti-CD20 therapies, limited data are available regarding the evolution of post-vaccinal immunity. METHODS: This retrospective study compared anti-Spike antibody titres at 6 and 12 months from SARS-CoV-2 vaccination between patients vaccinated before switching to anti-CD20 ('Switch') and two control groups: (1) patients vaccinated under disease-modifying therapies (DMTs) other than fingolimod and anti-CD20 ('Other DMTs'); (2) patients vaccinated on anti-CD20 ('Anti-CD20'). Anti-Spike-specific T-cell responses were compared between 'Switch' and 'Anti-CD20' groups. RESULTS: Fifty-three patients were included in the 'Switch' group, 54 in the 'Other DMTs' group and 141 in the 'Anti-CD20' group. At 6 months, in the subset of patients who received a booster dose, the 'Switch' group had lower anti-Spike titres compared with the 'Other DMTs' group (median 241.0 IQR (88.0; 504.0) BAU/mL vs 2034 (1155; 4634) BAU/mL, p<0.001), and less patients in the 'Switch' group reached the protective threshold of 264 BAU/mL. The 'Switch' group had higher anti-Spike titres than the 'Anti-CD20' group (7.5 (0.0; 62.1) BAU/mL, p=0.001). Anti-Spike titres were not different between the 'Switch' and 'Other DMTs' groups before booster administration. These results were similar at 12 months. Spike-specific T-cell positivity was similar between the 'Switch' and 'Anti-CD20' groups at 6 and 12 months (60.4% vs 61.0%, p=0.53, and 79.4% vs 87.5%, p=0.31, respectively). CONCLUSIONS: Despite a primary vaccination performed before the first anti-CD20 cycle, our results suggest weaker immune responses at 6 and 12 months and decreased booster efficacy after introducing anti-CD20. Patients vaccinated prior to anti-CD20 introduction might falsely be considered as fully protected by vaccination.

Three to four mRNA COVID-19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization.

BACKGROUND AND PURPOSE: An enhanced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen could improve humoral vaccine response in patients with multiple sclerosis (MS) treated by anti-CD20. The aim was to evaluate the serological response and the neutralizing activity after BNT162b2 primary and booster vaccination in MS patients, including patients on anti-CD20 receiving a primary vaccine regimen enhanced with three injections. METHODS: In this prospective longitudinal cohort study of 90 patients (47 on anti-CD20, 10 on fingolimod, 33 on natalizumab, dimethylfumarate or teriflunomide), anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G antibodies were quantified and their neutralization capacity was evaluated by enzyme-linked immunosorbent assay (GenScript) and a virus neutralization test against B.1 historical strain, Delta and Omicron variants, before and after three to four BNT162b2 injections. RESULTS: After the primary vaccination scheme, the anti-RBD positivity rate was strongly decreased in patients on anti-CD20 (28% [15%; 44%] after two shots, 45% [29%; 62%] after three shots) and fingolimod (50% [16%; 84%]) compared to other treatments (100% [90%; 100%]). Neutralization activity was also decreased in patients on anti-CD20 and fingolimod, and notably low for the Omicron variant in all patients (0%-22%). Delayed booster vaccination was performed in 54 patients, leading to a mild increase of anti-RBD seropositivity in patients on anti-CD20 although it was still lower compared to other treatments (65% [43%; 84%] vs. 100% [87%; 100%] respectively). After a booster, Omicron neutralization activity remained low on anti-CD20 and fingolimod treated patients but was strongly increased in patients on other treatments (91% [72%; 99%]). DISCUSSION: In MS patients on anti-CD20, an enhanced primary vaccination scheme moderately increased anti-RBD seropositivity and anti-RBD antibody titre, but neutralization activity remained modest even after a fourth booster injection. TRIAL REGISTRATION INFORMATION: COVIVAC-ID, NCT04844489, first patient included on 20 April 2021.

Levosimendan in patients undergoing extracorporeal membrane oxygenation after cardiac surgery: an emulated target trial using observational data.

BACKGROUND: Retrospective cohorts have suggested that levosimendan may facilitate the weaning of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We therefore studied this clinical question by emulating a randomized trial with observational data. METHODS: All patients with refractory postcardiotomy cardiogenic shock and assisted with VA-ECMO, admitted to a surgical intensive care unit at La Pitié-Salpêtrière Hospital between 2016 and 2019, were eligible. To avoid immortal-time bias, we emulated a target trial sequentially comparing levosimendan administration versus no levosimendan administration in patients treated with VA-ECMO. The primary outcome was time to successful ECMO weaning. The secondary outcomes were 30-day and 1-year mortality. We performed a multivariable analysis to adjust for confounding at baseline. RESULTS: Two hundred and thirty-nine patients were included in the study allowing building a nested trials cohort of 1434 copies of patients. No association of levosimendan treatment and VA-ECMO weaning was found (HR = 0.91, [0.57; 1.45], p = 0.659 in multivariable analysis), or 30-day mortality (OR = 1.03, [0.52; 2.03], p = 0.940) and 1-year mortality (OR = 1.00, [0.53; 1.89], p = 0.999). CONCLUSIONS: Using the emulated target trial framework, this study did not find any association of levosimendan treatment and ECMO weaning success after postcardiotomy cardiogenic shock. However, the population of interest remains heterogeneous and subgroups might benefit from levosimendan.

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

High seroconversion rate and SARS-CoV-2 Delta neutralization in people with HIV vaccinated with BNT162b2.

OBJECTIVES: To assess humoral responses to SARS-CoV-2 Delta-variant in people with HIV (PWH) after BNT162b2-vaccination. DESIGN: Multicenter cohort study of PWH with CD4 + cell count less than 500 cells/µl and viral load less than 50 copies/ml on stable antiretroviral therapy for at least 3 months. METHODS: Anti-SARS-CoV-2 receptor-binding-domain IgG antibodies (anti-RBD IgG) were quantified and neutralization capacity was evaluated by ELISA/GenScript and virus-neutralization-test against the D614G-strain, beta and delta variants before vaccination (day 0) and 1 month after complete schedule (M1). RESULTS: We enrolled 97 PWH, 85 received two vaccine shots. The seroconversion rate for anti-RBD IgG was 97% [95% confidence interval (CI) 90-100%] at M1. Median (IQR) anti-RBD IgG titer was 0.97 (0.97-5.3) BAU/ml at D0 and 1219 (602-1929) at M1. Neutralization capacity improved between D0 (15%; 50% CI 8-23%) and M1 (94%; 95% CI 87-98%) ( P  < 0.0001). At M1, NAbs against the D614G strain, beta and delta variants were present in 82, 77, and 84% PWH, respectively. The seroconversion rate and median anti-RBD-IgG level were 91% and 852 BAU/ml, respectively, in PWH with CD4 + cell count less than 250 ( n  = 13) and 98% and 1270 BAU/ml for CD4 + greater than 250 ( n  = 64) ( P  = 0.3994). NAbs were present in 73% of PWH with CD4 + less than 250 and 97% of those with CD4 + cell count greater than 250 ( P  = 0.0130). NAbs against beta variant were elicited in 50% in PWH with CD4 + cell count less than 250 and in 81% of those with CD4 + cell count greater than 250 ( P  = 0.0292). CD4 + and CD8 + T-cell counts were unchanged, whereas CD19 + B-cell counts decreased after vaccination(208 ±â€Š124 at D0 vs. 188 ±â€Š112 at M1, P  < 0.01). No notable adverse effects or COVID-19 cases were reported. CONCLUSION: Seroconversion rates were high, with delta-neutralization rates similar to those for the D61G strain, after a two-dose BNT162b2 vaccination in PWH.

Immunochemotherapy versus rituximab in anti-myelin-associated glycoprotein neuropathy: A report of 64 patients.

Monoclonal immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%-50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti-MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin scale (mRS). From 2011 to 2018, 64 patients were studied: 34 were treated with R and 30 with ICT. According to our treatment decision-making process, the median mRS was higher in the ICT group (mRS 2) than in the R group (mRS 1). At one year, improvements of the mRS rates were 46% and 18% in the ICT and R groups of patients respectively, with median times to response of eight and 13 months (p = 0.023). Adverse effects were higher in the ICT group: 62% vs 15% (p Ë‚ 0.01), all grades included. One secondary acute leukaemia occurred five years after treatment with ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti-MAG neuropathy symptoms.

Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer's disease with an implantable ultrasound device.

BACKGROUND: Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer's disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device. METHODS: An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of - 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial. CONCLUSIONS: These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03119961.

Defining biomarkers in oral cancer according to smoking and drinking status.

Introduction: Oral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis. Materials and Methods: Cells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay. Results: Normal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p<0.05 for blood), of monocytes-macrophages (p<0.01 for blood) and of CD4+ T cells expressing CD45RO and CCR6 (p<0.001 for blood; p<0.0001 for TME) as well as higher levels of IL-6 (p<0.01 for sera, p<0.05 for tumor supernatant) were observed in SD patients as compared to NSND OSCC patients and HD. High percentages of CD4+ T cells expressing CD45RO and CCR6 cells in tumor tissue (p=0.05) and blood (p=0.05) of SD OSCC patients were also associated with a poorer prognosis while a high percentage of regulatory T cells (Treg) in tumor tissue was associated with a more favorable prognostic factor (p=0.05). Also, a higher percentage of blood CD8+ T lymphocytes among CD45+ cells in NSND patients was associated with a better disease-free survival (p=0.004). Conclusion: Granulocytes, monocytes-macrophages, and CD4+ T cells expressing CD45RO and CCR6 in blood and TME as well as serum IL-6 can therefore distinguish OSCC SD and NSND patients. Quantifying the proportion of CD4+ T cells expressing CD45RO and CCR6 and of Treg in SD patients and CD8+ T cells in NSND patients could help defining the prognostic of OSCC patients.

Real-life practice of thyroid hormone use in hypothyroid and euthyroid patients: A detailed view from the THESIS questionnaire survey in France.

AIM: To describe practices of French physicians regarding thyroid hormone therapy, focusing on available LT4 formulations. MATERIAL AND METHODS: Members of the French Endocrine Society (FES) and affiliated societies (the Endocrine Tumor Group, French College of Teachers of Endocrinology, Diabetes and Metabolic Diseases and the Union of Endocrinology, Diabetology, Metabolic Diseases and Nutrition Specialists) were invited to participate in an online survey. RESULTS: Five hundred and thirty four of the 2,094 persons contacted (25.5%) completed the survey and were included in the analysis. The vast majority (99.4%) reported that levothyroxine (LT4) is the treatment of choice for hypothyroidism. 7.1% and 14.2% of respondents respectively considered liothyronine (LT3) or a combination of LT4 and LT3 for the treatment of hypothyroidism, mainly when symptoms persisted despite achieving normal TSH concentrations with LT4 therapy. For 44% of respondents, thyroid hormone treatment is never indicated in euthyroid patients, while the remainder would consider treating euthyroid patients with a goiter growing over time (40.2%) and/or euthyroid women with positive anti-TPO antibodies and infertility (31.7%). LT4 tablets were the preferred LT4 formulation. A significant proportion of FES members expected no major clinical differences upon changing to formulations such as soft-gel capsules or liquid solutions, even in specific scenarios such as poor biochemical control or suspicion of malabsorption. CONCLUSION: The treatment of choice for hypothyroidism in France is LT4. LT3-based therapy is considered by some physicians in case of persistent symptoms of hypothyroidism despite normal TSH level. A significant proportion of respondents (66.0%) would consider treating euthyroid patients, contrary to the present state of knowledge. These outdated practices should be addressed by professional bodies such as the FES.

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study.

BACKGROUND: Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use. METHODS: We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months). RESULTS: Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology. CONCLUSIONS: Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov ( NCT01956552 ).

Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial.

BACKGROUND: Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis. METHODS: This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45-80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days -15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT02481453. FINDINGS: Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI -10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients. INTERPRETATION: We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus. FUNDING: Institut national de la santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies.

Progression-free survival as a surrogate for overall survival in oncology trials: a methodological systematic review.

BACKGROUND: Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology. Validation of PFS as a surrogate must be done for each indication and each intervention. We aimed to identify all studies evaluating the validity of PFS as a surrogate for OS in oncology, and to describe their methodological characteristics. METHODS: We conducted a systematic review by searching MEDLINE via PubMed and the Cochrane Library with no limitation on time, selected relevant studies and extracted data in duplicate on how surrogacy was evaluated (meta-analytic approach, assessment of correlation and level of evaluation). RESULTS: We identified 91 studies evaluating the validity of PFS as a surrogate for OS in 24 cancer localisations. Although a meta-analytic approach was used in 83 (91%) studies, the methods used to validate PFS as a surrogate of OS were heterogeneous across studies. Of the 47 studies concluding that PFS is a good surrogate for OS, for 15 (32%), there was no quantitative argument for surrogacy. CONCLUSIONS: Although most studies used a meta-analytic approach as recommended, our methodological review highlights heterogeneity in methods and reporting, which stresses the importance of developing and applying clear recommendations in this area.

Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma.

PURPOSE: The blood-brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. PATIENTS AND METHODS: A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. RESULTS: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. CONCLUSIONS: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity.See related commentary by Sonabend and Stupp, p. 3750.