Dyspnea is severe and associated with a higher intubation rate in de novo acute hypoxemic respiratory failure.

BACKGROUND: Dyspnea is a key symptom of de novo acute hypoxemic respiratory failure. This study explores dyspnea and its association with intubation and mortality in this population. METHODS: This was a secondary analysis of a multicenter, randomized, controlled trial. Dyspnea was quantified by a visual analog scale (dyspnea-VAS) from zero to 100 mm. Dyspnea was measured in 259 of the 310 patients included. Factors associated with intubation were assessed with a competing risks model taking into account ICU discharge. The Cox model was used to evaluate factors associated with 90-day mortality. RESULTS: At baseline (randomization in the parent trial), median dyspnea-VAS was 46 (interquartile range, 16-65) mm and was ≥ 40 mm in 146 patients (56%). The intubation rate was 45%. Baseline variables independently associated with intubation were moderate (dyspnea-VAS 40-64 mm) and severe (dyspnea-VAS ≥ 65 mm) dyspnea at baseline (sHR 1.96 and 2.61, p = 0.023), systolic arterial pressure (sHR 2.56, p < 0.001), heart rate (sHR 1.94, p = 0.02) and PaO2/FiO2 (sHR 0.34, p = 0.028). 90-day mortality was 20%. The cumulative probability of survival was lower in patients with baseline dyspnea-VAS ≥ 40 mm (logrank test, p = 0.049). Variables independently associated with mortality were SAPS 2 ≥ 25 (p < 0.001), moderate-to-severe dyspnea at baseline (p = 0.073), PaO2/FiO2 (p = 0.118), and treatment arm (p = 0.046). CONCLUSIONS: In patients admitted to the ICU for de novo acute hypoxemic respiratory failure, dyspnea is associated with a higher risk of intubation and with a higher mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier # NCT01320384.

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.

[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.

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.

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.

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.

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.

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort.

This corrects the article DOI: 10.1038/bjc.2017.85.

Multiparametric MRI for Suspected Recurrent Prostate Cancer after HIFU:Is DCE still needed?

PURPOSE: To assess the added value of the dynamic contrast-enhanced sequence (DCE) to combination T2-weighted imaging (T2w) + diffusion-weighted imaging (DWI) in detecting prostate cancer (PCa) recurrence after HIFU (high-intensity focused ultrasound). METHODS: Forty-five males with clinical and biological suspected PCa recurrence were retrospectively selected. All underwent multi-parametric MRI (mpMRI) before biopsies. Two readers independently assigned a Likert score of cancer likelihood on T2w + DWI + DCE and T2w + DWI images. Prostatic biopsies were taken as the gold standard. RESULTS: Recurrent PCa was identified at biopsy for 37 patients (82%). Areas under the receiver-operating curve of T2w + DWI and T2w + DWI + DCE imaging were not significantly different for both readers. Using a Likert score ≥ 3 for the PCa diagnosis threshold, sensitivity at the lobe level for the (1) senior and (2) junior reader for T2w +DWI +DCE sensitivity was (1) 0.97 and (2) 0.94 vs. (1) 0.94 and (2) 0.97 for T2w + DWI. CONCLUSION: Accuracy of mpMRI was not significantly improved by adding DCE to T2w + DWI. Sensitivity was high for T2w + DWI + DCE and T2w + DWI with no significant difference for either the junior or senior reader. KEY POINTS: • MpMRI has the capability to detect PCa recurrence in post-HIFU monitoring. • The sensitivity of T2w and DWI for detecting PCa recurrence was not improved by DCE. • Readers with different degrees of experience did not improve their performance with DCE.

Opioid-related genetic polymorphisms do not influence postoperative opioid requirement: A prospective observational study.

BACKGROUND: Among the various factors that may influence the pharmacological response to opioids, genetic polymorphisms [single nucleotide polymorphisms (SNP)] have generated some interest. OBJECTIVES: To examine the influence on morphine dose requirements and adverse events in the postoperative period of four SNP [opioid receptor mu1 (OPRM1), ATP-binding cassette subfamily B, member 1 (ABCB1) ex-21 and ex-26, catechol-o-methyltransferase (COMT)] in candidate genes involved in morphine pharmacodynamics and pharmacokinetics. DESIGN: A single centre prospective study. SETTING: University Hospital, Paris, France, from 2 January 2007 to 15 November 2011. PATIENTS: A total of 438 white adults scheduled for major orthopaedic surgery (spine, hip and knee) under general anaesthesia. The main exclusion criteria were receiving opioids for chronic pain, nonopioid drugs within 2 days prior to surgery, pregnancy, renal insufficiency, sleep apnoea obstruction syndrome, morbid obesity, severe hepatic impairment, cognitive dysfunction. INTERVENTIONS: Assays of plasma concentrations of morphine and metabolites (morphine 3-glucuronide and morphine 6-glucuronide) were performed and common polymorphisms in four candidate genes [OPRM1 A118G rs1799971; P-glycoprotein (ABCB1) T3435C (rs1045642) and G2677T/A (rs2032582); COMT Val 158 Met (rs4680)] were analysed.Morphine was titrated by staff in the postanaesthesia care unit (PACU) and in the ward patient-controlled intravenous analgesia was used for 24 h. MAIN OUTCOME MEASURES: The dose of morphine required to achieve pain relief and the influence of SNP in genes involved in morphine pharmacodynamics and kinetics on morphine dose requirements. Secondary endpoints were the concentrations of morphine, morphine 6-glucuronide and morphine 3-gluguronide, the proportion of patients requiring a rescue analgesic and the proportion of morphine-related adverse events. RESULTS: A total of 404 patients completed the study to final analysis. The mean ±â€ŠSD morphine dose to achieve pain relief was 15.8 ±â€Š8.8 mg in the PACU and 22.7 ±â€Š18.6 mg during patient-controlled intravenous administration. Morphine-related adverse events were observed in 37%. There was no relationship between any genetic polymorphisms and morphine dose, morphine 3-gluguronide and morphine 6-glucuronide concentration, morphine-related adverse events or pain level. In the PACU only, P-glycoprotein polymorphisms (ex-21; ex-26) were significantly associated with morphine concentration but the prediction of the model was poor (R = 0.04) CONCLUSION: No major relationship has been demonstrated between SNP of OPRM1, ABCB1, COMT and morphine requirement, pain level or adverse effects in the postoperative period. TRIAL REGISTRATION: NCT00822549 (www.clinicaltrials.gov).

Closed-form variance estimator for weighted propensity score estimators with survival outcome.

Propensity score (PS) methods are widely used in observational studies for evaluating marginal treatment effects. PS-weighting is a popular PS-based method that allows for estimating both the average treatment effect on the overall population (ATE) and the average treatment effect on the treated population (ATT). Previous research has shown that the variance of the treatment effect is accurately estimated only if the variance estimator takes into account the fact that the propensity score is itself estimated from the available data in a first step of the analysis. In 2016, Austin showed that the bootstrap-based variance estimator was the only existing estimator resulting in approximately correct estimates of standard errors when evaluating a survival outcome and a Cox model was used to estimate a marginal hazard ratio (HR). This author stressed the need to develop a closed-form variance estimator of the marginal HR accounting for the estimation of the PS. In the present research, we developed such variance estimators both for the ATE and ATT. We evaluated their performance with an extensive simulation study and compared them to bootstrap-based variance estimators and to naive variance estimators that do not account for the estimation step. We found that the performance of the proposed variance estimators was similar to that of the bootstrap-based estimators. The proposed variance estimators provide an alternative to the bootstrap estimator, particularly interesting in situations in which time-consumption and/or reproducibility are an important issue. An implementation has been developed for the R software and is freely available (package hrIPW).

Prevalence and Prognosis Impact of Patient-Ventilator Asynchrony in Early Phase of Weaning according to Two Detection Methods.

BACKGROUND: Patient-ventilator asynchrony is associated with a poorer outcome. The prevalence and severity of asynchrony during the early phase of weaning has never been specifically described. The authors' first aim was to evaluate the prognosis impact and the factors associated with asynchrony. Their second aim was to compare the prevalence of asynchrony according to two methods of detection: a visual inspection of signals and a computerized method integrating electromyographic activity of the diaphragm. METHODS: This was an ancillary study of a multicenter, randomized controlled trial comparing neurally adjusted ventilatory assist to pressure support ventilation. Asynchrony was quantified at 12, 24, 36, and 48 h after switching from controlled ventilation to a partial mode of ventilatory assistance according to the two methods. An asynchrony index greater than or equal to 10% defined severe asynchrony. RESULTS: A total of 103 patients ventilated for a median duration of 5 days (interquartile range, 3 to 9 days) were included. Whatever the method used for quantification, severe patient-ventilator asynchrony was not associated with an alteration of the outcome. No factor was associated with severe asynchrony. The prevalence of asynchrony was significantly lower when the quantification was based on flow and pressure than when it was based on the electromyographic activity of the diaphragm at 0.3 min (interquartile range, 0.2 to 0.8 min) and 4.7 min (interquartile range, 3.2 to 7.7 min; P < 0.0001), respectively. CONCLUSIONS: During the early phase of weaning in patients receiving a partial ventilatory mode, severe patient-ventilator asynchrony was not associated with adverse clinical outcome, although the prevalence of patient-ventilator asynchrony varies according to the definitions and methods used for detection.

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort.

BACKGROUND: Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment. METHODS: We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed. RESULTS: pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P<0.0001). DFS also differed significantly between patients receiving adjuvant trastuzumab or not (hazard ratio=4.84, 95% CI (2.52; 9.31), P<0.001). We analysed 199 patients given neoadjuvant and adjuvant trastuzumab. Multivariate analysis identified older age and hormone receptor-negative tumours as independent predictors of pCR. T stage (hazard ratio=2.55, 95% CI (1.01; 6.48), P=0.05) and strict pCR (hazard ratio=9.15, 95% CI (1.22; 68.83), P=0.03) were independent predictors of DFS. The latter association was significant in the HR-negative subgroup (P=0.02) but not in the HR-positive subgroup (P=0.12). CONCLUSIONS: Major pCR and DFS gains in HER2-positive BC were observed since 'trastuzumab' era. Further improvements rely on the enrollment of accurately selected patients into clinical trials.

From prospective biobanking to precision medicine: BIO-RAIDs - an EU study protocol in cervical cancer.

BACKGROUND: Cervical cancer (CC) is -second to breast cancer- a dominant cause of gynecological cancer-related deaths worldwide. CC tumor biopsies and blood samples are of easy access and vital for the development of future precision medicine strategies. DESIGN: BIO-RAIDs is a prospective multicenter European study, presently recruiting patients in 6 EU countries. Tumor and liquid biopsies from patients with previously non-treated cervical cancer (stages IB2-IV) are collected at defined time points. Patients receive standard primary treatment according to the stage of their disease. 700 patients are planned to be enrolled. The main objectives are the discovery of -dominant molecular alterations, -signalling pathway activation, and -tumor micro-environment patterns that may predict response or resistance to treatment. An exhaustive molecular analysis is performed using 1° Next generation sequencing, 2° Reverse phase protein arrays and 3° Immuno-histochemistry. DISCUSSION: The clinical study BIO-RAIDs is activated in all planned countries, 170 patients have been recruited till now. This study will make an important contribution towards precision medicine treatments in cervical cancer. The results will support the development of clinical practice guidelines for cervical cancer patients to improve their prognosis and their quality of life. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02428842 , registered 10 February 2015.

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.

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).

The impact of single-nucleotide polymorphisms (SNPs) in OGG1 and XPC on the age at onset of Huntington disease.

The age at onset of Huntington disease (HD) shows a strong, negative correlation with the number of CAG repeats within the huntingtin (HTT) gene. However, this does not account for all the inter-individual variability seen among patients. In order to assess whether single-nucleotide polymorphisms (SNPs) in the OGG1 and XPC genes, both implicated in responses to oxidative stress, are associated with the age of onset of HD, 9 SNPs have been genotyped in 299 individuals with HD and 582 controls. After correction for multiple testing, two OGG1/XPC haplotypes were found to be associated with younger age at onset independently of the number of CAG repeats within the HTT gene. Both haplotypes contain XPC coding variants that would be expected to impact on protein function and/or variants in the 3'UTR that could result in altered protein levels via allele-specific mIR binding. One haplotype also contains the OGG1-326Cys (rs1052133) allele that has been associated with a lower 8-oxoG repair activity and is particularly sensitive to the cellular redox status. These results highlight the potential role of oxidative stress in determining the age at onset of HD.