Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. FUNDING: The Canadian Cancer Society and Merck & Co.

Preliminary results in tracheal replacement using stented aortic matrices for primary extensive tracheal cancer.

Objective: Recent studies have demonstrated the feasibility and favorable long-term results of tracheobronchial replacement using stented cryopreserved aortic allografts. We propose to investigate the outcomes of this emerging technique in the subgroup of patients with extensive tracheal cancer. Methods: This study was based on 13 patients with primary extensive tracheal cancer extracted from the prospective registry TRITON-01 (ClinicalTrials.gov Identifier: NCT04263129), which included 40 patients in total. We analyzed early and late outcomes in this subset of patients. Results: From March 2019 to September 2022, 13 patients were included in the study. There were 9 female and 4 male patients, with a mean age of 53.9 years [36-71 years]. They had tracheal replacement for extended adenoid cystic carcinoma (n = 11), squamous cell carcinoma (n = 1), and mucoepidermoid carcinoma (n = 1). A venovenous extracorporeal membrane oxygenation was used in the 6 last cases. The mean length of resection was 81 mm [50-120 mm]. There was no 30-day postoperative mortality. A complete resection (R0) was achieved in 11 patients. The main late complications consisted of tracheal granulomas related to the stent and requiring repeated bronchoscopies (n = 9), pneumonia (n = 3), airway infection (n = 1), bronchoesophageal fistula (n = 1), mechanical stent obstruction requiring change (n = 2), and mediastinitis treated by antibiotics, drainage, and omentoplasty (n = 1). With a maximal follow-up of 3 years and 7 months, cancer recurrence was observed in 2 patients. All patients were alive at last follow-up except 2 (84.6%). Conclusions: Airway replacement using stented CAA represents a feasible and promising solution for extensive tracheal cancer.

High flow nasal oxygen in frail COVID-19 patients hospitalized in intermediate care units and non-eligible to invasive mechanical ventilation.

BACKGROUND: In COVID-19 patients, older age (sixty or older), comorbidities, and frailty are associated with a higher risk for mortality and invasive mechanical ventilation (IMV) failure. It therefore seems appropriate to suggest limitations of care to older and vulnerable patients with severe COVID-19 pneumonia and a poor expected outcome, who would not benefit from invasive treatment. HFNO (high flow nasal oxygen) is a non-invasive respiratory support device already used in de novo acute respiratory failure. The main objective of this study was to evaluate the survival of patients treated with HFNO outside the ICU (intensive care unit) for a severe COVID-19 pneumonia, otherwise presenting limitations of care making them non-eligible for IMV. Secondary objectives were the description of our cohort and the identification of prognostic factors for HFNO failure. METHODS: We conducted a retrospective cohort study. We included all patients with limitations of care making them non-eligible for IMV and treated with HFNO for a severe COVID-19 pneumonia, hospitalized in a COVID-19 unit of the pulmonology department of Lyon Sud University Hospital, France, from March 2020 to March 2021. Primary outcome was the description of the vital status at day-30 after HFNO initiation, using the WHO (World Health Organization) 7-points ordinal scale. RESULTS: Fifty-six patients were included. Median age was 83 years [76.3-87.0], mean duration for HFNO was 7.5 days, 53% had a CFS score (Clinical Frailty Scale) >4. At day-30, 73% of patients were deceased, one patient (2%) was undergoing HFNO, 9% of patients were discharged from hospital. HFNO failure occurred in 66% of patients. Clinical signs of respiratory failure before HFNO initiation (respiratory rate >30/min, retractions, and abdominal paradoxical breathing pattern) were associated with mortality (p = 0.001). CONCLUSIONS: We suggest that HFNO is an option in non-ICU skilled units for older and frail patients with a severe COVID-19 pneumonia, otherwise non-suitable for intensive care and mechanical ventilation. Observation of clinical signs of respiratory failure before HFNO initiation was associated with mortality.

Piecewise Structural Equation Modeling of the Quantity Implicature in Child Language.

We review an array of experimental methodological factors that either contribute to or detract from the measurement of pragmatic implicatures in child language. We carry out a truth value judgment task to measure children's interpretations of the Spanish existential quantifier algunos in implicature-consistent and implicature-inconsistent contexts. Independently, we take measures of children's inhibition, working memory, attention, approximate number ability, phrasal syntax, and lexicon. We model the interplay of these variables using a piecewise structural equation model (SEM), common in the life sciences, but not in the social and behavioral sciences. By 6 years of age, the children in our sample were not statistically different from adults in their interpretations. Syntax, lexicon, and inhibition significantly predict implicature generation, each accounting for unique variance. The approximate number system and inhibition significantly predict lexical development. The statistical power of the piecewise SEM components, with a sample of 64 children, is high, in comparison to a traditional, globally estimated SEM of the same data.

Small Cell Carcinoma of the Vagina: First Systematic Review of Case Reports and Proposal of a Management Algorithm.

OBJECTIVES: Small cell carcinoma of the vagina (SmCCV) is an extremely rare disease. Evidence-based data and specific guidelines are lacking. We conducted the first systematic review of case reports to provide the most overall picture of SmCCV. MATERIALS AND METHODS: Literature search in PubMed and Scopus was performed using the terms "small cell carcinoma" and "vagina." English-language case reports of primary SmCCV up to January 2022 were included. RESULTS: Twenty-nine articles describing 44 cases met our inclusion criteria. We report a new case of our hospital. The global median overall survival (mOS) was 12.00 months (95% CI = 9.31-14.69). The mOS was not reached for stage I, and it was 12.00, 12.00, 9.00, and 8.00 months for stages II, III, IVA, and IVB, respectively (statistically significant differences between stage I and stages II, III, or IVA [log rank p = .003-.017]). Thirty-five cases received local treatments (77.8%). The mOS of patients treated with surgery ± complementary chemotherapy, radiotherapy ± complementary chemotherapy, chemoradiation ± complementary chemotherapy, and surgery + radiotherapy ± complementary chemotherapy were 11.00, 12.00, 17.00, and 29.00 months, respectively. The use of adjuvant or neoadjuvant chemotherapy (64.5%, mostly platinum + etoposide) showed longer mOS (77.00 vs 15.00 months). Four of 5 tested cases presented human papillomavirus infection, 3 of them presenting type 18. CONCLUSIONS: Small cell carcinoma of the vagina shows dismal prognosis. Multimodal local management plus complementary chemotherapy seems to achieve better outcomes. Human papillomavirus could be related to the development of SmCCV. A diagnostic-therapeutic algorithm is proposed.

Tracheal stent aspergillosis occurring after aortic allograft of the trachea.

BACKGROUND: Aspergillosis is a fungal infection with many clinical forms. Invasive aspergillosis is the most widely known severe manifestation, but other forms can need intensive care. AIM: Our purpose is to report a case of tracheal aspergilloma and provide a review of the literature concerning endobronchial aspergillus. METHOD: We report a case of tracheal aspergilloma causing tracheal obstruction in a patient admitted in the ICU for respiratory distress. The aspergilloma occurred in a tracheal stent implanted during tracheal allograft for tracheal cancer. A combination of local and systemic antifungal was used with successful result.

Molecular profiling of non-small-cell lung cancer patients with or without brain metastases included in the randomized SAFIR02-LUNG trial and association with intracranial outcome.

INTRODUCTION: Lung cancer remains the most frequent cause of brain metastases (BMs) and is responsible for high morbidity and mortality. Intracranial response to systemic treatments is inconsistent due to several mechanisms: genomic heterogeneity, blood-tumor barrier, and the brain-specific microenvironment. We conducted a study using data from the SAFIR02-LUNG trial. The primary objective was to compare the molecular profiles of non-small-cell lung cancer (NSCLC) with or without BMs. The secondary objective was to explore central nervous system (CNS) outcomes with various maintenance treatment regimens. METHODS: In total, 365 patients harboring interpretable molecular data were included in this analysis. Clinical and biological data were collected. Genomic analyses were based on array-comparative genomic hybridization and next-generation sequencing (NGS) following the trial recommendations. RESULTS: Baseline genomic analyses of copy number variations identified a 24-gene signature specific to lung cancer BM occurrence, all previously known to take part in oncogenesis. NGS analysis identified a higher proportion of KRAS mutations in the BM-positive group (44.3% versus 32.3%), especially G12C mutations (63% versus 47%). Protein interaction analyses highlighted several functional interactions centered on EGFR. Furthermore, the risk of CNS progression was decreased with standard pemetrexed maintenance therapy. The highest rate of CNS progression was observed with durvalumab, probably because of the specific intracranial immune microenvironment. CONCLUSION: This work identified a 24-gene signature specific to lung cancer with BM. Further studies are needed to precisely determine the functional implications of these genes to identify new therapeutic targets for the treatment of lung cancer with BM.

ß-Amyrin Synthase1 Controls the Accumulation of the Major Saponins Present in Pea (Pisum sativum).

The use of pulses as ingredients for the production of food products rich in plant proteins is increasing. However, protein fractions prepared from pea or other pulses contain significant amounts of saponins, glycosylated triterpenes that can impart an undesirable bitter taste when used as an ingredient in foodstuffs. In this article, we describe the identification and characterization of a gene involved in saponin biosynthesis during pea seed development, by screening mutants obtained from two Pisum sativum TILLING (Targeting Induced Local Lesions IN Genomes) populations in two different genetic backgrounds. The mutations studied are located in a gene designated PsBAS1 (ß-amyrin synthase1), which is highly expressed in maturing pea seeds and which encodes a protein previously shown to correspond to an active ß-amyrin synthase. The first allele is a nonsense mutation, while the second mutation is located in a splice site and gives rise to a mis-spliced transcript encoding a truncated, nonfunctional protein. The homozygous mutant seeds accumulated virtually no saponin without affecting the seed nutritional or physiological quality. Interestingly, BAS1 appears to control saponin accumulation in all other tissues of the plant examined. These lines represent a first step in the development of pea varieties lacking bitterness off-flavors in their seeds. Our work also shows that TILLING populations in different genetic backgrounds represent valuable genetic resources for both crop improvement and functional genomics.

A Cytokinin Signaling Type-B Response Regulator Transcription Factor Acting in Early Nodulation.

Nitrogen-fixing root nodulation in legumes challenged with nitrogen-limiting conditions requires infection of the root hairs by soil symbiotic bacteria, collectively referred to as rhizobia, and the initiation of cell divisions in the root cortex. Cytokinin hormones are critical for early nodulation to coordinate root nodule organogenesis and the progression of bacterial infections. Cytokinin signaling involves regulation of the expression of cytokinin primary response genes by type-B response regulator (RRB) transcription factors. RNA interference or mutation of MtRRB3, the RRB-encoding gene most strongly expressed in Medicago truncatula roots and nodules, significantly decreased the number of nodules formed, indicating a function of this RRB in nodulation initiation. Fewer infection events were also observed in rrb3 mutant roots associated with a reduced Nod factor induction of the Early Nodulin 11 (MtENOD11) infection marker, and of the cytokinin-regulated Nodulation Signaling Pathway 2 (Mt NSP2) gene. Rhizobial infections correlate with an expansion of the nuclear area, suggesting the activation of endoreduplication cycles linked to the cytokinin-regulated Cell Cycle Switch 52A (Mt CCS52A) gene. Although no significant difference in nucleus size and endoreduplication were detected in rhizobia-infected rrb3 mutant roots, expression of the MtCCS52A endoreduplication marker was reduced. As the MtRRB3 expression pattern overlaps with those of MtNSP2 and MtCCS52A in roots and nodule primordia, chromatin immunoprecipitation-quantitative PCR and protoplast trans-activation assays were used to show that MtRRB3 can interact with and trans-activate MtNSP2 and MtCCS52A promoters. Overall, we highlight that the MtRRB3 cytokinin signaling transcription factor coordinates the expression of key early nodulation genes.

Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors.

BACKGROUND: The impact of immune-related adverse events (irAE) on survival outcomes after single-agent immune checkpoint inhibitors (ICIs) remains unclear. We aimed to evaluate the association between irAEs and ICI efficacy in various malignancies. METHODS: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric series. The primary objective was to assess the impact of all type grade ≥II irAEs on progression-free survival (PFS) and overall survival (OS). IrAEs were first considered as a fixed covariate and included in Cox-regression models. In addition, as irAEs are time-related events and can occur at any point during follow-up, we analysed the occurrence of irAEs as a time-varying covariate. RESULTS: In this cohort of 410 patients, the majority of patients (70%) were treated for non-small cell lung cancer. The ICI was an anti-PD(L)1 for 356 patients (82%) and an anti-CTLA4 for 79 patients (18%). In total 126 (29%) of the patients presented at least one grade ≥II irAEs. The first occurrence of a grade ≥II irAE had a positive impact on PFS and OS when considered as a fixed or as a time-varying covariate (hazard ratio [HR] for PFS = 0.63, 95% confidence interval [CI] 0.50-0.81; P = 0.00022; HR for OS = 0.57, 95% CI 0.43-0.74, P < 0.0001). This overall finding was confirmed in patients treated with an anti-PD(L)1 and among patients with lung cancer. CONCLUSION: In this pooled multi-institutional cohort, the incidence of irAEs was associated with better long-term survival across different malignancies treated with ICI monotherapy.

Effectiveness and safety of nivolumab in the treatment of lung cancer patients in France: preliminary results from the real-world EVIDENS study.

EVIDENS is an ongoing, prospective, non-interventional study evaluating the effectiveness and safety of nivolumab in lung cancer patients in France (ClinicalTrials.gov NCT03382496). Adults with a pathologically confirmed diagnosis of lung cancer and initiating treatment with nivolumab were recruited from 146 sites in France. This analysis included only patients with non-small cell lung cancer (NSCLC) who received ≥1 nivolumab infusion, and evaluated patient characteristics at the time of nivolumab initiation and its effectiveness and safety after a median follow-up of 18 months. A total of 1,420 patients with NSCLC were included, most of whom had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 (82.9%), non-squamous histology (69.2%) and stage IV disease (91.4%). Brain metastases were present in 19.9% of patients. Nivolumab was a second-line or ≥third-line regimen in 73.6% and 26.1% of patients, respectively. Almost all patients had prior chemotherapy (99.7%). Median overall survival was 11.2 months (95% confidence interval [CI]: 10.0-12.4). ECOG PS, smoking status, corticosteroids at baseline, epidermal growth factor receptor mutation status, presence of symptomatic brain metastases and treatment-related adverse events (TRAEs) were independent predictors of survival. Grade 3 and 4 TRAEs were reported in 105 (7.4%) and 12 (0.8%) patients, respectively; no treatment-related deaths were reported. Preliminary results of the EVIDENS study confirm the effectiveness and safety of nivolumab, mostly in pre-treated advanced NSCLC patients, with similar benefits to those observed in the phase III randomized clinical trials, despite a broader study population.

Síntomas y signos de la hipofunción vestibular unilateral y bilateral / Symptoms and signs of unilateral and bilateral vestibular hypofunction

INTRODUCCIÓN Y OBJETIVO: La disfunción vestibular periférica implica a los órganos vestibulares o a los nervios vestibulares, produciendo una gran variedad de síntomas y signos clínicos. MÉTODO: Revisión narrativa. DISCUSIÓN: El otoneurólogo es el encargado de realizar una evaluación exhaustiva para llegar a identificar el trastorno que presenta el paciente que acude con vértigo o desequilibrio. La clave diagnóstica es la anamnesis profunda completada con un cuidadoso examen otoneurológico. Además, las nuevas tecnologías de estudio que han surgido en este campo permiten un cambio en la definición, caracterización y tratamiento de estas patologías. CONCLUSIONES: En la presente revisión narrativa se describirán los dos grandes grupos de deficiencia vestibular periférica: la vestibulopatía unilateral y bilateral

INTRODUCTION AND OBJECTIVE: Peripheral vestibular dysfunction involve the vestibular organs or the vestibular nerve producing a wide variety of symptoms and clinical signs. METHOD: Narrative revision. DISCUSSION: The otoneurologist is responsible for conducting an exhaustive evaluation to identify the pathology presented by the patient who has vertigo or imbalance. The key to the diagnosis is the deep history completed with a careful otoneurological examination. CONCLUSIONS: In the present narrative review, the two large groups of peripheral vestibular deficiency will be described: unilateral and bilateral vestibulopathy

Compensación vestibular / Vestibular compensation

INTRODUCCIÓN Y OBJETIVO: La compensación vestibular es el conjunto de procesos que se ponen en marcha cuando tiene lugar una lesión a nivel vestibular sea cual sea el origen y la magnitud de la misma. a vez establecida la lesión los mecanismos de compensación del daño son variados y se establecen diferentes líneas de actuación. Para conocer cómo mejorar el estado de nuestros pacientes es importante saber cómo funciona la compensación vestibular y a qué niveles podemos actuar para acelerar el proceso de recuperación. CONCLUSIONES: Es importante conocer los mecanismos de compensación vestibular para adecuar la terapia a cada paciente y así mejorar su calidad de vida

INTRODUCTION AND OBJECTIVE: Vestibular compensation is the term used to describe the mechanisms triggered when there is damage in the vestibular system regardless of its origin. When suffering from an injure in vestibular area there are a wide range of compensatory responses that will involve different approaches. In order to improve the quality of life for our patients and to correctly work with them to accelerate the restoration process it is important to become acquainted with how vestibular compensation works. CONCLUSIONS: Vestibular compensation mechanisms are important to adapt the therapy to each patient and thus improve their quality of life

Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting.

BACKGROUND: Age-related immune dysfunction might impair the efficacy of immune checkpoint inhibitors (ICIs) in older patients. We aimed to evaluate the impact of age on clinical outcomes and tolerance of ICIs in a real-life setting. METHODS: All patients receiving a single-agent ICI (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] or programmed death(ligand)1 [PD(L)-1] inhibitors) for the standard treatment of a locally advanced or metastatic cancer were included in this retrospective multicentric series. The primary end-point was overall survival (OS). Progression-free survival (PFS) and immune-related adverse events (irAEs) were secondary end-points. The impact of age was assessed using the threshold of 70 years. RESULTS: A total of 410 patients were included, for 435 lines of treatment, including 150 lines (34%) given to patients aged 70 years or older. The primary tumour types were lung cancer (n = 304, 74%), melanoma (n = 79, 19%) and urologic cancer (n = 27, 7%). Most of the administered treatments were PD(L)-1 inhibitors (n = 356, 82%). Median follow-up reached 46 months in the CTLA-4 cohort, and 20 months in the PD(L)-1 cohort. In both treatment cohorts, age did not impact OS (respectively, HR = 0.82, 95% CI 0.5-1.4; log-rank P = 0.49 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.27) or PFS (HR = 0.7, 95% CI 0.4-1.1; log-rank P = 0.13 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.19). Grade 3-4 irAEs rates were not statistically different between older and younger patients (11% vs 12%, P = 0.87). CONCLUSION: In a large real-world series of patients treated by ICI monotherapy, the long-term clinical outcomes were not statistically different between older or younger patients, with no increased immune-related toxicity.

Transcriptional Reprogramming of Pea Leaves at Early Reproductive Stages.

Pea (Pisum sativum L.) is an important source of dietary proteins. Nutrient recycling from leaves contributes to the accumulation of seed proteins and is a pivotal determinant of protein yields in this grain legume. The aim of this study was to unveil the transcriptional regulations occurring in pea leaves before the sharp decrease in chlorophyll breakdown. As a prelude to this study, a time-series analysis of 15N translocation at the whole plant level was performed, which indicated that nitrogen recycling among organs was highly dynamic during this period and varied depending on nitrate availability. Leaves collected on vegetative and reproductive nodes were further analyzed by transcriptomics. The data revealed extensive transcriptome changes in leaves of reproductive nodes during early seed development (from flowering to 14 days after flowering), including an up-regulation of genes encoding transporters, and particularly of sulfate that might sustain sulfur metabolism in leaves of the reproductive part. This developmental period was also characterized by a down-regulation of cell wall-associated genes in leaves of both reproductive and vegetative nodes, reflecting a shift in cell wall structure. Later on, 27 days after flowering, genes potentially switching the metabolism of leaves toward senescence were pinpointed, some of which are related to ribosomal RNA processing, autophagy, or transport systems. Transcription factors differentially regulated in leaves between stages were identified and a gene co-expression network pointed out some of them as potential regulators of the above-mentioned biological processes. The same approach was conducted in Medicago truncatula to identify shared regulations with this wild legume species. Altogether the results give a global view of transcriptional events in leaves of legumes at early reproductive stages and provide a valuable resource of candidate genes that could be targeted by reverse genetics to improve nutrient remobilization and/or delay catabolic processes leading to senescence.

Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.

BACKGROUND: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma. METHODS: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272. FINDINGS: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure). INTERPRETATION: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials. FUNDING: French Cooperative Thoracic Intergroup.

Unleashing meiotic crossovers in crops.

Improved plant varieties are important in our attempts to face the challenges of a growing human population and limited planet resources. Plant breeding relies on meiotic crossovers to combine favourable alleles into elite varieties1. However, meiotic crossovers are relatively rare, typically one to three per chromosome2, limiting the efficiency of the breeding process and related activities such as genetic mapping. Several genes that limit meiotic recombination were identified in the model species Arabidopsis thaliana2. Mutation of these genes in Arabidopsis induces a large increase in crossover frequency. However, it remained to be demonstrated whether crossovers could also be increased in crop species hybrids. We explored the effects of mutating the orthologues of FANCM3, RECQ44 or FIGL15 on recombination in three distant crop species, rice (Oryza sativa), pea (Pisum sativum) and tomato (Solanum lycopersicum). We found that the single recq4 mutation increases crossovers about three-fold in these crops, suggesting that manipulating RECQ4 may be a universal tool for increasing recombination in plants. Enhanced recombination could be used with other state-of-the-art technologies such as genomic selection, genome editing or speed breeding6 to enhance the pace and efficiency of plant improvement.

Utilidad del dispositivo portátil Piko-6 para la detección precoz de la enfermedad pulmonar obstructiva crónica en atención primaria / Usefulness of The Piko-6 Portable Device for Early COPD Detection in Primary Care

Introducción: La EPOC es una enfermedad de elevada prevalencia pero infradiagnosticada, debido a la escasa implantación de la espirometría forzada (EF) en atención primaria. Los microespirómetros, baratos y de manejo sencillo, que pueden medir FEV6 y FEV1/FEV6, podrían contribuir a reducir el infradiagnóstico. El objetivo del estudio ha sido validar el dispositivo Piko-6 para el cribado de la EPOC, demostrando una buena correlación con la EF convencional. Métodos: Se han realizado una EF y una determinación con Piko-6 a 155 pacientes susceptibles de padecer EPOC. Se han comparado las correlaciones, curvas ROC e índice de Youden con ambos métodos, considerando la EF como patrón de referencia. Resultados: Los coeficientes de correlación de FEV1, FVC y FEV6 y los cocientes FEV1/FVC y FEV1/FEV6 fueron de 0,87 (IC 95%: 0,836-0,909), 0,729 (IC 95%: 064-0,795) y 0,947 (IC 95%: 0,928-0,961) respectivamente. La curva ROC para el FEV1 determinado por Piko-6 alcanzó un área bajo la curva de 0,86 (IC 95%: 0,78-0,92). El índice de Youden para el punto de corte de 0,70 del FEV1/FEV6 fue 0,97. Conclusiones: El Piko-6 puede ser útil para el cribado de la EPOC en atención primaria. Sus determinaciones presentan buena correlación con las obtenidas mediante EF, especialmente el cociente FEV1/FEV6. Esto, junto a su bajo coste y facilidad de uso, puede contribuir a reducir el infradiagnóstico de la EPOC, aunque su rol exacto en el proceso diagnóstico está aún por determinar

Introduction: COPD is a highly prevalent but underdiagnosed disease, due to the limited availability of forced spirometry (FS) in primary care (PC). Microspirometers are inexpensive, easy-to-use devices that can measure FEV6 and FEV1/FEV6, and may help reduce underdiagnosis. The aim of this study was to validate the Piko-6 COPD screening device by demonstrating a good correlation with standard FS. Methods: FS and Piko-6 determinations were made in 155 patients suspected of having COPD. The correlations, ROC curves, and Youden's index of both methods were compared, taking FS as the gold standard. Results: FEV1, FVC and FEV6 correlation coefficients and FEV1/FVC and FEV1/FEV6 ratios were 0.87 (CI 0.836-0.909), 0.729 (CI 064-0.795) and 0.947 (95% CI 0.928-0.961), respectively. The ROC curve for FEV1 determined by Piko-6 achieved an area under the curve of 0.86 (95% CI: 0.78-0.92). Youden's index with a cut-off point of 0.70 for FEV1/FEV6 was 0.97. Conclusions: Piko-6 may be useful for COPD screening in PC. Measurements obtained with this device correlate well with those determined by FS, particularly the FEV1/FEV6 ratio. This, combined with its low cost and ease of use, may contribute to reducing COPD underdiagnosis, although its exact role in the diagnostic process remains to be determined

Targeting Induced Local Lesions IN Genomes (TILLING) in Medicago truncatula.

TILLING is a reverse genetics strategy that combines the high density of point mutations provided by traditional chemical mutagenesis with rapid screening of DNA pools from a mutagenized population for induced mutations (McCallum et al., Nat Biotechnol 18:455-457, 2000). This high-throughput technique allows the identification of point mutations in any gene of interest.

Usefulness of The Piko-6 Portable Device for Early COPD Detection in Primary Care. / Utilidad del dispositivo portátil Piko-6 para la detección precoz de la enfermedad pulmonar obstructiva crónica en atención primaria.

INTRODUCTION: COPD is a highly prevalent but underdiagnosed disease, due to the limited availability of forced spirometry (FS) in primary care (PC). Microspirometers are inexpensive, easy-to-use devices that can measure FEV6 and FEV1/FEV6, and may help reduce underdiagnosis. The aim of this study was to validate the Piko-6 COPD screening device by demonstrating a good correlation with standard FS. METHODS: FS and Piko-6 determinations were made in 155 patients suspected of having COPD. The correlations, ROC curves, and Youden's index of both methods were compared, taking FS as the gold standard. RESULTS: FEV1, FVC and FEV6 correlation coefficients and FEV1/FVC and FEV1/FEV6 ratios were 0.87 (CI 0.836-0.909), 0.729 (CI 064-0.795) and 0.947 (95% CI 0.928-0.961), respectively. The ROC curve for FEV1 determined by Piko-6 achieved an area under the curve of 0.86 (95% CI: 0.78-0.92). Youden's index with a cut-off point of 0.70 for FEV1/FEV6 was 0.97. CONCLUSIONS: Piko-6 may be useful for COPD screening in PC. Measurements obtained with this device correlate well with those determined by FS, particularly the FEV1/FEV6 ratio. This, combined with its low cost and ease of use, may contribute to reducing COPD underdiagnosis, although its exact role in the diagnostic process remains to be determined.