Protective effect of height on long-term survival of resectable lung cancer: a new feature of the lung cancer paradox.

INTRODUCTION: Unlike most malignancies, higher body mass index (BMI) is associated with a reduced risk of lung cancer and improved prognosis after surgery. However, it remains controversial whether height, one of determinants of BMI, is associated with survival independently of BMI and other confounders. METHODS: We extracted data on all consecutive patients with resectable non-small cell lung cancer included in Epithor, the French Society of Thoracic and Cardiovascular Surgery database, over a 16-year period. Height was analysed as a continuous variable, and then categorised into four or three categories, according to sex-specific quantiles. Cox proportional hazards regression was used to estimate the association of height with survival, adjusted for age, tobacco consumption, forced expiratory volume in one second (FEV1), WHO performance status (WHO PS), American Society of Anesthesiologists (ASA) score, extent of resection, histological type, stage of disease and centre as a random effect, as well as BMI in a further analysis. RESULTS: The study included 61 379 patients. Higher height was significantly associated with better long-term survival after adjustment for other variables (adjusted HR 0.97 per 10 cm higher height, 95% CI 0.95 to 0.99); additional adjustment for BMI resulted in an identical HR. The prognostic impact of height was further confirmed by stratifying by age, ASA class, WHO PS and histological type. When stratifying by BMI class, there was no evidence of a differential association (p=0.93). When stratifying by stage of disease, the prognostic significance of height was maintained for all stages except IIIB-IV. CONCLUSIONS: Our study shows that height is an independent prognostic factor of resectable lung cancer.

Impact of surgical approach on 90-day mortality after lung resection for nonsmall cell lung cancer in high-risk operable patients.

Introduction: Non-small cell lung cancer (NSCLC) is often associated with compromised lung function. Real-world data on the impact of surgical approach in NSCLC patients with compromised lung function are still lacking. The objective of this study is to assess the potential impact of minimally invasive surgery (MIS) on 90-day post-operative mortality after anatomic lung resection in high-risk operable NSCLC patients. Methods: We conducted a retrospective multicentre study including all patients who underwent anatomic lung resection between January 2010 and October 2021 and registered in the Epithor database. High-risk patients were defined as those with a forced expiratory volume in 1 s (FEV1) or diffusing capacity of the lung for carbon monoxide (DLCO) value below 50%. Co-primary end-points were the impact of risk status on 90-day mortality and the impact of MIS on 90-day mortality in high-risk patients. Results: Of the 46 909 patients who met the inclusion criteria, 42 214 patients (90%) with both preoperative FEV1 and DLCO above 50% were included in the low-risk group, and 4695 patients (10%) with preoperative FEV1 and/or preoperative DLCO below 50% were included in the high-risk group. The 90-day mortality rate was significantly higher in the high-risk group compared to the low-risk group (280 (5.96%) versus 1301 (3.18%); p<0.0001). In high-risk patients, MIS was associated with lower 90-day mortality compared to open surgery in univariate analysis (OR=0.04 (0.02-0.05), p<0.001) and in multivariable analysis after propensity score matching (OR=0.46 (0.30-0.69), p<0.001). High-risk patients operated through MIS had a similar 90-day mortality rate compared to low-risk patients in general (3.10% versus 3.18% respectively). Conclusion: By examining the impact of surgical approaches on 90-day mortality using a nationwide database, we found that either preoperative FEV1 or DLCO below 50% is associated with higher 90-day mortality, which can be reduced by using minimally invasive surgical approaches. High-risk patients operated through MIS have a similar 90-day mortality rate as low-risk patients.

Best imaging signs identified by radiomics could outperform the model: application to differentiating lung carcinoid tumors from atypical hamartomas.

OBJECTIVES: Lung carcinoids and atypical hamartomas may be difficult to differentiate but require different treatment. The aim was to differentiate these tumors using contrast-enhanced CT semantic and radiomics criteria. METHODS: Between November 2009 and June 2020, consecutives patient operated for hamartomas or carcinoids with contrast-enhanced chest-CT were retrospectively reviewed. Semantic criteria were recorded and radiomics features were extracted from 3D segmentations using Pyradiomics. Reproducible and non-redundant radiomics features were used to training a random forest algorithm with cross-validation. A validation-set from another institution was used to evaluate of the radiomics signature, the 3D 'median' attenuation feature (3D-median) alone and the mean value from 2D-ROIs. RESULTS: Seventy-three patients (median 58 years [43‒70]) were analyzed (16 hamartomas; 57 carcinoids). The radiomics signature predicted hamartomas vs carcinoids on the external dataset (22 hamartomas; 32 carcinoids) with an AUC = 0.76. The 3D-median was the most important in the model. Density thresholds < 10 HU to predict hamartoma and > 60 HU to predict carcinoids were chosen for their high specificity > 0.90. On the external dataset, sensitivity and specificity of the 3D-median and 2D-ROIs were, respectively, 0.23, 1.00 and 0.13, 1.00 < 10 HU; 0.63, 0.95 and 0.69, 0.91 > 60 HU. The 3D-median was more reproducible than 2D-ROIs (ICC = 0.97 95% CI [0.95‒0.99]; bias: 3 ± 7 HU limits of agreement (LoA) [- 10‒16] vs. ICC = 0.90 95% CI [0.85‒0.94]; bias: - 0.7 ± 21 HU LoA [- 4‒40], respectively). CONCLUSIONS: A radiomics signature can distinguish hamartomas from carcinoids with an AUC = 0.76. Median density < 10 HU and > 60 HU on 3D or 2D-ROIs may be useful in clinical practice to diagnose these tumors with confidence, but 3D is more reproducible. CRITICAL RELEVANCE STATEMENT: Radiomic features help to identify the most discriminating imaging signs using random forest. 'Median' attenuation value (Hounsfield units), extracted from 3D-segmentations on contrast-enhanced chest-CTs, could distinguish carcinoids from atypical hamartomas (AUC = 0.85), was reproducible (ICC = 0.97), and generalized to an external dataset. KEY POINTS: • 3D-'Median' was the best feature to differentiate carcinoids from atypical hamartomas (AUC = 0.85). • 3D-'Median' feature is reproducible (ICC = 0.97) and was generalized to an external dataset. • Radiomics signature from 3D-segmentations differentiated carcinoids from atypical hamartomas with an AUC = 0.76. • 2D-ROI value reached similar performance to 3D-'median' but was less reproducible (ICC = 0.90).

A novel Chr1-miR-200 driven whole transcriptome signature shapes tumor immune microenvironment and predicts relapse in early-stage lung adenocarcinoma.

BACKGROUND: In Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems. METHODS: A miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets. RESULTS: We identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets. CONCLUSION: This EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.

Middle lobe suffering due to malposition and 180° tilt of the 2 remaining lobes after right upper lobectomy.

Middle lobe (ML) suffering after right upper lobectomy (RUL) is rare but represents a major complication usually due to lobar torsion. We report 3 atypical consecutive cases of ML suffering due to malposition of the 2 remaining right lobes with a 180° tilt. All 3 female patients had surgery for non-small-cell carcinoma including RUL associated with radical hilar and mediastinal lymph node removal. Postoperative chest X-ray abnormalities appeared at days 1-3 respectively. The diagnosis of malposition of the 2 lobes was done on contrast-enhanced chest CT scan at days 7, 7 and 6, respectively. A reoperation for suspected ML torsion was required in all patients. Three repositionings of the 2 lobes and 1 middle lobectomy were performed. The postoperative courses were then uneventful, and the 3 patients were alive at a mean follow-up of 12 months. Before thoracic approach closure after RUL, systematic check of good positioning of the 2 reinflated remaining lobes is indispensable. It may prevent ML suffering secondary to 180° lobar tilt leading to whole pulmonary malposition.

Prognostic score and sex-specific nomograms to predict survival in resectable lung cancer: A French nationwide study from the Epithor cohort database.

Background: Prognostic assessment in patients undergoing cancer treatments is of paramount importance to plan subsequent management. In resectable lung cancer availability of an easy-to use nomogram to predict long-term outcome would be extremely useful to identify high-risk patients in the era of perioperative targeted and immune therapies. Methods: We retrieved clinical, surgical and pathological data of all consecutive patients included in Epithor, the database of French Society of Thoracic and Cardiovascular Surgery, and operated on between 2003 and 2020 for non-small cell lung cancer in a curative intent. The primary endpoint was overall survival up to 5 years. We assessed prognostic significance of available variables using Cox modelling, in the whole dataset, and in men and in women separately, and performed temporal validation. Finally, we constructed two sex-specific nomograms. Survivals by fifths of score were assessed in the development and temporal validation sets. Findings: The study included 62,633 patients (43,551 men and 19,082 women). Median survival time was 9.2 years. Nine factors had strong prognostic impact and were used to construct nomograms. The optimism-corrected c statistic for the prognostic score was 0.689 in the development sample, and 0.726 (95% CI 0.718-0.735) in the temporal validation sample. All differences between adjacent fifths of score were significant (P < 0.0001). Figures of 3-year OS by fifths of score were 92.2%, 83.0%, 74.3%, 64.0%, and 43.4%, respectively, in the development set and 93.3%, 88.4%, 81.0%, 73.7%, 55.7% in the temporal validation set. Performance of score was maintained when stratifying by stage of diseases. Interpretation: In the present work, we report evidence that long-term overall survival after resection of NSCLC can be predicted by an easy to construct and use composite score taking into account both host and tumour related factors. Funding: Epithor is funded by FSTCVS.

Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO).

BACKGROUND: The IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC). METHODS: In a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131). RESULTS: Forty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8-41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3-5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity. CONCLUSIONS: Neoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Challenge of a therapeutic sequence: rare case of heart failure in mitral valvular disease intensified by an extreme mediastinal shift from major diaphragmatic eventration.

Extreme mediastinal shift due to major diaphragm eventration is complex when mitral-valve repair is required. We report the case of a 59-year-old woman with diaphragmatic eventration who had 2 recent episodes of heart failure due to arrythmia associated with severe mitral-valve regurgitation (regurgitant orifice area 47 mm2). Forced expiratory flow-volume in the first second and vital capacity (VC) were at 32% and 33%, respectively,decreasing to 20% and 30% when she was in a supine position. We found it impossible to repair the valve first because of the extreme mediastinal shift and respiratory dysfunction. Therefore, we decided to perform diaphragm plication first followed 3 months later by mitral valve repair. Six months after the cardiac operation, the patient showed significant clinical improvement. Forced expiratory flow-volume in the first second and vital capacity increased to 58% and 55%, respectively. The decision to perform the thoracic operation first, followed by the cardiac operation, was the key to improving the patient's respiratory function and to medializing the heart to safely support cardiac surgery.

Prognostic value of CD4+ T lymphopenia in non-small cell lung Cancer.

BACKGROUND: There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. MATERIALS: Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of < 500/µL and < 224/µL respectively. The prognostic value of T lymphopenia was analyzed in the whole population, in local/loco-regional (stage I-IIIB) and in advanced (stage IV) NSCLC disease, using the Kaplan-Meier method and Cox regression models for survival curves and multivariate analysis, respectively. RESULTS: Between July 2010 and January 2014, 169 evaluable patients with clinical stage I to IV NSCLC were prospectively enrolled. The prevalence of CD4+ and CD8+ T lymphopenia was similar in the study population (around 29%). Patients with CD4+ T lymphopenia showed lower overall survival than those with CD4+ T lymphocytes count > 500/µL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1-2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9-3.8], p = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065-3.817] p = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/µL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. CONCLUSION: We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage. TRIAL REGISTRATION: EUDRACT: 2009-A00642-55.

The role of donor-recipient gender matching in lung transplantation: a systematic review.

INTRODUCTION: Donor to recipient (D-R) matching in lung transplantation (LTx) is firstly directed by blood group (identity or compatibility), immunological status and morphological criteria. Sex matching is ignored and impact on outcome less investigated. EVIDENCE ACQUISITION: Systematic review of English literature using PubMed (1990-2019) was performed to evaluate the potential role of D-R matching in determining long-term outcome in patients after LTx. Search terms included (LTx) AND (sex) OR (gender) OR (matching) OR (mismatch) OR (donor characteristics) and were restricted to articles' title. Only articles directly reporting LTx survival outcome according to gender match/mismatch and D-R gender combination in LTx were included. Two authors independently extracted articles using predefined data fields, including study quality indicators. MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies applied. EVIDENCE SYNTHESIS: Nine articles were analyzed and included into this study. All studies analyzed the effect of the different D-R gender combinations on survival while seven of them investigated exclusively the role of sex matching on LTx outcome. In this latter group two out of seven showed a trend towards an overall survival advantage for sex matching LTx combination. The worst survival results were reported for F to M gender combination in 3 studies and for M to F gender combination by 1 study. No differences were reported in remaining 4 studies. CONCLUSIONS: This systematic review suggests that sex matching and several gender combinations could play a role in determining overall survival rate after LTx. Data deriving from unbiased studies supported that matching female-female (F-F) and male-male (M-M) could improve LTx outcome while FD-MR combination should be avoided. Unfortunately, a good part of the analyzed data are affected by bias due to confounding factors. Up-to-date immunological, hormonal and morphological factors could explain the gender-based difference in LTx outcome. Further investigations should clarify their role and importance to define the effects of gender combinations on survival.

Prevalence and time-course of diaphragmatic dysfunction following lung resection: A repeated ultrasonic assessment.

PURPOSE: Ultrasound (US) allows non-invasive repeated assessments of diaphragmatic excursion (DE) and thickening fraction (DTF) at the bedside, reflecting diaphragmatic dysfunction (DD). We aimed at determining the prevalence and time-course of DD following elective thoracic surgery and the association with postoperative complications. MATERIAL AND METHODS: Prospective, single-centre, observational study with consecutive patients undergoing thoracic surgery. DE/DTF were measured by two observers blinded to each other at 3 different time-points: prior to surgery, immediately after extubation and on postoperative day 3. The changes in DE/DTF of both hemi-diaphragms over time were compared according to the side (operated/non-operated) using a two-way-ANOVA. The association with postoperative complications was assessed using logistic regression. RESULTS: Fifty patients, 60% males, aged 60 ± 15 years were included. Surgical procedures included lobectomy (n = 30), wedge-resection (n = 17) or pneumonectomy (n = 3). On the operated side, we observed a decrease in DE/DTF at D0 (-0.71 ± 0.12 mm, P < 0.05; -44 ± 30%, P < 0.05) and D3 (-0.82 ± 0.19 mm, P < 0.05; -39 ± 19%, P < 0.05) with respect to preoperative and non-operated side values over the study period. Persistent DD on the operated side was associated with an increased risk of lung infection (OR: 9.0, 95% CI [1.92-65.93], P = 0.001), ICU-admission (OR: 3.9, 95% CI [1.10-15.53], P = 0.04) according to univariate analysis and a prolonged length in hospital (OR: 1.3, 95% CI [1.1-1.7], P = 0.016) according to multivariate analysis. CONCLUSIONS: Thoracic surgery generates DD mainly observed on the operated side, which persists at least up to postoperative D3 and is associated with an increase in hospital stay.

Superior vena cava graft infection in thoracic surgery: a retrospective study of the French EPITHOR database.

OBJECTIVES: To report our experience on the management of superior vena cava graft infection. METHODS: Between 2001 and 2018, patients with superior vena cava synthetic graft or patch reconstruction after resection of intrathoracic tumours or benign disease were selected retrospectively from the French EPITHOR database and participating thoracic centres. Our study population includes patients with superior vena cava graft infection, defined according to the MAGIC consensus. Superior vena cava synthetic grafts in an empyema or mediastinitis were considered as infected. RESULTS: Of 111 eligible patients, superior vena cava graft infection occurred in 12 (11.9%) patients with a polytetrafluoroethylene graft secondary to contiguous contamination. Management consisted of either conservative treatment with chest tube drainage and antibiotics (n = 3) or a surgical graft-sparing strategy (n = 9). Recurrence of infection appears in 6 patients. Graft removal was performed in 2 patients among the 5 reoperated patients. The operative mortality rate was 25%. CONCLUSIONS: Superior vena cava graft infection may develop as a surgical site infection secondary to early mediastinitis or empyema. Graft removal is not always mandatory but should be considered in late or recurrent graft infection or in infections caused by aggressive microorganisms (virulent or multidrug resistant bacteria or fungi).

Diagnosis Yield and Safety of Surgical Biopsy in Interstitial Lung Diseases: A Prospective Study.

BACKGROUND: Surgical lung biopsy is essential in the diagnostic algorithm of interstitial lung disease (ILD) of unknown cause. Safety concerns have been recently reiterated. This study prospectively assessed the yield of diagnosis and safety of video-assisted thoracoscopic surgical lung biopsy (VATS-LB) for ILD diagnosis. METHODS: This prospective study, conducted in 6 ILD-referral Paris hospitals, included 103 patients with ILD. VATS-LB was proposed after initial multidisciplinary discussion. A final diagnosis was made after the procedure, during a second multidisciplinary discussion. The main outcome was to determine the final diagnoses and their proportion after VATS-LB. Other outcomes were the percentage of change in diagnosis and treatment propositions after VATS-LB and adverse events during 3 months after the operation, postoperative pulmonary function, quality of life, and pain. RESULTS: A definite diagnosis was reached in 87 patients (84.4%), and 16 remained unclassifiable (15.6%). After VATS-LB, the hypothesized diagnosis changed in 65 patients (63.1%) and treatment changed in 41 patients (39.8%). One patient died of acute exacerbation. In-hospital complications were predicted by a shorter preoperative 6-minute walking test distance and by forced vital capacity lower than 77%. Postoperative quality of life was not modified at 3 months, whereas forced vital capacity decreased slightly. Postoperative neuropathic pain was revealed in 5% of patients at 1 month and in 2% at 3 months. CONCLUSIONS: VATS-LB dramatically changed preoperative hypothetical diagnoses and treatment in ILD of unknown cause, with good patient survival in ILD referral centers.

Clinical assessment of the miR-34, miR-200, ZEB1 and SNAIL EMT regulation hub underlines the differential prognostic value of EMT miRs to drive mesenchymal transition and prognosis in resected NSCLC.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) receiving curative surgery have a risk of relapse, and adjuvant treatments only translate into a 5% increase in 5-year survival. We assessed the clinical significance of epithelial-mesenchymal transition (EMT) and explored its association with the [SNAIL/miR-34]:[ZEB/miR-200] regulation hub to refine prognostic information. METHODS: We validated a 7-gene EMT score using a consecutive series of 176 resected NSCLC. We quantified EMT transcription factors, microRNAs (miRs) of the miR-200, miR-34 families and miR-200 promoter hypermethylation to identify outcome predictors. RESULTS: Most tumours presented with an EMT-hybrid state and the EMT score was not predictive of outcome. Individually, all miR-200 were inversely associated with the EMT score, but only chromosome-1 miRs, miR-200a, b, 429, were associated with disease-free survival (p = 0.08, 0.05 and 0.025) and overall survival (p = 0.013, 0.003 and 0.006). We validated these associations on The Cancer Genome Atlas data. Tumour unsupervised clustering based on miR expression identified two good prognostic groups, unrelated to the EMT score, suggesting that miR profiling may have an important clinical value. CONCLUSION: miR-200 family members do not have similar predictive value. Core EMT-miR, regulators and not EMT itself, identify NSCLC patients with a low risk of relapse after surgery.

The Reality of Lung Cancer Paradox: The Impact of Body Mass Index on Long-Term Survival of Resected Lung Cancer. A French Nationwide Analysis from the Epithor Database.

Obesity could have a protective effect in patients with lung cancer. We assessed the prognostic role of preoperative BMI on survival in patients who underwent lung resection for NSCLC. A total of 54,631 consecutive patients with resectable lung cancer within a 15-year period were extracted from Epithor (the French Society of Thoracic and Cardiovascular Surgery database). Patient subgroups were defined according to body mass index (BMI): underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). Underweight was associated with lower survival (unadjusted HRs 1.24 (1.16-1.33)) compared to normal weight, whereas overweight and obesity were associated with improved survival (0.95 (0.92-0.98) and 0.88 (0.84-0.92), respectively). The impact of BMI was confirmed when stratifying for sex or Charlson comorbidities index (CCI). Among patients with obesity, a higher BMI was associated with improved survival. After adjusting for period of study, age, sex, WHO performance status, CCI, side of tumor, extent of resection, histologic type, and stage of disease, the HRs for underweight, overweight, and obesity were 1.51 (1.41-1.63), 0.84 (0.81-0.87), and 0.80 (0.76-0.84), respectively. BMI is a strong and independent predictor of survival in patients undergoing surgery for NSCLC.

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. METHODS: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. RESULTS: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. CONCLUSIONS: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.