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Introduction: Small-cell lung carcinoma (SCLC) is a high-grade neuroendocrine carcinoma of poor prognosis. Although immune checkpoint blockers have shown promising results in advanced SCLC, the tumor immune microenvironment (TME) remains poorly understood, with no validated prognostic or predictive biomarkers of efficacy., Methods: This retrospective study included surgically samples from 48 SCLC patients between 2009 and 2018. We assessed the TME using two quantitative 7-plex immunofluorescence panels focusing on T and B cells, and compared it to NSCLC (N = 10). Molecular subtypes were determined by assessing the expression of ASCL1, NEUROD1 and YAP1 using immunohistochemistry., Results: Immune-hot SCLC were defined as those exhibiting the highest immune cell and immune-related marker densities. They were associated with longer overall survival, significantly more frequently detected at early stages, and exhibited high PD-L1 expression in immune cells, but were not associated with molecular subtypes. Compared to NSCLC, SCLC had significantly lower densities of CD20 + cells and higher density of PD1 + cells, with no significant differences in CD4 + , CD8 + and plasma cell densities. In univariate analysis, the highest OS was significantly associated with early stage (p < 0.001), low expression of NEUROD1 (p = 0.047), high PD1 + cell density (p < 0.001) and high PD-L1 immune cell expression (p = 0.04). Only stage and PD1 + cell density emerged as independent prognostic markers., Conclusion: SCLC TME is highly heterogeneous. Immune-hot tumors were associated with OS but not with molecular classification. PD1 expression and PD-L1 expression by immune cells may thus serve as a prognostic marker., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The low incidence and heterogeneity of sarcomas limit understanding of their progression in metastatic cases. The use of metastasectomy is debated due to lack of consensus and evidence-based data. This study aimed to identify simple prognostic factors that could contribute to the therapeutic strategy., Methods: We retrospectively reviewed all patients undergoing pulmonary metastasectomy from sarcoma in our referral center between 2011 and 2022. Demographic, radiologic, pathologic, and operative data were collected. Oncological follow-up, survival, and risk factor analyses were performed., Results: 192 patients were identified (mean age 49.3 years). Primary sarcoma arose from the trunk (24.6 %) or limbs (75.4 %), and metastases were metachronous in 85.4 % of cases. The median number of operated lesions was 2, and anatomic resection were performed in 24.1 %. The postoperative course was uneventful in 91.3 % of cases. Post-operative chemotherapy followed lung resection in 68.7 %. 1-, 3-, and 5-year Overall Survival (OS) were 89.6 %, 69.8 %, 57.6 %, respectively, with a plateau phase beyond 5 years. Higher grade or trunk location of the primary sarcoma, incomplete or anatomic pulmonary resection, and post-operative systemic treatment were significantly associated with shorter OS. No histological subtype significantly impacted OS. Location of the primary, resection type, and post-operative systemic treatment independently influenced OS. Non-anatomic and repeated pulmonary resections, were independently associated with "long surviving"., Conclusion: In metastatic sarcoma, pulmonary resections offer prolonged survival in selected patients, supporting its essential role in the whole therapeutic strategy. Anatomic and sequential metastasectomy should be cautiously discussed., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: To evaluate the performance of artificial intelligence (AI) in the preoperative detection of lung metastases on CT., Materials and Methods: Patients who underwent lung metastasectomy in our institution between 2016 and 2020 were enrolled, their preoperative CT reports having been performed before an AI solution (Veye Lung Nodules, version 3.9.2, Aidence) became available as a second reader in our department. All CT scans were retrospectively processed by AI. The sensitivities of unassisted radiologists (original CT radiology reports), AI reports alone and both combined were compared. Ground truth was established by a consensus reading of two radiologists, who analyzed whether the nodules mentioned in the pathology report were retrospectively visible on CT. Multivariate analysis was performed to identify nodule characteristics associated with detectability., Results: A total of 167 patients (men: 62.9 %; median age, 59 years [47-68]) with 475 resected nodules were included. AI detected an average of 4 nodules (0-17) per CT, of which 97 % were true nodules. The combination of radiologist plus AI (92.4 %) had significantly higher sensitivity than unassisted radiologists (80.4 %) (p < 0.001). In 27/57 (47.4 %) patients who had multiple preoperative CT scans, AI detected lung nodules earlier than the radiologist. Vascular contact was associated with non-detection by radiologists (OR:0.32[0.19, 0.54], p < 0.001), whilst the presence of cavitation (OR:0.26[0.13, 0.54], p < 0.001) or pleural contact (OR:0.10[0.04, 0.22], p < 0.001) was associated with non-detection by AI., Conclusion: AI significantly increases the sensitivity of preoperative detection of lung metastases and enables earlier detection, with a significant potential benefit for patient management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Thoracic endometriosis syndrome gives rise to various clinical and radiological manifestations. We reviewed the records of patients operated for intrathoracic migration of abdominal viscera through a diaphragmatic hernia secondary to thoracic endometriosis., Methods: We retrospectively reviewed the single-center prospective collected database of all patients operated for thoracic endometriosis during the twenty years. All cases in which an abdominal organ was found to be herniated into the thoracic cavity were retrieved. Clinical and pathological data are presented and analyzed., Results: Twenty women of median age 36 (range 25-58) years were operated for endometriosis-related diaphragmatic hernia. The hernia was diagnosed concomitantly with endometriosis-related pneumothorax in 13 cases and during the exploration of catamenial thoracic pain in seven cases. There were 18 cases on the right side and two cases on the left side. The median diameter of the hernia was 8 cm (2.5-20 cm). In seventeen cases, the hernia was repaired by direct suture, and in three cases a heterologous prosthesis was positioned. At follow-up, two patients had an episode of recurrent pneumothorax., Conclusions: Diaphragmatic hernia should be ruled out in the presence of endometriosis-related pneumothorax or catamenial thoracic pain. Surgery is indicated to make a pathological diagnosis, restore anatomy, and prevent recurrence in patients presenting with pneumothorax., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background: Patients with initially unresectable advanced non-small cell lung cancer (NSCLC) might experience prolonged responses under immune checkpoint inhibitors (ICIs). In this setting, Multidisciplinary Tumor Board (MTB) seldomly suggest surgical resection of the primary tumor with the ultimate goal to eradicate macroscopic residual disease. Our objective was to report the perioperative outcomes of patients who underwent anatomic lung resection in these infrequent circumstances., Methods: We set a retrospective multicentric single arm study, including all patients with advanced-staged initially unresectable NSCLC (stage IIIB to IVB) who received systemic therapy including ICIs and eventually anatomical resection of the primary tumor in 10 French thoracic surgery units from January 2016 to December 2020. Coprimary endpoints were in-hospital mortality and morbidity. Secondary endpoints were the rate of complete resection of the pulmonary disease, major pathologic response, risk factors associated with post-operative complications, and overall survival., Results: Twenty-one patients (median age 64, female 62%) were included. Eighteen patients (86%) progressed after first line chemotherapy and received second line ICI. The median time between diagnosis and surgery was 22 months [interquartile range (IQR) 18-35 months]. Minimally-invasive approach was used in 10 cases (48%), with half of these requiring conversion to open thoracotomy. Nine patients (43%) presented early post-operative complications, and one patient died from broncho-pleural fistula one month after surgery. Rates of complete resection of the pulmonary disease and major pathologic response were 100% and 43%, respectively. In univariable analysis, diffusing capacity for carbon monoxide (DLCO) was the only factor associated with the occurrence of postoperative complications (P=0.027). After a median follow-up of 16.0 months after surgery (IQR, 12.0-30.0 months), 19 patients (90%) were still alive., Conclusions: Anatomic lung resections appear to be a reasonable option for initially unresectable advanced NSCLC experiencing prolonged response under ICIs. Nonetheless, minimally invasive techniques have a low applicability and post-operative complications remains higher in patients who had lower DLCO values. The late timing of surgery may also contribute to complications., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-704/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Objective: To investigate risk factors for nodal upstaging in patients with lung carcinoids and to understand which type of lymphadenectomy is most appropriate., Methods: Data regarding patients with lung carcinoids, who underwent surgical resection and lymphadenectomy in five institutions from January 1, 2005 to December 31, 2019, were collected and retrospectively analyzed. Clinical and pathological tumor characteristics were correlated to analyze lymph node upstaging., Results: The analysis was conducted on 283 patients. Pathology showed 230 typical and 53 atypical carcinoids. Nodal and mediastinal upstaging occurred in 33 (11.6%) and 16 (5.6%) patients, respectively. At the univariable analysis, nodal upstaging was significantly correlated with central location (p = 0.003), atypical histology (p < 0.001), pT dimension (p = 0.004), and advanced age (p = 0.043). The multivariable analysis confirmed atypical histology (odds ratio [OR]: 11.030; 95% confidence interval [CI]: 4.837-25.153, p < 0.001) and central location (OR: 3.295; 95% CI: 1.440-7.540, p = 0.005) as independent prognostic factors for nodal upstaging. Atypical histology (p < 0.001), pT dimension (p = 0.036), number of harvested lymph node stations (p = 0.047), and type of lymphadenectomy (p < 0.001) correlated significantly with mediastinal upstaging. The multivariable analysis confirmed atypical histology (OR: 5.408; 95% CI: 1.391-21.020, p = 0.015) and pT (OR: 1.052; 95% CI: 1.021-1.084, p = 0.001) as independent prognostic factors., Conclusion: Atypical histology, dimension, and central location are associated with a high-risk for occult hilo-mediastinal metastases, and mediastinal radical dissection may predict nodal upstaging. Thus, we suggest radical mediastinal lymph node dissection in high-risk tumors, reserving sampling, or lobe-specific dissection in peripheral, small typical carcinoids., (© 2022 Wiley Periodicals LLC.)

NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others). In this review, we highlight how these oncogenic factors are interconnected with cell metabolism (aerobic glycolysis, glutaminolysis and lipid synthesis). Also, we stress the key role of four metabolic enzymes (PFK1, dimeric-PKM2, GLS1 and ACLY), which promote the activation of these oncogenic pathways in a positive feedback loop. These four tenors orchestrating the coordination of metabolism and oncogenic pathways could be key druggable targets for specific inhibition. Since PFK1 appears as the first tenor of this orchestra, its inhibition (and/or that of its main activator PFK2/PFKFB3) could be an efficacious strategy against NSCLC. Citrate is a potent physiologic inhibitor of both PFK1 and PFKFB3, and NSCLC cells seem to maintain a low citrate level to sustain aerobic glycolysis and the PFK1/PI3K/EGFR axis. Awaiting the development of specific non-toxic inhibitors of PFK1 and PFK2/PFKFB3, we propose to test strategies increasing citrate levels in NSCLC tumors to disrupt this interconnection. This could be attempted by evaluating inhibitors of the citrate-consuming enzyme ACLY and/or by direct administration of citrate at high doses. In preclinical models, this "citrate strategy" efficiently inhibits PFK1/PFK2, HIF-1α, and IGFR/PI3K/AKT axes. It also blocks tumor growth in RAS-driven lung cancer models, reversing dedifferentiation, promoting T lymphocytes tumor infiltration, and increasing sensitivity to cytotoxic drugs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: SMARCA4/BRG1 loss of expression occurs in 5-10% of non-small cell lung carcinomas (NSCLC). We investigated the pathological, molecular and immune environment characteristics of this deficiency among NSCLC, its impact on overall survival (OS) of resected patients and the sensitivity to anti-PD1 inhibitors in metastatic patients., Materials and Methods: BRG1 expression was assessed by immunohistochemistry to identify SMARCA4-deficient NSCLC (SD-NSCLC) from the cancer tissue collection of Cochin Hospital (Paris, France). Molecular profiles were analyzed by targeted NGS covering 28 genes in 63 resected SD-NSCLC. The balance of immune cells between CD8+, FOXP3+ cells and neutrophils (CD66b+) was characterized by multiplex immunohistochemistry and compared to non-SD NSCLC. Clinical outcome after anti-PD-1 therapy was evaluated in 7 SD-NSCLC out of 77 NSCLC patients., Results: SD-NSCLCs were more commonly found in TTF1-negative high-grade adenocarcinomas and pleomorphic carcinomas. They were associated with few targetable alterations (KRAS G12C and MET amplification). Their immune environment was characterized by an increased of FOXP3+ cell and neutrophil densities, but not of CD8+ T cells, compared to non-SD NSCLC. SD-NSCLC patients had a significantly shorter OS in early stages of resected patients and in metastatic patients treated by anti-PD1 treatment., Conclusion: BRG1-loss in NSCLC confers a poor prognosis and is associated with an immunosuppressive environment that could be responsible of limited efficacy to anti-PD1 inhibitors. The identification of SD-NSCLC by BRG1 immunohistochemistry is desirable for an optimal management of NSCLC patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A prognostic score including T-dimension, age, histology and lymph node ratio was previously proposed in absence of an external validation dataset. The aim of the current study was to validate the proposed prognostic score using an independent dataset. Methods: Data of patients with lung carcinoids, who underwent surgical resection and lymphadenectomy in five institutions from 1 January 2005 to 31 December 2019, were retrospectively analyzed. Two risk groups were created based on the following data: age, histology, node ratio and pT for disease-free survival (DFS); age, sex, node ratio and pT for overall survival (OS). The previously proposed score was validated, identifying two groups of patients: a high risk (HRG) and low risk (LRG) group. Results: The final analysis was conducted on 283 patients. Regarding DFS, 230 (81.3%) patients were assigned to the LRG and 53 (18.7%) to the HRG. Considering OS, 268 (94.7%) were allocated in the LRG and 15 (5.3%) in the HRG. The 5-year DFS was 92.7% in the LRG vs. 67% in the HRG (p < 0.001) while the 5-year OS was 93.6% in the LRG vs. 86.2% in the HRG (p = 0.29) with clear curve separation. Conclusion: Our analysis confirmed the validity of the composite score for DFS in lung carcinoids. Regarding OS, statistical significance was not reached because of a low number of deaths and patients in the HRG.

Background: Prediction of prognosis is a key step of malignant pleural mesothelioma (MPM) management and treatment assignment. Aim of this study was to identify simple prognostic factors, focusing on inflammation-related parameters., Methods: Baseline clinical and laboratory data were extracted from a single-center 20-year cohort of consecutive patients exhibiting a proven MPM. Inflammation-related ratios and composite scores were evaluated as prognostic indicators., Results: 468 patients were identified. Mean age and BMI were 73.0 years and 25.1 kg/m 2 . The histologic subtype was epithelioid, sarcomatoid, or biphasic in 80.3%, 6.2%, and 13.5% of cases, respectively. Mean Neutrophil to Lymphocyte Ratio (NLR), systemic Inflammation Index (SII) and Advanced Lung cancer inflammation Index (ALI) were 5.8, 1,836.6, and 29.6. Median survival was 13.0 months. Univariate analyses revealed that age > 70 years, persistent asthenia, hemoglobin < 13 g/dL, and non-epithelioid histologic type were associated with poorer survival, as well as the following high-inflammation-related criteria: CRP > 25 mg/L, white blood cell count (WBC) > 10 9 /dL, NLR > 5, SII > 1,270, and ALI < 18. Multivariate regression showed that age, histology, hemoglobin, and WBC were independent predictors of survival. Also, the inflammation-related factors ALI and NLR were independently associated with survival. Interestingly, hemoglobin was statistically significant predictor of survival in all multivariate models. We found higher proportion of survival > 18 months (66th percentile) in patients exhibiting SII < 2,000 and NLR < 5., Conclusion: The prognosis of MPM is strongly influenced by systemic inflammation and patients exhibiting higher NLR, SII and lower ALI have shorter survival, which strengthens the level of evidence about the major role played by inflammation in MPM., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Lung cancer is the most common cause of cancer mortality worldwide, and non-small cell lung cancer (NSCLC) represents 80% of lung cancer subtypes. Patients with localized non-small cell lung cancer may be considered for upfront surgical treatment. However, the overall 5-year survival rate is 59%. To improve survival, adjuvant chemotherapy (ACT) was largely explored and showed an overall benefit of survival at 5 years < 7%. The evaluation of recurrence risk and subsequent need for ACT is only based on tumor stage (TNM classification); however, more than 25% of patients with stage IA/B tumors will relapse. Recently, adjuvant targeted therapy has been approved for EGFR-mutated resected NSCLC and trials are evaluating other targeted therapies and immunotherapies in adjuvant settings. Costs, treatment duration, emergence of resistant clones and side effects stress the need for a better selection of patients. The identification and validation of prognostic and theranostic markers to better stratify patients who could benefit from adjuvant therapies are needed. In this review, we report current validated clinical, pathological and molecular prognosis biomarkers that influence outcome in resected NSCLC, and we also describe molecular biomarkers under evaluation that could be available in daily practice to drive ACT in resected NSCLC.

COVID-19 pandemic has been characterized by a pattern of consecutive declines and regrowth in European countries in 2020. After being partially regressed during the summer, the reappearance of the infection during fall 2020 in many temperate countries strongly suggests that temperature and cold may play a role in influencing the infectivity and virulence of SARS-CoV-2. While promoting medicine as an art, Hippocrates interpreted with logical reasoning the occurrence of diseases such as epidemics, as a consequence of environmental factors, in particular climatic variations. During the Renaissance, Sanctorius was one of the first to perform quantitative measurements, and Harvey discovered the circulation of blood by performing experimental procedures in animals. We think that a reasoning mixing various observations, measurements and experiments is fundamental to understand how cold increases infectivity and virulence of SARS-CoV-2. By this review, we provide evidence linking cold, angiotensin-II, vasoconstriction, hypoxia and aerobic glycolysis (the Warburg effect) to explain how cold affects the epidemiology of COVID-19. Also, a low humidity increases virus transmissibility, while a warm atmosphere, a moderate airway humidity, and the production of vasodilator angiotensin 1-7 by ACE2 are less favorable to the virus entry and/or its development. The meteorological and environmental parameters impacting COVID-19 pandemic should be reintegrated into a whole perspective by taking into account the different factors influencing transmissibility, infectivity and virulence of SARS-CoV-2. To understand the modern enigma represented by COVID-19, an interdisciplinary approach is surely essential., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Infection of the pleural cavity invariably leads to hospitalisation, and a fatal outcome is not uncommon. Our aim was to study the epidemiology of pleural empyema on a nationwide basis in the whole population and in three subgroups of patients, namely post-lung resection, associated cancer and those with no surgery and no cancer., Methods: Data from patients aged ≥18 years hospitalised with a diagnosis of pleural infection in France between January 2013 and December 2017 were retrieved from the medical-administrative national hospitalisation database and retrospectively analysed. Mortality, length of stay and costs were assessed., Results: There were 25 512 hospitalisations for pleural empyema. The annual rate was 7.15 cases per 100 000 habitants in 2013 and increased to 7.75 cases per 100 000 inhabitants in 2017. The mean age of patients was 62.4±15.6 years and 71.7% were men. Post-lung resection, associated cancer and no surgery-no cancer cases accounted for 9.8%, 30.1% and 60.1% of patients, respectively. These groups were significantly different in terms of clinical characteristics, mortality and risk factors for length of stay, costs and mortality. Mortality was 17.1% in the whole population, 29.5% in the associated cancer group, 17.7% in the post-lung resection group and 10.7% in the no surgery-no cancer group. In the whole population, age, presence of fistula, higher Charlson Comorbidity Index ( > 3), alcohol abuse, arterial hypertension, hyperlipidaemia, atheroma, atrial fibrillation, performance status > 3 and three subgroups of pleural empyema independently predicted mortality., Conclusions: Empyema is increasing in incidence. Factors associated with mortality are recent lung resection and associated diagnosis of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The tumor microenvironment is a complex mix of cancerous and noncancerous cells (especially immune cells and fibroblasts) with distinct metabolisms. These cells interact with each other and are influenced by the metabolic disorders of the host. In this review, we discuss how metabolic pathways that sustain biosynthesis in cancer cells could be targeted to increase the effectiveness of cancer therapies by limiting the nutrient uptake of the cell, inactivating metabolic enzymes (key regulatory ones or those linked to cell cycle progression), and inhibiting ATP production to induce cell death. Furthermore, we describe how the microenvironment could be targeted to activate the immune response by redirecting nutrients toward cytotoxic immune cells or inhibiting the release of waste products by cancer cells that stimulate immunosuppressive cells. We also examine metabolic disorders in the host that could be targeted to inhibit cancer development. To create future personalized therapies for targeting each cancer tumor, novel techniques must be developed, such as new tracers for positron emission tomography/computed tomography scan and immunohistochemical markers to characterize the metabolic phenotype of cancer cells and their microenvironment. Pending personalized strategies that specifically target all metabolic components of cancer development in a patient, simple metabolic interventions could be tested in clinical trials in combination with standard cancer therapies, such as short cycles of fasting or the administration of sodium citrate or weakly toxic compounds (such as curcumin, metformin, lipoic acid) that target autophagy and biosynthetic or signaling pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Diffuse pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pre-invasive disease whose pathophysiology remains unclear. We aimed to assess long-term evolution in imaging of DIPNECH, in order to propose follow-up recommendations. Patients with histologically confirmed DIPNECH from four centers, evaluated between 2001 and 2020, were enrolled if they had at least two available chest computed tomography (CT) exams performed at least 24 months apart. CT exams were analyzed for the presence and the evolution of DIPNECH-related CT findings. Twenty-seven patients, mostly of female gender ( n = 25/27; 93%) were included. Longitudinal follow-up over a median 63-month duration (IQR: 31-80 months) demonstrated an increase in the size of lung nodules in 19 patients (19/27, 70%) and the occurrence of metastatic spread in three patients (3/27, 11%). The metastatic spread was limited to mediastinal lymph nodes in one patient, whereas the other two patients had both lymph node and distant metastases. The mean time interval between baseline CT scan and metastatic spread was 70 months (14, 74 and 123 months). Therefore, long-term annual imaging follow-up of DIPNECH might be appropriate to encompass the heterogeneous longitudinal behavior of this disease.

Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

Introduction: Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) is a rare disease often associated with carcinoid tumors. We aimed at evaluating the impact of DIPNECH on characteristics and prognosis of patients who underwent radical treatment of pulmonary carcinoid tumors., Material and Methods: We reviewed all patients operated on for curative-intent resection of carcinoid tumor in our department from 2001 to 2020. Cases exhibiting both pathological and radiological features of DIPNECH, as assessed by respective thoracic expert physicians, were analyzed separately., Results: 172 cases of resected carcinoid tumors were identified, including 25 (14.5 %) harboring pathological criteria of DIPNECH and radiologic features like mosaic attenuation (92.0 %), multiple nodules < 5 mm (76.0 %), and mucoid impactions (32 %). In DIPNECH patients, major pulmonary resections were usually performed (92.0 %) and resected tumors were mostly classified as pT1 (92 %). Mean Ki67 staining was 3.7 ± 5.2 %. The early postoperative period was mostly uneventful (96.0 %) and 5-year survival was 92.9 ± 6.9 %. Compared to non-DIPNECH cases, we found that patients were older (mean 65.6 ± 9.3 versus 54.1 ± 17.9, p = 0.002), more frequently female (84.0 % versus 56.5 %, p = 0.009), and exhibiting diabetes mellitus (45.8 % versus 18.5 %, p < 0.001) or hypertension (45.8 % versus 24.1 %, p = 0.039). The rate of atypical carcinoid tumors was significantly higher in DIPNECH patients (40.0 % versus 19.9 %, p = 0.027), as well as rate of mediastinal lymph-nodes involvement (pN2+) (36.0 % versus 4.1 %, p < 0.001). At multivariate analysis, only DIPNECH pattern and atypical histology were independent factors of pN2 invasion which was the only predictor of poorer prognosis on Log-Rank test., Conclusion: Carcinoid tumors with proven DIPNECH are associated with negative pathological features and may deserve a dedicated perioperative management., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite advances, malignant pleural mesothelioma (MPM) remains a challenging disease in terms of diagnosis, treatment, and overall management. Herein, we analyzed, in a large-scale single-center cohort, the characteristics and perioperative course of patients undergoing surgical diagnosis of MPM. We identified a total of 514 consecutive patients, 71.4% male and 28.6% female, with mean age 71.3 +/- 13.6 years. Most exhibited pleural, respiratory, or general symptoms and American Society of Anesthesiologists (ASA) score was ≥3 in 68.3% of cases. Thoracoscopy was the most frequent approach (92.0%) and short open thoracotomy was performed in the remaining patients. Pleurodesis was simultaneously performed in 74.3% of cases. Diagnostic failure led to redo surgery in 3.7% of patients. Non-epithelioid histology was found in 19.5% of MPMs and was significantly more frequent in right-sided MPM ( p = 0.04), and in patients without history of cancer ( p = 0.03), or pleural nodules at thoracoscopy ( p = 0.01). Minor only or major complications occurred in respectively 7.8% and 3.6% of cases. They were more frequent in patients ≥ 70 years ( p = 0.05) and Performance Status > 2 ( p = 0.05). The mean hospital stay was 7.5 days. The 30-day and 90-day early mortality rates were 2.3% and 6.4%, respectively. Surgical diagnosis of MPM is a reliable procedure but is associated with significant morbidity and hospital-stay duration.

Background: The coronavirus disease 2019 (COVID-19) outbreak was officially declared in France on March 14, 2020. The objective of this study is to report the incidence and outcome of COVID-19 after surgical resection of non-small cell lung cancer in Paris Public Hospitals during the pandemic., Methods: We retrospective analyzed a prospective database including all patients who underwent non-small cell lung cancer resection between March 14, 2020, and May 11, 2020, in the 5 thoracic surgery units of Paris Public Hospitals. The primary endpoint was the occurrence of SARS-CoV-2 infection during the first 30 days after surgery., Results: Study group included 115 patients (male 57%, age 64.6 ± 10.7 years, adenocarcinoma 66%, cT1 62%, cN0 82%). During the first month after surgery, 6 patients (5%) were diagnosed with COVID-19. As compared with COVID-negative patients, COVID-positive patients were more likely to be operated on during the first month of the pandemic (100% vs 54%, P = .03) and to be on corticosteroids preoperatively (33% vs 4%, P = .03). Postoperative COVID-19 was associated with an increased rate of readmission (50% vs 5%, P = .004), but no difference in 30-day morbidity (for the study group: grade 2, 24%; grade 3, 7%; grade 4, 1%) or mortality (n = 1 COVID-negative patient, 0.9%). Immediate oncologic outcomes did not differ significantly between groups (R0 resection 99%, nodal upstaging 14%, adjuvant chemotherapy 29%)., Conclusions: During the COVID-19 pandemic, surgical treatment of non-small cell lung cancer was associated with a rate of postoperative COVID-19 of 5% with a significant impact on readmissions but not on other outcomes studied., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities., Methods: Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1-3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking., Results: The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P<0.001) or traineeship skill grades (r = 0.17, P = 0.001), respectively, and not with traineeship behavior grades (P>0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking., Conclusion: This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools., Competing Interests: The authors have declared that no competing interests exist.

Current mortality due to the Covid-19 pandemic (approximately 1.2 million by November 2020) demonstrates the lack of an effective treatment. As replication of many viruses - including MERS-CoV - is supported by enhanced aerobic glycolysis, we hypothesized that SARS-CoV-2 replication in host cells (especially airway cells) is reliant upon altered glucose metabolism. This metabolism is similar to the Warburg effect well studied in cancer. Counteracting two main pathways (PI3K/AKT and MAPK/ERK signaling) sustaining aerobic glycolysis inhibits MERS-CoV replication and thus, very likely that of SARS-CoV-2, which shares many similarities with MERS-CoV. The Warburg effect appears to be involved in several steps of COVID-19 infection. Once induced by hypoxia, the Warburg effect becomes active in lung endothelial cells, particularly in the presence of atherosclerosis, thereby promoting vasoconstriction and micro thrombosis. Aerobic glycolysis also supports activation of pro-inflammatory cells such as neutrophils and M1 macrophages. As the anti-inflammatory response and reparative process is performed by M2 macrophages reliant on oxidative metabolism, we speculated that the switch to oxidative metabolism in M2 macrophages would not occur at the appropriate time due to an uncontrolled pro-inflammatory cascade. Aging, mitochondrial senescence and enzyme dysfunction, AMPK downregulation and p53 inactivation could all play a role in this key biochemical event. Understanding the role of the Warburg effect in COVID-19 can be essential to developing molecules reducing infectivity, arresting endothelial cells activation and the pro-inflammatory cascade., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Objectives: Sarcopenia is associated with poor outcome in cancer-patients. However, the methods to define sarcopenia are not entirely standardized. We compared several morphometric measurements of sarcopenia and their prognostic value in short-term-outcome prediction after pneumonectomy., Material and Methods: Consecutive lung-cancer patients undergoing pneumonectomy from January 2007 to December 2015 and having a pre-operative computed tomography (CT) scan were retrospectively included. Sarcopenia was assessed by the following CT-based parameters measured at the level of the third lumbar vertebra: cross-sectional Total Psoas Area (TPA), cross-sectional Total Muscle Area (TMA), and Total Parietal Muscle Area (TPMA), defined as TMA without TPA. Measures were obtained for entire muscle surface, as well as by excluding fatty infiltration based on CT attenuation. Findings were stratified for gender, and a threshold of 33rd percentile was set to define sarcopenia. Acute Respiratory Failure (ARF), Acute Respiratory Distress Syndrome (ARDS), and 30-day mortality were assessed as parameters of short-term-outcome., Results: Two hundred thirty-four patients with pneumonectomy (right, n = 107; left, n = 127) were analysed. Postoperative mortality rate was 9.0 % (21/234), 17.1 % of patients (40/234) experienced ARF requiring re-intubation, and 10.3 % (24/234) had ARDS. All parameters describing sarcopenia gave significant results; the best discriminating parameter was TMA after excluding fat (p < 0.001). While right sided pneumonectomy and sarcopenia were independently associated to the three short-term outcome parameters, Charlson Comorbidity Index only independently predicted ARF., Conclusions: Sarcopenia defined as the sex-related 33rd percentile of fat-excluded TMA at the level of the third lumbar vertebra is the most discriminating parameter to assess short-term-outcome in patients undergoing pneumonectomy., (Copyright © 2020 Elsevier B.V. All rights reserved.)