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.

A surgical series on endometriosis-related diaphragmatic hernia.

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.

Neutrophil-to-lymphocyte ratio is correlated to driver gene mutations in surgically-resected non-small cell lung cancer and its post-operative evolution impacts outcomes.

BACKGROUND: We sought to evaluate prognostic value of neutrophil-to-lymphocyte ratio (NLR) in surgically resected non-small cell lung cancer (NSCLC) and its correlation to oncogenic drivers. We retrospectively reviewed data of patients who underwent anatomic lung resection for NSCLC and whose mutational status was known, from 4 department of thoracic surgery, over the period 2008 to 2019. Primary endpoints were overall survival (OS) and time to recurrence (TTR). Clinical and molecular factors were investigated in the univariate and multivariate analysis for their association with the primary endpoints. RESULTS: 2027 patients were included in the analysis. Correlations between NLR and OS (R2=0.21), NLR and TTR (R2=0.085) were significant (P<0.0001), with corresponding Pearson R of -0.46 (P<0.0001) and -0.292 (P<0.001), respectively. ROC curve analysis defined NLR cut-off value at 4.07. In the univariable analysis, the median OS was 66 months (95% CI: 62.94 - 69.06) in case of pre-operative NLR ≤ 4.07 and 38 months (95% CI: 36.73 - 39.27) in case of pre-operative NLR > 4.07 (P<0.0001), with corresponding 5-y OS of 72% and 29% respectively. Median TTR was associated with pre-operative NLR. Median TTR was 25 months (95% CI: 21.52 - 28.48) in case of pre-operative NLR ≤ 4.07 and 17 months (95% CI: 16.04 - 17.96) in case of pre-operative NLR > 4.07 (P<0.0001), with corresponding 5-years TTR of 18% and 9% respectively. Significant correlations between NLR >4.07 and KRAS (Cramer's V = 0.082, P < 0.0001) and EGFR mutations (Cramer's V = 0.064, P = 0.004) were observed. CONCLUSIONS: Low pre-operative NLR is associated with longer OS in patients with resected NSCLC. Low pre-operative NLR is not associated with longer TTR in multivariate analysis. Correlation between the high NLR and KRAS/EGFR mutations were observed.

Enhanced Recovery Pathway in Lung Resection Surgery: Program Establishment and Results of a Cohort Study Encompassing 1243 Consecutive Patients.

INTRODUCTION: In spite of increasing diffusion, Enhanced Recovery Pathways (ERP) have been scarcely assessed in large scale programs of lung cancer surgery. The aim of this study was auditing our practice. METHODS: A two-step audit program was established: the first dealing with our initial ERP experience in patients undergoing non-extended anatomical segmentectomies and lobectomies, the second including all consecutive patients undergoing all kind of lung resections for NSCLC. The first step aimed at auditing results of ERP on occurrence of postoperative complications and at assessing which ERP components are associated with improved short-term outcomes. We also audited late results by assessing long-term survival of patients in the first step of our study. The second step aimed at auditing on large-scale short-term results of the ERP in a real-life setting. RESULTS: Over a one-year period, 166 patients were included. The median number of ERP procedures per patient was three (IQR 3-4). No postoperative death occurred. The overall adverse events rate was 30%. In multivariate analyzes, the only element associated with reduced adverse postoperative events was chest tube withdrawal within POD2 (OR = 0.21, 95% CI (0.10-0.46)). The 1-, 3-, and 5-year survival rates were 97%, 86.1%, and 76.3%, respectively. In the second period, 1077 patients were included in our ERP; 11 patients died during the postoperative period or within 30 days of operation (1.02%). The overall postoperative adverse event rate was 30.3%, major complication occurring in 134 (12.4%), and minor ones in 192 (17.8%). Respiratory complications occurred in 64 (5.9%). Thoracoscore independently predicted postoperative death, the occurrence of complications (all-kind, minor, major, or respiratory ones). CONCLUSIONS: Compliance to ERP procedures and early chest tube removal are associated with reduced postoperative events in patients with lung resection surgery. In a large setting scale, ERP can be applied with satisfactory results in terms of mortality and morbidity. Thoracoscore is a useful tool in predicting mortality and postoperative adverse events.

Pulmonary metastasectomy in renal cell carcinoma: a mainstay of multidisciplinary treatment.

Renal cell carcinoma (RCC) remains a public health issue and seems to be increasing. A significant proportion of RCC patients will develop pulmonary metastasis at some point in their evolution. In this review, we aimed to update the surgical management of pulmonary metastases as well as systemic therapy, including targeted therapies, according to recent data in the literature. We retrospectively reviewed studies evaluating the benefit of pulmonary metastasectomy in RCC patients and evaluating the place of different chemotherapies, targeted therapies and immunotherapies through November 1, 2019. Several retrospective studies have shown the benefit of pulmonary metastasectomy in metastatic RCC (mRCC), most in a situation with only pulmonary metastases. According to the prognostic criteria of the IMDC risk model, the patient is classified into a prognostic group to identify the best systemic treatment. With the development of targeted therapies, the modalities are multiple and may involve tyrosine kinase inhibitors/checkpoint inhibitors and soon vaccine therapy or CAR-T cells. At the local level, in patients who cannot benefit from surgery, stereotactic radiotherapy or radiofrequency has a place to be considered. Although there is a lack of a randomized study, pulmonary metastasectomy appears to be feasible and effective. The place and modalities of systemic therapies in the era of targeted therapies remain to be more clearly defined.

Lung carcinoid tumors with Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) exhibit pejorative pathological features.

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.

Total Psoas Area and Total Muscular Parietal Area Affect Long-Term Survival of Patients Undergoing Pneumonectomy for Non-Small Cell Lung Cancer.

There is no standardization in methods to assess sarcopenia; in particular the prognostic significance of muscular fatty infiltration in lung cancer patients undergoing surgery has not been evaluated so far. We thus performed several computed tomography (CT)-based morphometric measurements of sarcopenia in 238 consecutive non-small cell lung-cancer patients undergoing pneumonectomy from 1 January 2007 to 31 December 2015. Sarcopenia was assessed by the following CT-based parameters: 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 performed at the level of the third lumbar vertebra and were obtained for the entire muscle surface, as well as by excluding fatty infiltration based on CT attenuation. Findings were stratified for gender, and a threshold of the 33rd percentile was set to define sarcopenia. Furthermore, we assessed the possibility of being sarcopenic at both the TPA and TPMA level, or not, by taking into account of not fatty infiltration. Five-year survival was 39.1% for the whole population. Lower TPA, TMA, and TPA were associated with lower survival at univariate analysis; taking into account muscular fatty infiltration did not result in more powerful discrimination. Being sarcopenic at both psoas and parietal muscle level had the optimum discriminating power. At the multivariable analysis, being sarcopenic at both psoas and parietal muscles (considering the whole muscle areas, including muscular fat), male sex, increasing age, and tumor stage, as well as Charlson Comorbidity Index (CCI), were independently associated with worse long-term outcomes. We conclude that sarcopenia is a powerful negative prognostic factor in patients with lung cancer treated by pneumonectomy.

Sarcopenia as independent risk factor of postpneumonectomy respiratory failure, ARDS and mortality.

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.

Normalized Pulmonary Artery Diameter Predicts Occurrence of Postpneumonectomy Respiratory Failure, ARDS, and Mortality.

Hypothesizing that pulmonary artery diameter is a marker of subclinical pulmonary hypertension, we assessed its impact on postoperative outcome in patients requiring pneumonectomy. Morphometric, clinical, and laboratory data were retrospectively retrieved from files of 294 consecutive patients treated by pneumonectomy for malignancy (289 NSCLC). Pulmonary artery was measured at bifurcation level on CT scan and normalized by body surface area. Median normalized pulmonary artery diameter (cut-off for analyses) was 14 mm/m2. Postoperatively, 46 patients required re-do intubation and 30 had acute respiratory distress syndrome (ARDS). Multivariate analysis showed that Charlson Comorbidity Index >5 (p = 0.0009, OR 3.8 [1.76-8.22]), right side of pneumonectomy (p = 0.013, OR 2.37 [1.20-4.71]), and higher normalized pulmonary artery diameter (p = 0.029, OR 2.16 [1.08-4.33]) were independent predictors of re-do intubation, while Charlson Comorbidity Index >5 (p = 0.018, OR 2.55 [1.17-5.59]) and higher normalized pulmonary artery diameter (p = 0.028, OR = 2.52 [1.10-5.77]) were independently associated with occurrence of ARDS. Post-operative mortality was 8.5%. Higher normalized pulmonary artery diameter, (p = 0.026, OR 3.39[1.15-9.95]), right side of pneumonectomy (p = 0.0074, OR 4.11 [1.46-11.56]), and Charlson Comorbidity Index >5 (p = 0.0011, OR 5.56 [1.99-15.54]) were independent predictors of postoperative death. We conclude that pre-operative normalized pulmonary artery diameter predicts the risk of re-do intubation, ARDS and mortality in patients undergoing pneumonectomy for cancer.

Nivolumab increases pulmonary artery pressure in patients treated for non-small cell lung cancer.

PURPOSE: The widespread use of Nivolumab results in an increasing number of side effects and adverse events. Herein, we evaluated the impact of Nivolumab on crude and normalized pulmonary artery diameter (PAD). METHODS: We analyzed clinical, morphometric, pathological and radiological data of lung cancer patients treated by Nivolumab in an 18-month period. Blinded radiological evaluation was performed, by three observers measuring axial PAD and Aorta diameter (AoD) in secondarily matched pre- and post-Nivolumab CT-scans. Correlation between ΔPAD and clinicopathological data was investigated. RESULTS: 59 patients receiving Nivolumab for treatment of advanced lung carcinoma were identified. Pre-and post-Nivolumab comparison of CT-scan measures revealed that mean PAD was 26.3 ± 2.8 mm versus 28.0 ± 3.0 mm (p < 0.001), and mean PAD/AoD ratio was 0.82 ± 0.09 versus 0.87 ± 0.11 (p < 0.001), respectively. Median ΔPAD was 0.05 [0.01-0.122] was significantly higher in hypometabolic patients exhibiting low Rest Energy Expenditure (p = 0.03). Patients exhibiting ΔPAD > 1% had significantly lower serum albumin level (p = 0.03), and higher nutritional risk (p = 0.02), compared to others. Unlike Nivolumab therapy, there was no increase of PAD after chemotherapy in the same cohort of patients with available scans (n = 45, 25.9 ± 2.9 mm pre-chemotherapy versus 25.7 ± 2.4 mm post-chemotherapy, p = 0.51). Anti-PD-1 treatment was associated with immune-related adverse events in 11 (18.6%) cases including 2 cases of life-threatening acute pulmonary hypertension, both exhibiting post-treatment PAD/AoD ratio > 1. CONCLUSION: Nivolumab is associated to PAD enlargement, a potential marker of pulmonary hypertension, sometimes leading to lethal adverse events. Careful CT-scan and echocardiographic evaluation of PAD should be part of the therapeutic work-up of patients receiving Nivolumab, especially those suffering cancer-associated malnutrition.

[Surgical management of resectable non-small cell lung cancer: Towards new paradigms]. / Prise en charge chirurgicale du cancer bronchique non à petites cellules opérable : vers de nouveaux paradigmes.

Adapting therapies and providing personalized care for patients with resectable non-small cell lung cancer represent major challenges. This involves integrating several parameters into the patient's management, not only crude pathologic results, but also a better understanding of the mechanisms involved in tumor progression. Many studies have looked at the impact of host and tumor characteristics and their interactions through inflammatory processes or tumor immune environment. Beyond tumor stage, poor nutrition, sarcopenia and inflammatory state have been identified as independent factors that can directly impact postoperative outcome. The development of Enhanced Recovery After Surgery (ERAS), in which patient becomes the main player in their own management, seems to be an interesting answer since it seems to allow a reduction in postoperative complications, length of stay and indirectly reduction in costs. A broader and more complete vision including morphometric evaluation of the patient, physical performances, inflammatory state and nutritional state would provide additional discriminating information which can predict postoperative outcome and help in adapting therapies in a personalized way.