Publications by authors named "Marco Alifano"

188 Publications

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

Lung Cancer 2021 Apr 30;156:117-121. Epub 2021 Apr 30.

Department of Thoracic Surgery, Hôpital Cochin, APHP.CUP, Université de Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.024DOI Listing
April 2021

New Therapeutic Strategies for Lung Cancer.

Cancers (Basel) 2021 Apr 16;13(8). Epub 2021 Apr 16.

Thoracic Surgery, Cochin Hospital, AP-HP Centre-University of Paris, 75014 Paris, France.

Non-small cell lung cancer (NSCLC) accounts for approximately 27% of all cancer-related deaths worldwide, thus representing a major health problem [...].
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http://dx.doi.org/10.3390/cancers13081937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072685PMC
April 2021

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

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Department of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, 75014 Paris, France.

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.
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http://dx.doi.org/10.3390/cancers13081888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071015PMC
April 2021

Epidemiology and prognostic factors of pleural empyema.

Thorax 2021 Mar 30. Epub 2021 Mar 30.

Thoracic Surgery, Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France.

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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215267DOI Listing
March 2021

Tertiary Lymphoid Structure-B Cells Narrow Regulatory T Cells Impact in Lung Cancer Patients.

Front Immunol 2021 8;12:626776. Epub 2021 Mar 8.

Sorbonne Université, UMRS 1135, Faculté de Médecine Sorbonne Université, Paris, France.

The presence of tertiary lymphoid structures (TLS) in the tumor microenvironment is associated with better clinical outcome in many cancers. In non-small cell lung cancer (NSCLC), we have previously showed that a high density of B cells within TLS (TLS-B cells) is positively correlated with tumor antigen-specific antibody responses and increased intratumor CD4 T cell clonality. Here, we investigated the relationship between the presence of TLS-B cells and CD4 T cell profile in NSCLC patients. The expression of immune-related genes and proteins on B cells and CD4 T cells was analyzed according to their relationship to TLS-B density in a prospective cohort of 56 NSCLC patients. We observed that tumor-infiltrating T cells showed marked differences according to TLS-B cell presence, with higher percentages of naïve, central-memory, and activated CD4 T cells and lower percentages of both immune checkpoint (ICP)-expressing CD4 T cells and regulatory T cells (Tregs) in the TLS-B tumors. A retrospective study of 538 untreated NSCLC patients showed that high TLS-B cell density was even able to counterbalance the deleterious impact of high Treg density on patient survival, and that TLS-B Treg patients had the best clinical outcomes. Overall, the correlation between the density of TLS-B tumors with early differentiated, activated and non-regulatory CD4 T cell cells suggest that B cells may play a central role in determining protective T cell responses in NSCLC patients.
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http://dx.doi.org/10.3389/fimmu.2021.626776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983944PMC
March 2021

To Vaccinate or not: Influenza Virus and Lung Cancer Progression.

Trends Cancer 2021 Mar 9. Epub 2021 Mar 9.

Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France. Electronic address:

Influenza virus infection leads to severe and complicated disease, particularly in patients with lung cancer. It alters the tumor microenvironment (TME), which may potentiate lung cancer progression and disrupt responses to antitumoral treatments. Consequently, influenza vaccination and antiviral treatments should be recommended to all patients with lung cancer.
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http://dx.doi.org/10.1016/j.trecan.2021.02.006DOI Listing
March 2021

Metabolic Strategies for Inhibiting Cancer Development.

Adv Nutr 2021 Feb 2. Epub 2021 Feb 2.

Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris-Descartes University, Paris, France.

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.
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http://dx.doi.org/10.1093/advances/nmaa174DOI Listing
February 2021

The Impact of Previous History of Bariatric Surgery on Outcome of COVID-19. A Nationwide Medico-Administrative French Study.

Obes Surg 2021 04 18;31(4):1455-1463. Epub 2020 Nov 18.

Thoracic Surgery Department, Cochin Hospital, APHP Centre, University of Paris, Paris, France.

Purpose: To determine the risk of invasive mechanical ventilation and death in obese individuals with a history of bariatric surgery (BS) admitted for COVID-19.

Methods: All obese inpatients recorded during a hospital stay by the French National Health Insurance were included, and their electronic health data were reviewed retrospectively. Patients who had undergone bariatric surgery comprised the BS group and patients with obesity but no history of BS served as controls. The primary outcome was COVID-19-related death and the secondary outcome was the need for invasive mechanical ventilation.

Results: 4,248,253 obese individuals aged 15-75 years were included and followed for a mean observation time of 5.43 ± 2.93 years. 8286 individuals with a previous diagnosis of obesity were admitted for COVID-19 between January 1 and May 15, 2020. Of these patients, 541 had a history of BS and 7745 did not. The need for invasive mechanical ventilation and death occurred in 7% and 3.5% of the BS group versus 15% and 14.2% of the control group, respectively. In logistic regression, the risk of invasive mechanical ventilation was independently associated with increasing age, male sex, and hypertension, and mortality was independently associated with increasing age, male sex, history of heart failure, cancer, and diabetes, whereas BS had an independent protective effect. Two random exact matching tests confirmed the protective effect of BS.

Conclusion: This nationwide study showed that BS is independently associated with a reduced risk of death and invasive mechanical ventilation in obese individuals with COVID-19.
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http://dx.doi.org/10.1007/s11695-020-05120-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673863PMC
April 2021

The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response.

Biochimie 2021 Jan 12;180:169-177. Epub 2020 Nov 12.

Service de Chirurgie Thoracique, Hôpital Cochin, Paris University Hospitals, APHP, France; INSERM U1224, Cellular Homeostasis and Cancer, Paris University, Paris, France.

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.
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http://dx.doi.org/10.1016/j.biochi.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659517PMC
January 2021

Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein.

Biochimie 2021 Jan 9;180:143-148. Epub 2020 Nov 9.

Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy. Electronic address:

There is increasing evidence that ACE2 gene polymorphism can modulate the interaction between ACE2 and the SARS-CoV-2 spike protein affecting the viral entry into the host cell, and/or contribute to lung and systemic damage in COVID-19. Here we used in silico molecular docking to predict the effects of ACE2 missense variants on the interaction with the spike protein of SARS-CoV-2. HDOCK and FireDock simulations identified 6 ACE2 missense variants (I21T, A25T, K26R, E37K, T55A, E75G) with higher affinity for SARS-CoV-2 Spike protein receptor binding domain (RBD) with respect to wild type ACE2, and 11 variants (I21V, E23K, K26E, T27A, E35K, S43R, Y50F, N51D, N58H, K68E, M82I) with lower affinity. This result supports the hypothesis that ACE2 genetic background may represent the first "genetic gateway" during the disease progression.
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http://dx.doi.org/10.1016/j.biochi.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834737PMC
January 2021

Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions.

J Immunother Cancer 2020 10;8(2)

Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France

Background: Natural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype.

Objective: We aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME.

Methods: NK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs.

Results: In the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1) and overexpression of C-X-C chemokine receptor type 5 (CXCR5) and C-X-C chemokine receptor type 6 (CXCR6). Second, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and killer cell lectin like receptor (KLRC1) inhibitory molecules were increased in intratumoral NK cells, and CTLA-4 blockade could partially restore MHC class II level on dendritic cell (DC) that was impaired during the DCs/NK cell cross talk. Finally, NK cell density impacts the positive prognostic value of CD8 T cells in NSCLC.

Conclusions: These findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC.
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http://dx.doi.org/10.1136/jitc-2020-001054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570244PMC
October 2020

Maintaining Surgical Treatment of Non-Small Cell Lung Cancer During the COVID-19 Pandemic in Paris.

Ann Thorac Surg 2021 05 8;111(5):1682-1688. Epub 2020 Oct 8.

Department of Vascular Surgery, Thoracic Surgery, and Lung Transplantation, Hôpital Bichat, Université de Paris, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543779PMC
May 2021

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

Lung Cancer 2020 11 28;149:130-136. Epub 2020 Sep 28.

University of Paris, Paris, France; Department of Thoracic Surgery, APHP Centre - Université de Paris, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.009DOI Listing
November 2020

Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

Strahlenther Onkol 2021 May 24;197(5):396-404. Epub 2020 Sep 24.

Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center, IRCSS, Via Manzoni 56, Rozzano, 20089, Italy.

Introduction: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting.

Materials And Methods: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events.

Results: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm (D1cm) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm (D0.1cm) of heart (p = 0.036), respectively.

Conclusion: V95% PTV > 85% and GTV < 90 cm are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.
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http://dx.doi.org/10.1007/s00066-020-01687-9DOI Listing
May 2021

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

Cancer Chemother Pharmacol 2020 10 16;86(4):497-505. Epub 2020 Sep 16.

Thoracic Surgery Department, Cochin Hospital, AP-HP.Center-University of Paris, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.

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.
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http://dx.doi.org/10.1007/s00280-020-04142-9DOI Listing
October 2020

Platinum Drug Sensitivity Polymorphisms in Stage III Non-small Cell Lung Cancer With Invasion of Mediastinal Lymph Nodes.

Cancer Genomics Proteomics 2020 Sep-Oct;17(5):587-595

Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania

Background/aim: Patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) with no progression after induction chemotherapy are usually selected for surgery. Nowadays, response to chemotherapy is not predictable. We aimed to identify genomic predictive markers for response to induction chemotherapy in stage IIIA (N2) NSCLC patients.

Patients And Methods: Whole-exome sequencing (WES) was performed on samples from 11 patients with no response after induction chemotherapy and 6 patients with documented pathological response, admitted to the Hotel Dieu Hospital, Paris or Allegemeines Krakenhaus University, Vienna.

Results: A higher alternative allele frequency was found on SENP5, rs63736860, rs1602 and NCBP2, rs553783 in the non-responder group, and on RGP1, rs1570248, SLFN12L, rs2304968, rs9905892, and GBA2, rs3833700 in the responder group.

Conclusion: These polymorphisms contribute to inter-individual sensibility to chemotherapy response. Interrogation of these genetic variations may have potential applicability when deciding the treatment strategy for patients with stage III NSCLC (N2).
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http://dx.doi.org/10.21873/cgp.20215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472447PMC
May 2021

[Fusion transcripts: Therapeutic targets in thoracic oncology].

Bull Cancer 2020 Sep 3;107(9):896-903. Epub 2020 Aug 3.

Université de Paris, faculté de médecine, Paris, France; Centre de recherche des Cordeliers, Team « Inflammation, Complement and Cancer », Inserm, Paris, France; AP-HP Centre, hôpital Cochin, service de génétique et biologie moléculaires, 27, rue du faubourg Saint-Jacques, Paris, France. Electronic address:

Five to ten percent of lung adenocarcinoma harbor chromosomal rearrangements affecting the ALK, ROS1, NTRK and RET genes. These rearrangements are associated with the production of fusion transcripts that lead to the synthesis of chimeric proteins with constitutive kinase activity. These abnormal proteins induce an oncogenic dependency that may be targeted by tyrosine kinase inhibitors. In this review, we will summarize the clinical and molecular epidemiology of chromosomal rearrangements affecting ALK, ROS1, NTRK and RET genes. We will describe the mechanisms of resistance to tyrosine kinase inhibitors that have been reported. We will present the molecular techniques that can be used to detect these rearrangements and the strategies set-up by the molecular oncology laboratories to diagnose these genetic alterations.
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http://dx.doi.org/10.1016/j.bulcan.2020.05.008DOI Listing
September 2020

[Surgical management of resectable non-small cell lung cancer: Towards new paradigms].

Bull Cancer 2020 Sep 14;107(9):904-911. Epub 2020 Jul 14.

AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bulcan.2020.05.010DOI Listing
September 2020

Systemic immune-inflammation index and prognosis of advanced non-small cell lung cancer.

Authors:
Marco Alifano

Ann Transl Med 2020 Jun;8(11):667

Department of Thoracic Surgery, Cochin Hospital, AP-HP Centre - University of Paris, Paris, France.

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http://dx.doi.org/10.21037/atm.2020.03.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327370PMC
June 2020

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

Cancers (Basel) 2020 Jun 10;12(6). Epub 2020 Jun 10.

Department of Thoracic Surgery, Cochin Hospital, AP-HP Center University of Paris, 75014 Paris, France.

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 ( = 0.0009, OR 3.8 [1.76-8.22]), right side of pneumonectomy ( = 0.013, OR 2.37 [1.20-4.71]), and higher normalized pulmonary artery diameter ( = 0.029, OR 2.16 [1.08-4.33]) were independent predictors of re-do intubation, while Charlson Comorbidity Index >5 ( = 0.018, OR 2.55 [1.17-5.59]) and higher normalized pulmonary artery diameter ( = 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, ( = 0.026, OR 3.39[1.15-9.95]), right side of pneumonectomy ( = 0.0074, OR 4.11 [1.46-11.56]), and Charlson Comorbidity Index >5 ( = 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.
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http://dx.doi.org/10.3390/cancers12061515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353069PMC
June 2020

Perspective: Do Fasting, Caloric Restriction, and Diets Increase Sensitivity to Radiotherapy? A Literature Review.

Adv Nutr 2020 09;11(5):1089-1101

Université Caen Normandie, Normandie University, UNICAEN, Medical School, CHU de Caen, Caen, France.

Caloric starvation, as well as various diets, has been proposed to increase the oxidative DNA damage induced by radiotherapy (RT). However, some diets could have dual effects, sometimes promoting cancer growth, whereas proposing caloric restriction may appear counterproductive during RT considering that the maintenance of weight is a major factor for the success of this therapy. A systematic review was performed via a PubMed search on RT and fasting, or caloric restriction, ketogenic diet (>75% of fat-derived energy intake), protein starvation, amino acid restriction, as well as the Warburg effect. Twenty-six eligible original articles (17 preclinical studies and 9 clinical noncontrolled studies on low-carbohydrate, high-fat diets popularized as ketogenic diets, representing a total of 77 patients) were included. Preclinical experiments suggest that a short period of fasting prior to radiation, and/or transient caloric restriction during treatment course, can increase tumor responsiveness. These regimens promote accumulation of oxidative lesions and insufficient repair, subsequently leading to cancer cell death. Due to their more flexible metabolism, healthy cells should be less sensitive, shifting their metabolism to support survival and repair. Interestingly, these regimens might stimulate an acute anticancer immune response, and may be of particular interest in tumors with high glucose uptake on positron emission tomography scan, a phenotype associated with poor survival and resistance to RT. Preclinical studies with ketogenic diets yielded more conflicting results, perhaps because cancer cells can sometimes metabolize fatty acids and/or ketone bodies. Randomized trials are awaited to specify the role of each strategy according to the clinical setting, although more stringent definitions of proposed diet, nutritional status, and consensual criteria for tumor response assessment are needed. In conclusion, dietary interventions during RT could be a simple and medically economical and inexpensive method that may deserve to be tested to improve efficiency of radiation.
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http://dx.doi.org/10.1093/advances/nmaa062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490158PMC
September 2020

Obesity and COVID-19: ACE 2, the Missing Tile.

Obes Surg 2020 11;30(11):4615-4617

Thoracic Surgery Department, University Hospital of Paris, Cochin Hospital, APHP Centre, Paris, France.

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http://dx.doi.org/10.1007/s11695-020-04734-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246964PMC
November 2020

Renin-angiotensin system at the heart of COVID-19 pandemic.

Biochimie 2020 Jul 16;174:30-33. Epub 2020 Apr 16.

Digestive Disease Department, Archet 2 Hospital, Nice University Hospital, University of Nice Côte d'Azur, Nice, France; Inserm, U1065, Team 8 "Hepatic Complications of Obesity", University Nice Côte d'Azur, France.

Significant aspects of COVID-19 pandemic remain obscure. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system, whose expression dominates on lung alveolar epithelial cells, is the human cell receptor of SARS-CoV-2, the causative agent of COVID-19. We strongly encourage the concept that thorough considerations of receptor-ligand interactions should be kept at the heart of scientific debate on infection. In this idea, the whole renin-angiotensin system has to be evaluated. We hypothesize that factors related to ethnicity, environment, behaviors, associated illness, and medications involving this complex system are probably responsible for situations regarded as anomalous from both an epidemiological and a clinical point of view, but, taken together, such factors may explain most of the aspects of current outbreak. We decided to use the analogy of a play and speculate about the possible impact in this tragedy of 1) air pollution via the interference of nitrogen dioxide on ACE2 expression; 2) the dual role of nicotine; 3) the hypothetical involvement of ACE2 polymorphisms, the relationships of which with ethnic factors and susceptibility to cardiovascular disease seems intriguing; 4) the impact on the severity of infection of hypertension and related medications acting on the renin/angiotensin system, and, finally, 5) the possible helpful role of chloroquine, thanks to its capacity of modifying ACE2 affinity to the viral spike protein by altering glycosylation. This hypothesis paper is an urgent call for the development of research programs that aim at questioning whether the putative protagonists of this tragedy are real-life actors in COVID-19.
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http://dx.doi.org/10.1016/j.biochi.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161528PMC
July 2020

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study.

Cancers (Basel) 2020 Feb 18;12(2). Epub 2020 Feb 18.

Drug Biology-Toxicology, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of -mutated () NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55-109) vs. 658 days (222-not reached); HR: 4.12 (1.95-8.71), = 0.0002) and OS (HR: 3.99(1.63-9.80), = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17-6.08), = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30-0.80), = 0.004) and OS (HR: 0.39, 95%CI (0.21-0.71), = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.
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http://dx.doi.org/10.3390/cancers12020473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072584PMC
February 2020

Costal cartilage resection for the treatment of slipping rib syndrome (Cyriax syndrome) in adults.

J Thorac Dis 2020 Jan;12(1):10-16

Thoracic Surgery Department, Paris Center University Hospital, Assistance Publique - Hôpitaux de Paris, Paris Descartes University, Paris, France.

Background: Slipping rib syndrome is an overlooked cause of low chest or upper abdominal pain. Costal cartilage excision has been described as an effective treatment of this disorder. We review our experience with surgically treated slipping rib syndrome in the adult patient.

Methods: This is a single institution retrospective analysis from January 2000 to March 2019 of adult patients operated on for treatment of a slipping rib syndrome.

Results: Nineteen patients were diagnosed with slipping rib syndrome and underwent costal cartilage excision. All patients presented with unilateral and life disturbing chest pain (8 left sided). In all cases, point tenderness was observed with palpation and hooking maneuver was positive. Each patient underwent imaging and ultrasonography suggested slipping rib syndrome in one case. A mean of 1±0.2 cartilages was excised. Early postoperative course was uneventful in all the cases. Follow-up was complete for all patients over a median of 18.7±12 [3-132] months. At postoperative month 2 follow-up, 15 on 19 patients had complete resolution of their symptoms. At late interviews, 6 out of 19 patients described recurrent pain, whose intensity was significantly lower. We observed significant differences about pre-operative and post-operative visual analog pain (EVA) (8.07±0.75 2±2.3, P<0.005), weekly pain crises (6.25±2.7 1.6±2.1, P<0.005) and morphinics consomption (9/19 2/19, P=0.029). Fourteen patients out of 19 nineteen strongly recommended surgical intervention.

Conclusions: Slipping rib syndrome of the adult is an overlooked cause of chest or abdominal pain which diagnosis and treatment are often delayed. Costal cartilage excision allows short to mid-terms effective and reliable treatment to reduce symptoms and life disturbance but does not exclude late pain recurrence.
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http://dx.doi.org/10.21037/jtd.2019.07.83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995823PMC
January 2020

Is there a real need for a remotely actuated magnetic chest drain device?

J Thorac Dis 2019 Dec;11(12):5677-5679

Department of Thoracic Surgery, Cochin Hospital, Paris Center University Hospitals, APHP, Paris, France.

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http://dx.doi.org/10.21037/jtd.2019.12.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988035PMC
December 2019

Pre-Disease and Pre-Surgery BMI, Weight Loss and Sarcopenia Impact Survival of Resected Lung Cancer Independently of Tumor Stage.

Cancers (Basel) 2020 Jan 22;12(2). Epub 2020 Jan 22.

Thoracic Surgery Department, Paris Center University Hospitals, AP-HP, 75014 Paris, France.

Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung resection for NSCLC.

Methods: A retrospective analysis of a prospectively collected database was made on 304 consecutive patients.

Results: Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 5% and 44.4% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m ( < 0.000001). Overall survival was positively affected by pre-disease ( = 0.036) and pre-surgery ( 0.017) BMI > 25 kg/m, and, even more, in case of BMI > 25 kg/m and increasing weight ( = 0.012). Long-term outcome was negatively influenced by low muscle mass ( = 0.042) and weight loss ( 0.0052) as well as age ( 0.017), ASA categories ( 0.025), extent of resection ( 0.0001), pleural invasion ( 0.0012) and higher pathologic stage ( < 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.66[0.49-0.89], 0.006) and pre-surgery BMI (RR 0.72[0.54-0.98], 0.034), and the absence of low muscle mass (RR 0.56[0.37-0.87], 0.0091).

Conclusions: Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered.
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http://dx.doi.org/10.3390/cancers12020266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072703PMC
January 2020