Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy.

Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the ALK gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8+ T cells expressing PD-1. To more effectively integrate all of these potential biomarkers of clinical response to immunotherapy, we have developed a multiparametric immunofluorescence technique with automated immune cell counting to comprehensively analyze the tumor microenvironment of ALK-positive adenocarcinoma (ADC). When analyzed as either a continuous or a dichotomous variable, the mean number of tumor cells expressing PD-L1 (p = 0.012) and the percentage of tumor cells expressing PD-L1 were higher in ALK-positive ADC than in EGFR-mutated ADC or WT (non-EGFR-mutated and non-KRAS-mutated) NSCLC. A very strong correlation between PD-L1 expression on tumor cells and intratumoral infiltration by CD8+ T cells was observed, suggesting that an adaptive mechanism may partly regulate this expression. A higher frequency of tumors combining positive PD-L1 expression and infiltration by intratumoral CD8+ T cells or PD-1+CD8+ T cells was also observed in ALK-positive lung cancer patients compared with EGFR-mutated (p = 0.03) or WT patients (p = 0.012). These results strongly suggest that a subgroup of ALK-positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies.

Induction of resident memory T cells enhances the efficacy of cancer vaccine.

Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGß decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them.

Time trends in surgery for lung cancer in France from 2005 to 2012: a nationwide study.

The aim of this study was to assess the evolution of survival in patients treated surgically for non-small cell lung cancer (NSCLC) between 2005 and 2012.From January 2005 to December 2012, 34 006 patients underwent pulmonary resection for NSCLC and were included in the French national database Epithor. Patients' characteristics, procedures and survival were analysed. Survival according to the management was evaluated for each 2-year period separately: 2005-2006, 2007-2008, 2009-2010 and 2011-2012.The proportions of early-stage cancers and adenocarcinomas increased significantly over the periods. 3-year overall survival (OS) increased significantly from 80.5% for the first period to 81.4% for the last period. For the periods 2005-2006 and 2007-2008, 3-year OS was lower after segmentectomy than after lobectomy (77 and 73% versus 82 and 83%, respectively). For the periods 2009-2010 and 2011-2012, 3-year OS in the two sub-groups was similar. OS after bi-lobectomy or pneumonectomy was lower than after lobectomy for all periods analysed. Systematic nodal dissection increased OS for all periods. Chemotherapy but not radiotherapy improved OS in the first 12 postoperative months for all periods.Changes in histological type and stage linked to advances in surgical and medical practices since 2005 led to an increase in OS in patients with surgical-stage NSCLC.

High grade neuroendocrine lung tumors: pathological characteristics, surgical management and prognostic implications.

Among non-small cell lung cancers (NSCLC), large cell carcinoma (LCC) is credited of significant adverse prognosis. Its neuroendocrine subtype has even a poorer diagnosis, with long-term survival similar to small cell lung cancer (SCLC). Our purpose was to review the surgical characteristics of those tumors. The clinical records of patients who underwent surgery for lung cancer in two French centers from 1980 to 2009 were retrospectively reviewed. We more particularly focused on patients with LCC or with high grade neuroendocrine lung tumors. High grade neuroendocrine tumors were classified as pure large cell neuroendocrine carcinoma (pure LCNEC), NSCLC combined with LCNEC (combined LCNEC), and SCLC combined with LCNEC (combined SCLC). There were 470 LCC and 155 high grade neuroendocrine lung tumors, with no difference concerning gender, mean age, smoking habits. There were significantly more exploratory thoracotomies in LCC, and more frequent postoperative complications in high grade neuroendocrine lung tumors. Pathologic TNM and 5-year survival rates were similar, with 5-year ranging from 34.3% to 37.6% for high grade neuroendocrine lung tumors and LCC, respectively. Induction and adjuvant therapy were not associated with an improved prognosis. The subgroups of LCNEC (pure NE, combined NE) and combined SCLC behaved similarly, except visceral pleura invasion, which proved more frequent in combined NE and less frequent in combined SCLC. Survival analysis showed a trend toward a lower 5-year survival in case of combined SCLC. Therefore, LCC, LCNEC and combined SCLC share the same poor prognosis, but surgical resection is associated with long-term survival in about one third of patients.

Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy.

PURPOSE: There is a scarce clinical experience about adjuvant helical tomotherapy (HT) in patients affected by malignant pleural mesothelioma (MPM) even though it appears as a useful technique to treat complex volume as the pleural cavity, and seems to have better dose distribution than the "classic" intensity modulated radiotherapy (IMRT). METHODS AND MATERIALS: Twenty-four patients received adjuvant radiotherapy (RT) by HT from August 1st, 2007 to December 1st, 2009 at Curie Institute (Paris) and René Gauducheau Cancer Center (Nantes). Thirteen patients had neoadjuvant chemotherapy. Extrapleural pleuropneumonectomy (EPP) was done in 23 patients. Median dose to PTV was 50Gy [48.7-55.9Gy] (2Gy/fraction). Acute and long term toxicities, disease free survival (DFS), overall survival (OS) and relapses are presented. RESULTS: Average follow up after RT was 7 months. The disease was staged mostly as T2-T3, N1-N2. Nineteen patients had epithelial type histology. Most patients tolerated radiotherapy with grade 1-2 side effects: redness of the skin, light cough or dyspnea, fatigue, nausea and odynophagia, mild increase of the post-operative thoracic pain. Grade 3 pneumonitis was suspected in 2 patients. Two grade 5 pneumonitis were also suspected. Eleven patients had a follow up of more than 6 months and no long term side effects related with HT were noted. At 24 months, 51.8% of patients were free of disease. Thirty percent of patients relapsed, with 2 patients presenting local relapses. Two patients died from recurrence. CONCLUSION: With limited follow up, HT has comparable toxicity to those observed with traditional IMRT. Higher radiation dose and good coverage results in excellent local control.

Current indications and results for thoracoplasty and intrathoracic muscle transposition.

OBJECTIVES: Thoracoplasty has lost much of its popularity and is being supplanted by space-reduction operations using muscle flaps. Our purpose is to retrospectively study the remaining indications and the evolving modifications of this ancient technique in our current surgical practice. PATIENTS AND METHODS: From 1994 to 2008, 35 patients underwent a thoracoplasty procedure in a single thoracic surgery centre for treatment of infectious complications of previous thoracic surgery. The number and length of ribs excised were dictated by the size and location of the thoracic cavity to obliterate. Muscle flaps were used to buttress bronchial fistulas and to fill out residual spaces. We reviewed the immediate and long-term results concerning infection control and procedure tolerance. RESULTS: The infectious complications of previous thoracic surgery were related to cancer in 25, tuberculosis in six, oesophageo-pleural fistula in two, ruptured lung abscess and pleural thickening in one each. The thoracoplasty procedure was performed for: (1) post-pneumonectomy empyema, n=20 (bronchial fistula, n=11; open window thoracostomy, n=14; mean number of resected ribs, n=7.5; associated intrathoracic muscle transposition, n=12; postoperative death, n=3); (2) post-lobectomy empyema, n=8 (bronchial fistula n=8; open window thoracostomy n=1; mean number of resected ribs n=3.6; associated intrathoracic muscle transposition n=7; no death); (3) other indications, n=7 (mean number of resected ribs n=4.8; associated intrathoracic muscle transposition n=3; no death). All patients discharged from the hospital except one were cured and did not complain of symptoms of secondary lung function and shoulder impairment. CONCLUSION: Although thoracoplasty is rarely indicated nowadays, this does not imply that the procedure should be avoided. Thoracoplasty may be associated with myoplasty, which permits achieving complete space obliteration by combining resection of a few rib segments and limited intrathoracic muscle transposition.

Recurrent pleural effusion complicating liver cirrhosis.

BACKGROUND: Pleural effusion (PE) is a rare complication of advanced liver cirrhosis, which may lead to an operation when uncontrolled. The purpose of this study was to evaluate the modality of the occurrence of pleural effusion and to describe its surgical management. METHODS: We studied 21 patients who were referred to the department of thoracic surgery because of massive and recurrent PE caused by liver cirrhosis. The PE was a transudate in 16 patients and an exudate in 5. Talc pleurodesis was attempted in all patients. The patients were divided into two groups. Video assisted thoracoscopy was performed in 13 patients in whom the clinical condition permitted general anesthesia; the pleural cavity was entirely explored before pleurodesis (group 1). Chest tube drainage alone was performed in 8 patients who were unable to undergo general anesthesia; talc pleurodesis was performed through the chest tube in these patients (group 2). RESULTS: In group 1 the PE was right-sided in 8 patients, left-sided in 3, and bilateral in 2. Diaphragmatic defects were observed in 2 patients, and a fluid leak oozing from the diaphragm was observed in 1 patient. Ten patients were considered cured and were without recurrence. Two patients underwent late recurrence before dying from their liver cirrhosis. Only 1 patient had an early recurrence that was cured by complementary talc slurry. In group 2 all patients presented with a right PE; of these, 3 patients died from septic shock caused by pleural infection. Three patients underwent early recurrence but were cured after repeat talc slurry. One patient had a midterm recurrence. One patient had an early recurrence treated by intrahepatic porto-systemic shunt with partial improvement. CONCLUSIONS: Passage of ascites through diaphragmatic defects appears to be the main cause of PE complicating cirrhosis. Patients may benefit from talc pleurodesis. Video assisted thoracoscopy pleurodesis is the technique of choice with consistent results. Repeated talc injection through the drain may prove useful for patients in poor clinical status.