Medical and Economic Evaluation of FOREseal Bioabsorbable Reinforcement Sleeves Compared With Current Standard of Care for Reducing Air Leakage Duration After Lung Resection for Malignancy: A Randomized Trial.

OBJECTIVE: The objective of this study was to determine the efficacy of alginate staple-line reinforcement of fissure openings as compared with stapling alone, with or without tissue sealant or glue, in reducing the incidence and duration of air leakage after pulmonary lobectomy for malignancy. SUMMARY BACKGROUND DATA: No randomized trial evaluating alginate staple-line reinforcement has been performed to date. METHODS: The Staple-line Reinforcement for Prevention of Pulmonary Air Leakage study was a multicenter randomized trial, with blinded evaluation of endpoints. Patients over 18 years of age scheduled for elective open lobectomy or bilobectomy for malignancy were eligible for enrollment. At thoracotomy, patients were deemed ineligible if an unanticipated pneumonectomy was indicated, or if air leakage occurred after the liberation of pleural adhesions. Otherwise, if the fissure was incomplete or the lung had an emphysematous appearance, patients were randomized to either standard management or interventional procedure consisting of fissure opening with linear cutting staplers buttressed with paired alginate sleeves (FOREseal). The number of eligible patients necessary in each randomization arm was estimated to be 190, and an outcomes analysis was performed on an intention-to-treat basis. RESULTS: Of the 611 patients consented to study enrollment, 380 met the inclusion criteria and were randomized. Based on an intention-to-treat analysis, the primary endpoint of air leak duration was not different between the 2 groups: 1 day (range: 0-2 d) in the FOREseal group and 1 day (range: 0-3 d) in the control group (P = 0.8357). In addition, the 2 groups were similar in terms of the proportion of patients presenting with prolonged air leakage (7.8% in the FOREseal group vs 11.3% in the control group, P = 0.264) and the average duration of chest drainage (P = 0.107). Procedure costs were comparable for both groups. CONCLUSIONS: FOREseal did not demonstrate a significant advantage over standard treatment alone.

Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis.

BACKGROUND: Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS: We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS: Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS: PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.

Repeated resection of colorectal cancer pulmonary oligometastases: pooled analysis and prognostic assessment.

BACKGROUND: Repeated resection of colorectal cancer pulmonary metastasis is associated with long-term survival. Nevertheless, very limited data addressing the best candidates for repeated pulmonary resection is available. PATIENTS AND METHODS: We searched the PubMed database for retrospective studies evaluating lung metastasectomy for metastatic colorectal cancer (CRC). We included studies with available data about repeated pulmonary metastasectomy. Potential prognostic factors were analyzed for possible impact on survival following the second metastasectomy through univariate and multivariate analysis. RESULTS: Between 1983 and 2008, 944 lung metastasectomies were carried out on 759 patients. Of those, 148 patients had a second metastasectomy. The 5-year survival rate was 52 % for patients who had 1 metastasectomy and 57.9 % from the second metastasectomy for patients who had repeated resection. More than 2 metastatic pulmonary nodules and maximum diameter of largest pulmonary nodule ≥3 cm were the only independent factors associated with inferior survival following repeated pulmonary resection. CONCLUSIONS: In selected patients with metastatic CRC, repeated pulmonary metastasectomy offers an excellent chance for long-term survival and is associated with a quite low operative mortality. Patients with more than 2 metastatic nodules and a maximum diameter of the largest metastatic lung nodule of ≥3 cm have a significantly inferior survival.

DeltaN TP63 reactivation, epithelial phenotype maintenance, and survival in lung squamous cell carcinoma.

Genes, active during normal development, are frequently reactivated during neoplastic transformation and may be related to progression. One of them, the transcription factor TP63, is crucial for pulmonary epithelial development and a possible target of the recurrent 3q amplifications in lung squamous cell carcinoma (SCC). Here, we explored whether TP63 reactivation could be associated to cancer progression in lung SCC through an epithelial to mesenchymal transition. We studied TP63 amplification and TP63 expression at RNA and protein levels and we analyzed the ΔNTP63/TATP63 ratio that quantifies the proportion of the isoform lacking the transactivation domain/the isoform containing the transactivation domain. We correlated TP63 status to survival and to the expression of epithelial (E-cadherin and plakoglobin) and mesenchymal (N-cadherin, vimentin, TWIST1, and SNAIL) markers. We found that high ΔN/TA TP63 ratio was related to high E-cadherin and plakoglobin mRNA levels (P < 0.05) and that E-cadherin mRNA level was the only marker related to survival. Kaplan-Meier survival curves stratified according to the expression level of E-cadherin showed, as already reported in breast cancer, that patients with low (first quartile) or high (last quartile) E-cadherin expression had a worse survival with respect to patients with intermediate E-cadherin expression. Altogether, our results indicate that a reactivation of ΔNTP63 is linked to the maintenance of epithelial markers and suggest that E-cadherin has a dual role in lung SCC.

Pulmonary carcinoid tumors and asbestos exposure.

OBJECTIVES: The hypothesis that asbestos exposure may have more specific associations with particular histological types of lung cancer remains controversial. The aim of this study was to analyze the relationships between asbestos exposure and pulmonary carcinoid tumors. METHODS: A retrospective case-control study was conducted in 28 cases undergoing surgery for pulmonary carcinoid tumors and aged >40 years and in 56 controls with lung cancer of a different histological type, matched for gender and age, from 1994 to 1999, recruited in two hospitals in the region of Paris. Asbestos exposure was assessed via expertise of a standardized occupational questionnaire and mineralogical analysis of lung tissue, with quantification of asbestos bodies (AB). RESULTS: Definite asbestos exposure was identified in 25% of cases and 14% of controls (ns). Cumulative asbestos exposure was significantly higher in cases than in controls (P < 0.05), and results of the quantification of AB tended to be higher in cases than in controls (24 and 9% had >1000 AB per gram dry lung tissue, respectively, P = 0.09). Mean cumulative smoking was lower in cases than in controls (P < 0.05). CONCLUSIONS: This study argues in favor of a relationship between asbestos exposure and certain pulmonary carcinoid tumors.

Association of ex vivo vascular and bronchial dysfunctions in smokers.

BACKGROUND: It has recently been shown that systemic endothelial dysfunction is associated with airflow limitation in COPD. We conducted this ex vivo study to assess whether endothelial dysfunction of pulmonary arteries of former smokers was associated with modifications of airway functions. METHODS: Pharmacological experiments were conducted on arterial and bronchial rings obtained from lung specimen of 20 patients: 13 smokers without COPD and 7 smokers with mild to moderate COPD (GOLD class I or II). The impairment of acetylcholine-mediated vasodilation (constriction) of preconstricted arterial rings defined endothelial dysfunction. Resting tone (initial and after a contraction test) and cGMP-mediated dilation of bronchial rings in response to zaprinast were evaluated. RESULTS: Initial airway resting tone was correlated with airflow limitation (FEV(1) % predicted: Rho = -0.49; p = 0.032). The acetylcholine response of arterial rings was correlated with zaprinast-induced bronchodilation (Rho = 0.54, p = 0.019). Patients with endothelial dysfunction (n = 5), as compared with those displaying no dysfunction (n = 15), were characterized by an increased resting tone (after contraction test), an impaired response to zaprinast but a similar degree of airflow limitation (FEV(1)). CONCLUSION: Endothelial dysfunction of pulmonary arteries is associated with increased resting tone and impaired cGMP-mediated dilation of airways in former smokers, suggesting common underlying mechanisms of pulmonary arterial and bronchial dysfunctions.

Non-small cell lung cancer invading the chest wall.

Non-Small cell lung cancer invading the chest wall represents an advanced stage of the disease. Chest wall resection may be achieved in up to 100% of the patients, and the ensuing defect requires to be reconstructed in 40% to 64% of cases. Once a surgical challenge, chest wall resection is no longer a technical problem and en bloc chest wall and lung resections regularly provide good results. However, survival rates are jeopardized by incompleteness of the resection and mediastinal lymph node involvement. Nowadays, the challenge is represented by the use of the other nonsurgical modalities (chemotherapy and radiation therapy) to increase the chance of performing a complete resection, the need to achieve a better control of probable lymphatic or hematogenous spread, and the reduction of the recurrence rate.

Role of video-assisted thoracoscopy in patients with ovarian cancer and pleural effusion.

OBJECTIVES: To evaluate the feasibility of video-assisted thoracoscopy (VAT) for staging advanced ovarian cancer, to measure the performance of preoperative computed tomography (CT) for diagnosing pleural metastases, to assess the correlation between pleural and abdominal involvement, and to measure the impact of VAT on patient management. METHODS: We retrospectively evaluated 16 VAT procedures in 15 patients with advanced ovarian malignancies and pleural effusions. The reason for VAT was either to evaluate unilateral or bilateral pleural effusions (n = 15) or to evaluate pleural metastases after neoadjuvant chemotherapy (n = 1). Preoperative CT was performed routinely, and findings were compared with those of VAT. The rates of involvement of the hepatic pedicle, mesentery, and right side of the diaphragm were compared with the rate of pleural involvement. RESULTS: The right side of the chest was examined 12 times; and the left side, 4 times. There were no complications; 1 procedure was stopped because of ventilatory intolerance. Video-assisted thoracoscopy identified metastases smaller than 1 cm in 5 patients and larger than 1 cm in 2 additional patients; there was no evidence of pleural involvement in 6 patients. Computed tomography had 14% sensitivity and 25% specificity for pleural status determination, using VAT biopsy as the reference standard. Pleural involvement did not correlate with involvement of the hepatic pedicle, mesentery, or right side of the diaphragm. CONCLUSIONS: Video-assisted thoracoscopy performs better than CT for evaluating pleural involvement in ovarian cancer. Video-assisted thoracoscopy supplies accurate data on thoracic involvement, which does not seem predictable from the peritoneal involvement. Video-assisted thoracoscopy may impact patient management.

[Immuno-histochemical study contribution in thoracic endometriosis: about an analysis of eight cases]. / Apport de l'étude immuno-histochimique dans les localisations intrathoraciques de l'endométriose : à propos de huit cas.

Thoracic endometriosis (TE) is rare with positive histological diagnosis sometimes difficult, particularly in atypical form. The aim of this study was to identify features which can increase performance of the histolological TE diagnosis and more particularly immuno-histochemical (IHC) contribution with hormonal receptors, smooth muscle actin, Ber-Ep4, CD10 and calretinin antibodies. To address this issue, we retrieved, retrospectively, a large series of 591 pneumothorax operated. Among them, 135 (23%) were females including eight (6%) cases related to TE. Those eight women were surgically treated with resection of pleura (n=6/8), lung (n=5/8) and diaphragmatic samples (n=6/8). Typical histological lesions of endometriosis were observed in six cases among eight. All diaphragmatic samples presented, macroscopically, holes responsible of thoraco-abdominal communication (n=6/6). Endometrial glands and/or endometrial stroma cells were found in the diaphragm (n=5/6) and in the pleura (n=2/6) but were never encountered in the lung (n=0/5). IHC study can confirm the five diaphragmatic localizations and can identify a new localization with expression of hormonal receptors, CD10 and smooth muscle actin in an island of fusiform cells. In conclusion, our study shows 1) the high frequency of diaphragmatic endometriosis localization which holes existence also can explain the pathogenesis, 2) the value of diaphragmatic samples in positive histological diagnosis of TE, 3) IHC interest to confirm endometriosis, particularly in atypical form and to differentiate from mesothelial cells inclusion.

Dynamic magnetic resonance imaging in unilateral diaphragm eventration: knowledge improvement before and after plication.

BACKGROUND: The assessment before surgical plication for unilateral hemidiaphragm (HD) eventration is not clearly defined and no precise criteria exist to really understand which patient is operated with which results depending on the technique used. The goal of this study was to evaluate the place of dynamic magnetic resonance imaging (dMRI) before and after plication by developing measurement criteria. METHODS: Between 2006 and 2017, 18 patients (group1: Gp1) were operated for eventrations, 15 left-sided (Gp1L) and 3 right-sided (Gp1R). All had preoperative and postoperative evaluations including dMRI and pulmonary function tests. Five healthy volunteer subjects (group2: Gp2) had the same imaging protocol. For each HD, we measured the respiratory excursion at three fixed points (S1, S2, S3) and the height of curvature on sagittal plane. We also searched for upward paradoxical diaphragm movements. RESULTS: Before surgery, no excursion (n=13) or extremely reduced excursion (n=5) was detected on the injured HD (IHD) in Gp1. Upward paradoxical movements were identified only in Gp1L (n=6). Compared with Gp2 subjects, the healthy HD for Gp1L patients had significantly reduced excursion values at three sites S1 (P=0.038), S2 (P=0.006), and S3 (P=0.004). After plication, the decreasing height of curvature confirmed a tightening of the IHD in all patients (median value from 100 to 39.5 mm in Gp1L and 92 to 74 mm in Gp1R, P=0.0001). All upward paradoxical movements disappeared. Healthy HD excursions in Gp1L normalised their values. All those imaging improvements were correlated with postoperative improvements of dyspnoea score (P<0.0001) and vital capacity (P=0.002). CONCLUSIONS: dMRI and the standardised grid we developed not only improve the knowledge of unilateral diaphragm eventration but also permit to evaluate the quality of its surgical repair. It also demonstrates that a dysfunction of the healthy HD contralateral to eventration is possible and reversible after plication of the IHD.

NF1 mutations identify molecular and clinical subtypes of lung adenocarcinomas.

The tumor suppressor gene neurofibromin 1 (NF1) is a major regulator of the RAS-MAPK pathway. NF1 mutations occur in lung cancer but were not extensively explored. We hypothesized that NF1-mutated tumors could define a specific population with a distinct clinical and molecular profile. We performed NF1 sequencing using next generation sequencing (NGS) in 154 lung adenocarcinoma surgical specimens with known KRAS, EGFR, TP53, BRAF, HER2, and PIK3CA status, to evaluate the molecular and clinical specificities of NF1-mutated lung cancers. Clinical data were retrospectively collected, and their associations with molecular profiles assessed. In this series, 24 tumors were NF1 mutated (17.5%) and 11 were NF1 deleted (8%). There was no mutation hotspot. NF1 mutations were rarely associated with other RAS-MAPK pathway mutations. Most of patients with NF1 alterations were males (74.3%) and smokers (74.3%). Overall survival and disease-free survival were statistically better in patients with NF1 alterations (N = 34) than in patients with KRAS mutations (N = 30) in univariate analysis. Our results confirm that NF1 is frequently mutated and represents a distinct molecular and clinical subtype of lung adenocarcinoma.

Strategies and outcomes in pulmonary and extrapulmonary metastases from renal cell cancer.

OBJECTIVE: Resected renal carcinoma related lung metastases (LM) are associated with higher survival rates, but surgery for extrapulmonary metastases affords good results too. Patients operated on for extrapulmonary metastases before thoracotomy are at high risk of death. The purpose of our analysis was to explore the surgical impact on the outcome of patients with such association. METHODS: We reviewed the data of 15 patients operated for LM and extrapulmonary metastases from 1984 to 2005. We studied demographic and clinical characteristics, surgical results and pathological staging of the primary tumour and LM in search of prognostic factors. RESULTS: Nephrectomy and metastasectomies were synchronous in only one patient. For the others, mean time interval between nephrectomy and surgery for LM was 74.2 months (range 19-228). Metastases were resected synchronously in two patients and metachronously in 13 of them (mean time interval: 28 months). Five-year survival of this group was 32%, median value of 18 months. The prognosis was better when the resected extrapulmonary metastases were located in the perirenal (pancreas, adrenal gland) or intrathoracic structures (lymph nodes, diaphragm) than in distant visceral organs (brain, bone, thyroid gland). The lymphatic drainage for these structures connects with the thoracic duct in a similar manner as kidneys do. CONCLUSION: Surgery for lung and extrapulmonary renal cell cancer-related metastases provides favourable results and is indicated when complete resection can be achieved. The role of the lymphatic system must be explored by further investigations.

Clinical and molecular characteristics of unicentric mediastinal Castleman disease.

BACKGROUND: Unicentric mediastinal Castleman disease (CD) is a rare condition, poorly characterized due to the small number of cases and the absence of genomic study. We analyzed clinical, radiological, histological and genomic patterns associated with mediastinal CD in a substantial case series.Methods: We retrospectively reviewed cases of unicentric mediastinal CD managed in 2 French thoracic surgery departments between 1988 and 2012. Clinical, radiological, surgical and pathological data were recorded. On available FFPE blocks we performed mutation screening by next-generation-sequencing, using AmpliSeq™ Cancer Hotspot v2 (Life Technologies) and immunohistochemistry (IHC) (AKT-mTOR pathway). RESULTS: Eleven patients were identified (mean age 41±15 years, sex-ratio 0.8, median follow-up 78 months). Surgical approach was thoracotomy (n=6), sternotomy (n=4), and VATS (n=1). Additional procedures included thymectomy in three cases, mediastinal lymphadenectomy in two cases, and bilobectomy in one case. One patient presented local relapse as a follicular dendritic cell sarcoma, leading to death 48 months after the first resection. Within 9 patients whose FFPE blocks were available, 2 mutations were found: VHL (p.F119L, 35%, n=1) and JAK3 (p.V718L, 53%, n=1). Phospho-AKT and phospho-mTOR stainings were negative in all cases, whereas phospho-S6RP staining was positive in eight cases, mainly in interfollicular cell cytoplasm. CONCLUSIONS: From this series of patients with unicentric mediastinal CD, we observed 2 cases of potential driver mutations and 8 cases of phospho-S6RP activation not related to AKT-mTOR. Larger studies are required to decipher more precisely the molecular abnormalities and potential therapeutic targets underlying this uncommon condition.

Intrapulmonary lymph node metastasis and renal cell carcinoma.

Intrapulmonary lymph node metastasis occuring after nephrectomy for renal cell carcinoma is a particular recurrence modality. Authors report two male patients presenting with this recurrence 2 and 4 years after treatment of the primary and who underwent surgery. Surgery confirmed the diagnosis and demonstrated station 7 minimal metastases and positive pleural lavage cytology in both patients. The first patient survived 2 years and the second was alive disease free at 33 months follow-up. Such metastases probably originate from the thoracic duct. Resection confirms the diagnosis and may be part of the treatment.

Bronchial arteries and lymphatics of the lung.

Bronchial arteries and bronchial lymphatics participate directly in the normal and pathologic conditions of the lungs and are of more than academic interest. Bronchial arteries and bronchial lymphatics usually are discussed separately, but they are linked when considered anatomically or physiologically. This article describes these highly variable structures.

Can mathematics replace anatomy to establish recommendations in lung cancer surgery?

The greater the number of lymph node (LN) sampled (NLNsS) during lung cancer surgery, the lower the risk of underestimating the pN-status and the better the outcome of the pN0-patients due to stage-migration. Thus, regarding LN sampling "to be or not to be", number is the question. Recent studies advocate removing 10 LNs. The most suitable NLNsS is unfortunately impossible to establish by mathematics. A too high NLNsS variability exists, based on anatomy, surgery and pathology. The methodology may vary according to Inter-institutional differences in the surgical approach regarding LN inspection and number sampling. The NLNsS increases with the type of resection: sublobar, lobectomy or pneumonectomy. Concerning pathology, one LN may be divided into several pieces, leading to number overestimation. The pathological examination is limited by the number of slices analyzed by LN. The examined LNs can arbitrarily depend on the probability of detecting nodal metastasis. In fact, the only way to ensure the best NLNsS and the best pN-staging is to remove all LNs from the ipsilateral mediastinal and hilar LN-stations as they are discovered by thoroughly dissecting their anatomical locations. In doing so, a deliberate lack of harvest of LNs is unlikely, number turns out not to be the question anymore and a low NLNsS no longer means incomplete surgery. This prevents from judging as incomplete a complete LN dissection in a patient with a small NLNsS and from considering as complete a true incomplete one in a patient with a great NLNsS. Precise information describing the course of the operation and furnished in the surgeon's reports is also advisable to further improve the quality of LN-dissection, which ultimately might be beneficial in the long-term to patients. However, that procedure is of limited interest in pN-staging if LNs are not thoroughly examined and also described by the pathologist.

Surgical resection of pulmonary inflammatory pseudotumors: long-term outcome.

Background Pulmonary inflammatory pseudotumors are rare lesions that remain problematic in several aspects, especially regarding the therapeutic strategy. The goal of this study was to evaluate long-term survival in a multicenter series of patients who required surgery for pulmonary inflammatory pseudotumors. Methods Thirty-six cases of pulmonary inflammatory pseudotumors, operated on in 3 French thoracic surgery departments between 1989 and 2015, were studied retrospectively. We recorded pre-, peri- and postoperative data for each patient, and long-term survival was analyzed. Results There were 22 men and 14 women. Mean age was 53.5 years (range 14-81 years). Three pneumonectomies, 1 bilobectomy, 19 lobectomies, 2 segmentectomies, 10 wedge resections, and 1 biopsy were performed. Complete resection was carried out in 32 (88.8%) patients. Median follow-up was 76 months. Five-year and 10-year survival rates were respectively 86.8% and 81.7% (96% and 90% for patients with R0 resection). Conclusions Long-term survival was excellent for patients with pulmonary inflammatory pseudotumors who benefited from surgery, especially when surgical resection was complete. These results confirm that surgical resection must be proposed as the first-line treatment for patients with pulmonary inflammatory pseudotumors.

Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer.

STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients. STK11 exons 1 or 2 mutations (STK11ex1-2) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11ex3-9). STK11ex1-2 and STK11ex3-9 mutations occurred in 5% and 14% of NSCLC. STK11 mutated patients were younger (P = .01) and smokers (P< .0001). STK11 mutations were significantly associated with KRAS and inversely with EGFR mutations. After a median follow-up of 7.2 years (95%CI 6.8-.4), patients with STK11ex1-2 mutation had a median OS of 24 months (95%CI 15-57) as compared to 69 months (95%CI 56-93) for wild-type (log-rank, P = .005) and to 91 months (95%CI 57-unreached) for STK11ex3-9 mutations (P = .003). In multivariate analysis, STK11ex1-2 mutations remained associated with a poor prognosis (P = .002). Results were validated in two public datasets. Western blots showed that STK11ex1-2 mutatedtumors expressed short STK11 isoforms. Finally using mRNAseq data from the TCGA cohort, we showed that a stroma-derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors. All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities.

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.

Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation.

In lung cancer, an association was made between drastic clinical response to epidermal growth factor receptor (EGFR) inhibitors and the presence of somatic mutations within the tyrosine kinase domain of the EGFR. In some cases, patients with partial response or disease stabilization do not always have EGFR-mutated tumors. To go further in the characterization of the EGF pathway, we screened EGFR, ERBB2, ERBB3, KRAS, BRAF, and PIK3CA for mutations in 2 groups of White patients with nonsmall cell lung cancer (45 cancers from women and 46 cancers from men). Associations between TP53 mutations, clinicopathologic parameters, and EGF pathway molecular alterations were analyzed. All mutations were exclusive and essentially found in EGFR and KRAS. We demonstrated that EGFR mutations were linked to female sex, absence of smoking, late age at diagnosis, and adenocarcinoma (ADC) with bronchioloalveolar (BAC) features. Moreover, in invasive ADC with BAC component, microdissection assays showed that mutations were retrieved in both tumor subtypes suggesting that EGFR mutations appear early in lung carcinogenesis. On the contrary, KRAS mutations correlated with smoking, younger age at diagnosis, and ADC subtype regardless of BAC differentiation. These results suggest the existence of distinct carcinogenesis pathways both leading to disruption of EGF regulation and targeted either by tobacco carcinogens or by unidentified toxic. The identification of BAC features in ADC helps clustering patients that are more likely to fit the EGFR-mutated group.