Visceral Pleura Invasion Research Articles

Exploring the molecular and immune-landscape of lung cancer associated with cystic airspaces

To explore the molecular biological characteristics of lung cancer associated with cystic airspaces (LCCA) and its potential roles on prognosis. A total of 165 LCCAs and 201 non-LCCAs were enrolled in this study. Bulk RNA sequencing was implemented in eight LCCAs and nine non-LCCAs to explore the differentially expressed genes. TCGA data were used to analyze LCCA-specific genes that associated with overall survival (OS). The median age was 60 (IQR 53 to 65) years in LCCA cohort. We found LCCA were predominant in men and had less visceral pleura invasion (VPI) or lympho-vascular invasion (LVI). Moreover, LCCA presented with higher histological heterogeneity. Kaplan-Meier analysis showed that patients of age more than 60 and positive VPI had significantly less PFS in LCCA. Cox regression suggested that LCCA, micropapillary subtype proportion and VPI were the independent risk factors for PFS. LCCA had up-regulated pathways associated with EMT, angiogenesis and cell migration. In addition, LCCA displayed higher levels of immunosuppressor infiltration (M2 macrophages, CAFs and MDSCs) and distinct cell death and metabolic patterns. BCR/TCR repertoire analysis revealed less BCR richness, clonality and high-abundance shared clonotypes in LCCA. Finally, Cox regression analysis identified that four cystic-specific genes, KCNK3, NRN1, PARVB and TRHDE-AS1, were associated with OS of lung adenocarcinoma (LUAD). And cystic-specific risk scores (CSRSs) were calculated to construct a nomogram, which performance well. Our study for the first time indicated significantly distinct molecular biological and immune characteristics between LCCA and non-LCCA, which provide complementary prognostic values in early-stage non-small cell lung cancer (NSCLC).

Postoperative CT surveillance in the evaluation of local recurrence after sub-lobar resection of neoplastic lesions of the lung

ObjectiveAs indications for sub-lobar resections increase, it will become more important to identify risk factors for postsurgical recurrence. We investigated retrospectively the association between local recurrence after sub-lobar resection of neoplastic lung lesions and pre- and post-operative CT imaging and pathologic features. Materials and methodsWe reviewed retrospectively neoplastic lung lesions with postoperative chest CT surveillance of sub-lobar resections in 2006–2016. We defined “suspicious” findings as nodularity ≥3 mm or soft tissue thickening ≥4 mm along the suture line and/or progression and explored their association with local recurrence. Primary lung cancer stage, tumoral invasion of lymphatics, visceral pleura or large vessels, bronchial and vascular margin distance were also assessed. ResultsOur study group included 45 cases of sub-lobar resection took for either primary (n = 37) or metastatic (n = 8) lung tumors. Local recurrence was observed in 16 of those patients. New nodularity ≥3 mm or soft tissue thickening ≥4 mm along the suture line on surveillance CT was significantly associated with local recurrence (p = 0.037). Additionally, solid nodule (p = 0.005), age at surgery ≤60 years (p = 0.006), two or more sites of invasion (p < 0.0001) and poor histologic differentiation (p = 0.0001) were also significantly associated with local tumor recurrence. Of 16 patients with surveillance post-surgical PET-CT, 15 had elevated FDG uptake. ConclusionThe postoperative changes along the suture line should follow a predictable time course demonstrating a pattern of stability, thinning or resolution on CT surveillance. New or increasing postoperative nodularity ≥3 mm or soft tissue thickening ≥4 mm along the suture line requires close diagnostic work-up. Surgical pathology characteristics added prognostic value on postoperative recurrence surveillance.

Clinicopathological Features and Prognosis of Lung Adenocarcinoma Patients With K-RAS Gene Mutation.

To investigate the relationship between K-RAS gene mutation and clinicopathological features and prognostic factors in lung adenocarcinoma. A total of 795 patients with lung adenocarcinoma diagnosed and tested for ten genes from January 1, 2016, to December 31, 2019, were reviewed. One hundred forty patients with K-RAS gene mutation lung adenocarcinoma were screened, of which 82 cases were included in this group, and complete follow-up data were obtained. PD-L1 immunohistochemistry was further performed, and the correlation between K-RAS mutation patients and clinicopathological features and related driver genes was analyzed. The survival curve was drawn by Kaplan-Meier curve. The effects of clinicopathological features on patients' survival were analyzed by Cox univariate and multivariate analysis. The age of onset of 82 patients with K-RAS gene mutation lung adenocarcinoma was 46 to 89 years old, and the median age of onset was 69 years old. There were 64 male patients (78.05%) and 18 female patients (21.95%), including 68 smokers (82.93%). Tumor size: 2 to 5.5 cm, with an average tumor size of 3.5 cm. Histopathologic types: solid type in 60 cases (73.17%), micropapillary type in 2 cases (2.43%), and invasive mucinous type in 20 cases (24.39%). The degree of tumor differentiation: well-differentiated: 0 cases, moderately differentiated: 10 cases (12.20%), poorly differentiated: 72 cases (87.80%). Fifty cases (60.98%), 29 cases (35.37%), 29 cases (35.37%), 59 cases (71.95%), and 35 cases (42.68%) were complicated with nerve invasion, vascular invasion, visceral pleura invasion, lymph node metastasis, and distant organ metastasis, respectively. Among them, distant organ metastasis included 24 cases (68.57%) of bone metastasis and 11 cases (36.67%) of brain metastasis. Tumor Ki-67 proliferation index ≥50%: 54 cases (65.85%). Related driver gene mutations: There were 6 cases (7.31%) with a deletion mutation of exon 19 in EGFR or L858R mutation of exon 21 in EGFR, respectively. Immune factor PD-L1 ≥50%: 65 cases (79.27%). The patients were followed up for 402 to 1221 days, with a median follow-up of 612 days. Thirty-five cases died during the follow-up. The 1-, 3-, and 5-year overall survival rates were 100%, 62.20%, and 57.31%, respectively. Cox univariate analysis showed that the degree of tumor differentiation, vascular invasion, distant organ metastasis, Ki-67 index, deletion mutation of exon 19 in EGFR, and high expression of PD-L1 (≥50%) could all affect the prognosis of patients ( P < 0.05). Cox multivariate analysis showed that high expression of PD-L1 (≥50%) was an independent predictor of prognosis in patients with K-RAS gene mutation in lung adenocarcinoma. K-RAS mutant lung adenocarcinoma is a malignant tumor with high invasiveness and high mortality. The degree of tumor differentiation, vascular invasion, distant organ metastasis, Ki-67 index, deletion mutation of exon 19 in EGFR, and high expression of PD-L1 (≥50%) in patients with K-RAS mutation lung adenocarcinoma can affect the overall survival time of patients. The high expression of PD-L1 (≥50%) is an independent risk factor affecting the prognosis (survival time).

Prognostic value of TLR from FDG PET/CT in patients with margin-negative stage IB and IIA non-small cell lung cancer.

To evaluate the prognostic value of TLR from PET/CT in patients with resection margin-negative stage IB and IIA non-small cell lung cancer (NSCLC) and compare high-risk factors necessitating adjuvant treatment (AT). Consecutive FDG PET/CT scans performed for the initial staging of NSCLC stage IB and IIA were retrospectively reviewed. The maximum standardized uptake value (SUVmax) of the primary tumor and mean SUV of the liver were acquired. The tumor-to-liver SUV ratio (TLR) was also calculated. Charts were reviewed for basic patient characteristics and high-risk factors for considering AT (poor differentiation, visceral pleura invasion, vascular invasion, tumors > 4cm, and wedge resection). Statistical analysis was performed using Cox regression analysis and the Kaplan-Meier method. Of the 112 patients included, 15 (13.4%) died, with a median overall survival (OS) of 43.8months. Twenty-two patients (19.6%) exhibited recurrence, with median disease-free survival (DFS) of 36.0months. In univariable analysis, pathology, poor differentiation, and TLR were associated with shorter DFS and OS. In multivariable analysis, TLR (hazard ratio [HR] = 1.263, p = 0.008) and differentiation (HR = 3.087, p = 0.012) were associated with shorter DFS. Also, TLR (HR = 1.422, p < 0.001) was associated with shorter OS. TLR from FDG PET/CT was an independent prognostic factor for recurrence and survival. PET parameters constitute risk factors for consideration in the decision-making for AT in margin-negative stage IB and IIA NSCLC. In this study, TLR from FDG PET/CT was an independent prognostic factor in stage IB-IIA non-small cell cancer patients. Although additional validation studies are warranted, TLR has the potential to be used to determine the need for adjuvant therapy. • High TLR is an independent poor prognostic factor in stage IB-IIA NSCLC. • Adjuvant treatment should be considered in patients with high TLR following complete tumor resection.

TUMOR FEATURES BEYOND TUMOR SIZE: A POPULATION-LEVEL ANALYSIS OF PATIENTS WITH SURGICALLY RESECTED NON-SMALL CELL LUNG CANCER (NSCLC) IN THE SEER MEDICARE DATABASE

TUMOR FEATURES BEYOND TUMOR SIZE: A POPULATION-LEVEL ANALYSIS OF PATIENTS WITH SURGICALLY RESECTED NON-SMALL CELL LUNG CANCER (NSCLC) IN THE SEER MEDICARE DATABASE

Research Progress on Spread Through Air Spaces of Lung Cancer

气腔扩散（spread through air spaces, STAS）是2015版世界卫生组织（World Health Organization, WHO）肺癌病理分类中首次提出的概念，是指在主瘤体边界外的气腔内出现微乳头状细胞簇、实性细胞巢或单个肿瘤细胞。除传统观念的肺腺癌浸润方式（间质、脉管及胸膜侵犯）外，STAS被确定为第四种肺浸润性腺癌的侵袭模式。近年来，关于STAS的研究成为热点，STAS的存在不仅与肺癌病理组织学、基因突变等因素相关，诸多研究也证实其可作为肿瘤复发及预后的独立相关因素。但是，也有研究认为人为因素可以造成STAS的形态学假象，需在临床工作中注意甄别。本文就STAS的分类、相关病理学特征、基因状态改变以及可能造成STAS假象的人为因素等方面的研究进展予以综述。

In Spite of Curative Radical Pulmonary Procedures, Lesser Pulmonary Resection Shows More Favorable Prognosis in Surgically Treated NSCLC With Synchronous Isolated Cranial Oligometastases.

Oligometastatic disease in lung cancer is not a rare condition as previously thought. Among 812 non-small cell lung cancer patients treated surgically with lung resection between October 2011 and October 2018 at the Department of Thoracic Surgery, Florence Nightingale Hospitals, Turkey, 28 patients (3.4%) had synchronous cranial metastases. We analyzed synchronous isolated cranial metastases patients treated by locally ablative treatments (surgery, radiotherapy, or both). Metastases existing at the diagnosis of primary cancer were considered as synchronous, and their treatment was performed before (at least 1 month) or after (for maximum 1 month) surgery of the primary lung lesion. Prognostic factors affecting survival are evaluated retrospectively to identify clinical factors predicting survival in an effort to better select patients for surgery. Patients having T1-T2 primary lung tumors, no mediastinal lymph node metastasis, receiving minor anatomical lung resection, receiving neoadjuvant chemotherapy, having single cranial metastasis, and receiving surgical cranial metastasectomy were found to have better survival. According to tumor histology, having adenocarcinoma, and not having lymphovascular or visceral pleura invasion correlated with better survival. Average survival time was 52.1 months and median survival was 32 months. The last mortality during the follow-up was at 24 months; cumulative survival was 48.3% at that time. Our study was designed to define the criteria for patients with oligometastatic disease who may benefit from lung resection.

Predictive value of radiological features on spread through air space in stage cIA lung adenocarcinoma.

BackgroundSpread through air space (STAS) is a risk factor for disease recurrence in patients with stage IA lung adenocarcinoma (LUAD) who undergo limited resection. Preoperative prediction of STAS could help intraoperative surgical decision-making in small LUAD patients. The aim of the study was to evaluate the predictive value of radiological features on STAS in stage cIA LUAD.MethodsA case-control study was designed through retrospective analysis of the radiological features of patients who underwent curative surgery for LUAD with a clinical tumor size ≤3 cm. Univariable and multivariable analyses were used to identify the independent risk factors for STAS. The predicted probability of STAS was calculated by a specific formula. Receiver operating characteristic (ROC) curves were used to determine a cut-off value with appropriate specificity while maintaining high sensitivity for STAS positivity.ResultsSTAS was frequently observed in acinar predominant (P<0.001), micropapillary predominant (P<0.001) and solid predominant (P<0.001) tumors and was significantly associated with larger pT size (P<0.001), presence of micropapillary component (P<0.001), lymphovascular invasion (LVI) (P<0.001), visceral pleura invasion (VPI) (P<0.001), both N1 and N2 lymph node metastasis (P<0.001) and ALK rearrangement (P<0.001). STAS-positivity was significantly associated with the presence of cavitation (P=0.047), lobulation (P=0.009), air bronchogram (P<0.001), and vascular convergence (P=0.016) and was also associated with greater maximum tumor diameter (P<0.001), maximum solid component diameter (P<0.001), maximum tumor area (P<0.001), consolidation/tumor ratio (CTR) (P<0.001), tumor disappearance ratio (TDR) (P<0.001) and computed tomography (CT) value (P<0.001). Multivariable analysis showed that STAS was associated with air bronchogram (P=0.042), maximum tumor diameter (P=0.015), maximum solid component diameter (P=0.022) and CTR (P<0.001). The ROC curve showed that the area under the curve (AUC) was 0.726 in the model for predicting STAS, with a sensitivity and specificity of 95.2% and 36.8%, respectively.ConclusionsSTAS-positive LUAD was associated with air bronchogram, maximum tumor diameter, maximum solid component diameter and CTR. These radiological features could predict STAS with excellent sensitivity but inferior specificity.

Mutational profiling of lung adenocarcinoma in China detected by next-generation sequencing.

NSCLC is the most common type of lung cancers. The purpose of this study is to screen cancer-related mutations in early LUAD in China through NGS technology, determine their correlation with clinical characteristics and provide basis for treatment decisions. In this study, we performed a 583 gene panel to detect the mutational spectrum of the tumors which were collected from 98 LUAD patients. The sequencing data and clinical characteristics were analyzed. Mutations were identified in 94.9% of patients. EGFR had the highest mutation frequency which was detected in 66% of the patients and was significantly associated with female gender and non-smoking history. Other genes with high mutation frequency were TP53 (37%), ERBB2 (24%), BCOR (22%), ZFHX3 (19%), BTG1 (17%), ATR (16%), WWTR1 (15%), etc. TP53 mutations were significantly associated with medium and low differentiation of tumors; BCOR and BLM mutations with gender; WWTR1 mutations with age; and ATR mutations with visceral pleura invasion were observed. 61% of the patients harbored at less one actionable alteration associated with FDA-recognized or investigational drugs. Multiple mutations in LUAD patients in this study have not previously been reported in NSCLC. Moreover, mutations in driver genes including EGFR, TP53, BCOR, BLM, WWTR1, and ATR were significantly related to clinical features. The panel used in this study is an effective approach for molecular analysis and can be applied in personalized treatment decision-making and drug development.

Sublobar resections in early-stage non-small cell lung cancer.

This study aims to evaluate the outcomes of sublobar resections in patients with early-stage non-small cell lung cancer and to investigate the factors affecting survival. Medical files of a total of 63 patients (52 males, 11 females; mean age 64 years; range, 39 to 81 years) who underwent sublobar resection for suspected or known early-stage non-small cell lung cancer between January 2001 and August 2013 were retrospectively reviewed. Data including demographic characteristics of the patients, comorbid conditions, smoking status, surgical margin, visceral pleura invasion, distance from surgical margin to tumor, tumor size, pathological N status, cell type, tumor localization, and recurrences were recorded. Survival was significantly longer in the patients with negative surgical margin for tumor (R0) than in those with positive margin (R1) (94.1 months vs. 32.2 months, p<0.01). Survival was also significantly longer in the patients without lymphatic invasion (p<0.01). In early-stage lung tumors, sublobar resection can be performed, if complete resection is performed. Lymphatic invasion is a negative prognostic factor for survival following sublobar resection.

Correlation between image characteristics and pathologic findings in non small cell lung cancer patients after anatomic resection.

IntroductionTumor characteristics in computed tomography (CT) are correlated to pathologic presentation and survival. However, most studies have been based on thin slice thickness CT while lymph node metastatic pattern has remained unclear. The aim of this study was to analyze the correlation between image characteristics under 5 mm slice thickness and pathology findings in non small lung cancer patients who have received curative resection.Materials and methodsFrom January 2010 to May 2014, 440 patients who underwent curative resection were included and medical records were reviewed retrospectively. The tumor size and consolidation tumor ratio were simultaneously evaluated and measured by a physician, a thoracic surgeon, and a radiologist. The correlation between image and pathology characteristics and its survival impact was analyzed.ResultsTumor sizes, as measured by CT and by pathologic measurement were highly coincident. (p < 0.001) GGO predominant lesions were correlated to well-differentiated adenocarcinoma, (p< 0.001), and less tumor necrosis (p<0.0001), lymphocyte infiltration (p = 0.0042) and tumor purity (p <0.0001). In addition, less risk of visceral pleura (p < 0.0001) and angiolymphatic invasion, and fewer metastases to N1 lymph node (p = 0.004) involvement were identified. No lymph node metastasis (0/12) was identified in sub-centimeter pure GGO lesion. The consolidation tumor ratio could be used to differentiate patients’ survival and excellent 5-year overall survival was identified in pure GGO lesion cases.ConclusionNo lymph node metastasis was identified in sub-centimeter pure GGO lesion. The consolidation tumor ratio could be used to differentiate patients’ disease status and overall survival, while excellent 5-year overall survival was identified in cases with pure GGO lesion.

P3.16-013 Prognostic Effect of EGFR Gene Mutation for Recurrence in Completely Resected Lung Adenocarcinoma

Prognostic effect of EGFR gene mutation in disease progression which affecting recurrence pattern and recurrence dynamics after complete resection of lung adenocarcinoma has not been well established. We investigated the relationship between EGFR gene mutation and recurrence dynamics in completely resected lung adenocarcinoma. We retrospectively review 527 patients who underwent curative surgery for lung adenocarcinoma from January 2006 to December 2009. Demographics, clinic-pathologic data, and prognosis data were obtained by review of medical records. The EGFR gene mutation was analyzed by nested polymerase chain reaction followed by bidirectional direct sequencing in case of recurrence. Adenocarcinoma patients who experienced recurrence and had data of EGFR mutation were included in the analysis. Pathologic stage IV were excluded. Patients were divided into M group (mutant EFGR gene) or W group (wild-type EGFR gene). Sites of recurrence and disease-free times (DFT) of two groups were compared. Median follow-up duration was 72 months. Overall 5-year survival rate was 80.1%. Recurrence was detected in 153 patients and 5-year disease-free rate was 58.2%. EGFR gene sequencing was performed in 118 (77.1%) patients. There were 38 (32.2%) loco-regional recurrences and 80 (67.8%) distant metastases. Any mutation of EGFR gene was detected in 66 (59.9%) patients (M group) and 52 patients had wild-type EGFR gene (W group). Sites of recurrence in M group were loco-regional in 25 (37.9%) and distant metastasis in 41 (62.1%) patients. Site of recurrence in W group were loco-regional in 13 (25%) and distant metastasis in 39 (75%) patients. Sites of recurrence of both groups were not significantly different. (p=0.14) Median DFT of two groups were significantly different (M = 20.3 months vs W = 15.1 months, p=0.039). Visceral pleura invasion (p=0.045) and EGFR gene mutation (p=0.039) were prognostic factor for DFT in univariable analysis. In multivariable analysis, EGFR gene mutation was the only prognostic factor for DFT. (HR – 0.676, 95% CI – 0.371 ∼ 0.986, p=0.042) No significant factor for DFT was identified in loco-regional recurrence. EGFR gene mutation, however, was the only significant prognostic factor for DFT of distant metastasis (HR – 0.561, 95% CI – 0.356 ∼ 0.885, p=0.013) in univariable and multivariable analysis. In recurrent lung adenocarcinoma, EGFR gene mutation group showed longer DFT than wild-type EGFR group. EGFR gene mutation is a prognostic factor in lung adenocarcinoma and slow-growing nature of adenocarcinoma with EGFR gene mutation should be considered in surveillance after surgery.

P3.13-001 Clinical Significance of Chest Tomography Characteristics in Non-Small Cell Lung Cancer Patients Who Received Anatomic Resection

Characteristics of CT image, including tumor size and component were correlated to survival. However, most studies discuss the survival impact of image characteristics in early clinical stage populations. No articles were discussed the issue from the view of pathology stage, i.e. actual disease presentations of non-small cell lung cancer patients who presented as resectable disease. The aim of study was to analyze radiologic and pathologic findings of non-small lung cancer patients who received curative resection in order to clarify he clinical correlation between image characteristics and survival impaction. From 2010 January to 2014 May, 440 patients who underwent curative resection, i.e. anatomic resection and mediastinal lymph node resection, were included and medical record were reviewed retrospectively. Chest CT characteristics, including tumor size and consolidation-tumor ratio, were re-evaluated and re-measured by radiologists. The correlation between image and pathology characteristics and its survival impaction were analyzed. We identified tumor size presented in CT and pathologic measurements were highly coincidence (p-value<0.001). The presentation of pure GGO and GGO predominant lesion were adenocarcinoma (p<0.001). Majority of these lesions (61/76, 80.2%) were well differentiated (p<0.0001). In addition, pure GGO lesion has less risk for visceral pleura (p <0.0001), angiolymphatic invasion (p <0.002), and lower risk with N1 lymph node metastasis (p = 0.004) In addition, we found excellent disease free and disease free survival for patients who was identified GGO predominant lesion with size ≤2cm. (Fig 3) The difference of disease free (p= 0.0032, log rank test; Fig 3A) and overall survival (p= 0.0066, log rank test; Fig 3B) of these four subgroups was statistically significance. Non-small cell lung cancer patients who presented with ground glass opacity were corrected with well differentiated adenocarcinoma. In addition, less visceral pleura invasion, less angiolymphatic invasion, and less intrapulmonary lymph node metastases risk were also identified. Our results showed lung cancer patients who presented as GGO predominant lesions and size less than 2 cm may had excellent disease free and overall survival.

PD-L1 expression in pleomorphic, spindle cell and giant cell carcinoma of the lung is related to TTF-1, p40 expression and might indicate a worse prognosis.

Lung sarcomatoid carcinoma of the lung is a rare tumor with a poor prognosis. More than 90% of them are pleomorphic, spindle cell and giant cell carcinoma (PSCGCC). This rare subtype of lung cancer is thought to be more resistant to chemotherapy, and a small subset of them seems to exhibit targetable mutations. Immunotherapy against PD1/PDL-1 is a new emerging treatment, and might be of interest in PSGSCC because they frequently express PD-L1. The aim of our work is to evaluate PD1 and PDL-1 expression in a surgical series of lung PSCGCC and their relationship with morphological and immunohistochemical parameters and prognosis. Thirty-six patients who underwent surgical resection of a PSGSCC were included. PD-L1 (E1L3N) expression on tumor cells and PD1 (NAT105) expression by tumor infiltrating lymphocytes (TILs) were performed by immunohistochemistry. Results were compared to immunohistochemistry tests of TTF1, Napsin A, p40 and to molecular study of EGFR, KRAS, BRAF and HER2. Seventy-five % of PSCGCC were considered as positive for PD-L1.PD-L1 expression in PSGSCC is associated with TTF-1 and/or Napsin A expression (47.2%, p = 0.039). Few p40 positive PSCGCC expressed PD-L1 (8.3%, p = 0.013). PD1 expression was not related to TTF-1 and/or Napsin A expression (p = 0.47), p40 expression (p = 0.68) or survival (p = 0.14). PD-L1 or PD1 expression were not related to the age, gender, pT, pN, stage, visceral pleura invasion, histopathological subtype, the presence of giant cell component, the predominance of sarcomatoid component, and the presence of EGFR or BRAF or HER2 or PIK3CA mutation (p>0.05). PD-L1 expression was correlated with a worse overall survival in PSCGCC (p = 0.045). PD-L1 expression is frequent in PSCGCC and might be associated with the expression of adenocarcinoma markers (TTF-1, Napsin A) or the lack of expression of squamous cell carcinoma marker (p40).

Elderly male smokers with right lung tumors are viable candidates for KRAS mutation screening.

Genetic aberrations in tumor driver genes provide specific molecular targets for therapeutic intervention, which can greatly improve therapeutic outcomes. Here, we analyzed the mutational frequency of EGFR and KRAS gene, as well as EML4-ALK rearrangement, and summarized the clinicopathological characters of Chinese lung cancer patients. We detected the mutation spectrum of 1033 primary lung cancer patients. The analyzed clinicopathological parameters included gender, age at diagnosis, smoking status, pathological TNM stage, tumor morphology and location, visceral pleural invasion, and histological type. A total of 618 patients had mutations in EGFR or KRAS gene as well as rearrangement of EML4-ALK. Exon 19 deletions and L858R in the EGFR gene were the most frequent mutations. Left-side lung cancer was more common in female patients carrying the KRAS mutation. Rearrangement of EML4-ALK was more common in non-tobacco-using male patients, who also exhibited a higher likelihood of visceral pleura invasion. Elderly females who never smoked and possessed 1–20 mm stage I adenocarcinomas in the right side exhibited a higher frequency of EGFR mutations. Elderly male smokers with right lung tumors were viable candidates for KRAS mutation screening.

On adjuvant therapy after limited resections for NSCLC Stage IA in patients with high risk of recurrence: waiting for the announced 8th Edition 2017 of TNM Staging System

The adjuvant therapy in NSCLC Stage IA still remains a controversial issue even in the interdisciplinary decision making after limited resections of the neoplasm as an alternative to lobectomy. The Authors accept from literature that this mainly concerns specific sub-group of patients, the istopathological post-resection diagnosis of whom highlights linfovascular o perineural as well as visceral pleura invasion. There is confidence that the presently depersonalizing rigidity in the guidelines implementation is overcome in the presence of clear istological signs of invasion. As a consequence the interdisciplinary team should reasonably consider as correct the adjuvant treatment.

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.

Adenosquamous Carcinoma of the Lung: Surgical Management, Pathologic Characteristics, and Prognostic Implications

Adenosquamous carcinoma (ASC) is a mixed glandular and squamous cell carcinoma with a more aggressive behavior than the other histologic subtypes of lung cancer. We revisited the pathologic characteristics and surgical results associated with ASC. Patients who underwent surgical resection of non-small cell lung cancer in two French centers were retrospectively reviewed. Patients presenting with ASC (n=141) were compared to those with adenocarcinomas (AC, n=2415) and squamous cell carcinomas (SCC, n=2662) regarding preoperative data, histologic characteristics, and outcome. The frequency of ASC and SCC decreased over time. ASC patients were similar to AC patients regarding age, sex, and smoking habits. The type of resections performed in ASC patients was intermediary between SCC (more pneumonectomy) and AC (more lobectomy) patients. ASC was associated with larger size, more frequent visceral pleura invasion, microinvasion of the lymphatic vessels, and ipsilateral second nodules, compared with SCC and AC. Among the 135 patients with documented ASC, 48% presented with a combination of AC and SCC tumor cells ranging between 40% and 60% of each component, and 55% of cases were associated with undifferentiated large cells. ASC was associated with a lower 5-year survival rate (37%) than SCC and AC (43.4% and 42.8%, respectively, p=0.017). For ASC patients, survival was better during the last decade or in cases of balanced AC/SCC components. ASC is characterized by both histologic aggressiveness and adverse prognosis. In this setting, the impact of adjuvant therapies needs to be reevaluated.

Re-evaluation of the prognostic value of visceral pleura invasion in Stage IB non-small cell lung cancer using the prospective multicenter ACOSOG Z0030 trial data set

PurposeThis study seeks to clarify the modern prognostic significance of visceral pleura invasion (VPI) in Stage IB (T2aN0M0) non-small cell lung cancer (NSCLC) within the context of the 7th edition TNM classification using the data set from a recent prospective multicenter trial. Patients and methods1111 early-stage NSCLC patients participating in the ACOSOG Z0030 trial (1990–2004) underwent curative pulmonary resection. After excluding T2b tumours (>5cm and ≤7cm) and non-size-based T2 factors other than VPI, 289 patients were categorized as Stage IB NSCLC – T2aN0M0 – according to the AJCC 7th edition classification. The patients were divided into three groups according to size and VPI: tumours≤3cm with VPI (Group I, “VPI-alone”, n=83), tumours>3cm and ≤5cm without VPI (Group II, “Size-alone”, n=156), and tumours>3cm and ≤5cm with VPI (Group III, “VPI+Size”, n=50). Multivariate Cox regression analysis was used to assess the association of VPI and size with survival, adjusting for age, gender, histology and type of resection. ResultsVPI in Stage IB was identified in 133 patients (46.0%). Survival analysis in these patients identified an optimal cutpoint for survival based on size of 3.1cm. Group III (VPI+Size) had a 5-year survival rate of 55.0% significantly shorter when compared to Group I (VPI-alone=68.3%, p=0.009), and Group II (Size-alone=67.2%, p=0.021). No difference was found between Groups I and II. Multivariable analysis showed that VPI associated with size was an independent negative prognostic factor of long-term survival, along with older age and limited resection. ConclusionsStage IB patients with VPI and tumours>3cm and ≤5cm have significantly worse prognosis than those with ‘T2a’ tumours on the basis of VPI or tumour size alone. This finding would suggest upstaging these patients from the current IB status to Stage IIA.

MicroRNA‐133b inhibits the growth of non‐small‐cell lung cancer by targeting the epidermal growth factor receptor

Both the deregulation of microRNAs and epidermal growth factor receptor (EGFR) are emerging as important factors in non-small-cell lung cancer (NSCLC). Here, miR-133b was found to be associated with tumor stage, the extent of regional lymph node involvement, stage, visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC. Bioinformatic analysis and luciferase reporter assay revealed that miR-133b can interact specifically with the 3'-UTR of EGFR mRNA. Functionally, miR-133b transfection showed regulatory activity in translationally repressing EGFR mRNA. Moreover, miR-133b transfection may modulate apoptosis, invasion and sensitivity to EGFR-TKI through the EGFR signaling pathways, especially in EGFR-addicted NSCLC cells. Taken together, our findings show that miR-133b can inhibit cell growth of NSCLC through targeting EGFR and regulating its downstream signaling pathway. This finding has important implications for the development of targeted therapeutics for a number of EGFR-addicted cancers.