Delayed cut-end recurrence after wedge resection for pulmonary ground-glass opacity adenocarcinoma despite negative surgical margin.

Most pulmonary ground-glass opacity (GGO) nodules are pathologically well differentiated adenocarcinomas. We performed a limited resection trial of GGO lesions 2 cm or smaller from 2003 to 2009, in which 95 patients were accumulated. We confirmed negative surgical cut-end during surgery by margin lavage cytology. In the trial, a 51-year-old man underwent right lower lobe wedge resection for a 1.7 cm mixed GGO lesion. The tumor was papillary predominant adenocarcinoma, pT1NxM0. The resection scar became thicker and was diagnosed as adenocarcinoma by needle biopsy 10 years after the initial surgery. We performed a right lower lobectomy and lymph node dissection. Pathologically, the second tumor was adenocarcinoma similar to the initial one, papillary predominant, and was diagnosed as cut-end recurrence. Small papillary predominant adenocarcinoma might develop delayed cut-end recurrence more than 5 years after limited resection. Careful follow-up with special attention to the cut-end is necessary ideally for 10 years.

Stapling cartridge lavage cytology in limited resection for pulmonary malignant tumors: assessment of cytological status of the surgical margin.

INTRODUCTION: Sublobar resection in primary lung cancer and pulmonary metastatic tumor can result in recurrence at the surgical margin. Confirming the absence of tumor cells at the cut-end is important. We sought to evaluate the efficacy of intraoperative lavage cytology (ILC) of autostapling cartridges in preventing local failure. MATERIALS AND METHODS: An intraoperative cytology examination was performed in 262 consecutive patients undergoing wedge or segmental resection for 311 lesions, including primary lung cancers and pulmonary metastatic tumors, between April 2004 and April 2010. The data of patients with positive cytology results and those who developed local failure were retrospectively reviewed. RESULTS: A total of 139 primary lung cancers and 172 pulmonary metastatic tumors (primary site: 120 colorectal and 52 others) were investigated. The results revealed 22 (7%) positive cytology results (11 primary and 11 metastatic). The resection margins of 19 of the 22 lesions with positive cytology were additionally resected. With a median follow-up period of 42 months, recurrence at the margin developed in 2 of the 19 lesions in which additional resection was performed (11%, 1 primary and 1 metastatic). Recurrence at the margin developed in 2 (67%, 1 primary and 1 metastatic) of the 3 lesions in which additional resection was abandoned. Among the 289 lesions showing negative cytology results, recurrence at the margin developed in 7 (2%, 6 primary and 1 metastatic). CONCLUSIONS: ILC of autostapling cartridges in sublobar resection for pulmonary malignant tumor may be useful for assessing the cytological status of the surgical margin.

Survival and prognostic factors after pulmonary metastasectomy of head and neck cancer: what are the clinically informative prognostic indicators?

OBJECTIVES: The purpose of this study was to elucidate the surgical outcomes and identify the prognostic factors after pulmonary metastasectomy for head and neck cancer (HNC) using a recent, large, single-institutional cohort. METHODS: We retrospectively reviewed the clinicopathological profiles of 77 consecutive patients who underwent metastasectomy for pulmonary metastases (PMs) arising due to HNC from 1992 to 2013. The prognostic factors associated with overall survival (OS) after pulmonary metastasectomy were evaluated using the univariable and multivariable Cox proportional hazard models. The cut-off value of continuous variables was determined by a receiver operating characteristic analysis. RESULTS: The most predominant histology was squamous cell carcinoma (75%). The median disease-free interval between the treatment of primary HNC and the diagnosis of PMs was 17 months. Recurrence before lung metastasectomy was observed in 32% of patients. The median size of the PM was 2.2 cm. The median survival time after lung metastasectomy was 66 months, and the 5-year OS was 54%. In the multivariable analysis, squamous cell histology [hazard ratio (HR) 2.92, 95% confidence interval (CI) 1.00-8.57], disease-free interval (<18 months, HR 3.23, 95% CI 1.49-7.02), recurrence before lung metastasis (HR 2.39, 95% CI 1.19-4.80) and size of the PM (>2.5 cm, HR 2.75, 95% CI 1.33-5.69) were independent predictors of a poor prognosis. The OS of patients with 3 or more factors was significantly worse than that of patients with 2 or less factors (3-year OS 20% vs 83%, P < 0.01). CONCLUSIONS: Surgical resection of PMs from HNC can achieve favourable survival in a selected population. The number of prognostic factors may be useful information for determining the surgical indications and for predicting survival for PMs from HNC.

Extended bronchoplasty for locally advanced left lower lobe lung cancer: surgical technique and outcomes.

Extended bronchoplasty combined with left lower lobectomy plus lingulectomy can be indicated for some locally advanced left lower lobe cancers to avoid pneumonectomy, but its outcome has not been well studied. We retrospectively analysed the surgical outcomes of 10 patients since 2008, when we introduced this procedure. The median age was 67 years (range 42-80). Squamous cell carcinoma was the most common histology. The indication for this procedure was bulky or extranodal metastasis in an interlobar node in 9 patients and massive tumour invasion to the lingula in 1 patient. Bronchoplasty was performed by a sleeve (n = 7) or deep-wedge (n = 3) resection of the left main and superior division bronchi, according to the type of tumour extension. One of the sleeve cases resulted in anastomotic kinking and was converted to left pneumonectomy intraoperatively, but no postoperative morbidity or mortality was observed. Locoregional recurrence was not found with a median follow-up of 31 months (range 13-83). This type of extended bronchoplasty can be a safe alternative to left pneumonectomy for left lower lobe cancers invading an interlobar node or lingula in which R0 resection is difficult by a simple or standard sleeve left lower lobectomy.

Long-term survival after complete resection of non-small-cell lung cancer in patients with interstitial lung disease.

OBJECTIVES: Patients with lung cancer and interstitial lung disease (ILD), usual interstitial pneumonia in particular, are known to have a poor outcome. The aim of this study was to evaluate the prognostic impact of ILD in patients with non-small-cell lung cancer. METHODS: A total of 2054 consecutive patients underwent complete resection of Stage IA-IIIA non-small-cell lung cancer in our institution between January 2002 and March 2013. The presence of ILD was diagnosed and categorized based on high-resolution computed tomography images. Multivariate analysis was performed to identify the prognostic factors. RESULTS: There were 106 (5%) patients with ILD. There were significantly more patients who developed severe complications (P < 0.01) in the ILD group, with 4 (4%) patients developing acute exacerbation. Although the difference in postoperative mortality rate was marginal between the groups (P = 0.07), the 5-year overall survival and cancer-specific survival rates of the ILD patients were significantly worse than those of the non-ILD group (overall survival: 40.4% vs 72.0%, P < 0.01; cancer-specific survival 55.4% vs 78.6%, P < 0.01). The results of multivariate analysis showed that coexistence of ILD (hazard ratio 1.45; P = 0.01) was an independent, unfavourable prognostic factor. CONCLUSIONS: The presence of ILD led to a much poorer survival after complete resection of non-small-cell lung cancer.

Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia.

INTRODUCTION: Lung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions. However, the characteristic biological and genetic features of LCOP are not fully clarified. MATERIALS AND METHODS: We used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n=44) and other lepidic-predominant adenocarcinomas (non-LCOP, n=56). We also analyzed the genomic mutation features of LCOP (n=4) by whole-exome sequencing (WES). RESULTS: All LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence-free survival, compared to non-LCOP patients (95.5% and 74.4%; P=0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P=0.001 and P=0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH-1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P=0.021 and P=0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP. CONCLUSIONS: Our results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer.

Effectiveness of Bone Suppression Imaging in the Detection of Lung Nodules on Chest Radiographs: Relevance to Anatomic Location and Observer's Experience.

OBJECTIVE: To evaluate the effectiveness of bone suppression imaging (BSI) software in lung-nodule detection on chest radiographs (CXRs) in relation to nodule location and observer's experience. MATERIALS AND METHODS: The CXRs of 80 patients, of which 40 had a lung nodule (8 to 30 mm in diameter) and 40 did not have any nodules, were interpreted by 20 observers comprising of 7 pulmonologists with >10 years of experience and 13 pulmonology residents. Each patient's image was sequentially read, first using the standard CXR and thereafter with the BSI software. The nodule location and confidence level with regard to the presence of a lung nodule were recorded. Receiver operating characteristic analysis was used to evaluate observer performance. RESULTS: The average area under the curve (AUC) for the observers' receiver operating characteristic significantly improved from 0.867 to 0.900 (P=0.004) with the use of the BSI software. The average AUC for experienced pulmonologists improved from 0.877 to 0.924 (P=0.017) for lung nodules located in the apical and peripheral areas but not for those in the inner area. The average AUC for residents improved regardless of nodule location. CONCLUSION: The use of BSI software improved the performance in lung-nodule detection on CXRs regardless of observer's experience and was more effective for observers with limited experience.

Long-term survival outcome after postoperative recurrence of non-small-cell lung cancer: who is 'cured' from postoperative recurrence?

OBJECTIVES: Since survival after postoperative non-small-cell lung cancer (NSCLC) recurrence is extremely poor, the long-term post-recurrence outcomes are not well understood. The purpose of this study was to evaluate the long-term post-recurrence outcomes and clarify who are possibly 'cured' in recent clinical practice. METHODS: We reviewed the medical records of 635 patients who developed postoperative recurrence until 2012 after R0 resection for pathological Stage IA-IIIA NSCLC between 1993 and 2006. Factors associated with post-recurrence survival (PRS) and the characteristics of the long-term (≥5 years) survivors were analysed retrospectively. RESULTS: The 5-year PRS rate of all 635 patients was 13%. Multivariable analysis revealed that female [hazard ratio (HR) = 0.78], adenocarcinoma (HR = 0.77), locoregional (only) recurrence (HR = 0.59) and longer recurrence-free survival (HR = 0.99) were favourably associated with PRS. A total of 51 patients achieved 5-year PRS; however, 32 (63%) were cancer-bearing patients in their fifth post-recurrent year who were mainly treated by epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Subsequent PRS curves for cancer-controlled and cancer-bearing groups were different (8-year PRS: 94% vs 31%, P = 0.003). Among 19 cancer-controlled patients in their fifth post-recurrent year, 17 (89%) patients initially received radical local therapy for their recurrence. CONCLUSIONS: Two-thirds of 5-year survivors after postoperative NSCLC recurrence had a cancer-bearing status and showed deteriorated subsequent survival. Curability of postoperative NSCLC recurrence should be evaluated in terms of the 'cancer-controlled' status, and 'cured' population is included in the patients who are 'cancer controlled' at the fifth post-recurrent year.

A Phase II Study of Partial and Subtotal Thymectomy for Thymoma (JART02).

BACKGROUND: We believe the merit of preservation of a part of the thymus following surgery for thymoma. We evaluated the efficacy of partial or subtotal thymectomy for early-stage thymoma in the prospective study. METHODS: The Japanese Association for Research on the Thymus conducted a multiple institutional study of thymectomy for thymoma localized in the thymus without total thymectomy. Patients without autoimmune disease who had an anterior mediastinal tumor that had been clinically diagnosed as an early-stage thymoma were enrolled in the study. Patients who were positive for anti-acetylcholine receptor antibodies were excluded. RESULTS: Sixty-three patients were enrolled preoperatively; 27 patients were judged as being inappropriate based on the other thymic pathologies or tumor invasion. The remaining 36 cases were diagnosed as early-staged thymoma and analyzed. The mean age of the patients was 61 years. The mean maximal tumor diameter in the resected specimens was 3.6 cm. The most common pathological types of thymoma were AB (n = 10) and B1 (n = 10). The Masaoka stages were classified as stage I (n = 22) and II (n = 14). The mean observation period was 63 months. Two patients died due to respiratory dysfunction, which was not related to thymoma. One hundred percent of the patients remained recurrence-free. CONCLUSIONS: This prospective study suggested the efficacy of partial or subtotal thymectomy for early-stage thymoma in patients without any apparent evidence of autoimmune disease. We can preserve a part of the thymus even following surgery for thymoma to prepare the possible second malignancies or diseases in future.

Is cancer history really an exclusion criterion for clinical trial of lung cancer? Influence of gastrointestinal tract cancer history on the outcomes of lung cancer surgery.

Objective: Exclusion of patients with a history of other cancer treatment except in situ situation has been considered to be inevitable for clinical trials investigating survival outcome. However, there have been few reports confirming these influences on surgical outcome of lung cancer patients ever. Methods: Multi-institutional, individual data from patients with non­small cell lung cancer resected between 2000 and 2013 were collected. The patients were divided into two groups: those with a history of gastrointestinal tract cancer (GI group) and those without any history (non-GI group). We compared the outcomes with well-matched groups using propensity scoring to minimize bias related to the nonrandomness. The influence of gastrointestinal tract cancer stage, disease-free interval, and treatment method for gastrointestinal tract cancer on the surgical outcome of non­small cell lung cancer was examined. Results: We analyzed 196 patients in the GI group and 3732 in the non-GI group. In unmatched cohort, multivariate analyses showed that a history of gastrointestinal tract cancer did not affect overall survival or recurrence-free survival. Independent predictors of poor prognosis included older age, male sex, high carcinoembryonic antigen levels and advanced clinical stage of non­small cell lung cancer. The two groups in the matched cohort demonstrated equivalent overall survival and recurrence-free survival, even in patients with clinical stage I. Gastrointestinal tract cancer stage, disease-free interval and treatment method for gastrointestinal tract cancer were not associated with outcomes. Conclusions: History of early gastrointestinal tract cancer completely resected is not always necessary for exclusion criteria in clinical trial of lung cancer.

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung.

PURPOSE: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. EXPERIMENTAL DESIGN: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). RESULTS: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%). CONCLUSIONS: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757-65. ©2016 AACR.

Histology is a Prognostic Indicator After Pulmonary Metastasectomy from Renal Cell Carcinoma.

OBJECTIVES: There are only a few detailed reports concerning the prognosticators following surgical resection of pulmonary metastases (PMs) from renal cell carcinoma (RCC). We investigated the prognosis of patients with RCC PMs undergoing pulmonary metastasectomy and identified prognostic factors in a multi-institutional retrospective study. METHODS: We retrospectively evaluated 84 patients who underwent resection of PMs from RCC between 1993 and 2014. We assessed the clinicopathological characteristics, focusing on the histological findings of PMs. We classified the histology into three types: pure clear cell carcinoma (N = 68), clear cell carcinoma combined with other histology type (N = 8), and non-clear cell carcinoma (N = 8). We examined the relationship between these histological types and the prognosis of patients with PMs from RCC. RESULTS: Complete resection was achieved in 78 patients (93%). The 5-year overall survival rate after metastasectomy was 59.7%. In multivariate analysis, three factors were found to be independent favorable prognostic factors of overall survival after lung metastasectomy [tumor size <2 cm, hazard ratio (HR) = 0.31, 95% confidence interval (CI) 0.13-0.78, P = 0.012; clear cell type, HR = 0.37, 95% CI 0.16-0.83, P = 0.025; and complete resection, HR = 0.27, 95% CI 0.10-0.78, P = 0.015]. CONCLUSIONS: This study indicates that a histological finding of the clear cell type is a significant favorable prognostic factor in addition to complete resection and a tumor size <2 cm. Histological evaluation of PM lesions is important for predicting survival after metastasectomy.

Limited resection for early-stage non-small cell lung cancer as function-preserving radical surgery: a review.

Since 'radical lobectomy' was reported by Cahan in 1960, the standard surgical care for lung cancer has been lobectomy, in which units of the lobe are excised with their specific regional hilar and mediastinal lymphatics. However, pulmonary function-preserving limited resection for lung cancer has gradually become more prevalent in the late 20th century. In 1995, Ginsberg et al. conducted a randomized controlled trial in which limited resection (segmentectomy and wide-wedge resection) and lobectomy for stage I lung cancer were compared and reported that limited resection should not be applied to healthy patients with clinical stage IA lung cancer. The detection of small-sized and early-stage lung cancers has improved with advancement in diagnostic technology. Ground-glass opacity of lung nodules, as recognized on thin-slice computed tomography, has also been widely recognized as being correlated with less-invasive pathological findings of alveolar epithelial cell replacement of cancer cells. The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group conducted a cohort study of early peripheral lung cancer and investigated the validity thin-slice computed tomography criteria to diagnose non-invasive lung adenocarcinoma for the preoperative prediction of pathological non-invasive cancer. Following this observational study, the on-going JCOG0802/WJOG4607L, JCOG0804/WJOG4507L and JCOG1211 trials were initiated to confirm the validity of limited resection for stage I lung cancer patients stratified according to preoperative thin-slice computed tomography findings; these trials will clarify whether limited resection for lung cancer is not function-preserving but also only curative surgery.

Clinicopathological significance of caveolin-1 expression by cancer-associated fibroblasts in lung adenocarcinoma.

PURPOSE: Caveolin is an essential constituent of caveolae and has many biological functions. Expression of caveolin-1 in cancer cells was reported to be a prognostic marker in several types of cancers, the prognostic significance of its expression in cancer-associated fibroblasts (CAFs) has not been investigated. This study aimed to evaluate the clinicopathological significance of expression by CAFs in lung adenocarcinoma. METHODS: We examined caveolin-1 expression in both CAFs and cancer cells in stage I invasive lung adenocarcinoma (n = 412) and analyzed the relationship between the expression and clinicopathological factors. RESULTS: Caveolin-1 expression by CAFs and cancer cells was observed in 12.1% and 7.8% of adenocarcinomas, respectively. Tumors with caveolin-1-positive CAFs had vascular and pleural invasion significantly more frequently than those with caveolin-1-negative CAF (p < 0.05). This was also the cases with tumors with caveolin-1-positive cancer cells (p < 0.01). Caveolin-1 expression by CAFs and that by cancer cells were significant predictors of shorter recurrence-free survival (p < 0.001). Caveolin-1 expression by CAFs and cancer cells was found in 25% and 30% of solid predominant subtype, respectively, but only 9.2% and 2.7% of non-solid predominant subtype, respectively. The frequency of cases with caveolin-1-positive CAFs or cancer cells was significantly higher in the solid predominant subtype than in non-solid predominant subtype (p < 0.001). CONCLUSIONS: Our current results highlight the prognostic importance of caveolin-1 expression by CAFs in stage I lung adenocarcinoma and provide new insights into the biological significance of caveolin-1 in the tumor microenvironment, especially in microenvironment of solid predominant adenocarcinoma.

The role of pulmonary resection in tumors metastatic from esophageal carcinoma.

OBJECTIVE: The purposes of this study were to determine the role of surgical treatment and to identify factors affecting survival of patients undergoing resection of pulmonary metastatic tumors from esophageal carcinoma. METHODS: We reviewed 33 patients who had undergone resection of pulmonary metastatic tumors from esophageal carcinoma after definitive treatment. RESULTS: The operative morbidity rate was only 5%, no patients died within 30 days after resection, and complete resection was achieved in 30 patients. The overall 1-, 3- and 5-year survival rates after pulmonary metastasectomy were 79.4, 47.8 and 43.0%, respectively, and the median survival time was 17.9 months. The factors found on univariate analysis to affect survival significantly were disease-free interval <16 months and nodal involvement of the primary tumor. The most frequent pattern of initial recurrence after pulmonary resection was distant metastasis (70%). CONCLUSIONS: We demonstrated the safety and effectiveness of surgical resection for selected patients with pulmonary metastatic tumors from esophageal carcinoma. However, with a high recurrence rate in patients with negative prognostic factors, adjuvant systemic chemotherapy after pulmonary resection should be considered.

Thin-section computed tomography findings of lung adenocarcinoma with inherent metastatic potential.

PURPOSE: The solid component of lung ground-glass nodules on thin-section computed tomography (TSCT) reflects cancer cell progression and invasiveness. The purpose of this study was to clarify the cut-off value of preoperative TSCT findings in treating a lesion suspected of being adenocarcinoma and to recognize the timing of surgical resection for lung nodules. METHODS: We reevaluated the TSCT findings in 392 patients with clinical stage IA lung adenocarcinoma who underwent surgical resection between 2003 and 2007. We identified the clinical parameters that were most useful for predicting recurrence and identified a cut-off level for each parameter. RESULTS: Recurrence was observed in 75 (19 %) of 392 patients (median follow-up: 7 years). The size of internal consolidation of a lung nodule (SCL) and the ratio of the SCL to the maximum tumor diameter (C/T ratio) were extracted as independent factors that predicted recurrence. Only 1 (0.3 %) patient each with a lung nodule C/T ratio ≤0.5 and SCL ≤10 mm recurred. These conditions were associated with a significantly better overall survival and recurrence-free survival. CONCLUSION: In patients with clinical stage I lung adenocarcinoma with a C/T ratio ≤0.5 and/or SCL ≤10 mm on TSCT, surgery is extremely likely to achieve a cure.

The ratio of cancer cells to stroma after induction therapy in the treatment of non-small cell lung cancer.

PURPOSE: Induction therapy induces degenerative changes of various degrees in both cancerous and non-cancerous cells of non-small cell lung cancer (NSCLC). The effect of induction therapy on histological characteristics, in particular the ratio of residual cancer cells to non-cancerous components, is unknown. METHODS: Seventy-four NSCLC patients treated with induction therapy followed by surgery were enrolled. Residual cancer cells were identified using anti-pan-cytokeratin antibody (AE1/AE3). We analyzed and quantified the following three factors via digital image analysis; (1) the tumor area containing cancer cells and non-cancerous components (TA), (2) the total area of AE1/AE3 positive cancer cells (TACC), (3) the percentage of TACC to TA (%TACC). These factors were also analyzed in a matched control group (surgery alone, n = 80). RESULTS: The median TACC of the induction therapy group was significantly lower than that of the control group (p < 0.01). In addition, the median %TACC of the induction therapy group (5.9 %) was significantly lower than that of the control group (58.6 %) (p < 0.01). TACC had a strong positive correlation with TA in the control group (r = 0.93), but not in the induction therapy group. Conversely, TACC had a strong positive correlation with %TACC in the induction therapy group (r = 0.95), but not in the control group. CONCLUSION: Unlike the control group, the smaller the total area of residual cancer cells, the higher residual tumor contained non-cancerous components in the induction group, which may be the characteristic histological feature of NSCLC after induction therapy.

Microenvironmental changes in the progression from adenocarcinoma in situ to minimally invasive adenocarcinoma and invasive lepidic predominant adenocarcinoma of the lung.

OBJECTIVES: Invasive lepidic predominant adenocarcinoma (LPA) of the lung is thought to progress in a stepwise fashion from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The aim of this study was to investigate the microenvironmental changes during the development from AIS to LPA. MATERIALS AND METHODS: Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3cm (LPA-S, n=113), and LPA larger than 3cm (LPA-L, n=47) were analyzed. We then evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), stem-cell-related molecules (ALDH-1), and growth factor receptors (c-Met, EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed. RESULTS: No significant difference in these characteristics was found between LPA-S and LPA-L. Laminin-5 expression in the non-invasive carcinoma component of MIA was significantly higher than that of AIS (p<0.001). During the progression from MIA to LPA-S, the expression level of laminin-5 in the invasive carcinoma component was significantly elevated (p<0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p<0.05, CD204+ TAMs; p<0.001, CD34+ microvessel; p<0.05). Ezrin expression in the invasive carcinoma component of LPA-L was significantly increased (p<0.05) compared to LPA-S; however, the number of tumor-promoting stromal cells were not different between these two groups. CONCLUSION: Our current results indicated that microenvironmental molecular changes occur during the progression from MIA to LPA-S and suggested that this process may play an important role in disease progression from AIS to LPA.

The Outcomes of a Limited Resection for Non-Small Cell Lung Cancer Based on Differences in Pathology.

OBJECTIVE: A precise preoperative diagnosis of in situ or minimally invasive carcinoma may identify patients who can be treated by limited resection. Although some clinical trials of limited resection for lung cancer have started, it will take a long time before the results will be published. We have already reported a large-scale study of limited resection. We herein report the data for a subclass analysis according to differences in pathology. METHODS: Data from multiple institutions were collected on 1710 patients who had undergone limited resection (segmentectomy or wedge resection) for cT1N0M0 non-small cell carcinoma. The disease-free survival (DFS) and recurrence-free proportion (RFP) were analyzed. Small cell carcinomas and carcinoid tumors were excluded from this analysis. Adenocarcinomas were sub-classified into four groups using two factors, the ratio of consolidation to the tumor diameter (C/T) and the tumor diameter alone. RESULTS: The median patient age was 64 (20-75) years old. The mean maximal diameter of the tumors was 1.5 ± 0.5 cm. The DFS and RFP at 5 years based on the pathology were 92.2 and 94.7 % in adenocarcinoma (n = 1575), 76.3 and 82.4 % in squamous cell carcinoma (SqCC) (n = 100), and 73.6 and 75.9 % in patients with other tumors (n = 35). The prognosis of adenocarcinoma in both groups A (C/T ≤0.25 and tumor diameter ≤2.0 cm) and B (C/T ≤0.25 and tumor diameter >2.0 cm) was good. In SqCC, only segmentectomy was a favorable prognostic factor. In the groups with other pathologies, large cell carcinomas were worse in prognosis (the both DFS and RFP: 46.3 %). CONCLUSION: Knowing the pathological diagnosis is important to determine the indications for limited resection. Measurement of the tumor diameter and C/T was useful to determine the indications for limited resection for adenocarcinoma. Limited resection for adenocarcinomas is similar with a larger resection, while the technique should be performed with caution in squamous cell carcinoma and other pathologies.