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Background: Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling., Methods: Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo., Results: The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells., Conclusion: As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors., (© 2022. Society of Surgical Oncology.)

Purpose: Exosomes and their cargo microRNAs play a significant role in various biological processes in cancer. We hypothesized that microRNAs in exosomes secreted by gefitinib-resistant lung cancer cells might induce resistant phenotypes in otherwise gefitinib-sensitive lung cancer cells., Methods: We isolated exosomes generated by the gefitinib-resistant human lung adenocarcinoma cell line PS-9/ZD. PC-9, which is a gefitinib-sensitive cell line, was treated with the PC-9/ZD exosomes, and these PC-9 cells were analyzed for cell proliferation after treatment with gefitinib. miRNA arrays were analyzed in PC-9 and PC-9/ZD cells, and we isolated microRNAs that were expressed at elevated levels in PC-9/ZD cells. Furthermore, we transfected these microRNAs into PC-9 cells and analyzed the effects on the cells' sensitivity to gefitinib., Results: Exosomes isolated from PC-9/ZD cells significantly increased the proliferation of PC-9 cells during gefitinib treatment. A microRNA array analysis showed that miR-564, miR-658, miR-3652, miR-3126-5p, miR-3682-3p and miR-6810-5p were significantly upregulated in PC-9/ZD cells. PC-9 cells transfected with miR-564 or miR-658 showed chemo-resistant phenotypes., Conclusion: Exosomal miR-564 and miR-658 derived from gefitinib-resistant lung cancer cells induce drug resistance in sensitive cells. Cell-to-cell interaction via exosomal microRNAs may be a novel mechanism and therapeutic target of resistance against gefitinib.

Background: We investigated whether the expression of transforming growth factor-beta-induced protein (TGFBI) and intratumoral immune cells including CD8- and Forkhead box protein P3 (Foxp3)-positive T cells in clinical lung cancer patients could predict the therapeutic response to nivolumab., Methods: Thirty-three patients who were treated with nivolumab were enrolled in this study. Immunohistochemical analyses of TGFBI, PD-L1, CD8, Foxp3, and vimentin expression were conducted. Serum concentrations of TGFBI and transforming growth factor-beta1 (TGF-β1) were determined by enzyme-linked immunosorbent assay (ELISA)., Results: Cancer TGFBI was not associated with prognosis and therapeutic response to nivolumab, but cancer stromal TGFBI and intratumoral CD8-positive T cells were associated with them. Therefore, we evaluated cancer stromal TGFBI and intratumoral CD8-positive T cells. The high-TGFBI-expression group had poorer clinical responses than did the low-TGFBI-expression group (p < 0.0001). The number of times nivolumab was administered in the high-CD8-expression group was significantly higher than that in the low-CD8-expression group (p = 0.0046). The high-CD8-expression group had better clinical responses than did the low-CD8-expression group (p = 0.0013). Interestingly, all patients in the high-TGFBI/low-CD8-expression group had progressive disease (PD). In contrast, all patients in the low-TGFBI/high-CD8-expression group had PR + SD (partial response + stable disease) by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)., Conclusions: The dual evaluation of stromal TGFBI and intratumoral CD8-positive T cells could be a useful predictive marker for nivolumab.

Immunotherapy targeting immune checkpoint molecules has provided remarkable clinical benefits in cancer patients but no clinically relevant biomarker for predicting treatment outcomes exists. Recently, we demonstrated that glycan structures of serum α 1 -acid glycoprotein (AGP) changed dramatically in cancer patients and that α1,3fucosylated AGP (fAGP) levels increased along with disease progression and decreased responding to chemotherapy treatments. Here, the fAGP was analyzed in sera prospectively obtained from 39 patients with advanced lung cancer who underwent immunotherapy with anti-PD-1 antibody, nivolumab. Twenty-three patients had significantly high fAGP levels above the cut-off value (H-fAGP) at one month after starting the treatment and 20 patients in this group, whose tumor sizes did not decrease, maintained high fAGP levels continuously and subsequently died. However, the other 16 patients, whose fAGP levels decreased or maintained below the cut-off value (L-fAGP), survived during a 2-year observation even though 5 patients in this group had no tumor shrinkage. Accordingly, the overall survival rate was found to significantly correlate with the fAGP level. Multivariate analyses revealed that the H-fAGP was an independent risk factor for cancer progression. Therefore, the fAGP level appeared to be a reliable biomarker for predicting clinical efficacy of immunotherapy with nivolumab.

Background: Lung combined neuroendocrine carcinomas (NECs) comprise NEC and non-NEC components, such as adenocarcinoma and squamous cell carcinoma. Mutation of epidermal growth factor receptor (EGFR) often is observed in non-NEC but is very rare in sporadic NEC, which almost always has p53 mutation. Therefore, we hypothesized the following research concept: mutation analysis of EGFR and p53 in each component of combined NEC tissues can provide important information on whether such components originate from the same tumor cells or incidentally arise as collision cancers., Methods: We compared the mutations of EGFR and p53 in laser-microdissected NEC and non-NEC from lungs of eight cases affected by combined NEC. We examined the expression of EGFR and NEC markers in the combined NECs by immunohistochemistry., Results: Five of eight cases of combined NEC had the same mutations of EGFR and/or p53 in both non-NEC and NEC. One case had EGFR mutation in only the non-NEC component, and two cases did not have these mutations. Replacement transformation was observed in borderline areas between non-NEC and NEC. The signal of activated EGFR in non-NEC with the same EGFR mutation was more intense than that in NEC components., Conclusions: Our study suggests the mechanism behind the carcinogenesis of lung combined NEC, which is partially caused by the transformation from epithelial carcinoma of non-NEC to NEC.

Objectives: Depletion in skeletal muscle is closely associated with limited physical ability and high mortality. In this study, we evaluated the prognostic significance of skeletal muscle depletion in patients with early-stage non-small-cell lung cancer., Methods: A retrospective analysis of patients with pathological stages I-II lung cancer, who underwent curative resection between 2009 and 2013, was conducted. The truncal muscle index (TMI) (area/height2) at the first lumbar vertebral level was measured by preoperative axial computed tomography. Overall survival and recurrence-free survival were compared between the lowest gender-specific quartile of the TMI and the other quartiles., Results: A total of 314 subjects were included in the study. The cumulative 5-year recurrence-free and overall survival rates were significantly shorter in patients with lower TMIs (69% vs 83.5%, P = 0.028; 64.8% vs 80.1%, P = 0.003, respectively). In multivariable models, the TMI was identified as an independent prognostic factor for overall survival (P =  0.017, hazard ratio 1.84, 95% confidence interval 1.12-3.05), after adjusting for age, gender, preoperative serum albumin, carcinoembryonic antigen, neutrophil to lymphocyte ratio and pathological stage., Conclusions: A low preoperative TMI was associated with a poor postoperative outcome in patients with early-stage non-small-cell lung cancer. This factor may be included in the preoperative assessment of patients, for whom surgical intervention is considered., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: 2-Deoxy-2-[fluorine-18] fluoro-d-glucose with positron emission tomography ( 18 F-FDG-PET) is a clinically useful tool for cancer evaluation. 18 F-FDG accumulation in tumor cells is known to be correlated with the presence of glucose transporter 1 (GLUT1) and hypoxia-inducible factor-1α (HIF-1α). Although anti-programmed death-1 (PD-1) antibody treatments have been approved, no suitable predictor of significant responders has been identified. Based on the existing information, we investigated the relationship between tumor immunity (including PD-L1) and 18 F-FDG uptake in patients with surgically resected pulmonary squamous-cell carcinoma (SQC)., Materials and Methods: This study included 167 patients (153 men and 14 women) with SQC who underwent 18 F-FDG PET. Tumor sections were stained by immunohistochemistry for GLUT1, HIF-1α, PD-L1, CD4, CD8, and Foxp3. The relationship between clinicopathological features and 18 F-FDG uptake was analyzed. Student's t-test, the χ 2 test, non-parametric Spearman's rank test and the Kaplan-Meier method were used to show associations between variables., Results: The rate of positive PD-L1 expression was 79% (132/167), and PD-L1 expression was significantly associated with GLUT1 (P < 0.01), HIF-1α (P < 10 -4 ), and CD8 (P < 1 × 10 -3 ) expression. The SUV max of 18 F-FDG was significantly correlated with PD-L1 (P = 0.02) and GLUT1 (P < 0.01) expression. Multivariate analysis demonstrated that advanced stage, elevated PD-L1 expression, and elevated SUV max were independent prognostic factors for predicting poor OS. Among patients with a high SUV max , multivariate analysis confirmed that advanced stage and high PD-L1 expression were independent prognostic factors for poor OS; however, there was no significant difference among patients with a low SUV max ., Conclusion: High SUV max on 18 F-FDG-PET is associated with PD-L1 expression but is an independent prognostic factor for OS in our population of surgically resected pulmonary squamous-cell carcinoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The standard approach for treating recurrence after complete resection of primary non-small cell lung cancer has been controversial. We present here a multidisciplinary strategy for postoperative recurrence in patients with primary lung cancer., Patients and Methods: Over the last 7 years, we examined the disease-free survival and overall survival of 70 patients who underwent multidisciplinary treatment for recurrence after surgical resection of primary lung cancer., Results: The median overall survival was 32.3 months after surgery and 17.4 months after recurrence developed, indicating significantly better prognoses in females and in patients with adenocarcinoma, stage I disease, driver mutation positivity, a longer postoperative disease-free period, and never smokers. Eight patients survived more than 5 years after recurrence;of these patients, all had adenocarcinomas, 7 had oligometastases and/or tumor dormancy, and 5 received multiple-drug regimens., Conclusion: Multidisciplinary treatment for recurrence after resection of primary lung cancer was effective for patients receiving various drug regimens. In patients with oligometastases, disease control was achieved by a combination of local treatments targeting each involved organ. In patients with tumor dormancy, follow-up or a drug holiday was important to maintain the patient's quality of life.

Objectives: The lung is one of the most common organs of metastasis from colorectal cancer (CRC), and we have encountered lung cancer patients with a history of CRC. There have been few studies regarding methods used to discriminate between primary lung cancer (PLC) and pulmonary metastasis from CRC (PM-CRC) based only on preoperative findings. We retrospectively investigated predictive factors discriminating between these lesions in patients with a history of CRC., Methods: Between 2006 and 2015, 117 patients with a history of CRC (44 patients with 47 PLC and 73 patients with 102 PM-CRC) underwent subsequent or concurrent resection of pulmonary lesions. We compared the clinical and radiological characteristics of 100 patients with solitary lesions (43 PLC and 57 PM-CRC). Using univariate and multivariate analyses, we examined predictive factors for discrimination of these two lesions., Results: All tumors with findings of ground-glass opacity (GGO) were PLC (n = 19). In a multivariate analysis of 81 radiologically solid tumors, two factors were found to be significant independent predictors of PLC: a history of stage I CRC and presence of pleural indentation. All tumors in 26 patients with either GGO or both a stage I CRC history and pleural indentation were PLC, while most tumors in patients without all three factors were PM-CRC (43/44; 97.7%)., Conclusions: The presence or absence of GGO, pathological CRC stage, and pleural indentation could be useful factors to distinguish between PLC and PM-CRC.

Background: Known as a microtubule-destabilizing protein, STMN1 (gene symbol: STMN1) regulates the dynamics of microtubules, cell cycle progress, and chemo-resistance against taxane agents. It is highly expressed in various human cancers and involved in cancer progression as well as poor prognosis., Methods: Expression of STMN1 was examined by immunohistochemistry using FFPE tissue sections from 186 patients with lung squamous cell carcinoma (LSCC). Analysis of STMN1 suppression was performed for STMN1 small interfering RNA (siRNA)-transfected LSCC cell lines to determine the change in proliferation, invasive and apoptosis abilities, and paclitaxel sensitivity., Results: The cytoplasmic STMN1 expression in LSCC was higher than in normal tissues. The high expression was significantly associated with vascular invasion (P = 0.0477) and poor prognosis. In addition, the proliferating and invasive abilities were decreased, and the apoptosis ability and paclitaxel sensitivity were increased in STMN1-suppressed LSCC cells compared with control cells., Conclusion: The results suggest that STMN1 is a prognostic factor that also is associated with caner progression and chemo-resistance. Therefore, STMN1 could be a predictor for poor prognosis and a potential therapeutic target in LSCC.

To date, anatomic subsuperior segment (S∗) segmentectomy has not yet been reported. Herein we report the technical details of thoracoscopic anatomic S∗ segmentectomy and the anatomic features of the S∗., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The technical details and anatomic features of medial-basal segment (S 7 ) segmentectomy have not been reported. We report here thoracoscopic S 7 segmentectomy and S 7 a subsegmentectomy and explain the anatomic knowledge necessary to perform S 7 segmentectomy, especially the importance of recognizing bronchus (B 7 ) branching patterns before surgery., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Stathmin 1 is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes in various cancers, including non-small cell lung cancer. We aimed to determine differences in overall survival and disease-free proportion in patients with lung adenocarcinoma stratified by stathmin 1 tumor expression., Methods: With the use of immunohistochemistry, stathmin 1 expression was determined in resection specimens from 303 patients with adenocarcinoma. Associations between stathmin 1 protein expression and overall and disease-free proportion were assessed (Kaplan-Meier survival curves compared with log-rank statistics). Cox proportional hazards regression determined the hazard for death stratified by stathmin 1, adjusting for clinicopathologic characteristics., Results: During follow-up, 74 (24.4%) recurrences and 73 (24.1%) all-cause deaths were recorded. Expressed in 53.8% of adenocarcinoma cases, overall survival and disease-free proportion were significantly worse in stathmin 1-positive patients (log-rank P < .001 and P < .001, respectively). When adjusted for clinical and pathologic factors, stathmin 1 expression was an independent prognostic variable for both overall survival (hazard ratio, 2.21; 95% confidence interval, 1.28-3.80) and disease-free proportion (hazard ratio, 2.02; 95% confidence interval, 1.13-3.63) and for disease-free proportion even in the subset of patients with stage I (hazard ratio, 2.79; 95% confidence interval, 1.07-7.27). There was no significant difference between the stathmin 1-positive patients with stage IA and patients with stage IB in overall survival (P = .975) and disease-free proportion (P = .490), respectively., Conclusions: Stathmin 1 expression was an independent prognostic factor for adenocarcinoma, even when restricted to patients with early-stage cancer., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of antitumor immunity as a dynamic spatiotemporal process is required for each individual patient. To this end, we developed an immunogram for the cancer-immunity cycle by using next-generation sequencing., Methods: Whole exome sequencing and RNA sequencing were performed in 20 patients with NSCLC (12 with adenocarcinoma, seven with squamous cell carcinoma, and one with large cell neuroendocrine carcinoma). Mutated neoantigens and cancer germline antigens expressed in the tumor were assessed for predicted binding to patients' human leukocyte antigen molecules. The expression of genes related to cancer immunity was assessed and normalized to construct a radar chart composed of eight axes reflecting seven steps in the cancer-immunity cycle., Results: Three immunogram patterns were observed in patients with lung cancer: T-cell-rich, T-cell-poor, and intermediate. The T-cell-rich pattern was characterized by gene signatures of abundant T cells, regulatory T cells, myeloid-derived suppressor cells, checkpoint molecules, and immune-inhibitory molecules in the tumor, suggesting the presence of antitumor immunity dampened by an immunosuppressive microenvironment. The T-cell-poor phenotype reflected lack of antitumor immunity, inadequate dendritic cell activation, and insufficient antigen presentation in the tumor. Immunograms for both the patients with adenocarcinoma and the patients with nonadenocarcinoma tumors included both T-cell-rich and T-cell-poor phenotypes, suggesting that histologic type does not necessarily reflect the cancer immunity status of the tumor., Conclusions: The patient-specific landscape of the tumor microenvironment can be appreciated by using immunograms as integrated biomarkers, which may thus become a valuable resource for optimal personalized immunotherapy., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Sleeve resection of the pulmonary artery (PA) is always required for lung-sparing operations in which half or more of the vessel circumference is infiltrated by the primary tumor or metastatic hilar nodes. Following sleeve resection, conduit reconstruction may be indicated if there is excessive distance between the two vascular stumps, because there is a high degree of tension when repaired by direct anastomosis. We herein present a case of PA reconstruction using a tailor-made bovine pericardial conduit after sleeve resection of PA during lung cancer surgery. The length of resection was longer than 3 cm, and the difference in diameter between the conduit and peripheral PA stump was larger than 0.5 cm. We describe the surgical and oncological merits of a bovine pericardial conduit, and provide details of our reconstruction technique, focusing on adjustment of diameter between the conduit and peripheral PA (dog-ear method).

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.

Background Virtual-assisted lung mapping is a novel bronchoscopic preoperative lung marking technique in which virtual bronchoscopy is used to predict the locations of multiple dye markings. Post-mapping computed tomography is performed to confirm the locations of the actual markings. This study aimed to examine the accuracy of marking locations predicted by virtual bronchoscopy and elucidate the role of post-mapping computed tomography. Methods Automated and manual virtual bronchoscopy was used to predict marking locations. After bronchoscopic dye marking under local anesthesia, computed tomography was performed to confirm the actual marking locations before surgery. Discrepancies between marking locations predicted by the different methods and the actual markings were examined on computed tomography images. Forty-three markings in 11 patients were analyzed. Results The average difference between the predicted and actual marking locations was 30 mm. There was no significant difference between the latest version of the automated virtual bronchoscopy system (30.7 ± 17.2 mm) and manual virtual bronchoscopy (29.8 ± 19.1 mm). The difference was significantly greater in the upper vs. lower lobes (37.1 ± 20.1 vs. 23.0 ± 6.8 mm, for automated virtual bronchoscopy; p < 0.01). Despite this discrepancy, all targeted lesions were successfully resected using 3-dimensional image guidance based on post-mapping computed tomography reflecting the actual marking locations. Conclusions Markings predicted by virtual bronchoscopy were dislocated from the actual markings by an average of 3 cm. However, surgery was accurately performed using post-mapping computed tomography guidance, demonstrating the indispensable role of post-mapping computed tomography in virtual-assisted lung mapping.

The importance of neoantigens for cancer immunity is now well-acknowledged. However, there are diverse strategies for predicting and prioritizing candidate neoantigens, and thus reported neoantigen loads vary a great deal. To clarify this issue, we compared the numbers of neoantigen candidates predicted by four currently utilized strategies. Whole-exome sequencing and RNA sequencing (RNA-Seq) of four non-small-cell lung cancer patients was carried out. We identified 361 somatic missense mutations from which 224 candidate neoantigens were predicted using MHC class I binding affinity prediction software (strategy I). Of these, 207 exceeded the set threshold of gene expression (fragments per kilobase of transcript per million fragments mapped ≥1), resulting in 124 candidate neoantigens (strategy II). To verify mutant mRNA expression, sequencing of amplicons from tumor cDNA including each mutation was undertaken; 204 of the 207 mutations were successfully sequenced, yielding 121 mutant mRNA sequences, resulting in 75 candidate neoantigens (strategy III). Sequence information was extracted from RNA-Seq to confirm the presence of mutated mRNA. Variant allele frequencies ≥0.04 in RNA-Seq were found for 117 of the 207 mutations and regarded as expressed in the tumor, and finally, 72 candidate neoantigens were predicted (strategy IV). Without additional amplicon sequencing of cDNA, strategy IV was comparable to strategy III. We therefore propose strategy IV as a practical and appropriate strategy to predict candidate neoantigens fully utilizing currently available information. It is of note that different neoantigen loads were deduced from the same tumors depending on the strategies applied., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Two strategies for selecting neoantigens as targets for non-small cell lung cancer vaccines were compared: (1) an "off-the-shelf" approach starting with shared mutations extracted from global databases and (2) a personalized pipeline using whole-exome sequencing data on each patient's tumor., Methods: The Catalogue of Somatic Mutations in Cancer database was used to create a list of shared missense mutations occurring in more than 1% of patients. These mutations were then assessed for predicted binding affinity to HLA alleles of 15 lung cancer patients, and potential neoantigens (pNeoAgs) for each patient were selected on this basis. In the personalized approach, pNeoAgs were selected from missense mutations detected by whole-exome sequencing of the patient's own samples., Results: The list of shared mutations included 22 missense mutations for adenocarcinoma and 18 for squamous cell carcinoma (SCC), resulting in a median of 10 off-the-shelf pNeoAgs for each adenocarcinoma (range 5-13) and 9 (range 5-12) for each SCC. In contrast, a median of 59 missense mutations were identified by whole-exome sequencing (range 33-899) in adenocarcinoma and 164.5 (range 26-232) in SCC. This resulted in a median of 46 pNeoAgs (range 13-659) for adenocarcinoma and 95.5 (range 10-145) for SCC in the personalized set. We found that only one or two off-the-shelf pNeoAgs were included in the set of personalized pNeoAgs-and then in only three patients, with no overlap seen in the remaining 12 patients., Conclusions: Use of an off-the-shelf pipeline is feasible but may not be satisfactory for most patients with non-small cell lung cancer. We recommend identifying personal mutations by comprehensive genome sequencing for developing neoantigen-targeted cancer immunotherapies., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To prevent oral problems in lung cancer patients, dental intervention should be performed in conjunction with cancer treatment in cancer base hospitals. This paper reports on the perioperative oral care management of lung cancer patients., Patients and Methods: From January 2013 to August 2015, perioperative oral management was performed in 123 patients undergoing pulmonary lobectomy. We ensure cooperation between the departments of medicine and dentistry. First, the dentist plans oral management based on the patient's individual oral status. Then, the actual oral management is performed by an in-hospital dentist and at the regional dental clinic., Results: The patients comprised 70 males and 53 females with an average age of 69.4 years;118 had primary lung cancer and 5 had metastatic lung cancer. Abnormal findings were detected in approximately 50% of the patients, of whom 6 received oral treatment before starting their cancer treatment. Two patients(1.3%)had postoperative complications. In all cases, the oral care support team provided both tooth and oral mucosal care., Conclusion: About half of the referred patients required oral treatment. There were no serious adverse events due to the oral care intervention. Further investigation is necessary to establish appropriate treatment policy guidelines for dental disease requiring oral maintenance.

Background: We performed a prospective, multi-institutional, phase-II, clinical trial of a docetaxel, nedaplatin, and 5-fluorouracil (DNF) regimen in patients with unresectable esophageal cancer. Our goal was to determine the efficacy and feasibility of this DNF protocol., Methods: Thirty-four patients with unresectable esophageal cancer were enrolled and received DNF therapy. The DNF regimen was repeated every 4 weeks for up to 8 weeks, based on the following recommended doses: docetaxel, 60 mg/m(2) (day 1); nedaplatin, 70 mg/m(2) (day 1); and 5-fluorouracil, 700 mg/m(2) (days 1-5). The primary endpoint was the response rate. The secondary endpoints were overall survival and chemotherapy toxicities., Results: The complete response rate and response rate were 5.9 and 47.1 %, respectively. The 2-year overall survival rate and progression-free survival rate were 44.3 and 27.3 %, respectively. The median survival time was 594 days. The median progression-free time was 277 days. No treatment-related deaths occurred. Thirty patients (30/34) with grade 3, 4 neutropenia improved relatively quickly with administration of granulocyte colony-stimulating factor., Conclusions: DNF combination chemotherapy is a useful regimen with relatively minor adverse events and may serve as an effective protocol in patients with unresectable esophageal cancer.

Background: Despite advances in the development of various therapeutic agents, non-small cell lung cancer (NSCLC) is associated with a poor prognosis. To improve the prognosis of patients with NSCLC, new therapeutic targets for overcoming drug resistance are required. The process of autophagy is required to support the tumorigenesis and drug resistance of cancer cells. We investigated the clinical significance of SIRT6, a member of the NAD(+) -dependent deacetylase family, which regulates a variety of cancer-related processes, including autophagy., Methods: Immunohistochemistry analysis of SIRT6 expression and localization in 98 NSCLC clinical specimens and in vitro analysis using SIRT6-knockout lung carcinoma cell lines were performed., Results: Patients with high cytoplasmic expression and low nuclear expression of SIRT6 (n = 33) had more aggressive cancer, shorter overall survival, and shorter recurrence-free survival than did patients with different SIRT6 expression profiles (P < 0.05). In vitro analysis revealed that SIRT6 knockdown lung adenocarcinoma cell line improved paclitaxel sensitivity (P < 0.05) and reduced the expression levels of both nuclear factor kappaB and autophagy marker Beclin1., Conclusion: Our data demonstrated that SIRT6 expression in NSCLC could be a useful prognostic marker and that SIRT6 might represent a novel target gene for predicting sensitivity of chemotherapy in lung adenocarcinoma., (© 2015 Wiley Periodicals, Inc.)

Purpose: Small pulmonary lesions that include ground-glass attenuation have been increasingly discovered because of progressive imaging diagnostic technologies. Despite the detection of such small lesions, sometimes it is quite difficult to localize them because of their size or considerable depth from the visceral pleura. In the present study, we examined the usefulness of computed tomography-guided lipiodol marking for thoracoscopic resection of impalpable pulmonary nodules., Methods: Fifty-six patients with an undiagnosed peripheral lesion(s) of the lung who had undergone preoperative computed tomography-guided lipiodol marking followed by video-assisted thoracoscopic surgery were studied., Results: All of the nodules were successfully marked by computed tomography-guided lipiodol marking, and all except for one case were localized by means of intraoperative fluoroscopy as clear spots. With regard to complications, pneumothorax occurred in 21 patients (37.5%), and only one patient required transient drainage. Although hemorrhaging in the lung parenchyma and hemosputum occurred in nine patients (16.1%) and one patient (1.8%), respectively, no patients were in serious condition. No intra- or postoperative mortality or morbidity was observed., Conclusion: Preoperative computed tomography-guided lipiodol marking of small or impalpable pulmonary nodules is a safe and useful procedure for thoracoscopic resection of the lung.

Background: Schwannoma is a tumor that develops on peripheral nerves or spinal roots. Although any part of the body can be affected, axillar and supraclavicular lesions are unusual for schwannoma. We report two cases of schwannoma arising in the brachial plexus, which were detected by 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT)., Case 1: A 75-year-old Japanese woman showed high FDG accumulation in a subclavicular or axillary lesion found by FDG-PET/CT. Axillar-subclavicular lymph node metastasis was suspected and surgical excision was performed. Histological evaluation revealed schwannoma., Case 2: A 75-year-old Japanese woman was diagnosed with suspected primary lung cancer with brain metastases. She showed high FDG uptake at a subclavicular or axillary lesion found by FDG-PET/CT. Surgical excision was performed to arrive at a definitive diagnosis. The mass was located at the trunk of the brachial plexus and was identified as a schwannoma., Conclusion: Although schwannoma within an axillar or subclavicular lesion is relatively rare, brachial plexus schwannoma should be considered in the diagnosis of masses detected by FDG-PET/CT.

Objectives: Although 30-day mortality rate is adapted to evaluate perioperative mortality after surgery, whether 90-day mortality rate adequately evaluates perioperative mortality remains unknown. Therefore, we analyzed 30- and 90-day mortality rates after pulmonary resection in patients with primary lung cancer., Methods: A total of 2207 pulmonary resections for primary lung cancer performed between 1996 and 2010 at the Aichi Cancer Center Hospital were analyzed and divided into two groups of almost equal number: the early period group (1070 patients, 1996-2004) and the late period group (1137 patients, 2005-2010). Sixty-six and 34 patients died within a year during the early and late periods, respectively. The causes of death (recurrence, bleeding, sudden death, respiratory failure, and adverse event of chemotherapy), and 30- and 90-day mortality rates were investigated., Results: The 30-/90-day mortality rates in the early and late period groups were 0.56/0.75 and 0.35/0.79 %, respectively. The postoperative survival days of 75 patients who died from recurrence within 1 year after pulmonary resection and 7 patients from bleeding or sudden death were more than 91 days and <30 days, respectively. The median postoperative survival of patients who died from respiratory failure was 67 days (range 20-142 days) in the early period and 100 days (range 47-149 days) in the late period. In the late period, it was difficult to assess perioperative mortality of pulmonary complications with 30-day mortality., Conclusions: A risk assessment of perioperative mortality after pulmonary resection should be performed using the 30- and 90-day mortality.

Background/aims: We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients., Methodology: All unresectable metastatic colorectal cancer patients who began receiving bevacizumab at participating facilities from 2006 to 2011 were retrospectively analyze to determine the safety and efficacy. The primary end points were Progression Free Survival (PFS) and Overall Survival (OS). The secondary end points were adverse events., Results: A total of 101 patients were enrolled in the study. The primary tumor site was the colon in 53 patients and the rectum in 48 patients. The most common metastatic sites were the liver (63.4%), lung (31%), and peritoneum (10%). In first-line therapy, 76 (75.2%) patients received the FOLFOX regimen. Among these patients, 33 (43.4%) patients received FOLFOX alone, and 43 (56.6%) received FOLFOX plus bevacizumab. The addition of bevacizumab to first-line chemotherapy was associated with increases in median PFS (12.5 vs. 6.0 months; P = .00001) and median OS (24.0 vs. 16.0 months; P = 0.0221). The risks of adverse events were not significantly increased with the addition of bevacizumab., Conclusions: The addition of bevacizumab to first-line therapy in CRC patients provided clinically significant patient benefit, including statistically significant improvement in OS and a favorable tolerability profile.

We describe a case of lung adenocarcinoma with multiple postoperative bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. A 76-year-old man with moderately differentiated adenocarcinoma underwent a radical left upper lobectomy and mediastinal lymph node dissection. Three and a half years after the operation, serum carcinoembryonic antigen (CEA) was elevated and 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) revealed multiple bone metastases. Pretreatment evaluation of EGFR mutations in the resected primary adenocarcinoma specimen showed an L858R mutation in exon 21. Gefitinib was started as first-line treatment. However, evaluation 1 month after administration revealed progressive disease. Erlotinib was started as second-line treatment, and evaluation 1 month after administration revealed that the disease was stable. Administration of zoledronic acid was then begun with continuation of erlotinib. After 2 courses of zoledronic acid, the serum CEA level had not changed but the maximum standardized uptake values of each region uniformly decreased. Furthermore, the uptake of 18FDG completely disappeared after 6 courses. Subsequently, the serum CEA level continued to decrease and the disappearance of 18FDG uptake was confirmed after 10 courses (12 months after initiation of erlotinib administration). Our results suggest that the combined administration of both drugs is effective against bone metastases.We experienced a case of lung adenocarcinoma with postoperative recurrence of multiple bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. Our results suggest that the combined treatment of both drugs is an effective therapy against bone metastases.

Purpose: Recent advances in image diagnostic technology have enhanced the discovery of peripheral small size lung cancers. Here, we examined the utility of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of grade of tumor malignant potency., Methods: Seventy-nine patients with peripheral small lung cancers (≤2 cm) who underwent surgical resections and preoperative FDG-PET were enrolled. The correlations between the maximum standardized uptake value (SUVmax) and various clinicopathological features related to tumor invasiveness, nodal metastasis, and recurrence were analyzed., Results: The median SUVmax of all tumors was 2.4 (range, 0-16.1). The SUVmax was significantly higher in patients with vascular invasion (5.6 ± 3.5 vs. 2.4 ± 2.4; P <0.0001), lymphatic invasion (4.9 ± 3.7 vs. 2.7 ± 2.6; P = 0.0029), lymph node metastasis (6.1 ± 4.4 vs. 3.0 ± 2.7; P = 0.0022), and recurrences (5.8 ± 3.3 vs. 3.1 ± 3.1; P = 0.0219). Patients with SUVmax ≥2.5 had a significantly higher incidence rate of vascular invasion (56% vs. 7%; P <0.0001), lymphatic invasion (51% vs. 15%; P = 0.0006), lymph node metastasis (26% vs. 3%; P = 0.0033), and recurrence (18% vs. 3%; P = 0.0289). The patients with SUVmax ≥1.5 also had a significantly higher incidence of vascular invasion, lymphatic invasion, lymph node metastasis, and recurrence. It is particularly worth noting that patients with SUVmax <1.5 had no vascular invasion, lymph node metastasis, or recurrence., Conclusion: Preoperative SUVmax of peripheral small lung cancers were significantly associated with tumor malignancy.

Video-assisted thoracic surgery (VATS) has been enthusiastically used as a less-invasive diagnostic or therapeutic surgical procedure in recent years. VATS results in considerably less postoperative pain than traditional thoracotomy incisions. The current trend is to reduce the number of ports and minimize the length of incisions to further reduce postoperative pain, chest wall paresthesia, and length of hospitalization. Although several accounts of reduced port surgery, such as single-incision laparoscopic surgery (SILS), have been reported, there are few descriptions of single-incision thoracoscopic surgery (SITS) using a thin puncture device for a variety of diseases. Herein, we describe a minimally invasive SITS technique using a thin puncture device.

Unlabelled: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I-specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7., Implications: FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg., (©2013 AACR.)

Basaloid squamous cell carcinoma (BSCC) of the esophagus is a relatively rare variant of esophageal malignancies. It is regarded as a disease with a poor prognosis because of the high frequency of distant metastases. We managed a case of resected solitary pulmonary metastasis of BSCC of the esophagus in a 78-year-old female. We performed curative thoracic esophagectomy with three-field lymph node dissection for her disease. After two years and nine months, a thoracoscopic partial resection of the left lung was performed for the solitary pulmonary metastasis. At present, one year after the surgery, the patient is doing well without any recurrence. There have been few reports of case of resected pulmonary metastases. In addition, no treatment strategy for pulmonary metastases from BSCC of the esophagus has been established because of the limited number of cases. Additional cases are required to determine the treatment method.

A 35-year-old female presented with multiple bilateral pulmonary nodules on a chest X-ray during a regular health checkup. Chest computed tomography revealed multiple well-defined nodular shadows in the lung. She had undergone a myomectomy 7 years previously for leiomyoma of the uterus. Thoracoscopic resection of one of the nodules was performed to establish a pathological diagnosis. Pathological findings were consistent with benign metastasizing leiomyoma. Estrogen and progesterone receptors showed strong positives by immunohistostaining of the tumor. The patient is currently receiving outpatient treatment for a benign metastasizing leiomyoma by administration of a GnRH analog drug.

Purpose: The indications for pulmonary resection in elderly patients with lung cancer concomitant with another disease are unclear. We conducted this retrospective study to establish the risk factors of complications and survival to improve patient selection., Methods: The subjects were 295 patients aged ≥ 75 years, who underwent pulmonary resection for lung cancer. We assessed comorbidity according to the Charlson comorbidity index (CCI) and examined risk factors for morbidity and the prognostic factors., Results: Postoperative complications developed in 55 patients (morbidity 18.6 %). The median survival time was 59.3 months and the 5-year survival rate was 69.7 %. Multivariate logistic regression analyses selected smoking and thoracotomy as risk factors for complications, and a history of cerebrovascular disease, cancer stage, and thoracotomy as risk factors for a prolonged hospital stay (PHS). Video-assisted thoracic surgery (VATS) decreased the risk of morbidity and PHS, and influenced survival. Multivariate analysis with the Cox proportional hazard model identified CCI ≥ 2, morbidity, and PHS as unfavorable survival factors, in addition to age ≥ 80 and cancers that were non-adenocarcinoma or advanced., Conclusions: Although CCI ≥ 2 was associated with poorer survival, it was not necessarily a risk factor of postoperative complications or PHS. Performing VATS when possible could reduce the incidence of postoperative complications and PHS in elderly patients.

It is often difficult to differentiate metachronous primary lung cancers from local pulmonary recurrences when the histopathological findings are similar. A 43-year-old man underwent right upper lobectomy with lymph node dissection for primary lung adenocarcinoma (p-T2aN0M0, stage IB). Fifteen years later, he developed a lung nodule in his right middle lobe. The tumor was preoperatively thought to be a metachronous second primary lung adenocarcinoma, and was surgically resected. Histopathological findings for both tumors were of poorly differentiated adenocarcinoma with mucus production. Both tumors also harbored the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene (variant 3a+b). Based on this molecular finding, the pulmonary nodule was considered to be a recurrence after very long latent period., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The appearance of pulmonary metastasis more than 15 years after primary treatment for breast cancer is rare. We herein report the case of a breast cancer patient with solitary pulmonary metastasis, after an 18-year disease-free period, treated with resection. A 66-year-old Japanese woman was found to exhibit an abnormal shadow on a chest X-ray. She had undergone a left mastectomy for breast cancer 18 years previously. The nodule was suspected to be either metastatic or primary lung cancer, and thus thoracoscopic surgery was performed. The histologic diagnosis was metastasis from breast cancer. Pulmonary resection in breast cancer recurrence is an important diagnostic tool that allows for a differential diagnosis with primary lung cancer. The clinical implication of surgery for a solitary pulmonary metastasis from breast cancer is discussed in this report.

Here, we report a rare case of a 39-year-old male who presented with left forearm pain and swelling as the initial manifestation of non-small cell lung cancer (NSCLC). The patient underwent chemoradiotherapy followed by surgical resection of the primary lesion as a salvage treatment. Four years and 7 months after his first presentation, the patient is alive with no symptoms of recurrence or metastasis. Although the optimal treatment for skeletal muscle metastasis from NSCLC has not been determined, aggressive treatment for the primary and the solitary metastatic lesion could be considered as a potentially successful treatment option.

Background: Activating mutation in the kinase domain of the human EGF receptor 2 (HER2) gene (also known as ERBB2 or neu) is reported to be present in a small fraction of lung adenocarcinomas. However its prognostic and predictive implications are not yet established., Patients and Methods: We examined 504 Japanese lung cancer patients who underwent pulmonary resection for HER2 mutations by direct sequencing and evaluated their prognostic and predictive implications. Updated prognostic data of 14 Japanese patients with HER2 mutation from previous two reports were also gathered., Results: HER2 mutations were identified in 13 of 504 cases (2.6%). Patients with HER2 mutations were common in female, nonsmokers and adenocarcinomas as those with EGFR mutations. When confined to the subgroup of nonsmokers with adenocarcinoma or adenosquamous cell carcinoma without EGFR mutations, the frequency of HER2 mutations was 14.1% (11/78). There was no difference in the overall survival of patients with HER2 mutations, compared with patients harboring EGFR mutations and patients harboring wild types for both EGFR and HER2. Within the patients with HER2 mutation, two of three with TP53 mutation and one of 13 without TP53 mutation died of the disease, suggesting negative prognostic role of the TP53 mutation. Three patients with HER2 mutations did not respond to platinum-based chemotherapy and EGFR-TKIs. Of note, one patient with the most common HER2 mutations, YVMA776-779ins, responded to trastuzumab plus vinorelbine after failure of multiple round of platinum-based chemotherapy and gefitinib., Conclusion: HER2 mutations are present in a subset of patients with lung cancer having distinct clinical features. HER2 mutations were not associated with the prognosis of patients with lung cancers. Patients with HER2 mutations might benefit from anti-HER2 therapy., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We report a resected case of malignant lymphoma with hypersensitivity pneumonitis. A 62-year-old woman, who presented with fever, wheeze and dry cough was referred to our department under the diagnosis of malignant B cell lymphoma in lower lobe of the left lung and hypersensitivity pneumonitis. She underwent left lower lobectomy as a therapy for malignant lymphoma. Pathological findings showed multiple small nodules macroscopically, which was observed as bronchiolocentric interstitial pneumonitis with lymphocytes microscopically. Post operative course was uneventful and no sign of acute exacerbation was seen. It is rare that lung with hypersensitivity pneumonitis is observed as a macroscopical specimen. Hypersensitivity pneumonitis differs from idiopathic pulmonary fibrosis, but we have to take care of post operative course because post operative acute exacerbation was reported.

The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.

Only the kinase domain of ERBB4 has been analyzed in East Asian populations, but a recent large-scale mutation analysis has indicated a higher incidence of mutations in the extracellular domain. Mutations in the extracellular and kinase domains of ERBB4 were examined by direct sequencing in 72 patients with primary lung cancer and 8 cell lines. In addition, ERBB4 expression was determined in 60 patients by quantitative real-time polymerase chain reaction. We investigated the relationship between ERBB4 expression and clinicopathologic characteristics including prognosis. One patient possessed Q793Q polymorphism in the kinase domain. However, we detected no mutations in extracellular or kinase domains of ERBB4. There was no significant difference in the clinicopathologic characteristics including prognosis of patients with high or low expression of ERBB4. The clinical significance of ERBB4 in lung cancers is negligible.

Objective: Predicted postoperative forced expiratory volume in 1s (ppoFEV1) is estimated in lung cancer patients before pulmonary resection, as well as the clinical stage. This study aims to evaluate ppoFEV1 and ppo-vital capacity (ppoVC) on postoperative day 7 (POD7) and to compare the results following video-assisted thoracic surgery (VATS) and open thoracotomy procedures., Methods: Of the 155 patients who underwent pulmonary resection, 70 had VATS; 30 had muscle-sparing thoracotomy (anterior limiting thoracotomy (AL)); and 55 had postero-lateral thoracotomy (PL). VC and FEV1 were measured on POD7 and compared with the VC and FEV1 before surgery using analysis of covariance (ANCOVA). The ratio of the actual- and the ppoVC and FEV1 was evaluated to identify factors associated with variations in postoperative residual VC/FEV1., Results: There were significant differences by analysis of covariance (ANCOVA) in the VC/FEV1 among the three surgical approaches. In the VATS group, the VC ratio and the FEV1 ratio were 96.5% and 94.7%, respectively; they were significantly higher in the VATS group than in the thoracotomy group (AL: 90.4% and 90.1%, respectively; PL: 87.4% and 87.6%, respectively). Non-chronic obstructive pulmonary disease (COPD) and upper lobectomy were also associated with a low VC ratio and FEV1 ratio., Conclusion: Predicted postoperative pulmonary function might be overestimated in COPD patients or in those undergoing VATS or lower lobectomy., (Copyright 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Purpose: Overexpression of EGFR is found in several malignancies including lung cancers. Recently, EGFR mutation has been shown to correlate with responsiveness to tyrosine kinase inhibitors (TKI). Although antibodies against phophorylated EGFR have been used in vitro, phosphorylated EGFR has yet not been examined well in resected non-small cell lung cancers (NSCLCs)., Experimental Design: We studied the immunohistochemistry of anti-EGFR and phosphorylated EGFR in 97 resected NSCLCs, examined the relationship with EGFR mutation, and performed quantitative RT-PCR of the EGFR gene in the TaqMan assay., Result: EGFR mutation was seen in 27% of 97 NSCLCs and 37% of 70 adenocarcinomas. EGFR was stained in 60% of 97 NSCLCs. Phosphorylation of tyrosine 845 (pY845) and 1068 (pY1068) was positive in 49% and 48%, respectively. The observed correlation with EGFR mutation and pY845 or pY1068 was statistically significant (P=0.0001 for pY845, P<0.0001 for pY1068, chi square test), although phospho-EGFR status was not associated with a particular mutation type. pY1068-positive tumors also correlated with female, light smoker, and adenocarcinoma histology, but not with mRNA expression. Moreover, patients with pY1068-positive tumors showed prolonged survival (P=0.0093, log-rank test)., Conclusion: It is possible that immunohistochemistry of phosphorylated EGFR can substitute for EGFR mutation analysis. Further investigation is necessary to determine whether phospho-EGFR immunohistochemistry predicts response to TKIs and survival benefit.

Introduction: MET (Met proto-oncogene) activation either by gene amplification or mutation is implicated in various types of human cancers. For lung cancer, MET gene amplification is reported to occur in a subset of adenocarcinomas. Although somatic mutations of MET in lung adenocarcinomas are rare, all but one of those reported so far entail a splice mutation deleting the juxtamembrane domain for binding the c-Cbl E3-ligase; normally such binding leads to ubiquitination and receptor degradation, and loss of this domain leads to MET activation. The purpose of this study was to clarify in the role of MET activation in lung carcinogenesis., Materials and Methods: MET gene copy number was determined by real-time quantitative polymerase chain reaction in 187 of the patients with lung cancer and the MET gene splice mutation deleting the juxtamembrane domain was examined by direct sequencing in 262. The results were correlated with various clinical and pathologic features including mutations of the epidermal growth factor receptor, KRAS, and HER2 genes., Results: All the instances of MET activation occurred in patients with adenocarcinomas. The prevalences of MET gene amplification and splice mutations were 1.4% (2 of 148) and 3.3% (7 of 211), respectively. We identified four different intronic mutations that disrupted a splice consensus sequence in genomic DNA. Activation of MET and mutations of the epidermal growth factor receptor, KRAS, and HER2 genes had strict mutual exclusionary relationships., Conclusions: About 5% of pulmonary adenocarcinomas in this cohort of Japanese patients were driven by activated MET by gene amplification or splice mutations. Such patients would be candidates for targeted therapy against MET.

Introduction: Although mutation of the epidermal growth factor receptor (EGFR) gene is predictive for the response to EGFR-tyrosine kinase inhibitor, its prognostic impact for patients without EGFR-tyrosine kinase inhibitor treatment remains controversial. We examined for EGFR, KRAS or TP53 mutations in a consecutive large cohort of patients with lung adenocarcinoma, and evaluated their prognostic impact., Methods: We analyzed 397 patients with lung adenocarcinoma who underwent potentially curative pulmonary resection. Total ribonucleic acid was extracted and direct sequencing of each gene was performed after reverse transcription-polymerase chain reaction., Results: We found that 196 patients (49%) had EGFR mutations. Of these, 83 were exon 19 deletions (42%) and 92 were L858R (47%). Univariate analysis showed that patients with EGFR mutations survived for a longer period than those without mutations (p = 0.0046). However, there was no difference in overall survival between the patients with exon 19 deletion and those with L858R (p = 0.4144). Patients with KRAS mutations or TP53 mutations tended to survive for a shorter period (p = 0.2183 and 0.0230, respectively). Multivariate analysis using the Cox proportional hazards model revealed that smoking status (p = 0.0310) and disease stage (p < 0.0001) were independent prognostic factors. However, none of the gene mutations was independent prognostic factors (EGFR, p = 0.3225; KRAS, p = 0.8500; TP53, p = 0.3191)., Conclusions: EGFR, KRAS, and TP53 gene mutations were not independently associated with the prognosis for Japanese patients with surgically treated lung adenocarcinoma.

Mutation of the LKB1 gene (also known as STK11) is regarded as a cause of Peutz-Jeghers syndrome. In Caucasian patients, LKB1 somatic mutations occur in approximately one-third of lung adenocarcinomas. The aim of the present study was to examine the LKB1 gene in Japanese patients with lung cancer and to evaluate its clinical and pathological implications. We sequenced the LKB1 gene in 22 lung cancer cell lines and 100 Japanese patients with lung cancer (including 81 adenocarcinomas, 14 squamous cell carcinomas and five other histological types) who had undergone curative pulmonary resection. We also determined expression levels of the LKB1 gene by quantitative real-time reverse transcription-polymerase chain reaction and correlated these results with the clinical and pathological features of patients. Among the 22 cell lines, four had mutations and three of these were in adenocarcinoma cells. Of 100 primary lung cancers, only three had LKB1 gene mutations (3%). All of them were male smokers with adenocarcinomas. Hence, when confined to this subset of patients, the mutation frequency was 9% (3/33). No significant correlation was observed between the expression level of LKB1 and patient clinicopathological features. In conclusion, LKB1 gene mutations were relatively rare in Japanese patients with lung cancer compared with Caucasian patients. LKB1 gene mutations appear to be frequent in male, smoking patients of Caucasian origin, in contrast to EGFR or HER2 mutations that are frequent in non-smoking, female patients of Asian origin.

Although distinguishing metastatic colorectal adenocarcinoma from primary lung adenocarcinoma is often difficult, pre- or intra-operative identification is very important, as the resection areas for each diagnosis differ substantially. CDX2, a recently cloned homeobox gene, represents a highly specific and sensitive marker of colorectal adenocarcinoma. We evaluated CDX2 expression using pre- and intra-operative biopsy specimens. The study examined 50 consecutive colorectal adenocarcinoma metastases to the lung, including 20 biopsy specimens and 66 resected specimens, and 21 primary lung adenocarcinomas. All specimens were immunohistochemically stained for CDX2, cytokeratin (CK) 7, CK20 and thyroid transcription factor (TTF)-1, and scored in a semi-quantitative manner. Mean staining score in biopsy specimens was significantly higher for CDX2 than for CK20. Sensitivities for CDX2 and CK7-/20+ in biopsy specimens were 95.0 and 65.0%, respectively. If CDX2 immunostaining had not been performed, 8 biopsy specimens (40%), and 20 resected specimens (30.3%) might have been diagnosed as equivocal cases either as primary lung cancer or metastatic colorectal cancer, using other markers. These results suggest that positive CDX2 staining represents a highly sensitive and specific marker of metastatic colorectal carcinoma in both biopsy and resected specimens, and is superior to staining for the CK7-/20+ phenotype.