The efficacy of a machine learning algorithm for assessing tumour components as a prognostic marker of surgically resected stage IA lung adenocarcinoma.

BACKGROUND: The importance of the stromal components in tumour progression has been discussed widely, but their prognostic role in small size tumours with lepidic components is not fully understood. Applying digital tissue image analysis to whole-slide imaging may enhance the accuracy and reproducibility of pathological assessment. This study aimed to evaluate the prognostic value of tumour components of lung adenocarcinoma by measuring the dimensions of the tumour consisting elements separately, using a machine learning algorithm. METHODS: Between September 2002 and December 2016, 317 patients with surgically resected, pathological stage IA adenocarcinoma with lepidic components were analysed. We assessed the whole tumour area, including the lepidic components, and measured the epithelium, collagen, elastin areas and alveolar air space. We analysed the prognostic impact of each tumour component. RESULTS: The dimensions of the epithelium and collagen areas were independent significant risk factors for recurrence-free survival (hazard ratio, 8.38; 95% confidence interval, 1.14-61.88; P = 0.037, and hazard ratio, 2.58; 95% confidence interval, 1.14-5.83; P = 0.022, respectively). According to the subgroup analysis when combining the epithelium and collagen areas as risk factors, patients with tumours consisting of both large epithelium and collagen areas showed significantly poor prognoses (P = 0.002). CONCLUSIONS: We assessed tumour components using a machine learning algorithm to stratify the post-operative prognosis of surgically resected stage IA adenocarcinomas. This method might guide the selection of patients with a high risk of recurrence.

Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database.

PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART). METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors. RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases. CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.

Molecular and expressional characterization of tumor heterogeneity in pulmonary carcinosarcoma.

The genetic concordance and heterogeneity of the two components of pulmonary carcinosarcoma (PCS), carcinoma, and sarcoma, have not been fully elucidated because of its rare occurrence. We performed targeted sequencing of the carcinoma and sarcoma components of four PCSs to identify genetic similarities and differences. Formalin-fixed paraffin-embedded tissue samples were macroscopically or microscopically dissected. DNA was extracted from each component, and genetic alterations were analyzed separately. Moreover, we performed RNA-seq analysis on both components of one PCS to compare differences in gene expression profiles. The carcinoma part consisted of adenocarcinoma in two cases, squamous cell carcinoma in one, and adenosquamous carcinoma in the last. TP53 mutation was observed in three samples from the trunk, although it was detected only in the sarcoma part in one case. No specific driver gene mutation was observed; however, KRAS mutations were observed in one case in the trunk. RNA-seq analysis revealed that the rhabdomyosarcoma component expressed various genes related to muscle development, whereas the carcinoma component did not; and that gene expression overall was completely different between the two components. Our study revealed that the two different components of PCS shared common gene mutations in most cases. Although gene expression was different among components, if driver genes such as KRAS were detected in PCS, molecular targeted therapy could be beneficial even when the tumor contains a sarcoma component.

A risk model for prolonged air leak after lobectomy using the National Clinical Database in Japan.

PURPOSE: The objective of our study was to develop a clinical prediction model for prolonged air leak (PAL) after lobectomy for lung cancer using preoperative variables in a large patient dataset from the National Clinical Database (NCD) in Japan. METHODS: The preoperative characteristics of 57,532 and 30,967 patients who had undergone standard lobectomy for lung cancer were derived from the 2014 to 2015 and 2016 NCD datasets, respectively. PAL was defined as air leak persisting ≥ 7 days postoperatively or requiring postoperative interventional treatment, such as pleurodesis or reoperation. Risk models were developed from the 2014 to 2015 dataset and validated using the 2016 dataset. When performing model derivation, the least absolute shrinkage and selection operator (LASSO) method were applied for parameter selection. RESULTS: The rate of PAL was 4.5% in 2014-2015 and 5.3% in 2016. The age, sex, body mass index, comorbid interstitial pneumonia, smoking habits, forced expiratory volume in 1 s, tumor histology, multiple lung cancer, and tumor location were selected as important variables for PAL. Our risk model for predicting PAL was fair with a concordance index of 0.6895. CONCLUSION: The LASSO-based risk model for PAL after lobectomy provided important preoperative variables for PAL and risk weighting for each variable.

[Procedures of Video-assisted Thoracoscopic Surgery for Patients with Intrathoracic Pleural Adhesions].

With the progress of surgical instruments and surgical techniques, endoscopic surgery has become remarkably widespread, and techniques of the thoracoscopic surgery are considered to have become common. It is not uncommon to encounter cases with intrathoracic pleural adhesions, such as not only a history of intrathoracic inflammatory disease, but also second cancer after resection of early-stage lung cancer and multiple operations for metastatic lung tumor. It is important for thoracic surgeons to have a technique that enables thoracoscopic adhesiolysis without open thoracotomy to maintain the quality of life (QOL) and activity of daily living (ADL) of the patient. In this article, we would like to describe the concept of video-assisted thoracoscopic surgery for cases with intrathoracic pleural adhesions to avoid a conversion to open thoracotomy.

Diagnostic value of 18F-FDG-PET to predict the tumour immune status defined by tumoural PD-L1 and CD8+tumour-infiltrating lymphocytes in oral squamous cell carcinoma.

BACKGROUND: Lately, immune checkpoint proteins, such as programmed death 1 (PD-1) and its ligand-1 (PD-L1), have garnered attention as a new target in oral squamous cell carcinoma (OSCC). Reportedly, fluoro-D-glucose (FDG)-uptake alteration by anti-PD-1 antibody treatment depicts the response in patients with lung cancer. This study aims to elucidate the correlations between tumour immune status, clinicopathological factors, 18F-FDG-uptake and cold tumour phenotypes as low PD-L1 expression/low CD8+tumour-infiltrating lymphocytes (TILs) in OSCC. METHODS: We performed immunohistochemical analysis of PD-L1, hypoxia-inducible factor 1 A (HIF-1A), glucose transporter type 1 (GLUT1), CD8, E-cadherin and Ki-67 on 59 operable OSCC samples. We assessed the correlations between these factors and preoperative 18F-FDG-uptake, clinicopathological characteristics and prognosis. RESULTS: Low expression of PD-L1 in OSCC correlated with cancer aggressiveness, poor prognosis, high 18F-FDG-uptake with HIF-1A/GLUT1 and low E-cadherin expression and low CD8. Cold tumour phenotypes as low PD-L1 tumour cells and low stromal CD8 correlated with the poor prognosis, high 18F-FDG-uptake and E-cadherin suppression. Furthermore, the high level of preoperative 18F-FDG-uptake in OSCC was an independent predictor of the cold tumour immune status. CONCLUSIONS: 18F-FDG-uptake is an independent predictor of cold tumour in OSCC. 18F-FDG-PET imaging could be a promising diagnostic tool to estimate tumour immune status.

High Stromal TGFBI in Lung Cancer and Intratumoral CD8-Positive T Cells were Associated with Poor Prognosis and Therapeutic Resistance to Immune Checkpoint Inhibitors.

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-ß1) 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.

Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: a theranostic study for the precision medicine.

BACKGROUND: Lung squamous cell carcinoma (LSCC) remains a challenging disease to treat, and further improvements in prognosis are dependent upon the identification of LSCC-specific therapeutic biomarkers and/or targets. We previously found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role in lesion growth and, therefore, clinical outcomes in LSCC patients through regulation of tumor protein p63 (TP63) ubiquitination. METHODS: To clarify the impact of STXBP4 and TP63 for LSCC therapeutics, we assessed relevance of these proteins to outcome of 144 LSCC patients and examined whether its action pathway is distinct from those of currently used drugs in in vitro experiments including RNA-seq analysis through comparison with the other putative exploratory targets and/or markers. RESULTS: Kaplan-Meier analysis revealed that, along with vascular endothelial growth factor receptor 2 (VEGFR2), STXBP4 expression signified a worse prognosis in LSCC patients, both in terms of overall survival (OS, p = 0.002) and disease-free survival (DFS, p = 0.041). These prognostic impacts of STXBP4 were confirmed in univariate Cox regression analysis, but not in the multivariate analysis. Whereas, TP63 (ΔNp63) closely related to OS (p = 0.013), and shown to be an independent prognostic factor for poor OS in the multivariate analysis (p = 0.0324). The action pathway of STXBP4 on suppression of TP63 (ΔNp63) was unique: Ingenuity pathway analysis using the knowledge database and our RNA-seq analysis in human LSCC cell lines indicated that 35 pathways were activated or inactivated in association with STXBP4, but the action pathway of STXBP4 was distinct from those of other current drug targets: STXBP4, TP63 and KDR (VEGFR2 gene) formed a cluster independent from other target genes of tumor protein p53 (TP53), tubulin beta 3 (TUBB3), stathmin 1 (STMN1) and cluster of differentiation 274 (CD274: programmed cell death 1 ligand 1, PD-L1). STXBP4 itself appeared not to be a potent predictive marker of individual drug response, but we found that TP63, main action target of STXBP4, might be involved in drug resistance mechanisms of LSCC. CONCLUSION: STXBP4 and the action target, TP63, could afford a key to the development of precision medicine for LSCC patients.

Significance of RAS mutations in pulmonary metastases of patients with colorectal cancer.

BACKGROUND: RAS/BRAF mutations of colorectal cancer (CRC) play a crucial role in carcinogenesis and cancer progression and need to be considered for the therapeutic strategy choice. We used next-generation-sequencing (NGS) technology to assess RAS/BRAF mutation differences between primary CRC and corresponding pulmonary metastases (PMs). METHODS: We examined the mutation statuses of the KRAS 12/13/61/146, NRAS 12/13/61/146, and BRAF 600 codons in genomic DNA from fresh-frozen or formalin-fixed paraffin-embedded tissues derived from 34 primary lesions and 52 corresponding PMs from 36 patients with CRC. RESULTS: We found RAS mutations in 76% (26/34) of primary CRC lesions and in 86% (31/36) of PMs. While 27% (7/26) of the primary CRC RAS mutations were heterogeneous, all the RAS mutations in PMs were homogeneous. Of the mutations in PMs, 71% (22/31) were KRAS G>A transitions, of which 82% (18/22) were KRAS G12D or G13D. The RAS mutation discordance between primary tumors and PMs was 12.1% (4/33). RAS mutations with the same genotyping were detected in all synchronous and metachronous PMs from 9 patients. We found no BRAF mutations in either primary or pulmonary tissues. CONCLUSION: Our NGS analysis suggests that RAS mutations of PM of patients with CRC are more common than initially thought. The presence of KRAS mutations in CRC specimens, especially G12D or G13D mutations, seems to promote PM formation.

Cancer exosomal microRNAs from gefitinib-resistant lung cancer cells cause therapeutic resistance in gefitinib-sensitive cells.

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.

Genetic and Immunohistochemical Studies Investigating the Histogenesis of Neuroendocrine and Carcinomatous Components of Combined Neuroendocrine Carcinoma.

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.

[Wedge Resection as an Alternative Procedure for Primary Pulmonary Carcinoma in Poor-risk Patients].

BACKGROUND: We present wedge resection as an alternative procedure for primary pulmonary carcinoma in poor-risk patients. PATIENTS AND METHODS: We examined the overall survival of 94 patients who underwent wedge resection for pN0M0 primary pulmonary carcinoma over the last 20 years because of their intolerance of lobectomy. RESULTS: In the wedge resection group, the postoperative 5-year survival in all causes of death was 59.6%, indicating significantly better prognoses in patients with adenocarcinoma aged less than 75 years old. The 5-year survival in the lobectomy group was 77.5%, while the 5-year survival in terms of primary causes of death in the wedge resection and lobectomy groups was 89.3% and 88.0%, respectively. There was a significant difference between wedge resection and lobectomy in all causes of death, but not between groups in primary causes of death. CONCLUSION: Because there were many non-primary deaths in the wedge resection group, care should be taken to follow comorbidities that cause limited lung resection. Survival in the wedge resection group was not inferior to that in the lobectomy group in analyses of the primary causes of death. We suggest that wedge resection should be a favorable procedure for primary pulmonary carcinoma in poor-risk patients to obtain a large enough sample volume of tumor cells.

Metabolic activity by 18F-FDG-PET/CT is predictive of early response after nivolumab in previously treated NSCLC.

BACKGROUND: Nivolumab, an anti-programmed death-1 (PD-1) antibody, is administered in patients with previously treated non-small cell lung cancer. However, little is known about the established biomarker predicting the efficacy of nivolumab. Here, we conducted a preliminary study to investigate whether 18F-FDG-PET/CT could predict the therapeutic response of nivolumab at the early phase. METHODS: Twenty-four patients were enrolled in this study. 18F-FDG-PET/CT was carried out before and 1 month after nivolumab therapy. SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were calculated. Immunohistochemical analysis of PD-L1 expression and tumour-infiltrating lymphocytes was conducted. RESULTS: Among all patients, a partial metabolic response to nivolumab was observed in 29% on SUVmax, 25% on MTV, and 33% on TLG, whereas seven (29%) patients achieved a partial response (PR) based on RECIST v1.1. The predictive probability of PR (100% vs. 29%, p = 0.021) and progressive disease (100% vs. 22.2%, p = 0.002) at 1 month after nivolumab initiation was significantly higher in 18F-FDG on PET/CT than in CT scans. Multivariate analysis confirmed that 18F-FDG uptake after administration of nivolumab was an independent prognostic factor. PD-L1 expression and nivolumab plasma concentration could not precisely predict the early therapeutic efficacy of nivolumab. CONCLUSION: Metabolic response by 18F-FDG was effective in predicting efficacy and survival at 1 month after nivolumab treatment.

Clinical and Radiological Discrimination of Solitary Pulmonary Lesions in Colorectal Cancer Patients.

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.

Prognostic value of metabolic tumor volume of pretreatment 18F-FAMT PET/CT in non-small cell lung Cancer.

BACKGROUND: This study aimed to determine the prognostic value of positron emission tomography (PET) metabolic parameters-namely metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion retention (TLR)-on fluorine-18 (18F) fluorodeoxyglucose (FDG) and L- [3-18F]-α-methyltyrosine (18F-FAMT) PET/CT in patients with non-small-cell lung cancer (NSCLC). METHODS: The study group comprised 112 NSCLC patients who underwent 18F-FDG and 18F-FAMT PET/CT prior to any therapy. The MTV, TLG, TLR, and maximum standardized uptake value (SUVmax) of the primary tumors were determined. Automatic MTV measurement was performed using PET volume computer assisted reading software. (GE Healthcare). Cox proportional hazards models were built to assess the prognostic value of MTV, TLG (for 18F-FDG), TLR (for 18F-FAMT), SUVmax, T stage, N stage, M stage, clinical stage, age, sex, tumor histological subtype, and treatment method (surgery or other therapy) on overall survival (OS). RESULTS: Higher TNM, higher clinical stage, inoperable status, and higher values for all PET parameters (both 18F-FAMT and 18F-FDG PET) were significantly associated (P < 0.05) with shorter OS. Multivariate analysis revealed that a higher MTV of 18F-FAMT (hazard ratio [HR]: 2.88, CI: 1.63-5.09, P < 0.01) and advanced clinical stage (HR: 5.36, CI: 1.88-15.34, P < 0.01) were significant predictors of shorter OS. CONCLUSIONS: MTV of 18F-FAMT is of prognostic value for OS in NSCLC cases and can help guide decision-making during patient management.

[Multidisciplinary Approach to Recurrence after Resection of Primary Lung Cancer].

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.

High STMN1 Expression is Associated with Cancer Progression and Chemo-Resistance in Lung Squamous Cell Carcinoma.

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.

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.

Prognostic significance of ß2-adrenergic receptor expression in malignant melanoma.

Recent studies cite ß2-adrenergic receptor (ß2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The ß2AR has shown to be expressed in malignant melanoma. However, it remains unclear whether the ß2AR expression has a clinical and pathological significance in patients with cutaneous malignant melanoma. We herein conducted a clinicopathological study to investigate the protein expression of ß2AR in malignant melanoma of the skin and its prognostic significance. One hundred thirty-three patients with surgically resected cutaneous malignant melanoma were evaluated. Tumor sections were stained by immunohistochemistry for ß2AR, Ki-67, the microvessel density (MVD) determined by CD34, and p53. ß2AR was highly expressed in 44.4 % (59 out of 133) of the patients. The expression of ß2AR was significantly associated with the tumor thickness, ulceration, T factor, N factor, disease stage, tumor size, cell proliferation (Ki-67), and MVD (CD34). Using Spearman's rank test, the ß2AR expression was correlated with Ki-67 (r = 0.278; 95 % CI, 0.108 to 0.432; P = 0.001), CD34 (r = 0.445; 95 %CI, 0.293 to 0.575; P < 0.001), and the tumor size (r = 0.226; 95 % CI, 0.053 to 0.386; P = 0.008). Using a univariate analysis, the tumor thickness, ulceration, disease stage, ß2AR, Ki-67, and CD34 had a significant relationship with the overall and progression-free survivals. A multivariable analysis confirmed that ß2AR was an independent prognostic factor for predicting a poor overall survival (HR 1.730; 95 % CI 1.221-2.515) and progression-free survival (HR 1.576; 95 % CI 1.176-2.143) of malignant melanoma of the skin. ß2AR can serve as a promising prognostic factor for predicting a worse outcome after surgical treatment and may play an important role in the development and aggressiveness of malignant melanoma.

Risk factors associated with recurrence of surgically resected node-positive non-small cell lung cancer.

PURPOSE: The aim of this study was to identify risk factors for recurrence in non-small cell lung cancer (NSCLC) patients with lymph node metastases after surgical resection. METHODS: We reviewed 66 consecutive patients with surgically resected NSCLC who had pathologically proven positive lymph nodes (pN1 or pN2). All patients underwent a preoperative 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) evaluation. We analyzed the recurrence-free survival (RFS) and recurrence-free proportion (RFP) according to the clinicopathological factors. RESULTS: A total of 27 patients were pathologically N1 and 39 were N2. The 5-year overall survival rate and the RFS rate were 47.2 and 27.7 %, respectively. The cut-off values for the SUVmax of the tumor and the lymph node ratio (LNR) were determined to be 6.5 and 0.12, respectively, using a receiver operating characteristics curve analysis. Both univariate and multivariate analyses revealed three significant independent factors for RFS: namely, the SUVmax of the tumor, the LNR, and the use of adjuvant chemotherapy. Only the SUVmax was an independent significant predictor of the RFP. CONCLUSIONS: Both the SUVmax and the LNR can serve as prognostic factors for patients with pN + NSCLC. Our study suggests that the LNR could be a stronger prognostic factor than the N classification of the TNM system and the SUVmax may predict recurrence in node-positive NSCLC patients.