Initial perioperative outcomes of robot-assisted thoracoscopic lobectomy using a confronting setting.

PURPOSE: Most robot-assisted thoracoscopic surgery (RATS) is performed from the vertical view. This study evaluates the initial outcomes of our novel confronting RATS technique, in which the patient was viewed horizontally, as in open thoracotomy. METHODS: We reviewed data on patients who underwent thoracoscopic lobectomy between January, 2019 and April, 2022. Perioperative outcomes were compared between RATS and video-assisted thoracoscopic surgery (VATS), using propensity-score matching. RESULTS: RATS and VATS were performed for 83 and 571 patients, respectively. After propensity-score matching, data on 81 patients from each of the two groups were retrieved. The operative time was significantly longer for RATS than for VATS (199 ± 44 min vs. 173 ± 37 min, p < 0.001). There was no mortality or conversion to thoracotomy in either of the groups. The rates of overall complications and prolonged air leak did not differ significantly between the groups. The serum creatine phosphokinase level on postoperative day 4 was higher after RATS than after VATS. The number of resected lymph nodes and the rates of nodal upstaging did not differ significantly between the groups. CONCLUSION: The initial perioperative outcomes of RATS using the confronting settings were comparable to those of VATS.

Impact of postoperative complications on the long-term outcome in lung cancer surgery.

PURPOSE: Postoperative complications have a significant impact on perioperative outcomes; however, their association with the long-term prognosis remains unclear. We evaluated the impact of postoperative complications on the long-term outcomes after curative surgery in lung cancer patients. METHODS: This study included 1129 patients with primary lung cancer who underwent lobectomy between April 2011 and March 2017. Univariate and multivariate analyses were performed to assess the association of postoperative complications with the overall and recurrence-free survival. RESULTS: Postoperative complications were observed in 147 (13.0%) patients over a median follow-up period of 5-years. Compared to patients without complications, those with complications showed had worse long-term outcomes, including the 5-year overall survival (75.3% vs. 86.1%, p < 0.001) and 5-year recurrence-free survival (64.2% vs. 74.4%, p = 0.004). A multivariate analysis revealed that the incidence of postoperative complications was significantly associated with the overall survival (hazard ratio = 1.665, p = 0.006) and recurrence-free survival (hazard ratio = 1.416, p = 0.025) in all patients. The prognostic influence was greater in patients with pathological stages II and III cancer (overall survival: hazard ratio = 2.019, p = 0.005; recurrence-free survival: hazard ratio = 1.90, p = 0.001) than in those with pathological stage I cancer. CONCLUSION: Postoperative complications are independent predictors of the overall and recurrence-free survival in lung cancer patients, especially advanced-stage cancer patients.

Comparison of local therapy in patients with lung oligo-recurrence of non-small-cell lung cancer.

BACKGROUND AND OBJECTIVES: The effectiveness of local therapy has been reported in non-small-cell lung cancer (NSCLC) patients with oligo-recurrence. However, there is still no clear consensus on the choice of local therapy. We aimed to examine the choice of local therapy in NSCLC patients with lung oligo-recurrence. METHODS: Among 1760 consecutive NSCLC patients who underwent complete resection between 1990 and 2008, 535 patients developed recurrence. Lung oligo-recurrence was defined as 1-5 metachronous recurrences limited to the lungs only; such recurrence was found in 97 patients. We examined the differences in the prognosis of each therapy for these patients. RESULTS: The 5-year postrecurrence survival (PRS) rates in patients who underwent local therapy (n = 54) and those who did not (n = 43) were 55.6% and 31.1%, respectively; it was significantly higher in patients who underwent local therapy (p = 0.004). Among 47 patients who underwent resection or radiation therapy, the 5-year PRS rates were 61.5% and 47.6% (p = 0.258), and the 5-year postrecurrence progression-free survival rates were 30.3% and 24.7% (p = 0.665), respectively, without any significant difference. CONCLUSIONS: Patients with lung oligo-recurrence should consider local therapy individually, depending on their general condition.

Permissible Outcomes of Lobe-Specific Lymph Node Dissection for Elevated Carcinoembryonic Antigen in Non-Small Cell Lung Cancer.

Background and Objectives: Lobe-specific nodal dissection (L-SND) is currently acceptable for the dissection of early-stage non-small cell lung cancer (NSCLC) but not for cancers of more advanced clinical stages. We aimed to assess the efficacy of L-SND, compared to systemic nodal dissection (SND). Materials and Methods: We retrospectively collected the clinical data of patients with carcinoembryonic antigen (CEA) abnormality who underwent complete resection of NSCLC via lobectomy or more in addition to either SND or L-SND at two cancer-specific institutions from January 2006 to December 2017. Results: A total of 799 patients, including 265 patients who underwent SND and 534 patients who underwent L-SND, were included. On multivariate analysis, thoracotomy, more than lobectomy, cN1-2, advanced pathological stage, adjuvant treatment, and EGFR or ALK were strongly associated with SND. No significant differences were found in overall survival, disease-free survival, and overtime survival after propensity adjustment (p = 0.09, p = 0.11, and p = 0.50, respectively). There were no significant differences in local (p = 0.16), regional (p = 0.72), or distant (p = 0.39) tumor recurrence between the two groups. Conclusions: SND did not improve the prognosis of NSCLC patients with CEA abnormality. Complete pulmonary resection via L-SND seems useful for NSCLC patients with CEA abnormality.

Clinical significance of subcentimeter pulmonary nodules in patients undergoing hepatectomy for colorectal liver metastases.

BACKGROUND AND OBJECTIVES: The clinical significance of lung metastases regarded as subcentimeter pulmonary nodules (SPN) before hepatectomy for colorectal liver metastases (CLM) has not been assessed well. METHODS: The data from 569 patients undergoing hepatectomy for CLM from 2010 to 2016 were reviewed. The presence and final diagnosis of SPN were analyzed for their association with overall survival (OS). RESULTS: A total of 143 patients had SPN (25.1%). SPN were proved to be lung metastases in 43 patients (30.1%). Before hepatectomy, lung metastases were suspected in 25 patients (sensitivity: 58%; specificity: 100%). The 5-year OS of patients with lung metastases (45.4%) was worse than that of those with no pulmonary nodules (60.9%, P = .003). There was no significant difference in the 5-year OS between the patients with lung metastases diagnosed after hepatectomy (48.7%) and before hepatectomy (41.2%, P = .432). The 5-year OS of patients who underwent surgery for lung metastases after hepatectomy (60.5%) was similar to that of those with no pulmonary nodules and benign pulmonary nodules (60.9%, P = .6310; 44.0%, P = .899). CONCLUSION: Although diagnostic sensitivity for SPN before hepatectomy is low, timing of diagnosis does not affect OS. Conclusive lung resection offers OS similar to that of patients without lung metastases.

Outcomes after thoracoscopic surgery in octogenarian patients with clinical N0 non-small-cell lung cancer.

OBJECTIVE: The number of surgeries for elderly patients with lung cancer is increasing. In our institute, thoracoscopic lobectomy and hilar lymph node dissection are the standard procedure for octogenarian patients with clinical N0 non-small-cell lung cancer. The aim of this study was to determine the outcome of our strategy for octogenarian patients. METHODS: Seventy octogenarian patients with clinical N0 non-small-cell lung cancer who underwent surgery were enrolled (O group). As a control group, 205 septuagenarian patients were also enrolled (S group). We compared several clinicopathological factors and outcomes. RESULTS: The median age of the O group was 82. There was no significant difference in the comorbidity ratio between the two groups. The 5-year overall survival ratio for the O group (72.8%) was significantly worse than that for the S group (88.3%). However, multivariate analysis proved age was not an independent predictor of outcome. The rates of recurrences involving ipsilateral mediastinal lymph nodes were equal in the two groups. After propensity score matching, clinical T1 patients were dominant (85%) in two matched group and no statistically significant differences were observed in the 5-year overall survival between the two groups. CONCLUSIONS: Our strategy for octogenarian patients with non-small-cell lung cancer, including omission of mediastinal lymph node dissection, was determined to be feasible, in particularly with cT1N0 disease.

Mucinous lung adenocarcinoma, particularly referring to EGFR-mutated mucinous adenocarcinoma.

The current 2015 World Health Organization (WHO) classification of lung tumors does not adequately categorize mucinous lung adenocarcinoma. Thus far, only two variants of mucinous adenocarcinoma have been studied: invasive mucinous adenocarcinoma and colloid adenocarcinoma. Moreover, common types of invasive adenocarcinoma when they produce mucin are yet to be elucidated, particularly epidermal growth factor receptor (EGFR)-mutated mucinous adenocarcinoma. In this study, we extracted mucinous adenocarcinoma of both the common types and the two variants. Further, we immunohistochemically and molecular-biologically examined their clinicopathological characteristics, mutation patterns, and expressions of thyroid transcription factor-1 (TTF-1), hepatocyte nuclear factor-4 alpha (HNF-4a) and mucins, particularly referring to EGFR-mutated adenocarcinoma. Among 1159 surgically resected invasive adenocarcinomas, 189 mucinous adenocarcinomas (16%) were identified. Among these, 20%, 34% and 9.5% were EGFR mutated, KRAS mutated and ALK rearranged, respectively. Compared with EGFR-mutated nonmucinous adenocarcinoma, EGFR-mutated mucinous adenocarcinoma had no female predominance, lower grades of histological differentiation and lower TTF-1 and higher HNF-4a expressions. Moreover, for the first time, we indicated that mucin production was an independent prognostic factor for EGFR-mutated adenocarcinomas and the mucin-staining pattern of negative MUC5AC and positive MUC5B was characteristic in these adenocarcinomas. We suggest that EGFR-mutated mucinous adenocarcinoma has a different tumorigenic pathway than nonmucinous EGFR-mutated adenocarcinoma.

Recent fluorescence imaging technology applications of indocyanine green in general thoracic surgery.

Thoracic surgeons perform a wide variety of cancer operations, which are often associated with high morbidity and mortality. Thus, thoracic surgery involves many special challenges that require innovative solutions. The increased utilization of minimally invasive practices, poor overall cancer survival, and significant morbidity of critical operations remain key obstacles to overcome. Fluorescence imaging technology (FIT), involving the implementation of fluorescent dyes and imaging systems, is currently used as an adjunct for general thoracic surgery in many situations and includes sentinel lymph node mapping, pulmonary intersegmental plane identification, pulmonary nodule identification, pulmonary bullous lesion detection, evaluation of the anastomotic perfusion after tracheal surgery, and thoracic duct imaging for postoperative chylothorax. This technology enhances the surgeon's ability to perform operations, and has specific advantages. We review some of the key studies that demonstrate the applications of FIT in the field of general thoracic surgery, focusing on the use of indocyanine green.

[Completion Pneumonectomy and Perioperative Managements].

Completion pneumonectomy (CP) is the complete removal of lung tissue remaining after an initial ipsilateral partial pulmonary resection and is one of the most invasive operations in the field of general thoracic surgery. Mortality and morbidity rates are higher after CP than standard pneumonectomy. CP is a highly demanding procedure, usually due to major pleural and sometimes pericardial dense adhesions from previous surgery or infection. Intra-pericardial control of the pulmonary artery and veins is recommended to avoid vessel injury. Therefore, this operative intervention should be performed only by experienced thoracic surgeons on carefully selected patients in order to improve postoperative outcomes. Preoperative pulmonary and cardiac functions are decreased by the previous procedure. In addition, the rate of complications is high because of excessive operative invasiveness. Therefore, preoperative assessment, surgical indication, low invasive surgical technique, and good postoperative management are very important elements when CP is performed. On the other hands, CP may be a reasonable option for postoperative lung cancer recurrence or new primaries only in carefully selected patients, in whom the potential oncological benefits overweigh the surgical risk. This article reviews these operative knack and pitfalls.

Pattern of care in adjuvant therapy for resected Stage I non-small cell lung cancer: real-world data from Japan.

BACKGROUND: Adjuvant tegafur/uracil (UFT) chemotherapy is recommended for patients with completely resected Stage I non-small cell lung cancer (NSCLC) in Japan. A Phase III trial, the Japan Clinical Oncology Group (JCOG) 0707, comparing the survival benefit of UFT and S-1 (tegafur/gimeracil/oteracil) for this population is being conducted. However, the selection of patients in the randomized clinical trial (RCT) may not represent the real-world population. The present study aimed to investigate the pattern of care for patients receiving adjuvant chemotherapy for completely resected NSCLC. METHODS: Patients with completely resected pathological Stage I (T1 > 2 cm and T2 in 6th TNM edition) NSCLC eligible for the JCOG0707 trial but excluded from it during the enrollment period (2008-13) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient. RESULTS: This study enrolled 5006 patients, 85% of those initially considered for participation in the JCOG0707 trial (5006 of 5923 patients). Among them, 2389 were ineligible for the trial and 2617 had not been enrolled despite being eligible. The most frequent reason for non-enrollment despite eligibility was the decline in patients' participation, and the major reasons for trial ineligibility were concomitant malignancy and comorbidities. Of all the patients enrolled in our study, 1659 received adjuvant chemotherapy, mainly UFT. CONCLUSIONS: Our study indicates that only 15% of the real-world patients with completely resected NSCLC were enrolled into the adjuvant chemotherapy RCT, and among those not participating in the trial, one-third received adjuvant chemotherapy.

Efficiency of thoracoscopic palpation in localizing small pulmonary nodules.

PURPOSE: The thoracoscopic localization of small and deep pulmonary nodules can be challenging. We conducted this study to evaluate the efficiency of thoracoscopic palpation in tumor detection. METHODS: The subjects of this study were 229 patients with a collective 267 indeterminate pulmonary nodules ≤ 15 mm in diameter, in the outer third of the lung field. The nodules were localized by palpation using the forefinger or a metal suction probe. Based on the distance from the pleura-to-tumor size ratio (D/S), the nodules were classified into group A (D/S = 0), group B (0 < D/S ≤ 1), and group C (D/S > 1). RESULTS: The median tumor diameter was 10 mm. All 267 nodules were palpable and resected with negative margins via thoracoscopic wedge resection. The majority of the deep nodules had no pleural change (11%, 86%, and 100% in groups A, B, and C, respectively; P < 0.01). The median margins were 15, 16, and 14 mm in groups A, B, and C, respectively. In four patients (1.5%) with relatively short margins (2-7 mm), an additional intraoperative wedge resection was performed. CONCLUSION: Thoracoscopic palpation was effective for tumor detection when the nodules were located in the outer third of the lung.

[Thoracoscopic Segmentectomy Using Three-dimensional Computed Tomography and Indocyanine-green Fluorescence Navigation].

BACKGROUND: We investigated the feasibility and efficacy of thoracoscopic segmentectomy using 3-dimensional computed tomography( 3D-CT) and indocyanine-green( ICG) fluorescence navigation. METHODS: ICG fluorescence-navigated thoracoscopic segmentectomy was performed in 149 patients during 2013 and 2017. Each patient underwent preoperative evaluation by thin-section enhanced CT, which provided 3-dimensional simulations of vascular and bronchial structures. During the procedure, low-dose ICG( 0.15~0.25 mg/kg) was injected systemically after the target segmental pulmonary arteries and bronchus were divided. Under near-infrared thoracoscopic guidance, an intersegmental plane was clearly observed as a border between dark target region and bright residual region. The ICG fluorescent line was marked by electrocautery, followed by division of lung parenchyma along the line by endoscopic staples. RESULTS: An intersegmental line was visible in 98% of patients by ICG fluorescence navigation. No ICG-related adverse events occurred. No operative mortality was observed and morbidity rate was 8.7%. The 5-year overall survival rate and the 5-year recurrence free probability of 101 patients with primary lung cancer were 92% and 98%, respectively. Local recurrence at the resected site occurred in no patient with lung cancer and 1 patient with pulmonary metastasis. CONCLUSION: Thoracoscopic segmentectomy using 3D-CT and ICG fluorescence navigation is a useful therapeutic option.

Hyalinizing clear cell carcinoma of the bronchial glands: presentation of three cases and pathological comparisons with salivary gland counterparts and bronchial mucoepidermoid carcinomas.

Hyalinizing clear cell carcinoma of the bronchial glands is a very rare tumor. Since only five reports describing six tumors have been published to date, only a little is known about specific histologic findings and clinical features. Because of its rarity, hyalinizing clear cell carcinoma has not been described in the latest WHO classification of pulmonary tumors yet. Here we present three cases of bronchial hyalinizing clear cell carcinomas, confirmed by both fluorescence in situ hybridization (FISH) and RT-PCR, focusing on histologic and immunohistochemical characteristics in a comparison with three cases of salivary gland origin. In addition, we compared immunohistochemical features with bronchial mucoepidermoid carcinoma, a lesion that needs to be taken into account in differential diagnosis of hyalinizing clear cell carcinoma. All our bronchial hyalinizing clear cell carcinoma cases were surgically resected. Histologically, tumor cells showed clear to eosinophilic cytoplasm with hyalinizing stroma in various proportions, resembling those of salivary gland origin. Immunohistochemically, tumor cells were positive for CK7, CK5/6, p40, p63, and ATF1, while they were negative for TTF1, Napsin A, HMB45, and SOX10. The CK5/6 staining pattern varied in mucoepidermoid carcinomas, while that of hyalinizing clear cell carcinoma was uniformly positive. FISH revealed EWSR1-ATF1 fusion, and RT-PCR with sequencing confirmed specificity of the chimeric gene for hyalinizing clear cell carcinoma. Clinically, bronchial hyalinizing clear cell carcinoma was characterized by occurrence in the fourth to sixth decades, no link with smoking history, and a predilection for the right lung, in line with previous reports. In summary, our study confirmed that the bronchial hyalinizing clear cell carcinoma is a histologically and genetically identical tumor to that of salivary gland origin, and that gene rearrangement analysis can play a critical role in distinction from mucoepidermoid carcinoma.

Pulmonary Carcinoids and Low-Grade Gastrointestinal Neuroendocrine Tumors Show Common MicroRNA Expression Profiles, Different from Adenocarcinomas and Small Cell Carcinomas.

BACKGROUND: It is still uncertain whether small cell lung carcinomas (SCLCs), pulmonary carcinoids, and the gastrointestinal neuroendocrine tumors (GI-NETs) have a common origin. MicroRNA (miRNA) expression may clarify their genetic relationships and origin. METHODS: First, we compared the miRNA expression signature of formalin-fixed paraffin-embedded (FFPE) samples with frozen samples to verify the applicability of microarray analysis. Second, we compared the comprehensive miRNA expression patterns of pulmonary carcinoids and GI-NETs as well as other types of tumors and normal tissues from each organ using FFPE samples. These data were analyzed by hierarchical clustering and consensus clustering with nonnegative matrix factorization. RESULTS: We confirmed that FFPE samples retained the miRNA signatures. In the first hierarchical clustering comparing carcinoids/NETs with adenocarcinomas and normal tissues, most of the carcinoids (48/50) formed 1 major cluster with loose subpartitioning into each organ type, while all the adenocarcinomas (9/9) and normal tissues (15/15) formed another major cluster. The nonnegative matrix factorization approach largely matched the classification of the hierarchical clustering. In the additional cluster analysis comparing carcinoids/NETs with SCLCs, most carcinoids/NETs (17/22) formed a major cluster, while SCLCs (9/9) grouped together with pulmonary adenocarcinomas (3/3) and normal tissues (6/6) in another major cluster. Furthermore, a subset of miRNAs was successfully identified that exhibited significant expression in carcinoids/NETs. CONCLUSION: Carcinoids/NETs had a characteristic pattern of miRNA expression, suggesting a common origin for pulmonary carcinoids and GI-NETs. The expression profiles of pulmonary carcinoids and SCLCs were quite different, indicating the distinct histogenesis of these neuroendocrine neoplasms.

Preoperative predictors of distant recurrence in patients with clinical stage IA lung adenocarcinoma undergoing complete resection.

Objective: We aimed to identify patients with clinical Stage IA lung adenocarcinoma who are at high risk for distant recurrence to preoperatively organize treatment strategies. Methods: We analyzed correlations between preoperative clinical factors and the incidence of distant recurrence in 609 patients with clinical Stage IA lung adenocarcinoma that had been completely resected at four institutions. We excluded 24 patients with only locoregional recurrence and analyzed data from 585 patients. Results: Distant recurrence after complete resection was identified in 34 patients during a median follow-up period of 41.4 months. Multivariate Cox analysis identified solid tumor size on high-resolution computed tomography and the maximum standardized uptake value on F-18-fluorodeoxyglucose positron emission tomography/computed tomography as independent predictors for distant recurrence-free survival. Receiver operating characteristic analyses showed that solid tumor size ≥1.7 cm and the maximum standardized uptake value ≥3.3 were optimal criteria with which to detect patients at high risk for distant recurrence. In fact, 3-year distant recurrence rates were higher in patients who met the criteria for high risk (n = 85) than those who did not (n = 500) (28.1% vs. 3.7%; P < 0.001). A similar trend was also found in patients with pathological node negative. Conclusions: Solid tumor size on high-resolution computed tomography and the maximum standardized uptake value on F-18-fluorodeoxyglucose positron emission tomography/computed tomography were clinical predictors of distant recurrence among patients with clinical Stage IA lung adenocarcinoma. Our findings might be useful to determine personalized therapeutic strategies including systemic therapy.

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.

High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild-type epidermal growth-factor receptor cases.

A clinical implication of programmed cell death 1 ligand 1 (PD-L1) expression in lung adenocarcinoma has not been well established. We evaluated PD-L1 expression immunohistochemically on 296 surgically resected lung adenocarcinomas to investigate a clinical implication of PD-L1 expression especially in terms of smoking history and epidermal growth-factor receptor (EGFR) mutation status. Patients were classified into high- and low-PD-L1 expression groups. The high-expression group (n = 107) showed a significantly higher proportion of smokers and poor differentiation compared with the low-expression group (n = 189). Survival analysis showed that the prognosis of the high-expression group was worse in overall survival than that of the low-expression group (3-year overall survival 85 vs. 94%, P = 0.005). Stratified survival analyses showed that the prognoses of the high-expression group were worse than those of the low-expression group in both strata of smokers and wild-type EGFR (P = 0.009 and P = 0.007, respectively). We found that high PD-L1 expression was a poor prognostic factor in the smokers or the patients with wild-type EGFR, whereas it was not the case in those who never smoked or those with EGFR mutation, implying the importance of adenocarcinoma driver mutations and etiology.

RAS mutation is a prognostic biomarker in colorectal cancer patients with metastasectomy.

Studies have demonstrated a relationship between clinical outcomes after curative resection for colorectal cancer (CRC) and gene mutations of the EGFR pathway; however, no studies have examined metastatic CRC (mCRC) patients with metastasectomy. The aim of this study was to evaluate the relationship between gene mutations of EGFR pathway and clinical outcomes after metastasectomy in mCRC patients. A total of 1,053 patients histopathologically confirmed CRC received a genotyping test for the EGFR pathway from February 2012 to October 2013. Detailed information was obtained through review of medical records. Gene mutations of EGFR pathway were analyzed by Luminex assay. Overall survival (OS) and recurrence free survival were estimated by the Kaplan-Meier method and the log-rank test was used to compare the survival outcomes by gene mutation status. A total of 132 patients received metastasectomy. The frequencies of KRAS exon 2, KRAS exon 3.4, NRAS, BRAF, and PIK3CA mutations were 38.6% (51/132), 3.6% (5/132), 5.1% (7/132), 5.1% (7/132), and 8.7% (12/132), respectively. With a median follow-up of 84.1 months (57.2-NA) for a survivor, the 4-year OS rate was 65.6% for mCRC with RAS mutation, and 81.3% for mCRC with wild-type RAS (p < 0.05). We observed a statistically significant correlation for only the RAS mutation and OS. In multivariate analysis, RAS mutation and liver metastasis were independent factors for shorter OS. There were no significant differences between gene mutations of EGFR pathway and recurrence free survival. RAS mutation in mCRC metastasectomy patients was associated with shorter overall survival.

Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma.

Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome-wide methylation profile of SCLC. We investigated the genome-wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non-negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non-CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for treatment of the aggressive tumor.

Relationship of tumor PD-L1 expression with EGFR wild-type status and poor prognosis in lung adenocarcinoma.

BACKGROUND: Programmed death-ligand 1 is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Whereas programmed death-ligand 1 expression has been shown to be associated with the clinical response to anti-programmed death-ligand 1 antibody, the association of tumor programmed death-ligand 1 expression with clinicopathological/molecular features and with prognosis remains inconclusive in lung adenocarcinoma. We therefore examined the association of programmed death-ligand 1 expression with the clinicopathological/molecular features and prognosis of lung adenocarcinoma. METHODS: Using tissue microarrays of 268 consecutive cases of lung adenocarcinoma, we evaluated programmed death-ligand 1 expression by immunohistochemistry. We examined the association of programmed death-ligand 1 expression with clinicopathological and molecular features. We also examined the prognostic association of programmed death-ligand 1 expression, using the log-rank test as well as Cox proportional hazards regression models to compute the mortality hazard ratio (HR). RESULTS: Programmed death-ligand 1 immunoreactivity (at least 5% of the tumor cells) was observed in 43 (16%) of 268 cases of lung adenocarcinoma. Programmed death-ligand 1 positivity was associated with less tumor differentiation (P < 0.0001) and EGFR wild-type status (P = 0.0008). In a multivariable logistic regression analysis, less tumor differentiation was independently associated with programmed death-ligand 1 positivity (multivariable odds ratio, 6.54; 95% confidence interval [CI], 2.37-23.3; P = 0.0001). Programmed death-ligand 1 positivity was associated with a poor prognosis for lung cancer-specific survival (log-rank, P = 0.019; HR, 1.73; 95% CI, 1.06-2.72; P = 0.030) and overall survival (log-rank, P = 0.0014; HR, 1.88; 95% CI, 1.25-2.74). CONCLUSION: Our study demonstrated that programmed death-ligand 1 positivity in lung adenocarcinoma was associated with less tumor differentiation and EGFR wild-type status, as well as a poor prognosis.