Prognostic Significance of the Maximum Standardized Uptake Value on the Prognosis of Clinical Stage IA Lung Adenocarcinoma Based on the 8th Edition TNM Classification.

BACKGROUND: There are few reports on the utility of the maximum standardized uptake value (SUVmax) for predicting the prognosis of early-stage lung adenocarcinoma based on the latest tumor-node-metastasis (TNM) classification. This study aimed to determine whether clinicopathologic factors, including the SUVmax, affect prognosis in these patients. PATIENTS AND METHODS: We enrolled 527 patients with c-stage IA lung adenocarcinoma who underwent lobectomy or greater resection between 2011 and 2017. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and compared using the log-rank test. Factors associated with RFS and OS were determined using the Cox proportional hazards model. RESULTS: RFS was significantly different based on tumor stage. In contrast, there was no significant difference in OS between patients with stage IA2 and IA3 disease (p = 0.794), although there were significant differences in OS between patients with stage IA1 and IA2 disease (p = 0.024) and between patients with stage IA1 and IA3 disease (p = 0.012). Multivariate analysis demonstrated that SUVmax was independently associated with both RFS and OS among patients with c-stage IA lung adenocarcinoma (RFS, p = 0.017; OS, p = 0.047). Further, even though there was no significant difference in OS between patients with stage IA2 and IA3 disease (n = 410), SUVmax was able to stratify patients with high and low RFS and OS among these patients (RFS, p < 0.001; OS, p < 0.001). CONCLUSION: SUVmax was an important preoperative factor to evaluate prognosis among patients with c-stage IA lung adenocarcinoma as well as the current TNM classification.

A multicenter propensity score-matched analysis of lymphadenectomy in N1-positve lung cancer.

OBJECTIVES: Selective mediastinal lymph node dissection based on lobe-specific metastases is widely recognized in daily practice. However, the significance of mediastinal lymph node dissection for N1-positive tumors has not been elucidated. METHODS: We retrospectively reviewed 359 patients with N1-positive lung cancer who underwent lobectomy with systematic mediastinal lymph node dissection (systematic lymph node dissection) (n = 150) and lobe-specific mediastinal lymph node dissection (lobe-specific lymph node dissection) (n = 209). The operative and postoperative results and their propensity score-matched pairs were compared. The factors affecting survival were assessed using competing risk and multivariable analyses. RESULTS: The cumulative incidence of recurrence and the cumulative incidence of cancer-specific death were not significantly different between systematic and lobe-specific lymph node dissection in entire cohort. In the propensity score-matched cohort (83 pairs), systematic lymph node dissection tended to detect N2 lymph node metastasis more frequently (55.4 vs. 41%, P = 0.087). Eleven patients (13.2%) in the systematic lymph node dissection group had a metastatic N2 lymph node 'in the systematic lymph node dissection field' that lobe-specific lymph node dissection did not dissect. The oncological outcomes between patients undergoing systematic lymph node dissection (5-year cumulative incidence of recurrence, 62.1%; 5-year cumulative incidence of cancer-specific death, 27.9%) and lobe-specific lymph node dissection (5-year cumulative incidence of recurrence, 60.1%; 5-year cumulative incidence of cancer-specific death, 23.3%) were similar. The propensity score-adjusted multivariable analysis for cumulative incidence of recurrence revealed that the prognosis associated with systematic lymph node dissection was comparable with the prognosis with lobe-specific lymph node dissection (hazard ratio, 1.17; 95% confidence interval, 0.82-1.67; P = 0.37). CONCLUSIONS: The extent of lymph node dissection can affect accurate pathological staging; however, it was not associated with survival outcome in the treatment of N1-positive lung cancer.

Systematic Versus Lobe-Specific Mediastinal Lymphadenectomy for Hypermetabolic Lung Cancer.

BACKGROUND: The optimal extent of lymph node dissection (LND) for hypermetabolic tumors that are associated with high rates of nodal disease, recurrence, or mortality has not been elucidated. METHODS: We reviewed 375 patients who underwent lobectomy with lymphadenectomy for clinical T2-3 N0-1 M0 hypermetabolic non-small cell lung cancer (NSCLC) [maximum standard uptake value (SUVmax) ≥ 6.60] via a multicenter database. Extent of LND was classified into systematic mediastinal LND (systematic LND) and lobe-specific mediastinal LND (lobe-specific LND). Postoperative outcomes after lobectomy with systematic LND (n = 128) and lobe-specific LND (n = 247) were analyzed for all patients and their propensity-score-matched pairs. RESULTS: Cancer-specific survival (CSS) and recurrence-free interval (RFI) of the systematic LND group were not significantly different from those of the lobe-specific LND group in the nonadjusted whole cohort. In the propensity-score-matched cohort (101 pairs), systematic LND dissected significantly more lymph nodes (20.0 versus 16.0 nodes, P = 0.0057) and detected lymph node metastasis more frequently (53.5% vs. 33.7%, P = 0.0069). Six (5.9%) patients in the systematic LND group had a metastatic N2 lymph node "in the systematic LND field" that lobe-specific LND could not dissect. The systematic LND group tended to have better prognosis than the lobe-specific LND group (5-year CSS rates, 82.6% versus 69.6%; 5-year RFI rates, 56.6% vs. 47.3%). CONCLUSIONS: Systematic LND was found to harvest more metastatic lymph nodes and provide better oncological outcome than lobe-specific LND in a cohort of hypermetabolic NSCLC patients.

Appropriate Extent of Lymphadenectomy in Segmentectomy: A Multicenter Study.

BACKGROUND: The significance of lymphadenectomy is yet to be fully examined in segmentectomy. We compared the oncological outcomes of mediastinal lymph node dissection (LND) and hilar LND for lung cancer treated with segmentectomy via a multicenter database using propensity score-matched analysis. METHODS: We reviewed 357 clinical stage IA radiologically solid-dominant lung cancer patients who underwent segmentectomy with lymphadenectomy. The extent of LND was classified into systematic/lobe-specific mediastinal LND and hilar LND only groups. Postoperative results after segmentectomy with mediastinal LND (n = 179) and hilar LND (n = 178) were analyzed for all patients and their propensity score-matched pairs. RESULTS: Cancer-specific survival (CSS) and recurrence-free interval (RFI) rates for the mediastinal LND group were determined to be not significantly different compared with the hilar LND group in all non-adjusted cohorts. In the propensity score-matched cohort (129 pairs), mediastinal LND harvested more lymph nodes compared with hilar LND, and both groups had significantly different pathological stages (P = 0.015). Adjuvant chemotherapy was performed in 10 (7.8%) patients in the mediastinal LND group and 4 (3.1%) in the hilar LND group. The mediastinal LND group tended to have better prognosis than the hilar LND group (5-year CSS rates, 97.4% vs 93.2%; 5-year RFI rates, 93.5% vs 88.5%). CONCLUSIONS: Mediastinal LND was found to provide more appropriate pathological staging compared with hilar LND in patients with segmentectomy by harvesting more lymph nodes. In addition, mediastinal LND might lead to better oncological outcome than hilar LND in segmentectomy.

Risk of death due to other causes is lower among octogenarians with non-small cell lung cancer after wedge resection than lobectomy/segmentectomy.

OBJECTIVE: We aimed to determine the influences of surgical procedures on the postoperative death of octogenarians with clinical Stage IA non-small cell lung cancer excluding cT1mi. METHODS: We compared overall survival and the cumulative incidence of death due to all and other causes among 1 130 279, and 191 consecutive patients aged ≤79 and ≥80 years after lobectomy, segmentectomy and wedge resection at three institutions. Death due to other causes was defined as death due to any cause except non-small cell lung cancer. RESULTS: The median followup was 53 months. The 5-year overall survival rates for patients aged ≥ 80 and ≤ 79 years after lobectomy, segmentectomy and wedge resection were respectively, 78.0% (95% confidence interval, 63.8%-87.2%) versus 91.2% (95% confidence interval, 89.0%-92.9%), 68.1% (95% confidence interval, 45.2%-83.1%) versus 90.0% (95% confidence interval, 84.6%-93.5%), and 62.7% (95% confidence interval, 44.0-76.7%) versus 84.4% (95% confidence interval, 76.3%-89.9%) (P < 0.01 for all). The cumulative incidence of death due to other causes after wedge resection was similar between patients aged ≥ 80 and ≤ 79 years (P = 0.45), but significantly higher in those aged ≥ 80, than ≤ 79 years after lobectomy or segmentectomy (P = 0.00015 and 0.00091, respectively). CONCLUSIONS: The influence of wedge resection on death due to other causes was lower than that of lobectomy or segmentectomy in patients with non-small cell lung cancer aged ≥ 80 years. Wedge resection might be a useful option for octogenarians even if they can tolerate lobectomy/segmentectomy to avoid postoperative death due to causes other than non-small cell lung cancer.

Detection of EGFR mutation of pulmonary adenocarcinoma in sputum using droplet digital PCR.

BACKGROUND: It is still unclear whether epidermal growth factor receptor (EGFR) mutation of primary lung adenocarcinoma can be detected on sputum samples. This study aimed to examine EGFR mutations of primary lung adenocarcinoma in sputum samples using droplet digital polymerase chain reaction (ddPCR) and compare it with an EGFR mutation in surgically resected lung cancer. METHODS: Sputum was prospectively collected from the patients before complete resection of the primary lung cancer at Kanagawa Cancer Center from September 2014 to May 2016. ddPCR was performed to detect EGFR exon 21 L858R point mutation (Ex21) and EGFR exon 19 deletion mutation (Ex19) in sputum samples from patients with lung adenocarcinoma. The concordance of EGFR mutation status in sputum samples and tumors in surgically resected specimen was evaluated for each positive and negative cytology group. RESULTS: One hundred and eighteen patients with primary lung adenocarcinoma provided sputum samples. Sputum cytology was positive in 13 patients (11.0%). ddPCR detected two cases of Ex21 and two cases of Ex19 in sputum cytology positive cases. Compared to surgically resected specimens, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 80.0%, 100%, and 100%, respectively, in sputum cytology positive cases. In contrast, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 3.1%, 100%, and 100%, respectively, in sputum cytology negative cases. CONCLUSIONS: EGFR mutations in primary lung adenocarcinoma can be detected with high sensitivity in sputum samples if sputum cytology is positive.

Wedge resection as an alternative treatment for octogenarian and older patients with early-stage non-small-cell lung cancer.

OBJECTIVE: Anatomical resection with lymph node dissection is the standard treatment for early non-small cell lung cancer, whereas wedge resection is considered as a compromise. We aimed to determine whether wedge resection without lymph node dissection could be a treatment option for patients aged ≥80 years. METHODS: We assessed 669 patients with clinical stage IA non-small cell lung cancer, whole tumour sizes ≤2 cm and a consolidation to tumour ratio of >0.5 who underwent R0 resection at three institutions between 2010 and 2016. We selected 58 of them who were aged ≥80 years and analysed their clinicopathological findings and prognosis after surgical procedures over a median follow-up of 38 months. Propensity scores for surgical procedures were calculated using age, gender, smoking status and solid tumour size on computed tomography. RESULTS: Three-year overall and recurrence-free survival rates after wedge resection and after segmentectomy + lobectomy for patients aged ≥80 years did not significantly differ (overall survival: 88.9% [95% confidence interval, 69.4-96.3%] vs. 75.5% [95% confidence interval, 51.5-88.8%], P = 0.95; recurrence-free survival: 85.2% [95% confidence interval: 65.2-94.2%] vs. 68.0% [95% confidence interval, 44.4-83.2], P = 0.57). Multivariable Cox regression analysis of overall survival with propensity scores revealed that surgical procedure was not an independent predictor of a poor prognosis (hazard ratio: 0.86 (0.28-2.6), P = 0.78) in patients aged ≥80 years. CONCLUSIONS: Wedge resection might be an alternative to lobectomy or segmentectomy with lymph node dissection for patients aged ≥80 years with early non-small cell lung cancer.

A prophylaxis study of acute exacerbation of interstitial pneumonia after lung cancer surgery.

INTRODUCTION: Acute exacerbation of interstitial pneumonia (AE-IP) is a lethal complication after lung surgery. We conducted a prospective, multi-institutional phase II trial to assess the efficacy and safety of prophylactic measures. METHOD: Patients with lung cancer with dorsal subpleural fibrotic changes occupying three or more segments of both lower lobes and planned anatomical lung resection were enrolled. Prior to surgery, patients received a 125-mg bolus injection of methylprednisolone and continuous intravenous infusion of sivelestat sodium hydrate (sivelestat) for 2 days. RESULTS: Sixty-nine patients were analysed. Preoperative high-resolution computed tomography (HRCT) showed 37 (53.6%) cases presented with usual interstitial pneumonia (UIP) and possible UIP pattern. There were 60 lobectomies and 9 segmentectomies. Thirty-eight cases were in clinical stage I. No adverse events associated with prophylaxis were observed. There were four cases of AE-IP (5.8%), higher than the expected 2.0%. Three of the four cases showed inconsistencies with the UIP pattern in preoperative HRCT and were pathologically diagnosed as UIP. All patients died of respiratory failure. Overall, 89.9% were diagnosed as idiopathic interstitial pneumonias; UIP was found in 48 patients (69.6%). Severe post-operative complications occurred in 11.6% of the cases. There were 35 deaths, 17 cases of lung cancer and 11 cases related to interstitial pneumonias. The overall survival rate at 3 years was 41.8% of the total and 47.2% of cases with clinical stage I. CONCLUSIONS: Perioperative use of sivelestat and low-dose methylprednisolone in patients with anatomical lung resection was safe but did not prove to be a prophylactic effect for AE-IP.

Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.

Impact of the epidermal growth factor receptor mutation status on the prognosis of recurrent adenocarcinoma of the lung after curative surgery.

BACKGROUND: The prognosis of patients with epidermal growth factor receptor (EGFR) mutant adenocarcinoma of the lung (Mt) and EGFR wild-type adenocarcinoma (Wt) after complete resection of the lung differ; however, the mechanisms responsible for these differences remain unclear. The present study examined the post-operative prognosis of recurrent pulmonary adenocarcinoma patients to evaluate the clinicopathological nature of Mt and contribution of EGFR - tyrosine kinase inhibitors (TKI) to the prognosis of patients. METHODS: The subjects were 237 patients with recurrent pulmonary adenocarcinoma who underwent EGFR mutation analysis, and consisted of 108 patients with recurrent Mt and 129 with recurrent Wt. Multivariate analyses were performed to investigate whether the EGFR status is a prognostic factor for relapse-free survival (RFS) and post-relapse survival (PRS). RESULTS: RFS was significantly better in Mt than in Wt patients; median RFS were 20.2 and 13.3 months, respectively (p < 0.001). The multivariate analysis identified EGFR mutation as an independent prognostic factor for a favorable RFS (hazard ratio = 0.68; 95% confidence interval, 0.52-0.89). Although, no significant differences were observed in PRS between Mt and Wt patients (median PRS were 33.9 and 28.2 months, respectively; p = 0.360), PRS was significantly better in Mt with EGFR - TKI than in Wt and Mt patients without EGFR - TKI (p = 0.008 and p < 0.001, respectively). PRS was also significantly better in Wt than in Mt patients without EGFR - TKI (p < 0.001). The multivariate analysis identified the administration of EGFR - TKI as an independent prognostic factor for PRS (hazard ratio = 0.60; 95% confidence interval, 0.40-0.89). CONCLUSIONS: EGFR mutation tumors were associated with a significantly better RFS for recurrent pulmonary adenocarcinoma after curative resection of the lung, which represented the less aggressive nature of Mt tumors. However, patients with Mt did not have a favorable prognosis after recurrence unless they received EGFR - TKI.

[When Should We Perform Surgery for N2 Lung Cancer?;Induction Chemoradiotherapy or Surgery for Local Recurrence or Residual Tumor after Definitive Chemoradiotherapy].

BACKGROUND: Standard treatment for locally advanced clinical N2 lung cancer is definitive chemoradiotherapy, and induction chemoradiotherapy(IND-CRT) followed by surgery is an option. Most of them recurs remotely within a few years after initial therapy. Patients who received salvage surgery(SAL) after definitive chemoradiotherapy had no remote relapse for some period after definitive chemoradiotherapy, thus the outcome of SAL may be better than those of IND-CRT, but the operative risks of both procedures seem to be high. OBJECTIVE: To compare the prognosis and risk of SAL and IND-CRT. METHOD: From January 2001 through December 2015, 39 patients with clinical N2 primary lung cancer underwent surgery after chemoradiotherapy. Twenty-six patients received IND-CRT, and 13 underwent SAL. Perioperative factors, overall survival rates at 5 years, lung-cancer-specific mortality, relapse-free survival rates, and the rates of perioperative complications were compared between the groups. RESULT: The median follow up period was 41.0 months(5~120 months). Twelve patients were women, and 27 were men. The average age was 60.2 years. The patients comprised 1.7% of the 2,330 anatomical resections performed during the same period. The radiation dose was 46.4 Gy who received IND-CRT and 61.4 Gy in those who received SAL(p<0.001). In patients who received IND-CRT, median period from the end of the initial treatment to surgery was 1.2 months in IND-CRT and 17.2 months in SAL. Lobectomy was performed in 37 patients, pneumonectomy in 2 patients. In patients who received IND-CRT, an average operation time was 236 minutes, mean bleeding volume was 135 g. In patients who underwent SAL, they were 236 minutes and 188 g(p=0.998, p=0.365). There was no perioperative and in-hospital death in either group. Postoperative complications developed in 5 of INDCRT(19.2%)and 3 in SAL(23.1%). The 5-year overall survival rate of all cases was 60.4%(IND-CRT 53.9, SAL 81.8%;p=0.737). The lung cancer-specific survival rate at 5 years was 60.4% overall, 57.5% in IND-CRT, and 90.0% in SAL(p=0.176). The 5-year relapse-free survival rate was 52.7% overall, 37.6% in IND-CRT, 57.7% in SAL(p=0.175). Although the differences were not statistically significant, SAL tended to have better outcomes. CONCLUSION: SAL did not differ significantly from IND-CRT with respect to postoperative complications or surgical invasiveness in patients with clinical N2 lung cancer and had good outcomes. SAL and IND-CRT seem to be a sufficiently meaningful treatment but should be performed by surgeons with sufficient knowledge and experience.

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.

Detection of tumor spread through airspaces by airway secretion cytology from resected lung cancer specimens.

It currently remains unclear whether tumor spread through airspaces (STAS) actually exist in vivo or are an artifact. The morphologies of STAS and tumor cell clusters in airway secretions collected from the segmental or lobar bronchus of resected lung adenocarcinomas and squamous cell carcinomas were compared among 48 patients. The EGFR status of tumor cell clusters in airway secretions was also compared with that of the main tumor in EGFR mutant adenocarcinomas. Tumor cell clusters were observed in the airway secretion cytology of ten patients (20.8%), and eight patients were adenocarcinoma (20.0% of adenocarcinoma). The morphology of STAS closely resembled that of tumor cell clusters detected in airway secretion cytology. The positive rates of airway secretion cytology were 83.3%, 100%, and 50% in papillary adenocarcinoma, micropapillary adenocarcinoma, and invasive mucinous adenocarcinoma, respectively. Among three EGFR mutant adenocarcinomas, the EGFR mutation subtypes of the main tumors in FFPE sections and tumor cell clusters in airway secretions were identical. These indicate that STAS may be detected in the airway secretion cytology. STAS is common in papillary or micropapillary adenocarcinoma and may spread as far as the segmental or lobar bronchus at the time of surgery.

[Salvage Surgery for Residual and Recurred Tumor after Definitive Chemoradiotherapy].

BACKGROUND: Standard treatment for clinical N2-locally advanced lung cancer is definitive chemoradiotherapy (CRT). For local recurrence or residual tumor after definitive CRT, salvage surgery may have effective treatment option with relatively high operative risk. OBJECTIVE: To examine the prognosis and risk of salvage surgery. METHOD: In 2001 to 2016, postoperative complications, overall survival and relapse free survival rate were examined in 17 patients who underwent salvage surgery after definitive CRT for clinical N2 or more primary lung cancer. RESULT: Median observation period 26.4 months, male 15 female 2, average age 58.6 years. This was 0.6% of 2,630 anatomical resections during this period. Average dose of radiation was 63.5 Gy. Median period from initial treatment to surgery was 16.0 months.15 lobectomy and 2 pneumonectomy. Average operation time was 289 minutes;blood loss was 271 ml. Bronchial stump coverage was performed in all cases, using 10 pericardial fat, 5 omentum, 2 intercostal muscle. Median of postoperative hospital days was 10. There was no perioperative and in-hospital death, but complications occurred in 6 cases (35.3 %). For a prolonged air leakage and 2 anastomotic fistula, 3 reoperations were needed( 17.6%). 5-year overall survival rate was 80.7%, and 5-year relapse free survival rate was 51.0%. CONCLUSION: Salvage surgery for clinical N2 lung cancer has a high frequency of postoperative complications and becomes a patient's burden. Salvage surgery seems to be meaningful, but physicians should have sufficient knowledge and experience in conducting this treatment approach.

Highly sensitive detection of invasive lung cancer cells by novel antibody against amino-terminal domain of laminin γ2 chain.

The laminin γ2 chain, a subunit of laminin-332 (α3ß3γ2), is a molecular marker for invasive cancer cells, but its pathological roles in tumor progression remain to be clarified. It was recently found that the most N-terminal, domain V (dV) of γ2 chain has activities to bind CD44 and stimulate tumor cell migration and vascular permeability. In the present study, we prepared a mAb recognizing γ2 dV. Immunoblotting with this antibody, for the first time, showed that proteolytic fragments containing dV in a range of 15-80 kDa were highly produced in various human cancer cell lines and lung cancer tissues. In immunohistochemistry of adenocarcinomas and squamous cell carcinomas of the lung, this antibody immunostained the cytoplasm of invasive tumor cells and adjacent stroma much more strongly than a widely used antibody recognizing the C-terminal core part of the processed γ2 chain. This suggests that the dV fragments are highly accumulated in tumor cells and stroma compared to the processed γ2 protein. The strong tumor cell staining with the dV antibody correlated with the tumor malignancy grade. We also found that the laminin ß3 and α3 chains were frequently overexpressed in tumor cells and tumor stroma, respectively. The cytoplasmic dV detection was especially prominent in tumor cells infiltrating stroma, but low in the cells surrounded by basement membranes, suggesting that the active tumor-stroma interaction is critical for the aberrant γ2 expression. The present study suggests important roles of laminin γ2 N-terminal fragments in tumor progression.

Prognostic significance of vascular invasion in intermediate-grade subtype of lung adenocarcinoma.

OBJECTIVES: Although the recent reclassification of histological subtypes of lung adenocarcinoma reflects disease prognosis better, the prognosis of papillary and acinar-predominant adenocarcinoma, which are highly prevalent, is heterogeneity. The present study aimed to identify the prognostic indicators for papillary and acinar-predominant adenocarcinoma. METHODS: This retrospective study included 315 consecutive patients with completely resected pathological N0 lung adenocarcinoma tumors ≤3 cm from two institutions. Tumors were classified according to histologically predominant subtypes as low-grade (adenocarcinoma in situ, minimally invasive adenocarcinoma or lepidic predominant), intermediate-grade (papillary or acinar predominant) or high-grade (solid or micropapillary predominant). Prognostic factors in intermediate-grade group were assessed among clinicopathological factors of age, gender, surgical procedure, tumor size, pleural, lymphatic and vascular invasion using Cox proportion hazards analyses. RESULTS: There were 174 patients in the low-grade group, 109 in the intermediate-grade group and 32 in the high-grade group. The 3-year recurrence-free survival rates were 98.1%, 86.3% and 74.8% for these groups, respectively (P < 0.001). In the intermediate-grade group, the presence of vascular invasion was an independent prognostic factor on multivariate Cox regression analysis of recurrence-free survival (hazard ratio, 3.48; 95% confidence interval, 1.26-9.57, P = 0.01). Classification of intermediate-grade group based on vascular invasion revealed a clear division into favorable and unfavorable prognostic subgroups. CONCLUSIONS: Consideration of the vascular invasion status in addition to the predominant subtype could provide a more accurate assessment of malignant aggressiveness and prognosis of patients with early-stage lung adenocarcinoma.

Clonality analysis performed using human androgen receptor assay in a rare case of undifferentiated thymic carcinoma coexisting with type AB thymoma.

We report a very rare case of combined thymic carcinomas: undifferentiated thymic carcinoma coexisting with type AB thymoma. The precise mechanism underlying the coexistence of these tumors remains unknown. Therefore, we used clonality analysis to ascertain whether the two tumors were clonally related. A 63-year-old woman with thyroid cancer visited our hospital. Chest computed tomography also revealed an anterior mediastinal tumor. The patient was treated with total thyroidectomy and surgery for mediastinal tumors together with left upper lobe partial resection. The mediastinal tumor was pathologically diagnosed as undifferentiated thymic carcinoma coexisting with type AB thymoma. Multiple pulmonary metastases were detected in the patient and stage IV disease was diagnosed. The tumor was treatment-resistant, and the patient received fourth-line chemotherapy. We conducted clonality analysis using an improved human androgen receptor gene-amplification assay that involves random X-chromosome inactivation through methylation, followed by methylated gene-specific PCR amplification after sample DNA digestion with HpaII, a methylation-sensitive restriction enzyme. Clonality analysis demonstrated identical X-chromosome inactivation in cells present in both thymoma and thymic carcinoma areas, and thus revealed clonal proliferation. The two lesions in the patient might have arisen through the transformation of a preexisting thymoma into a more malignant lesion.

Identification of Tyrosine-Phosphorylated Proteins Upregulated during Epithelial-Mesenchymal Transition Induced with TGF-ß.

The epithelial-to-mesenchymal transition (EMT) is a unique process for the phenotypic changes of tumor cells characterized by a transition from polarized rigid epithelial cells to migrant mesenchymal cells, thus conferring the ability of tumor invasion and metastasis. A major challenge in the treatment of lung adenocarcinoma is to identify early stage patients at a high risk of recurrence or metastasis, thereby permitting the best therapeutic strategy and prognosis. In this study, we used a transforming growth factor-ß (TGF-ß)-induced EMT model to quantitatively identify protein tyrosine phosphorylation during the course of EMT in relation to malignant characteristics of lung adenocarcinoma cells. We performed relative quantitation analysis of tyrosine-phosphorylated peptides in TGF-ß-treated and -untreated lung adenocarcinoma cells and identified tyrosine-phosphorylated proteins that were upregulated in TGF-ß-treated cells. These include tensin-1 (TNS1) phosphorylated on Y1404, hepatocyte growth factor receptor (c-Met) phosphorylated on Y1234, and NT-3 growth factor receptor (TrkC) phosphorylated on Y516. We also found that these protein phosphorylation profiles were specifically observed in tissue samples of patients with poor prognostic lung adenocarcinoma. Tyrosine phosphorylations of these proteins represent possible candidates of prognostic prediction markers for lung adenocarcinoma.

Radiologic findings to predict low-grade malignant tumour among clinical T1bN0 lung adenocarcinomas: lessons from histological subtypes.

OBJECTIVE: Some clinical T1bN0 (cT1bN0) lung adenocarcinomas (2-3 cm) are thought to have less-aggressive and less-malignant behaviour although most cT1aN0 tumours (≤2 cm) are indolent. The present study aimed to identify pre-operative radiographic findings that can predict cT1bN0 lung adenocarcinoma with low-malignant aggressiveness in consideration of histological subtypes. METHODS: The clinicopathological features and prognoses of 224 consecutive patients (histological subtype set, n = 122; prognosis set, n = 224) with cT1bN0 lung adenocarcinoma were retrospectively examined. Adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic, node-negative papillary and node-negative acinar predominant invasive adenocarcinomas were defined as low-grade malignant, whereas solid, micropapillary, node-positive acinar and node-positive papillary predominant invasive adenocarcinoma were defined as high-grade malignant. RESULTS: Receiver operating characteristics analysis revealed that the criteria of solid tumour size ≤1.8 cm on high-resolution computed tomography and the maximum standardized uptake value ≤3.2 on positron emission tomography/computed tomography could predict low-grade malignant tumour in the histological subtype set. Among 95 (42.4%) of 224 patients who met the criteria for the prognosis set, 94 (98.9%) had no lymph node metastasis and 93 (97.9%) had no recurrence (median follow-up, 43.6 months). The 3 year recurrence-free survival rates were 94.9 and 79.0% in patients whose pre-operative findings met and did not meet the criteria, respectively. CONCLUSIONS: Pre-operative radiographic findings of solid tumour size and the maximum standardized uptake value could identify low-grade malignant tumour among cT1bN0 lung adenocarcinomas, which account for about half of all cT1bN0 tumours. Patients with pre-operative lung tumour findings that fulfill the criteria could be candidates for sublobar resection.