Junji Ichinose

Video-assisted thoracic surgery for pulmonary aspergilloma

The purpose of this retrospective study was to review our experience with video-assisted thoracic surgery (VATS) for pulmonary aspergilloma. The patients (n=20) were aged 62+/-12 years, and eight (40%) were aged 70 years or more. The disease types were simple aspergilloma (SA) in six patients and complex aspergilloma (CA) in 14. The surgical procedures performed were lobectomy in 14 patients, segmentectomy in two, and wedge resection in four. The operation time was shorter (143+/-69 min vs. 216+/-85 min; P=0.08) and the blood loss was less (10+/-17 ml vs. 307+/-346 ml; P<0.01) for patients with SA than those with CA. Postoperative death occurred in one patient with CA who developed a bronchial stump fistula (30-day mortality; 5.0%). During follow-up, three patients died from other non-disease-related causes, and the remaining 17 patients survived without recurrence. The 5-year survival rate was 89%. In suitable cases, VATS for pulmonary aspergilloma may not be inferior to open surgery with regard to safety and efficacy. In particular, SA is considered to be a good indication for VATS.

Significance of the Glasgow Prognostic Score as a prognostic indicator for lung cancer surgery.

OBJECTIVES The Glasgow Prognostic Score (GPS), which is calculated with C-reactive protein (CRP) and albumin (Alb) values, is a prognostic indicator for various types of cancers. However, its role in lung cancer still remains unclear, and its optimal cut-off values are controversial. Here, we evaluated the significance of the GPS and adjusted GPS (a-GPS) using our institutions cut-off values in patients undergoing resection for primary lung cancer. METHODS We analysed 1043 lung cancer patients who underwent resection between 1998 and 2012. The overall survival (OS) probabilities of the GPS subgroups were estimated using the Kaplan-Meier method and were compared using the log-rank test. The prognostic significance of the GPS and the a-GPS was assessed by the Cox proportional hazards model with clinicopathological variables and inflammation markers, such as the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR). The GPS was calculated based on cut-off values of 1.0 mg/dl for CRP and 3.5 g/dl for Alb, as previously reported. The a-GPS was calculated based on cut-off values 0.3 mg/dl for CRP and 3.9 g/dl for Alb, which are the standard thresholds used by our institution. RESULTS The GPS and the a-GPS were correlated with preoperative factors, such as age, sex, smoking status, the NLR and the PLR, and oncological factors, including the pathological stage, histological type and level of lymphovascular invasion. The 5-year OS rates were 82, 55 and 55% with GPS 0, 1 and 2 (1 vs 0: P < 0.01; 2 vs 1: P = 0.66), respectively, and 88, 67 and 59% with a-GPS 0, 1 and 2 (1 vs 0: P < 0.01; 2 vs 1: P = 0.04), respectively. Multivariable analysis revealed that the GPS [1 vs 0, hazard ratio (HR): 1.63, 2 vs 0, HR: 1.44] and the a-GPS (1 vs 0, HR: 2.00, 2 vs 0, HR: 2.10) were independent prognostic factors. The a-GPS classification showed a clearer prognostic distribution than the GPS classification. CONCLUSIONS The GPS is a useful prognostic indicator of the OS in lung cancer surgery. The optimal cut-off values for GPS estimation may need to be re-evaluated.

Histone methylation-mediated silencing of miR-139 enhances invasion of non-small-cell lung cancer

MicroRNA expression is frequently altered in human cancers, and some microRNAs act as oncogenes or tumor suppressors. MiR‐139‐5p (denoted thereafter as miR‐139) has recently been reported to function as a tumor suppressor in several types of human cancer (hepatocellular carcinoma, colorectal cancer, breast cancer, and gastric cancer), but its function in non‐small‐cell lung cancer (NSCLC) and the mechanism of its suppression have not been studied in detail. MiR‐139 was suppressed frequently in primary NSCLCs. MiR‐139 is located within the intron of PDE2A and its expression was significantly correlated with the expression of PDE2A. A chromatin immunoprecipitation assay revealed that miR‐139 was epigenetically silenced by histone H3 lysine 27 trimethylation (H3K27me3) of its host gene PDE2A and this process was independent of promoter DNA methylation. Pharmacological inhibition of both histone methylation and deacetylation‐induced miR‐139 with its host gene PDE2A. Ectopic expression of miR‐139 in lung cancer cell lines did not affect the proliferation nor the migration but significantly suppressed the invasion through the extracellular matrix. In primary NSCLCs, decreased expression of miR‐139 was significantly associated with distant lymph node metastasis and histological invasiveness (lymphatic invasion and vascular invasion) on both univariate and multivariate analyses. Collectively, these results suggest that H3K27me3‐mediated silencing of miR‐139 enhances an invasive and metastatic phenotype of NSCLC.

Results of Lung Cancer Surgery for Octogenarians.

PURPOSE Growing number of elderly lung cancer patients reflecting a lengthening life span has become a serious problem. Purpose of this study was to elucidate the short and long-term outcome of the surgery for octogenarians, and to evaluate the role of lung cancer surgery for this high age group. METHODS The patients with lung cancer aged 80 years or more who underwent the surgery at our institute from January 1998 through December 2012 were retrospectively analyzed by chart review, and the operative mortality, morbidity and the long-term survival were assessed. RESULTS Out of a total of 1107 patients with primary lung cancer who received surgery during the study period, 94 were octogenarians (8.5%). Sixty-nine patients (73.4%) had preoperative co-morbidity including hypertension in 50 (53.2%), coincidence of other malignancy in 35 (37.2%), anti-coagulant therapy in 29 (30.9%). Twenty-six patients (27.7%) had major or minor postoperative morbidity, and one (1.1%) died due to bronchopleural fistula. Overall-5-year survival rate was 57.5%. Univariative and multivariative analysis using Cox proportional hazard model revealed that male gender and non-adenocarcinoma histology were significant risk factors for poor prognosis. CONCLUSION Gender and histology should be taken into account in preoperative evaluation of indication for lung cancer in octogenarians.

Locoregional Control of Thoracoscopic Lobectomy With Selective Lymphadenectomy for Lung Cancer

BACKGROUND In this retrospective study, we review our experience with video-assisted thoracic surgery (VATS) lobectomy with selective lymphadenectomy for clinical stage I lung cancer and report the long-term results. METHODS From April 1999 to December 2006, 355 patients with clinical stage I lung cancer underwent a VATS lobectomy. The perioperative data, morbidity, mortality, and long-term survival of each patient were reviewed. RESULTS A thoracoscopic lobectomy was performed successfully in 348 patients (T1 N0, 237 patients; T2 N0, 111 patients), and a selective lymphadenectomy was performed in 268. Seven procedures (2.0%) were uneventfully converted to a thoracotomy and were excluded. The median operation time was 192 minutes, and the median blood loss was 100 mL. The median postoperative stay was 6 days. There were no intraoperative deaths; 2 patients died within 30 days of operation (mortality; 0.6%); 1 died of bacterial pneumonia and the other of postoperative interstitial pneumonia exacerbation. Postoperative complications occurred in 54 patients (16% morbidity). Major complications included prolonged air leak (3.7%), bacterial pneumonia (3.4%), and mild arrhythmia (3.4%). Pathologic upstaging was noted in 67 patients (19%). At a median follow-up of 43 months, total recurrence occurred in 66 cases (26 locoregional and 40 distant). The locoregional recurrence rate was 0.021 per person per year. The overall and 5-year locoregional recurrence-free survival rates were 78.5% and 76.6%, respectively. CONCLUSIONS Our findings suggest that performing VATS lobectomy with selective lymphadenectomy for clinical stage I lung cancer is safe and results in acceptable locoregional control.

Results of surgical treatment for secondary spontaneous pneumothorax according to underlying diseases

OBJECTIVES The outcome of surgical treatment for secondary spontaneous pneumothorax (SSP) has rarely been investigated. METHODS We retrospectively reviewed 183 patients who underwent surgery for SSP. We categorized the patients into three groups according to underlying diseases: Group A (chronic obstructive pulmonary disease), Group B (interstitial pneumonia [IP]) and Group C (others). We defined treatment success as surgery without hospital mortality, postoperative complications, death within 6 months or ipsilateral recurrence of pneumothorax within 2 years. We assessed the risk factors for unsuccessful treatment using a Cox regression hazard model. RESULTS There were 123 patients in Group A, 20 in Group B and 40 in Group C. The hospital mortality rates were 2, 15 and 0% in Groups A, B and C, respectively. The hospital mortality, morbidity and pneumothorax recurrence rates in the IP group were higher than in the other groups. The 5-year overall survival rates were 78, 32 and 84% in Groups A, B and C, respectively; the prognosis of the IP group was significantly poorer. The treatment success rates were 86, 45 and 83% in Groups A, B and C, respectively. SSPs caused by IP and SSPs requiring open surgery were identified as the risk factors for unsuccessful treatment. CONCLUSIONS Surgery for SSP caused by underlying diseases other than IP yielded favourable results. However, a careful examination of surgical indication and a realistic disclosure for informed consent are required for patients with SSP caused by IP, because of the high treatment failure rate.

Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non‐small cell lung cancer

Alternative polyadenylation (APA), which induces shortening of the 3′UTR, is emerging as an important phenomenon in gene regulation. APA is involved in development, cancer and cell proliferation. APA may lead to disruption of microRNA‐mediated gene silencing in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer. We selected the top 10 genes showing significant 3′UTR shortening in lung cancer, using the package of the Bioconductor for probe‐level analyses of expression microarrays. We established and evaluated the APA score by quantitative RT‐PCR in 147 clinical specimens of non‐small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA‐related genes, including PABPN1, CPEB1, E2F1 and proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and a poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both lower expression of PABPN1 and higher expression of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001). Our results indicate that the loss of PABPN1, a suppressor of APA, might promote tumor aggressiveness by releasing the cancer cells from microRNA‐mediated gene regulation.

Oncogenic TPM3-ALK activation requires dimerization through the coiled-coil structure of TPM3

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal tumor that can arise from anywhere in the body. Anaplastic lymphoma kinase (ALK) gene rearrangements, most often resulting in the tropomyosin 3 (TPM3)-ALK fusion gene, are the main causes of IMT. However, the mechanism of malignant transformation in IMT has yet to be elucidated. The purpose of this study was to clarify the role of the TPM3 region in the transformation of IMT via TPM3-ALK. Lentivirus vectors containing a TPM3-ALK fusion gene lacking various lengths of TPM3 were constructed and expressed in HEK293T and NIH3T3 cell lines. Focus formation assay revealed loss of contact inhibition in NIH3T3 cells transfected with full-length TPM3-ALK, but not with ALK alone. Blue-native polyacrylamide gel electrophoresis (BN-PAGE) revealed that TPM3-ALK dimerization increased in proportion to the length of TPM3. Western blot showed phosphorylation of ALK, ERK1/2, and STAT3 in HEK293T cells transfected with TPM3-ALK. Thus, the coiled-coil structure of TPM3 contributes to the transforming ability of the TPM3-ALK fusion protein, and longer TPM3 region leads to higher dimer formation.

Prognostic significance of red cell distribution width in elderly patients undergoing resection for non-small cell lung cancer

BACKGROUND The impact of red cell distribution width (RDW) on outcomes in elderly patients after surgery for non-small cell lung cancer (NSCLC) is not fully understood. METHODS We retrospectively analyzed 992 NSCLC patients who underwent curative resection between 1998 and 2012. The following variables were included in the analyses to evaluate the role of RDW: age, gender, smoking index, leukocyte count, neutrophil to lymphocyte ratio (NLR), hemoglobin, platelet count, albumin, C-reactive protein, carcinoembryonic antigen, respiratory function, histology, T factor, N factor, surgical approach, surgical procedures, complications and prognosis. RESULTS High RDW (>13.8) was an independent risk factor for morbidity [hazard ratio (HR) 2.1; P<0.01], recurrence (HR 2.0; P=0.01), overall survival (OS) (HR 2.1; P<0.01) and disease-free survival (DFS) (HR 2.0; P<0.01) in elderly patients (age ≥75 years, n=275), whereas it was not in younger patients (age <75 years, n=717). The surgical outcome was extremely poor in those older than 80 years with a RDW greater than 15% (morbidity, 56%; postoperative stay, 23 days; OS, 24%; DFS, 0%). RDW was unaffected by age (R =0.01; P=0.86) and elevated RDW without anemia was more prognostic than high RDW due to anemia in elderly patients. CONCLUSIONS High RDW was significantly associated with high morbidity and reduced survival in elderly patients who underwent resection for NSCLC. Therefore, this parameter should be taken into account when surgery is considered in the elderly.

Prognostic impact of the current Japanese nodal classification on outcomes in resected non-small cell lung cancer.

BACKGROUND The prognosis of N2 non-small cell lung cancer (NSCLC) has been reported to be heterogeneous. The recently revised Japanese nodal classification subcategorizes N2 disease according to the tumor-bearing lobe. We evaluated the prognostic impact of the Japanese nodal classification and its ability to define favorable N2 disease in resected NSCLC. METHODS A total of 496 patients with NSCLC who underwent lobectomy with systematic lymph node dissection between 1998 and 2009 were analyzed retrospectively. N2 status was subdivided into N2a-1 and N2a-2, according to the Japanese nodal classification. Overall survival (OS), disease-free survival (DFS), and clinicopathologic features were compared between the two groups. RESULTS There were 67 cases with N2 disease. The outcome of resected N2a-2 NSCLC was far poorer than that of the N2a-1 group (5-year OS, 28% vs 62%, P < .001; 5-year DFS, 5% vs 35%, P < .001). Multivariate analysis revealed that pathologic N2a-2 was an independent prognostic factor (hazard ratio, 2.86; P < .05). Patients in the N2a-2 group showed more involved nodes and stations, less skip metastasis, and more locoregional recurrence than did patients in the N2a-1 group. The outcome of the N2a-1 group was satisfactory, and there was no significant difference in OS and DFS between N1 and N2a-1. CONCLUSIONS The Japanese nodal classification is able to identify a favorable N2 subgroup in resected NSCLC. Nodal staging by the Japanese system should be considered when a clinical trial of N2 disease is designed.