Masao Chujo

Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma

Vascular endothelial growth factor C (VEGF‐C) plays an important role in lymphangiogenesis and activates VEGF receptor 3 (VEGFR‐3). By contrast, lymphatic spread is an important prognostic factor in patients with nonsmall cell lung carcinoma (NSCLC). The objective of the current study was to determine whether the expression of VEGF‐C and VEGFR‐3 correlates with clinicopathologic factors and prognosis in patients with primary NSCLC.

Comparative genomic hybridization analysis detected frequent overrepresentation of chromosome 3q in squamous cell carcinoma of the lung.

The aim of this study was to provide cytogenetic data about squamous cell carcinomas of the lung and to evaluate their characteristic alterations and histogenetic relations. We analyzed 41 squamous cell lung carcinomas by comparative genomic hybridization (CGH) technique. CGH was performed using directly fluorochrome-conjugated DNA. Chromosomal regions where the mean ratio fell below 0.75 were therefore considered to reflect DNA copy number loss (underrepresentation), whereas regions where the mean ratio exceeded 1.25 were considered gains (overrepresentations) in the tumor genome. Overrepresentations were considered to be high-level amplification when the fluorescence ratio exceeded 1.5. Chromosomal imbalances were observed in every case. Copy number gains frequently were detected at 3q, 5p, 8q, 12p, and Xq. Losses were found at 16p, 4q, 5q, 3p, 17p, and 16q. DNA amplifications were observed at 12 regions: 3q26.1-27, 8q13-23.1, 12p12.3-pter, 12q15, 2p14-16, 4q28-31.2, 5p13.1-pter, 6q21-22.3, 7p11.2-13, 13q21.2-32, 18p11.2-pter, and 20p11.2-pter. Gains on 3q were frequently detected not only in the more than 3 cm group (79%) but also in the 3 cm or less group (77%). The mean frequency of gained or lost chromosomal regions was 7.2+/-4.7 in the 3 cm or less group (n=13) and 10.2+/-6.3 in the more than 3 cm group (n=28) (P=0.4503). The mean frequency of gained or lost chromosomal regions was significantly higher in the carcinoma with lymph node metastasis group (12.5+/-7.6 regions) (n=12) than in the carcinoma without lymph node metastasis group (7.9+/-4.6) (n=29) (P=0.0251). In conclusion, an increased copy number at 3q may contribute to the development of squamous cell carcinoma of the lung.

Video-assisted thoracoscopic indocyanine green fluorescence imaging system shows sentinel lymph nodes in non-small-cell lung cancer.

OBJECTIVE The primary objective was to assess the feasibility and accuracy of intraoperative sentinel lymph node mapping by using a video-assisted thoracoscopic indocyanine green fluorescence imaging system in patients with clinical stage I non-small-cell lung cancer. METHODS Thirty-one patients who underwent operation between January 2009 and September 2009 were investigated for sentinel node biopsy. Indocyanine green fluorescence imaging was applied by an infrared light charge-coupled device, and sentinel nodes were identified intraoperatively and dissected. Histologic examination by hematoxylin-eosin staining was used to evaluate metastases. RESULTS Sentinel lymph nodes were identified by segmentectomy in 11 of 14 patients (78.5%) and by lobectomy in 14 of 17 patients (82.4%). The total identification rate was 80.7% (25/31 patients), the false-negative rate was 0% (0/24 patients), and the overall accuracy rate was 80.7% (25/31 patients). CONCLUSION Video-assisted thoracoscopic indocyanine green fluorescence image-guided surgery is feasible for sentinel node biopsy and may be a powerful tool to eliminate unnecessary lymph node dissection in patients with lung cancer.

Sentinel Node Navigation Surgery by Thoracoscopic Fluorescence Imaging System and Molecular Examination in Non-Small Cell Lung Cancer

PurposeThe application of sentinel node navigation surgery in non-small cell lung cancer (NSCLC) is not popular because of the difficulty of sentinel node identification and the low incidence of complications after systemic lymph node dissection. We report the intraoperative assessment of sentinel node metastasis by thoracoscopic ICG fluorescence imaging system and real-time reverse transcription-polymerase chain reaction (RT-PCR).MethodsSixty-one patients who underwent surgery between January 2009 and December 2010 were investigated for sentinel node biopsy. ICG fluorescence imaging was applied by an infrared light CCD system, and sentinel nodes were identified and dissected. Intraoperative real-time quantitative RT-PCR to determine the expression of cytokeratin 19 (CK-19) was performed for evaluation of metastasis and finally histologic examination of hematoxylin and eosin-stained, paraffin-embedded sections.ResultsSixteen (80%) of 20 patients with segmentectomy and 33 (80.5%) of 41 with lobectomy were identified for sentinel lymph nodes. The total identification rate was 80.3% (49 of 61). The false-negative rate was 2.1% (1 of 49). The overall accuracy rate was 78.7% (48 of 61 patients). Disease of four of these patients was upstaged to stage IIA by RT-PCR for CK-19 expression, which was positive for sentinel nodes and micrometastases.ConclusionsThese results demonstrated that thoracoscopic ICG fluorescence imaging-guided surgery and real-time quantitative RT-PCR were useful for sentinel node biopsy and might be a powerful tool for more focused pathologic or molecular evaluation for staging.

Prognostic significance of HE4 expression in pulmonary adenocarcinoma

We investigated the possibility of human epididymis 4(HE4) to predict survival for patients with pulmonary adenocarcinoma. One hundred and thirty-seven patients with pulmonary adenocarcinoma underwent surgery in our institute from 2000 to 2008. We used immunohistochemical analysis to determine the expression of HE4 and compared with the clinicopathological factors and survival. Serum levels of HE4 in lung adenocarcinoma were investigated by enzyme immunometric assay. Fifty-seven of 137 cases (41.6%) were HE4 positive. It was found that there was no correlation between HE4 expression by immunohistochemistry and clinicopathological factors, however, adenocarcinoma subtype was significantly associated with HE4 expression. Sera in lung adenocarcinoma were significantly higher than in healthy control. Five-year disease-free survival in the HE4-positive group (44.6%) was significantly different from that in the negative group (82.3%, p = 0.001) by immunohistochemistry. The five-year overall survival rate was 60.1% in the HE4-positive group, as compared with 90.8% in the HE4-negative group (p = 0.001). In multivariate Cox regression analysis, positive HE4 protein expression was a worse prognosis factor of disease-free and overall survival (HR = 3.7, 95%CI = [1.7–8.4], p = 0.001; HR = 5.5, 95%CI = [1.8–17.2], p = 0.003, respectively), in addition to nodal status as a powerful value. When HE4 expression in adenocarcinoma cases except the BAC were analyzed, nodal status and HE4 expression were independent prognostic factors in disease-free and overall survivals. These data showed that HE4 expression is associated with a worse prognosis and is a possible prognostic factor of lung adenocarcinoma.

Thoracoscopic segmentectomy for T1 classification of non-small cell lung cancer: a single center experience

OBJECTIVES Segmentectomy is one of the treatment options for small-sized non-small cell lung cancer (NSCLC). Although growing results support the feasibility and efficacy, it still remains unclear in segmentectomy. The International Association for the Study of Lung Cancer recommended a revised classification of TNM staging in 2009 (the seventh edition) and multidisciplinary classification of adenocarcinoma. We report here the outcome of totally thoracoscopic segmentectomy and lobectomy for T factor and adenocarcinoma. METHODS Ninety patients with Stage IA NSCLC underwent thoracoscopic segmentectomy between September 2003 and June 2011. A total of 124 patients were referred as a control group to compare the peri-operative outcome, local recurrence rate and survival. These survivals were analysed using the Kaplan-Meier method with the log-rank test and propensity score analyses. RESULTS The peri-operative outcome, including operative time, blood loss, duration of chest tube drainage and length of hospital stay, was not significantly different between groups. The number of dissected lymph nodes with segmentectomy was less than that with lobectomy. Morbidity and mortality were not significantly different between groups. Seven patients relapsed in each group and propensity score analysis in disease-free and overall survivals showed no differences between two groups in Stage IA. Subclass analyses revealed that disease-free and overall survivals in T1a and T1b were not significantly different between the two groups. CONCLUSIONS Our study demonstrated that thoracoscopic segmentectomy was feasible with regard to peri-operative and oncological outcomes for Stage IA NSCLC, especially T1a and carefully selected T1b descriptor.

Clinical Impact of Segmentectomy Compared with Lobectomy Under Complete Video-Assisted Thoracic Surgery in the Treatment of Stage I Non-Small Cell Lung Cancer

BACKGROUND Segmentectomy for small or early stage non-small cell lung cancer (NSCLC) has been controversial. Further, video-assisted thoracic surgery (VATS) for lung cancer was accepted during the past decade. We here compared the outcome between VATS segmentectomy and VATS lobectomy for stage I NSCLC. METHODS In the retrospective study, 109 consecutive patients in stage I underwent surgery at Oita University Hospital (Oita, Japan) between September 2003 and October 2008. VATS segmentectomy was performed in 38 patients and VATS lobectomy with systemic lymphadenectomy was performed in 71 patients. After clinicopathologic factors were compared in both groups, local recurrence rates and survivals were compared. RESULTS Five of 38 VATS segmentectomy and eight of 71 VATS lobectomy patients relapsed during the follow-up period (median 27.5 mo). In the relapsed patients after VATS segmentectomy, three (7.9%) were local recurrences and two (5.3%) were distant metastases. On the other hand, four (5.6%) were local recurrence and four (5.6%) were distant metastases in the VATS lobectomy group. There was no significant difference between the two groups. Furthermore, there was no difference in recurrence-free and overall survival between segmentectomy and lobectomy. CONCLUSIONS Although the sample size is small, VATS segmentectomy is one of the appropriate procedures for stage I NSCLC.

Spontaneous hemothorax in patients with von Recklinghausen's disease

Spontaneous massive intrathoracic bleeding is rare except for the rupture of aortic aneurysm or pleural adhesions in association with pneumothorax. We encountered two cases of critical massive hemothorax in patients with von Recklinghausens disease (type I neurofibromatosis). Case 1; a 59-year-old female suddenly experienced severe back pain followed by syncope and shock. The hemothorax was caused by a bleeding of diffuse type neurofibroma of the parietal pleura and she underwent thoracotomy and surgical ligation of the bleeding vessels. Case 2; a 46-year-old male suddenly suffered back pain and fainted while driving. An intercostal aneurysmal rupture caused a spontaneous hemothorax and he underwent chest tube drainage followed by endovascular coil embolization. We reviewed 23 cases reported in the literature, including our two cases. Spontaneous hemothorax in patients with von Recklinghausens disease is a life-threatening syndrome and may require emergency surgical or endovascular embolization.

Combination of p53AIP1 and survivin expression is a powerful prognostic marker in non-small cell lung cancer

Backgroundp53AIP1 is a potential mediator of apoptosis depending on p53, which is mutated in many kinds of carcinoma. High survivin expression in non-small cell lung cancer is related with poor prognosis. To investigate the role of these genes in non-small cell lung cancer, we compared the relationship between p53AIP1 or survivin gene expression and the clinicopathological status of lung cancer.Materials and methodsForty-seven samples from non-small cell lung cancer patients were obtained between 1997 and 2003. For quantitative evaluation of RNA expression by PCR, we used Taqman PCR methods.ResultsAlthough no correlation between p53AIP1 or survivin gene expression and clinicopathological factors was found, the relationship between survivin gene expression and nodal status was significant (p = 0.03). Overall survival in the p53AIP1-negative group was significantly worse than in the positive group (p = 0.04); however, although survivin expression was not a prognostic factor, the combination of p53AIP1 and survivin was a significant prognostic predictor (p = 0.04). In the multivariate cox proportional hazard model, the combination was an independent predictor of overall survival (p53AIP1 (+) survivin (+), HR 0.21, 95%CI = [0.01–1.66]; p53AIP1 (+) survivin (-), HR 0.01, 95%CI = [0.002–0.28]; p53AIP1 (-) survivin (-), HR 0.01, 95%CI = [0.002–3.1], against p53AIP1 (-) survivin (+), p = 0.03).ConclusionThese data suggest that the combination of p53AIP1 and survivin gene expression may be a powerful tool to stratify subgroups with better or worse prognosis from the variable non-small cell lung cancer population.

Contralateral mediastinal lymph node micrometastases assessed by video-assisted thoracoscopic surgery in stage I non-small cell left lung cancer

OBJECTIVES Survival of patients with left-sided stage I non-small cell lung cancer (NSCLC) is unsatisfactory, probably because of the high incidence of contralateral mediastinal node involvement. In this study, occult micrometastases to the right upper mediastinal nodes were retrospectively investigated in patients with left-sided stage I NSCLC. METHODS Nineteen patients with clinical stage I NSCLC underwent video-assisted thoracoscopic lobectomy and bilateral mediastinal node dissection (BMD). Clinical data and survival of patients with BMD were compared with those of 25 left-unilateral mediastinal node dissection (UMD) patients. Occult micrometastases were detected using the cytokeratin 19 mRNA reverse transcription-polymerase chain reaction method. RESULTS Pathological N2 disease was found in 1 patient, and 18 had pN0 disease. The operative time, blood loss, duration of chest tube drainage and duration of postoperative hospital stay were not different between BMD and UMD patients. Nodal micrometastases were detected in 11/19 (57.8%) patients. Skip micrometastases to the level N3 nodes without N1 and N2 node involvement were observed in 8/11 (72.7%) patients. Patients with BMD are all alive and have had no recurrence during the median follow-up period of 21.4 months. Overall 3-year survival and disease-free 3-year survival were not significantly different between the two groups. CONCLUSION In this preliminary study, occult micrometastases to the level N3 nodes occurred frequently in patients with left-sided clinical N0 stage I NSCLC. Postoperative survival of patients with occult micrometastases to the level N3 node does not appear to be poor. Further follow-up and work are needed.