Terumoto Koike

Limited Resection for Noninvasive Bronchioloalveolar Carcinoma Diagnosed by Intraoperative Pathologic Examination

BACKGROUND The establishment of limited resection procedures for non-small cell lung cancer is expected. Many groups have suggested noninvasive bronchioloalveolar carcinoma (BAC) to be a potential indication for limited resection. METHODS We designed a prospective phase II study evaluating limited resection for noninvasive BAC diagnosed by intraoperative pathologic examination. From 1999 to 2007, limited resection was the procedure in 46 patients (16 men and 30 women; median age, 69 years; range, 49 to 83) who were diagnosed intraoperatively as having noninvasive BAC. The first end point was the predictive value of the intraoperative pathologic examination for noninvasive BAC diagnosis. The second end point was overall survival, disease-free survival, and cancer-specific survival, calculated using the Kaplan-Meier method. RESULTS We performed wedge resections for 44 patients and segmentectomy for 2 patients. Permanent pathologic examination revealed 3 patients had primary lung adenocarcinomas other than noninvasive BAC. The predictive value of intraoperative pathologic examination for noninvasive BAC diagnosis was 94%. During a median 51-month follow-up, there were only 2 cancer unrelated deaths. The 5-year overall survival rate and the disease-free survival rate were 93%, and the 5-year cancer-specific survival rate was 100%. CONCLUSIONS The results of our prospective phase II study indicate that limited resection, mainly by wedge resection, is a potentially curative surgical procedure and may be an acceptable alternative to lobectomy for patients with noninvasive BAC. Furthermore, an intraoperative pathologic diagnosis of noninvasive BAC is strongly predictive and allows for an intraoperative decision to perform a limited resection in these patients.

Risk factor analysis of locoregional recurrence after sublobar resection in patients with clinical stage IA non-small cell lung cancer.

OBJECTIVE Although lobectomy is the standard surgical procedure for operable non-small cell lung cancer (NSCLC), sublobar resection also has been undertaken for various reasons. The aim of this study was to identify risk factors of locoregional recurrence and poor disease-specific survival in patients with clinical stage IA NSCLC undergoing sublobar resection. METHODS We retrospectively reviewed 328 patients with clinical stage IA NSCLC who underwent segmentectomy or wedge resection. Demographic, clinical, and pathologic factors were analyzed using the log-rank test as univariate analyses, and all factors were entered into a Cox proportional hazards regression model for multivariate analyses to identify independent predictors of locoregional recurrence and poor disease-specific survival. RESULTS The 5- and 10-year locoregional recurrence-free probabilities were 84.8% and 83.6%, respectively, and the 5- and 10-year disease-specific survivals were 83.6% and 73.6%, respectively. Four independent predictors of locoregional recurrence were identified: wedge resection (hazard ratio [HR], 5.787), microscopic positive surgical margin (HR, 3.888), visceral pleural invasion (HR, 2.272), and lymphatic permeation (HR, 3.824). Independent predictors of poor disease-specific survival were identified as follows: smoking status (Brinkman Index; HR, 1.001), wedge resection (HR, 3.183), microscopic positive surgical margin (HR, 3.211), visceral pleural invasion (HR, 2.553), and lymphatic permeation (HR, 3.223). All 4 predictors of locoregional recurrence also were identified as independent predictors of poor disease-specific survival. CONCLUSIONS Segmentectomy should be the surgical procedure of first choice in patients with clinical stage IA NSCLC who are being considered for sublobar resection. Patients having tumors presenting with no suspicious of pleural involvement would be suitable candidates for sublobar resection.

Absence of gene mutations in KIT-positive thymic epithelial tumors

BACKGROUND Overexpression of KIT, a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit, is observed in human neoplasms such as gastrointestinal stromal tumors (GISTs), myeloproliferative disorders, melanoma and seminoma. In patients with GIST, overexpression of mutated KIT within the tumor is predictive of response to molecular targeted therapy using imatinib. However, the role of KIT expression in thymic carcinoma is not fully understood. METHODS Thymic epithelial tumors from 37 patients (17 thymic carcinomas and 20 thymomas) were examined. Immunohistochemical staining with anti-KIT polyclonal antibody and anti-CD5 was performed. Mutation analyses in the juxtamembrane domains, exons 9 and 11, and in the tyrosine kinase domains, exons 13 and 17, were undertaken using polymerase chain reaction (PCR) and direct DNA sequencing in KIT-positive samples. RESULTS KIT- and CD5-positive staining was observed only in thymic carcinoma. Percentage of positive staining was 100% in squamous cell carcinoma, with no positive staining in other histologies, including atypical carcinoid. Mutation analysis of the KIT gene was performed in 11 squamous cell carcinomas, 1 adenocarcinoma and 1 adenosquamous cell carcinoma. None of the tested samples showed mutations in any of the four exons. CONCLUSIONS Squamous cell carcinoma of the thymus frequently expressed KIT and CD5 proteins, whereas other tumors did not. Unlike GIST, overexpression of KIT does not necessarily indicate gene mutation in thymic carcinoma. KIT and CD5 appear useful for evaluating and subtyping thymic epithelial tumors.

Predictive Risk Factors for Mediastinal Lymph Node Metastasis in Clinical Stage IA Non–Small-Cell Lung Cancer Patients

Introduction: Even for patients with clinical N0 non–small-cell lung cancer (NSCLC), several invasive tests are available to pathologically confirm the presumptive mediastinal stage by radiologic modalities. The aim of this study was to determine a high-risk population for mediastinal nodal metastasis in patients with clinical stage IA NSCLC, which would be suitable for mediastinal staging by invasive modalities, such as mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration. Methods: We retrospectively reviewed peripheral clinical stage IA NSCLC patients who had undergone surgical resection with systematic mediastinal lymphadenectomy from 1998 to 2011. To identify predictors for mediastinal nodal metastasis, univariate and multivariate logistic regression analyses were performed. For the significant factors, optimal cutoff points were determined with a receiver operating characteristic analysis. Results: Among the 894 patients eligible for this study, the overall prevalence of mediastinal nodal metastasis was 7.5%. The following four predictors for mediastinal nodal metastasis were identified: age, preoperative serum carcinoembryonic antigen level, tumor size on preoperative radiologic findings, and consolidation/tumor ratio on high-resolution computed tomography. Of the patients with all four predictors identified by the multivariate analyses and receiver operating characteristic analyses (age ⩽67 years, carcinoembryonic antigen ≥ 3.5 ng/ml, tumor size ≥ 2.0 cm, and consolidation/tumor ratio ≥ 89%), the prevalence of mediastinal nodal metastasis was 33.8%. Conclusions: Among the clinical stage IA NSCLC patients in whom all four predictors were identified, one third of the patients showed mediastinal nodal metastasis, and thus, those patients should be a target for mediastinal node assessment by invasive modalities, such as mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration.

Prognostic predictors in non-small cell lung cancer patients undergoing intentional segmentectomy.

BACKGROUND Despite recent studies reporting on the results of prospective intentional sublobar resection for patients with small non-small cell lung cancer (NSCLC), few studies have investigated predictors for prognosis or recurrence exclusively in patients undergoing intentional sublobar resection. METHODS We retrospectively reviewed 223 patients with small (2 cm or less) peripheral NSCLC who underwent intentional segmentectomy at the Niigata Cancer Center Hospital between 1992 and 2009. The significant demographic, clinical, and pathologic factors identified with the log rank test in univariate analyses were analyzed with the Cox proportional hazards regression model to examine independent predictors for prognosis and recurrence in multivariate analysis. RESULTS The 5-year and 10-year overall survival rates were 89.6% and 81.0%, respectively, and the 5-year and 10-year recurrence-free probabilities were 91.1% and 91.1%, respectively. Eight patients had locoregional recurrence, and 12 had distant recurrence. Multivariate analyses revealed that age more than 70 years (hazard ratio [HR] 2.389), male (HR 2.750), more than 75% consolidation/tumor ratio on high-resolution computed tomography (HR 2.750), and lymphatic permeation (HR 5.618) were independent poor prognostic factors, and lymphatic permeation (HR 16.257) was an independent predictor for recurrence. CONCLUSIONS The factors related to upstaging on pathologic diagnosis were not identified as independent predictors; therefore, the current patient selection criterion seems reasonable. If lymphatic permeation is present on pathologic findings, careful follow-up is recommended. The predictors identified in this study will support assessment and interpretation of the results of ongoing prospective randomized trials of lobar versus sublobar resection in patients with small peripheral NSCLC.

Lobectomy Versus Segmentectomy in Radiologically Pure Solid Small-Sized Non-Small Cell Lung Cancer.

BACKGROUND The indication for limited resection of radiologically pure solid non-small cell lung cancer (NSCLC) is controversial owing to its invasive pathologic characteristics. This study was performed to compare the outcomes after lobectomy and segmentectomy in these NSCLC patients. METHODS We retrospectively reviewed 251 patients with radiologically pure solid cT1a N0 M0 NSCLC who underwent lobectomy or segmentectomy, and the preoperative characteristics of the patients treated with the two operative techniques were matched using propensity score methods. Overall survival (OS) and disease-free survival (DFS) curves were compared using the log rank test, and differences in survival were also evaluated by the McNemar test. The preoperative factors and surgical procedure were analyzed with the multivariate Cox proportional hazards regression model to identify independent predictors of poor OS and DFS. RESULTS In the propensity score matched lobectomy and segmentectomy groups (87 patients per group), the 5-year and 10-year OS rates were 85% versus 84% and 66% versus 63%, respectively; and the 5-year and 10-year DFS rates were 80% versus 77% and 64% versus 58%, respectively. There were no significant differences between the two groups in OS or DFS by the log rank test, and also no significant differences in 3-year, 5-year, or 7-year OS or DFS by the McNemar test. Although age, smoking status, pulmonary function, and carcinoembryonic antigen were identified as significant predictors of both OS and DFS, the surgical procedure was not identified. CONCLUSIONS Similar oncologic outcomes after lobectomy and segmentectomy were indicated among patients with radiologically pure solid small-sized NSCLC.

Safety and reproducibility of virtual-assisted lung mapping: a multicentre study in Japan†

Abstract OBJECTIVES: Virtual-assisted lung mapping (VAL-MAP) is a preoperative bronchoscopic multispot dye-marking technique using virtual images. The purpose of this study was to evaluate the safety, efficacy and reproducibility of VAL-MAP among multiple centres. METHODS: Selection criteria included patients with pulmonary lesions anticipated to be difficult to identify at thoracoscopy and/or those undergoing sub-lobar lung resections requiring careful determination of resection margins. Data were collected prospectively and, if needed, compared between the centre that originally developed VAL-MAP and 16 other centres. RESULTS: Five hundred patients underwent VAL-MAP with 1781 markings (3.6 ± 1.2 marks/patient). Complications associated with VAL-MAP necessitating additional management occurred in four patients (0.8%) including pneumonia, fever and temporary exacerbation of pre-existing cerebral ischaemia. Minor complications included pneumothorax (3.6%), pneumomediastinum (1.2%) and alveolar haemorrhage (1.2%), with similar incidences between the original centre and other centres. Marks were identifiable during operation in approximately 90%, whereas the successful resection rate was approximately 99% in both groups, partly due to the mutually complementary marks. The contribution of VAL-MAP to surgical success was highly rated by surgeons resecting pure ground glass nodules (P < 0.0001), tumours ≤ 5 mm (P = 0.0016), and performing complex segmentectomy and wedge resection (P = 0.0072). CONCLUSIONS: VAL-MAP was found to be safe and reproducible among multiple centres with variable settings. Patients with pure ground glass nodules, small tumours and resections beyond conventional anatomical boundaries are considered the best candidates for VAL-MAP. Clinical Trial Registration Number: UMIN 000008031. University Hospital Medical Information Network Clinical Trial Registry (http://www.umin.ac.jp/ctr/).

Lobectomy and limited resection in small-sized peripheral non-small cell lung cancer

BACKGROUND Although lobectomy is the standard surgical procedure for non-small cell lung cancer (NSCLC), recent studies show favorable outcomes after limited resection in patients with small-sized peripheral tumors. We conducted a randomized controlled trial of such patients to estimate postoperative outcomes and pulmonary function following these surgical techniques. METHODS Between 2005 and 2008, eligible patients with tumors of 2 cm or less were randomly assigned 1:1 to undergo lobectomy or limited resection; 32 and 33 NSCLC patients in each group, respectively, were analyzed. The primary end points were 5-year overall survival (OS) and disease-free survival (DFS), while the secondary end points were postoperative pulmonary function including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). RESULTS The 5-year OS rates were 93.8% and 90.9% in the lobectomy and limited resection groups, respectively (P=0.921). The 5-year DFS rates were 93.8% and 90.9% in the lobectomy and limited resection groups, respectively (P=0.714). These rates did not differ significantly between the two resection groups. The median postoperative/preoperative FVC ratios were 84.1% and 90.0% in the lobectomy and limited resection groups, respectively, while the median postoperative/preoperative FEV1 ratios were 81.9% and 89.1%, respectively. Both ratios were significantly higher in the limited resection group (P=0.032 and P=0.005 for FVC and FEV1 ratios, respectively). CONCLUSIONS A similar outcome, with more preserved postoperative pulmonary function, was observed in patients who underwent limited resection compared to those who underwent lobectomy. Ongoing large-scale multi-institutional prospective randomized trials of lobar versus sublobar resection in patients with small peripheral NSCLCs will hopefully provide definitive information about intentional limited resection of small peripheral tumors.

Surgical Outcomes of Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema and Those with Idiopathic Pulmonary Fibrosis without Emphysema.

OBJECTIVES Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder. The aim of this study was to compare the surgical outcomes of lung cancer patients with CPFE and those with idiopathic pulmonary fibrosis (IPF) without emphysema. METHODS A total of 1548 patients who underwent surgery for primary lung cancer between January 2001 and December 2012 were retrospectively reviewed. RESULTS Of the 1548 patients, 55 (3.6%) had CPFE on computed tomography (CT), and 45 (2.9%) had IPF without emphysema. The overall and disease-free 5-year survival rates for patients with CPFE were not significantly worse than those for patients with IPF without emphysema (24.9% vs. 36.8%, p = 0.814; 39.8% vs. 39.3%, p = 0.653, respectively). Overall, 21 (38.1%) patients with CPFE and nine patients (20.0%) with IPF without emphysema developed postoperative cardiopulmonary complications. Patients with CPFE had significantly more postoperative cardiopulmonary complications involving pulmonary air leakage for >6 days, hypoxemia, and arrhythmia than patients with IPF without emphysema (p = 0.048). CONCLUSIONS There was no significant difference in survival after surgical treatment between CPFE patients and IPF patients without emphysema, but CPFE patients had significantly higher morbidity than IPF patients without emphysema.

Influence of normothermic cardiopulmonary bypass on body oxygen metabolism during lung transplantation.

Studies have demonstrated that cardiopulmonary bypass (CPB) adversely affects pulmonary circulation, which is involved in metabolism in the lung, and that pulmonary circulation after CPB can restore the prostaglandin E2 (PGE2) level mainly standing for levels of key vasostimulators augmented during CPB, which may influence systemic tissue perfusion and body oxygen metabolism. However, in lung transplantation (Lx), pulmonary circulation is restored to the graft, which might induce another CPB reaction. We prospectively examined the influence of CPB on body oxygen metabolism in Lx. Left Lx was successfully performed on 10 dogs (group-on: with normothermic CPB without cardiac arrest, group-off: without CPB; n = 5 vs. 5). At 30 minutes after graft perfusion, the right pulmonary artery and bronchus were clamped. Body weight, donor-to-recipient body weight ratio, and clinical parameters were comparable between the two groups, except for the hematocrit level during CPB. At 90 minutes after graft perfusion, mixed venous oxygen saturation (SvO2) was lower (p < 0.01) and O2 extraction rate (p < 0.01), PGE2 (p = 0.025), and arterial blood ketone body ratio (KBR) (p < 0.01) were higher in group-on than in group-off, whereas these parameters were comparable before graft perfusion between the two groups. O2 consumption and acetic acid were higher in group-on than in group-off, whereas O2 delivery and 3-hydroxy propioic acid were comparable between the groups. In conclusion, Lx during CPB may induce a new inflammatory reaction and influence body oxygen metabolism, contrary to the restoration of pulmonary circulation after CPB.