Hironobu Wada

Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.

BackgroundThe aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC).Materials and MethodsThe methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD.ResultsIL-12Rβ2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16INK4A and WNT antagonist genes was a negative prognostic factor in the non-COPD group.ConclusionsNovel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

Overexpression of KIF23 predicts clinical outcome in primary lung cancer patients.

OBJECTIVE High-level expression of kinesin family member 23 (KIF23), a member of microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division, has been observed in a variety of human malignancies. The aims of the present study were to observe the expression of KIF23 in lung cancer, examine the role of KIF23 in lung cancer cell growth and/or survival by small interfering RNA experiments, and explore its clinicopathologic significance and evaluate KIF23 expression as a prognostic marker. MATERIALS AND METHODS Quantitative reverse transcription-polymerase chain reaction analysis was performed to detect the expression of KIF23 mRNA using metastatic lymph nodes from patients with advanced lung cancer obtained by endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) and primary lung tumors through surgical sample. The role of KIF23 in cancer cell growth was examined by small interfering RNA experiments. A total of 339 lung cancers were analyzed immunohistochemically on tissue microarrays to examine the expression of KIF23 protein and its clinicopathologic significance. RESULTS KIF23 transcript was found to be overexpressed in the great majority of metastatic lymph nodes from advanced lung cancers and primary lung tumors. Inhibiting KIF23 expression effectively suppressed lung cancer cell growth. High-level KIF23 expression was observed in 67.8% of the 339 cases. Lung adenocarcinoma patients with tumors displaying a high-level of KIF23 expression was also identified as an independent prognostic factor by multivariate analysis (P=0.0064). CONCLUSION KIF23 not only provides additional prognostic information for surgical treatment of lung cancer, but may also be a novel therapeutic target for these patients.

Lymph Node Staging by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Patients With Small Cell Lung Cancer

BACKGROUND Surgical treatment of small cell lung cancer (SCLC) is limited to stage I disease. Therefore, accurate lymph node staging is mandatory in SCLC patients. The purpose of this study was to evaluate the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the evaluation of mediastinal and hilar lymph node metastasis in patients with SCLC. METHODS Forty patients with untreated SCLC who underwent EBUS-TBNA for lymph node staging between November 2002 and September 2008 were retrospectively analyzed. The convex probe endobronchial ultrasonography was used for EBUS-TBNA. Lymph nodes assessed by the convex probe endobronchial ultrasonography were aspirated until EBUS-TBNA revealed malignant cells by rapid on-site cytology. RESULTS Endobronchial ultrasound-guided transbronchial needle aspiration was successfully performed in all patients, and revealed lymph node status as follows: N0, 13 cases; N1, 5 cases; and N2, 22 cases. Among the 13 N0 cases, 9 patients underwent surgery, whereas 4 patients did not undergo surgical intervention because of enlargement of subaortic or paraaortic lymph nodes (stations 5 and 6) that precluded EBUS-TBNA assessment (n = 3) or poor performance status (n = 1). Pathologic examination of dissected nodes confirmed an N0 diagnosis in 8 patients, whereas 1 patient had hilar lymph node metastasis (N1). The sensitivity, specificity, and diagnostic accuracy rate of EBUS-TBNA were 96.4%, 100%, and 97.2%, respectively. The overall 5-year survival rate for the 9 patients who underwent surgery was 77.8%. CONCLUSIONS Endobronchial ultrasound-guided transbronchial needle aspiration has a high diagnostic yield for the evaluation of mediastinal and hilar lymph node metastasis in SCLC and has a high impact on patient management.

Prosthetic Reconstruction of the Superior Vena Cava for Malignant Disease: Surgical Techniques and Outcomes

BACKGROUND This retrospective study investigated long-term graft patency and outcomes for malignant diseases with invasion of the superior vena cava (SVC). METHODS From October 1995 to November 2008, 20 patients underwent combined surgical resection of malignant tumors and the SVC with vascular reconstruction using a ringed polytetrafluoroethylene graft (8 to 12 mm) Sigmoid-curved spatulation of the graft end at the right auricle was performed to obtain a wide orifice left graft. Anticoagulation therapy was routinely administered for 3 to 6 months. Postoperative graft patency was verified at 2 to 4 weeks, 3 months, and after 12 months. Indications were lung cancer in 9 patients, thymic tumors in 8, germ cell tumors in 2, and thyroid cancer in 1. RESULTS Procedures were single graft replacement in 9 patients, bilateral grafts in 10, and bilateral SVC grafts and 1 pulmonary artery graft in 1. All grafts were patent over a short-term period, but 1 limb of the bilateral grafts became occluded in 2 patients who received bilateral grafts during long-term follow-up. Bronchial dehiscence after lung cancer resection caused 1 in-hospital death. Mean follow-up was 44.7 months. Median survival was 22.1 months. Overall survival was 66.4% and 41.5% at 1 and 5 years, respectively. Survival for lung cancer was significantly worse at 5 years (62.5%) than thymic tumor (18.8%, p = 0.04). CONCLUSIONS Prosthetic reconstruction of the SVC for anterior mediastinal tumors and lung cancer is feasible. Reconstruction of the SVC using a single left graft to avoid total cross-clamping of the SVC is effective.

Applicability of the revised International Association for the Study of Lung Cancer staging system to operable non-small-cell lung cancers

OBJECTIVE A new staging system for lung cancer has been proposed by The International Association for the Study of Lung Cancer Staging Committee. We assessed the feasibility of this system for surgical patients. METHODS We reviewed the surgical outcome of 1623 consecutive patients with non-small-cell lung cancer (NSCLC), who underwent pulmonary resection in our institution, with regard to the subpopulations categorised in the current and proposed (2009) systems for postoperative pathologic staging. RESULTS The proportion of patients staged as IIA, IIB, IIIA and IV increased, while those staged as IB and IIIB decreased. Diseases staged as IIIA or earlier were significantly increased in the new system (current system: N=1281, 78.9% vs new system: N=1457, 89.8%). The 5-year survival rates of patients with new stages IB and IIA were clearly dissociated with 72.5% and 51.3%, respectively (P<0.0001). The 5-year survival rates of the newly classified T1 patients were 90.3% for T1aN0M0 and 81.5% for T1bN0M0 (P=0.009). Re-classification of T2bN0M0 as stages IIA and T3 (same lobe nodules) N0M0 as stage IIB appropriately emphasised prognostic differences, while T4 (ipsilateral different lobe nodules) N2-3M0 (stage IIIB) and M1a (pleural effusion, stage IV) did not. CONCLUSIONS This study demonstrated that the new system is superior to the current system in terms of the proportion and prognostic prediction of each stage, although it contains minor contradictions. Therefore, revision of the staging system will contribute to the decision for limited operation and adjuvant therapy of resected NSCLC.

Localization of Pulmonary Nodules Using Navigation Bronchoscope and a Near-Infrared Fluorescence Thoracoscope

BACKGROUND Video-assisted thoracoscopic wedge resection of multiple small, non-visible, and nonpalpable pulmonary nodules is a clinical challenge. We propose an ultra-minimally invasive technique for localization of pulmonary nodules using the electromagnetic navigation bronchoscope (ENB)-guided transbronchial indocyanine green (ICG) injection and intraoperative fluorescence detection with a near-infrared (NIR) fluorescence thoracoscope. METHODS Fluorescence properties of ICG topically injected into the lung parenchyma were determined using a resected porcine lung. The combination of ENB-guided ICG injection and NIR fluorescence detection was tested using a live porcine model. An electromagnetic sensor integrated flexible bronchoscope was geometrically registered to the three-dimensional chest computed tomographic image data by way of a real-time electromagnetic tracking system. The ICG mixed with iopamidol was injected into the pulmonary nodules by ENB guidance; ICG fluorescence was visualized by a near-infrared (NIR) thoracoscope. RESULTS The ICG existing under 24-mm depth of inflated lung was detectable by the NIR fluorescence thoracoscope. The size of the fluorescence spot made by 0.1 mL of ICG was 10.4 ± 2.2 mm. An ICG or iopamidol spot remained at the injected point of the lung for more than 6 hours in vivo. The ICG fluorescence spot injected into the pulmonary nodule with ENB guidance was identified at the pulmonary nodule with the NIR thoracoscope. CONCLUSIONS The ENB-guided transbronchial ICG injection and intraoperative NIR thoracoscopic detection is a feasible method to localize multiple pulmonary nodules.

A multimodal nano agent for image-guided cancer surgery

Intraoperative imaging technologies including computed tomography and fluorescence optical imaging are becoming routine tools in the cancer surgery operating room. They constitute an enabling platform for high performance surgical resections that assure local control while minimizing morbidity. New contrast agents that can increase the sensitivity and visualization power of existing intraoperative imaging techniques will further enhance their clinical benefit. We report here the development, detection and visualization of a dual-modality computed tomography and near-infrared fluorescence nano liposomal agent (CF800) in multiple preclinical animal models of cancer. We describe the successful application of this agent for combined preoperative computed tomography based three-dimensional surgical planning and intraoperative target mapping (>200 Hounsfield Units enhancement), as well as near-infrared fluorescence guided resection (>5-fold tumor-to-background ratio). These results strongly support the clinical advancement of this agent for image-guided surgery with potential to improve lesion localization, margin delineation and metastatic lymph node detection.

Thoracoscopic ultrasonography for localization of subcentimetre lung nodules.

OBJECTIVES Localization of small, non-visible and non-palpable subcentimetre nodules can be challenging during video-assisted thoracoscopic surgery (VATS). Intraoperative ultrasonography is an option for localization of such lesions, yet this technology has not been fully adapted to thoracic surgery. The objective of this study was to assess a newly developed thoracoscopic ultrasound for localization and biopsy of subcentimetre pulmonary nodules in animal models. METHODS A prototype convex probe ultrasound thoracoscope (XLTF-UC180, Olympus Medical Systems Corp.) was used in this study. Multiple 5% agar pseudo-tumours were created in porcine lungs (n = 10) and assessed for localization with different frequencies (5.0-12.0 MHz) in deflated lungs. The evaluated pseudo-tumours were divided into two groups based on the distinctness of the tumour margin on the ultrasound images and compared in terms of the size and depth of the tumours. The visualization of real tumours and the biopsy capability were assessed using rabbit VX2 lung tumour models (n = 7). RESULTS The thoracoscopic ultrasound clearly visualized normal lung structures within a 1.5-cm depth including small vessels and bronchioles less than 5 mm in diameter in the completely deflated lung. Twenty-eight of 30 agar pseudo-tumours (93.3%) were successfully detected in deflated lungs (average size: 8.5 ± 2.1 mm; average depth: 7.4 ± 7.5 mm and depth range: 0-24.8 mm). Two tumours were not detected due to residual air surrounding the tumour. Higher frequency (12 MHz) tended to show more distinct margins of the targets. Indistinct tumours were located significantly deeper in the lung than the distinct tumours (14.11vs 2.42 mm), regardless of them being in a similar size range. VX2 tumours were identified as heterogeneous isoechoic lesions and adequate tissue sampling for diagnosis was achieved using a dedicated needle. CONCLUSIONS The newly developed convex probe ultrasound thoracoscope was capable of localizing subcentimetre nodules in the porcine deflated lung as well as of obtaining sufficient sampling from lung tumours in the rabbit model, which may enable single-port VATS lung nodule biopsy in a human clinical setting. However, the depth of the tumours significantly influenced the quality of ultrasound images. Complete collapse of the lung and use of high frequency may facilitate achieving distinct visualization of the targets.

Assessment of the new thin convex probe endobronchial ultrasound bronchoscope and the dedicated aspiration needle: a preliminary study in the porcine lung.

Background:Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) allows for accurate minimally invasive mediastinal lymph node staging of lung cancer. The current convex probe EBUS (CP-EBUS) has limitations in the access to certain N1 lymph nodes (lobar and segmental) because of its size. The aim of this study was to assess the new thin CP-EBUS (TCP-EBUS) and an aspiration needle for sampling of N1 lymph nodes in a porcine model. Methods:The prototype TCP-EBUS (BF-Y0046, Olympus Medical Systems Corp.) with a thinner tip (5.9 mm) and larger bending angle (170 degrees upward) was used. Accessibility, operability, and TBNA capability of the TCP-EBUS were assessed and compared with the current CP-EBUS using porcine lungs. The endoscopic visibility range and the maximum reach were evaluated at the left upper lobe bronchus, tracheobronchus, and right lower lobe bronchus. The prototype aspiration needle (Olympus Medical Systems Corp.) was used for EBUS-TBNA. Results:In all of the evaluated bronchi (n=9), the TCP-EBUS had a greater reach (14.7 mm in the endoscopic visibility range, 16.0 mm in the maximum reach) than the current CP-EBUS. The TCP-EBUS was able to visualize 1 to 3 distal bifurcations farther compared with the current CP-EBUS. Adequate lymph node sampling from lobar and segmental lymph nodes was possible using the aspiration needle. Conclusions:The TCP-EBUS has improved accessibility to peripheral bronchi with excellent operability and is capable of sampling lobar and segmental lymph nodes using the dedicated aspiration needle.

Risk of lung cancer in patients with preinvasive bronchial lesions followed by autofluorescence bronchoscopy and chest computed tomography

OBJECTIVES To assess risk of lung cancer (LC) in patients with preinvasive bronchial lesions and to identify factors associated with higher risk. METHODS 124 patients with one or more preinvasive bronchial lesions and normal chest computed tomography (CT) (mean age 66.7 years, 121 males and 3 females), followed-up by white light and autofluorescence bronchoscopy (AFB) every 4-6 mo and chest CT every 6-12 mo, end points were development of carcinoma in situ (CIS) or LC. RESULTS Among 124 patients with 240 preinvasive bronchial lesions, 20 CIS or LC lesions were detected during follow-up in 20 (16%) patients, 7 were detected as new endobronchial lesions, 10 as new peripheral lesions and 3 as local progression from severe dysplasia to CIS. Median time to progression from the same site or development of CIS/LC elsewhere was 24 months (range: 6-54 mo). The Cumulative risk of development of CIS/LC was 7% at one year, 20% at three years and 44% at 5 years. Among detected lung cancers, 80% were stage 0 or stage I and underwent treatment with curative intent. Diagnosis of new SD during follow-up (p=0.0001), chronic obstructive pulmonary disease (COPD) (p=0.001) or smoking index >52 pack-year (p=0.042) was associated with higher risk. Even after controlling for other risk factors, COPD was associated with risk for lung cancer. Baseline lesion grade was not predictive of patient outcome (p=0.146). CONCLUSION Patients with preinvasive bronchial lesions, especially those with new SD during follow-up, COPD or smoking >52 pack-year are at high risk of LC, AFB and CT follow-up facilitated early detection and treatment with curative intent.