Haruaki Hino

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.

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.

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.

Rapid Cancer Fluorescence Imaging Using A γ-Glutamyltranspeptidase-Specific Probe For Primary Lung Cancer

BACKGROUND: We set out to examine the activity of γ-glutamyltranspeptidase (GGT) in lung cancer and the validity of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) for intraoperative imaging of primary lung cancer. METHODS: GGT activities and mRNA expression levels of GGT1 (one of the GGT subtypes) in five human lung cancer cell lines were examined by fluorescence imaging and quantitative reverse transcription polymerase chain reaction. In vivo imaging of an orthotopic A549 xenograft model in nude mice was performed to confirm its applicability to intraoperative imaging. Furthermore, ex vivo imaging of 73 specimens from lung cancer patients were performed and analyzed to calculate the sensitivity/specificity of gGlu-HMRG for lung cancer diagnosis. RESULTS: GGT activities and mRNA expression levels of GGT1 are diverse depending on cell type; A549, H441, and H460 showed relatively high GGT activities and expression levels, whereas H82 and H226 showed lower values. In the in vivo mouse model study, tiny pleural dissemination and hilar/mediastinal lymph node metastasis (less than 1 mm in diameter) were clearly detected 15 minutes after topical application of gGlu-HMRG. In the ex vivo study of specimens from patients, the sensitivity and specificity of gGlu-HMRG were calculated to be 43.8% (32/73) and 84.9% (62/73), respectively. When limited to female patients, never smokers, and adenocarcinomas, these values were 78.9% (15/19) and 73.7% (14/19), respectively. CONCLUSIONS: Although GGT activity of lung cancer cells vary, gGlu-HMRG can serve as an intraoperative imaging tool to detect small foci of lung cancer when such cells have sufficient GGT activity.

Bronchopleural fistula after lower lobectomy of the right lung following thoracic endovascular aortic repair

A 77-year old male patient was admitted for the treatment of a thoracic aortic aneurysm (TAA) and primary lung cancer. A saccular aneurysm, 4.8 cm in diameter, located in the proximal segment of the descending thoracic aorta and a pulmonary tumour, 3 cm in diameter, located at the right lower lobe, with lymph node swelling, were detected simultaneously. First, a thoracic endovascular aortic repair (TEVAR) was performed for TAA, and then 45 days later, a lobectomy and radical lymph node dissection by open thoracotomy were performed safely for primary lung cancer. The postoperative course was complicated by a bronchopleural fistula (BPF). Massive necrotic changes to the bronchial stump and the intercostal muscle flap were observed during an open window thoracotomy. Both the chronic use of corticosteroids and TEVAR may have been among the predisposing factors for the occurrence of the fistula. The patient died as a result of respiratory failure 68 days after the lobectomy. This is a first case report of a BPF after a staged operation of TEVAR and major lung surgery. We reviewed and discussed the surgical strategy and timing for both the primary lung cancer and the thoracic aortic aneurysm.

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.

Risk factors for postoperative complications and long-term survival in lung cancer patients older than 80 years

OBJECTIVES The number of octogenarian lung cancer patients undergoing radical surgery has been increasing recently. However, knowledge regarding the risk factors for postoperative complications and reliable predictive factors for long-term survival is limited. This study aimed to investigate the risk factors of postoperative complications, and reliable prognostic factors, in lung cancer patients older than 80 years. METHODS Lung cancer patients aged 80 years or older who underwent radical surgery were retrospectively studied; a multi-institutional analysis was conducted from January 1998 to December 2015. Preoperative and postoperative clinical data, including age, gender, smoking history, body mass index, respiratory function, Charlson Comorbidity Index, Glasgow Prognostic Score, surgical procedure, cancer histology, clinical and pathological stage, surgical result and survival time, were collected. RESULTS A total of 337 patients, comprising 216 (64.1%) men and 121 (35.9%) women were enrolled. The median age was 82 (range 80-92) years. Of the 337 patients, 205 (60.8%) had preoperative comorbidities. Postoperative complications were observed in 119 (35.3%) patients; postoperative mortalities occurred in 6 (1.8%) patients. Univariate and multivariate analyses showed that male gender (P = 0.01) and operation time (P = 0.047) were associated with postoperative complications; in contrast, pathological Stage III (P < 0.001), male gender (P = 0.01), Charlson Comorbidity Index ≥2 (P = 0.03) and Glasgow Prognostic Score = 1/2 (P = 0.04) were independent prognostic factors for overall survival. CONCLUSIONS The risk factors for postoperative complications (male gender and operation time) and the predictive factors affecting long-term survival (male gender, Charlson Comorbidity Index, Glasgow Prognostic Score and P-stage) should be taken into account for the effective management of patients older than 80 years with lung cancer, undergoing surgery.

Abstract 5113: Rapid Cancer Imaging By GGT-targeted Fluorescence Probe For Primary Lung Cancer

Introduction Lung cancer is the leading cause of cancer death in Japan, however, it has been difficult to detect and diagnose precisely lung cancer with a diameter less than 1cm to date. The purpose of this study is to investigate clinical application of novel GGT-targeted fluorescence probe for detecting the primary lung cancer in an intraoperative manner. Methods As a fluorescence probe for γ-glutamyltranspeptidase (GGT), γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) was used. gGlu-HMRG is non-fluorescent, but is converted to a highly fluorescent hydroxymethyl rhodamine green (HMRG) upon reaction with the enzyme, which tends to accumulate in GGT-overexpressing cancer cells. First, we examined GGT activity of lung cancer cell lines, A549, H460, H441, H82 and H226, by applying gGlu-HMRG and evaluating fluorescence intensities by confocal fluorescence microscopy. We also compared mRNA expression level of GGT1 (one of the subtypes of GGT) by qRT-PCR. Further, by transfecting siRNA targeted to GGT1, we investigated the target of gGlu-HMRG. Next we performed in vivo imaging of orthotopic A549 lung cancer xenograft model in nude mouse to confirm the validity of fluorescence imaging. Finally, we carried out ex vivo fluorescence imaging of 73 human lung cancers and normal lung tissues which were surgically resected, and the fluorescence intensities were analyzed by Receiver Operating Characteristics curve. Results A549, H460 and H441 cells with high GGT1 expression could be visualized with high fluorescence intensity after application of gGlu-HMRG within several minutes, whereas H82 and H226 cells with relatively low GGT1 expression could not. We ascertained that the target of gGlu-HMRG was GGT1 by fluorescence imaging and qRT-PCR with lung cancer cell lines transfected with siRNA for GGT1. In lung cancer xenograft model, pleural dissemination, hilar and mediastinal lymph node metastasis and the surface of lung cancer were clearly detected within 15 minutes after topical drip of gGlu-HMRG. We confirm that every fluorescent lesion was adenocarcinoma pathologically. In ex vivo human lung cancer fluorescence imaging, the sensitivity, specificity and accuracy were calculated to be 43.8% (32/73cases), 84.9% (62/73cases) and 64.4% (94/146), respectively. The adenocarcinomas, cancer of female or never smoker were more significantly detected by fluorescence imaging (p Conclusions We suggest that intraoperative application of gGlu-HMRG to detect pleural dissemination, small mediastinal lymph nodal metastasis, or other small foci of the lung cancer cells on surgical margin might be feasible when the cancer cells overexpress GGT. Intraoperative application of fluorescence probe is highly expected in near future. Citation Format: Haruaki Hino, Mitsuaki Kawashima, Tomonori Murayama, Junji Ichinose, Kentaro Kitano, Kazuhiro Nagayama, Jun-ichi Nitadori, Masaki Anraku, Tomohiro Murakawa, Kasue Mizuno, Sayaka Tanaka, Mako Kamiya, Nobuhiro Nishiyama, Kazunori Kataoka, Kohei Miyazono, Yasuteru Urano, Jun Nakajima. Rapid Cancer Imaging By GGT-targeted Fluorescence Probe For Primary Lung Cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5113. doi:10.1158/1538-7445.AM2015-5113

An Unusual Invasive Ectopic Thymoma in the Thyroid and Anterior Mediastinum

An 81-year-old woman with a 2-year history of dysphagia detected a cervical mass. Computed tomography showed a thyroid tumor extending through the superior and anterior mediastinum. Analysis of an incisional biopsy specimen revealed a thymoma. Total resection of the thyroid and mediastinal tumor was performed. The thymoma invaded the anterior tracheal wall and left brachiocephalic vein. Pathologic examination revealed thymoma type B1 concomitant with B2 and B3 (World Health Organization classification), Masaoka IVb, and T3 N2 M0-IVb, with cervical lymph node metastasis. Clinicians must be cautious during radical operations for invasive ectopic thymomas.

Combined operation for thymoma with myasthenia gravis and coronary artery disease in an octogenarian: Letters to the Editor

1 Bakker J, van Kersen F, Bellaar Spruyt J. Pneumopericardium and pneumomediastinum after polypectomy. Endoscopy 1991; 23: 46–47. 2 Maunder RJ, Pierson DJ, Hudson LD. Subcutaneous and mediastinal emphysema. Pathophysiology, diagnosis and management. Arch Intern Med 1984; 144: 1447–1453. 3 Lohsiriwat V. Colonoscopic perforation: incidence, risk factors, management and outcome. World J Gastroenterol 2010; 16: 425–430. 4 Castellvi J, Pi F, Sueiras A et al. Colonoscopic perforation: useful parameters for early diagnosis and conservative treatment. Int J Colorectal Dis 2011; 26: 1183–1190. 5 La Torre M, Velluti F, Giuliani G, Di Giulio E, Ziparo V, La Torre F. Promptness of diagnosis is the main prognostic factor after colonoscopic perforation. Colorectal Dis 2012; 14: e23–e26. 6 Hamdani U, Naeem R, Haider F et al. Risk factors for colonoscopic perforation: a populationbased study of 80118 cases. World J Gastroenterol 2013; 19: 3596–3601. 7 Gatto NM, Frucht H, Sundararajan V, Jacobson JS, Grann VR, Neugut AI. Risk of perforation after colonoscopy and sigmoidoscopy: a population-based study. J Natl Cancer Inst 2003; 95: 230–236. 8 Rabeneck L, Paszat LF, Hilsden RJ et al. Bleeding and perforation after outpatient colonoscopy and their risk factors in usual clinical practice. Gastroenterology 2008; 135: 1899–1906. 9 Levin TR, Zhao W, Conell C et al. Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med 2006; 145: 880–886. 10 Kavin H, Sinicrope F, Esker AH. Management of perforation of the colon at colonoscopy. Am J Gastroenterol 1992; 87: 161–167.