Tomonori Murayama

Adoptive immunotherapy for advanced non-small cell lung cancer using zoledronate-expanded γδTcells: a phase I clinical study.

Human &ggr;&dgr; T cells can recognize and kill non-small cell lung cancer (NSCLC) cells using the V&ggr;9V&dgr;2 T-cell receptor and/or NKG2D. We have established clinical grade large-scale ex vivo expansion of &ggr;&dgr; T cells from peripheral blood mononuclear cells by culturing with zoledronate and interleukin-2 (IL-2). A phase I study was conducted to evaluate safety and potential antitumor effects of re-infusing ex vivo expanded &ggr;&dgr; T cells in patients with recurrent or advanced NSCLC. Patients peripheral blood mononuclear cells were stimulated with zoledronate (5 &mgr;M) and IL-2 (1000 IU/mL) for 14 days. Harvested cells, mostly &ggr;&dgr; T cells, were given intravenously every 2 weeks without additional IL-2, a total of 6 times. The cumulative number of transferred &ggr;&dgr; T cells ranged from 2.6 to 45.1×109 (median, 15.7×109). Fifteen patients underwent adoptive immunotherapy with these &ggr;&dgr; T cells. There were no severe adverse events related to the therapy. Immunomonitoring data showed that with increasing numbers of infusions, the number of peripheral &ggr;&dgr; T cells gradually increased. All patients remained alive during the study period with a median survival of 589 days and median progression-free survival of 126 days. According to the Response Evaluation Criteria In Solid Tumors, there were no objective responses. Six patients had stable disease, whereas the remaining 6 evaluable patients experienced progressive disease 4 weeks after the sixth transfer. We conclude that adoptive transfer of zoledronate-expanded &ggr;&dgr; T cells is safe and feasible in patients with NSCLC, refractory to other treatments.

Outcome and survival analysis of pulmonary metastasectomy for hepatocellular carcinoma

OBJECTIVE The lung is the most common site for extrahepatic metastasis from hepatocellular carcinoma (HCC). We previously reported in a series of 20 patients that pulmonary metastasectomy for HCC is feasible in selected patients. The objective of this study was to re-evaluate the long-term outcomes and prognostic factors with an additional 25 patients. METHODS We retrospectively analyzed the records of 45 consecutive patients who underwent pulmonary metastasectomy due to HCC at our institution between 1990 and 2010. RESULTS Thirty-nine patients underwent hepatectomy or liver transplantation, whereas six patients underwent locoregional therapy for primary liver lesions. Twenty-seven patients died during a median 17.6-month follow-up period. The 2-year disease-free survival (DFS) was 19.5%. The 5-year overall survival (OS) was 40.9%. History of recurrence and serum des-gamma-carboxy prothrombin (DCP) level >40 mAU ml(-1) at initial pulmonary resection were unfavorably associated with OS in univariate analysis. CONCLUSIONS Pulmonary metastasectomy for HCC in selected patients resulted in relatively good outcomes with regard to OS. History of recurrence and serum DCP levels were shown to be candidates of prognostic factors for OS.

Resection of solitary pulmonary lesion is beneficial to patients with a history of malignancy.

BACKGROUND Solitary pulmonary lesion poses a diagnostic challenge, especially in patients with a history of malignancy. The purpose of this study was to evaluate the characteristics of solitary pulmonary lesions and the outcome of surgical resection. METHODS We retrospectively analyzed 243 patients with a history of cancer who underwent surgery for new-found solitary pulmonary lesion between January 1998 and December 2007. RESULTS The diagnosis was primary lung cancer in 92 patients, metastasis in 133, and benign lesions in 18. The 5-year survival rate was 67.9% in all patients, 74.6% in those with primary lung cancer, 62.8% in those with metastasis, and 79.9% in those with benign lesions (p = 0.56). In metastasis patients, history of extrapulmonary recurrence and larger diameter lesion were risk factors for recurrence by multivariate analysis. History of cancers other than colorectal and bone and soft tissue sarcoma and shorter disease-free interval were indicators of poor prognosis. Pathologic stage was the only indicator of prognosis for primary lung cancer, and none of the factors concerning antecedent cancer influenced prognosis. CONCLUSIONS Surgical resection of solitary pulmonary lesion is essential in patients with a history of cancer because substantial numbers of benign lesions are included. In the case of malignancy, metastasectomy had a life-prolonging effect for selected patients, and prognosis of primary lung cancer was no worse than for the general population if treated appropriately. It is important not to hesitate to take a surgical approach for a diagnosis and to treat with standard therapy for primary lung cancer.

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.

Identification of Individual Cancer-Specific Somatic Mutations for Neoantigen-Based Immunotherapy of Lung Cancer

Introduction: Two strategies for selecting neoantigens as targets for non–small cell lung cancer vaccines were compared: (1) an “off‐the‐shelf” approach starting with shared mutations extracted from global databases and (2) a personalized pipeline using whole‐exome sequencing data on each patients tumor. Methods: The Catalogue of Somatic Mutations in Cancer database was used to create a list of shared missense mutations occurring in more than 1% of patients. These mutations were then assessed for predicted binding affinity to HLA alleles of 15 lung cancer patients, and potential neoantigens (pNeoAgs) for each patient were selected on this basis. In the personalized approach, pNeoAgs were selected from missense mutations detected by whole‐exome sequencing of the patients own samples. Results: The list of shared mutations included 22 missense mutations for adenocarcinoma and 18 for squamous cell carcinoma (SCC), resulting in a median of 10 off‐the‐shelf pNeoAgs for each adenocarcinoma (range 5–13) and 9 (range 5–12) for each SCC. In contrast, a median of 59 missense mutations were identified by whole‐exome sequencing (range 33–899) in adenocarcinoma and 164.5 (range 26–232) in SCC. This resulted in a median of 46 pNeoAgs (range 13–659) for adenocarcinoma and 95.5 (range 10–145) for SCC in the personalized set. We found that only one or two off‐the‐shelf pNeoAgs were included in the set of personalized pNeoAgs—and then in only three patients, with no overlap seen in the remaining 12 patients. Conclusions: Use of an off‐the‐shelf pipeline is feasible but may not be satisfactory for most patients with non–small cell lung cancer. We recommend identifying personal mutations by comprehensive genome sequencing for developing neoantigen‐targeted cancer immunotherapies.

Validation of 7th TNM staging system for lung cancer, based on surgical outcomes.

Background Validation of the clinical classification for lung cancer of the 7th edition of the TNM staging system among surgical cases has not been reported previously. Methods Data of 489 males and 246 females, with a mean age of 67.6 years, who underwent surgical resection for non-small-cell lung cancer were analyzed retrospectively. Results The 5-year survival rate of these patients was 72.2% for clinical stage IA (n = 365), 58.4% for IB (n = 158), 51.2% for IIA (n = 77), 49.1% for IIB (n = 42), 36.8% for IIIA (n = 86), 80% for IIIB (n = 5) and 50% for IV (n = 2). The 5-year survival rate of patients was 100% for pathological stage 0 (n = 2), 86.1% for IA (n = 216), 73.8% for IB (n = 173), 46.1% for IIA (n = 97), 47.2% for IIB (n = 69), 33.3% for IIIA (n = 155), 33.3% for IIIB (n = 3) and 30.9% for IV (n = 20). Prognostic factors included female sex and 70 years of age or younger, as well as adenocarcinoma histology. Conclusions Deterioration in patient survival was indicated with the exception of stages IIIB and IV, each of which included only a small number of patients. Our study validated the current TNM staging system in surgical cases with regard to both clinical and pathological classifications.

Lung lobectomy in a patient with an implantable left ventricular assist device

Non-cardiac surgical procedures in patients with left ventricular assist devices (LVADs) pose a special challenge given the hemodynamic and hematologic considerations in these patients. During pulmonary procedures in patients with LVADs, special attention should be paid to hemodynamics because lung resection surgery requires a lateral decubitus position, single-lung ventilation and postoperative decrease in the pulmonary vascular bed, all of which may lead to inadequate preload to the LVAD. We present a case of lower lobectomy of the left lung for an adenocarcinoma found in a patient with an implantable continuous-flow LVAD.

Gender Differences in Long-Term Survival after Surgery for Non-Small Cell Lung Cancer.

Background This retrospective study examined gender differences in non-small cell lung cancer (NSCLC) by analyzing surgical cases at a single institution. Patients and Methods In this study, 735 NSCLC patients who underwent surgery from 1995 to 2010 were included. Clinical and pathological characteristics were retrieved by reviewing charts retrospectively, and variables between genders were compared. Results There were 489 males and 246 females in the study. The percentage of screening-detected lung cancers (83.7%), never smokers (82.9%), adenocarcinoma histology (90.7%), and pathological stage IA (42.7%) was higher in females than that in males (71.2, 8.2, 51.3, and 23.1%, respectively). Female patients had fewer cases of coronary artery disease (2.8%) and fewer pneumonectomy cases (2.0%) than the male patients (7.4 and 5.3%, respectively). The median follow-up period after surgery was 5.9 years. The overall survival rates at 5 years were 57.3% for males and 76.2% for females (p < 0.001, log-rank test). Based on univariate analysis, we report that histology, smoking history, and pathological stage were significant prognostic factors in addition to gender. Based on multivariate analysis, pathological stage III/IV (hazard ratio, 3.60; 95% confidence interval [CI], 2.84-4.54) and female gender (hazard ratio, 0.55; 95% CI, 0.37-0.82) were significant prognostic factors. Subgroup analysis demonstrated that female gender and adenocarcinoma histology were significant positive prognostic factors only in pathological stages I and II (n = 557). Conclusion Female gender as well as pathological stage was favorable prognostic factors. The survival advantage observed in female NSCLC patients was limited to those with cancer at stages I and II.

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