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Katakami N.,Kobe City Medical Center General Hospital | Tada H.,Osaka City General Hospital | Mitsudomi T.,Aichi Cancer Center | Kudoh S.,Osaka City University | And 6 more authors.
Cancer | Year: 2012

BACKGROUND: This study sought to ascertain whether induction-concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC). METHODS: Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m2 and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible. RESULTS: Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P =.187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P =.397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P =.001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P =.021). CONCLUSIONS: The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC. © 2012 American Cancer Society.


Hashimoto D.,University of Tampere | Hashimoto D.,Kumamoto University | Blauer M.,University of Tampere | Hirota M.,Kumamoto Regional Medical Center | And 3 more authors.
European Journal of Cancer | Year: 2014

Background and aim Autophagy is a regulated process of degradation and recycling of cellular constituents. The role of autophagy in pancreatic cancer is still not clear. Some studies indicate that in pancreatic cancer autophagy exerts cytoprotective effects, whereas others suggest that autophagy positively contributes to cell death by enhancing cytotoxicity of anticancer drugs. The aim of this study was to investigate the role of autophagy in pancreatic cancer, and to provide insights into new strategies for treatment. Materials and methods Pancreatic cancer cell lines PANC-1 and BxPC-3 were treated with anticancer drugs (5-fluorouracil or gemcitabine) alone and in combination with autophagy inhibitors (chloroquine or wortmannin). Biopsy samples were retrieved from patients from pancreatic normal tissue and adenocarcinoma. Western blot of microtubule-associated protein 1 light chain 3 (LC3)-II was performed to investigate the degree of autophagy and cell proliferation was assessed by a crystal violet assay. Results Autophagy was active in PANC-1 cells under basal conditions. Autophagy was significantly induced in pancreatic ductal adenocarcinoma compared to healthy pancreatic tissue in patients. Inhibition of autophagy by chloroquine suppressed the growth of PANC-1 and BxPC-3. Autophagy was markedly increased after treatment with 5-fluorouracil or gemcitabine. Inhibition of autophagy by chloroquine potentiated the inhibition of cell proliferation of PANC-1 and BxPC-3 by 5-fluorouracil and gemcitabine. Conclusions Our results with pancreatic cancer cell lines and human pancreatic adenocarcinoma suggest that autophagy contributes to pancreatic cancer cell growth. Autophagy has a cytoprotective effect against 5-fluorouracil and gemcitabine in pancreatic cancer cells. Combination therapy of these anticancer drugs and chloroquine should be investigated. © 2014 Elsevier Ltd. All rights reserved.


Ohmuraya M.,Kumamoto University | Sugano A.,Kobe University | Hirota M.,Kumamoto Regional Medical Center | Takaoka Y.,Kobe University | Yamamura K.-I.,Kumamoto University
Frontiers in Physiology | Year: 2012

Studies on hereditary pancreatitis have provided evidence in favor of central role for trypsin activity in the disease. Identification of genetic variants of trypsinogen linked the protease to the onset of pancreatitis, and biochemical characterization proposed an enzymatic gain of function as the initiating mechanism. Mutations of serine protease inhibitor Kazal type 1 gene (SPINK1) are shown to be associated with hereditary pancreatitis. We previously reported that Spink3 (a mouse homolog gene of human SPINK1) deficient mice showed excessive autophagy, followed by inappropriate trypsinogen activation in the exocrine pancreas. These data indicate that the role of SPINK1/Spink3 is not only trypsin inhibitor, but also negative regulator of autophagy. On the other hand, recent studies showed that high levels of SPINK1 protein detected in a serum or urine were associated with adverse outcome in various cancer types. It has been suggested that expression of SPINK1 and trypsin is balanced in normal tissue, but this balance could be disrupted during tumor progression. Based on the structural similarity between SPINK1 and epidermal growth factor (EGF), we showed that SPINK1 protein binds and activates EGF receptor, thus acting as a growth factor on tumor cell lines. In this review, we summarize the old and new roles of SPINK1/Spink3 in trypsin inhibition, autophagy, and cancer cell growth.These new functions of SPINK1/Spink3 may be related to the development of chronic pancreatitis. © 2012 Ohmuraya, Sugano, Hirota, Takaoka and Yamamura.


Hirota M.,Kumamoto Regional Medical Center | Kanemitsu K.,Saiseikai Kumamoto Hospital | Takamori H.,Kumamoto University | Chikamoto A.,Kumamoto University | And 5 more authors.
American Journal of Surgery | Year: 2010

Background: Pancreatoduodenectomy is the only effective treatment for cancers of the periampullary region. Because surgeons usually grasp tumors during pancreatoduodenectomy, this procedure may increase the risk of squeezing and shedding the cancer cells into the portal vein, retroperitoneum, and/or peritoneal cavity. In an effort to overcome these problems, we have developed a surgical technique for no-touch pancreatoduodenectomy. Methods: From March 2005 through May 2008, 42 patients have been operated on following this technique. Resected margins were microscopically analyzed. Results: We describe a technique for pancreatoduodenectomy using a no-touch isolation technique. We resect cancers with wrapping them within Gerota's fascia and transect the retroperitoneal margin along the right surface of the superior mesenteric artery and abdominal aorta without grasping tumors. Conclusions: No-touch pancreatoduodenectomy has many potential advantages that merit further investigation in future randomized controlled trials. © 2010 Elsevier Inc. All rights reserved.


Hashimoto D.,Kumamoto University | Chikamoto A.,Kumamoto University | Ohmuraya M.,Kumamoto University | Hirota M.,Kumamoto Regional Medical Center | Baba H.,Kumamoto University
Surgery Today | Year: 2014

Over the past 100 years, advances in surgical techniques and perioperative management have reduced the morbidity and mortality after pancreaticoduodenectomy (PD). Many techniques have been proposed for the reconstruction of the pancreaticodigestive anastomosis to prevent the development of a postoperative pancreatic fistula (POPF), but which is the best approach is still highly debated. We carried out a systematic review to determine and compare the effectiveness of various methods of anastomosis after PD. A meta-analysis and most randomized controlled trials (RCTs) showed that the mortality, POPF rate and incidence of other postoperative complications were not statistically different between the pancreaticogastrostomy and pancreaticojejunostomy (PJ) groups. One RCT showed that a binding PJ significantly decreased the risk of POPF and other postoperative complications compared with conventional PJ. External duct stenting reduced the risk of clinically relevant POPF in a meta-analysis and RCTs. The prophylactic use of octreotide after PD does not result in a reduced incidence of POPF. In conclusion, our findings suggest that the successful management of pancreatic anastomoses may depend more on the meticulous surgical technique, surgical volume, and other management parameters than on the type of technique used. However, some new approaches, such as binding PJ, and the use of external stents should be considered in further RCTs. © 2013 Springer.

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