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Kashiwabara K.,Kumamoto Regional Medical Center | Semba H.,Kumamoto Regional Medical Center | Fujii S.,Kumamoto Regional Medical Center | Tsumura S.,Kumamoto Regional Medical Center
Cancer Chemotherapy and Pharmacology | Year: 2017

Purpose: Several non-small cell lung cancer (NSCLC) cases of successful rechallenge with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) after recovery from gefitinib or erlotinib-induced interstitial lung disease (ILD) have been reported, but it is not clear whether the rechallenge affects the outcome. Methods: We retrospectively evaluated the difference in the outcome between advanced NCLC patients with active EGFR mutations who received EGFR-TKI rechallenge after recovery from EGFR-TKI-induced ILD and those who did not. Results: EGFR-TKI-induced ILD occurred in 11 (10%) of 110 patients receiving gefitinib, five (7%) of 73 patients receiving erlotinib and one (8%) of 13 patients receiving afatinib. Diffuse alveolar damage pattern ILD was observed in six cases, four of which had chemotherapy-related death. Five of 13 patients who had recovered from ILD received EGFR-TKI rechallenge with concurrent oral administration of prednisolone 0.5 mg/kg after the strict informed consent of the risk for the recurrence of severe ILD. All of the five patients achieved a partial response. The median overall survival from the occurrence of EGFR-TKI-induced ILD was longer in patients with EGFR-TKI rechallenge than that in patients without (15.5 vs. 3.5 months, p = 0.029). The adverse events of EGFR-TKI rechallenge were tolerable, but one case receiving EGFR-TKI rechallenge with the suspected drug exhibited the recurrence of grade 3 ILD after the discontinuation of prednisolone. Conclusions: EGFR-TKI rechallenge with concurrent prednisolone therapy might be salvage therapy in advanced NSCLC patients with active EGFR mutations after recovery from EGFR-TKI-induced ILD. © 2017, Springer-Verlag Berlin Heidelberg.


Hashimoto D.,Kumamoto Regional Medical Center | Hirota M.,Kumamoto Regional Medical Center | Sakata K.,Kumamoto Regional Medical Center | Yagi Y.,Kumamoto Regional Medical Center | Baba H.,Kumamoto University
Surgery Today | Year: 2012

Transmesenteric hernia is a rare cause of bowel obstruction in adults. We herein describe two cases that occurred in adult women, ages 27 and 19. Both cases presented with abdominal pain without muscular defense signs. Computed tomography of both cases showed features of small bowel obstruction by an internal hernia. A laparotomy showed mesenteric defects of the mesentery of the ileum in the former case and the mesentery of the transverse colon in the latter case, with a herniating ileum. The involved small bowel was viable in both cases, and the bowel was pulled out of the mesenteric defect without resection. The mesenteric defects were then successfully repaired. © Springer 2011.


Hashimoto D.,Kumamoto University | Hashimoto D.,Kumamoto Regional Medical Center | Hirota M.,Kumamoto Regional Medical Center | Yagi Y.,Kumamoto Regional Medical Center | Baba H.,Kumamoto University
Surgery Today | Year: 2013

In patients undergoing pancreaticoduodenectomy, leakage from the pancreatic anastomosis remains an important cause of morbidity and contributes to prolonged hospitalization and mortality. Recently, a new end-to-end pancreaticojejunostomy technique without the use of any stitches through the pancreatic texture or pancreatic duct has been developed. In this novel anastomosis technique, the pancreatic stump is first sunk into deeply and tightened with a purse string in the bowel serosa. We modified this method in an end-to-side manner to complete the insertion of the pancreatic stump into the jejunum, independent of the size of the pancreas or the jejunum. We tested this new anastomosis technique in four pilot patients and compared their outcomes with four control patients who underwent traditional pancreaticojejunostomy. No severe pancreatic fistulas were observed in either group. There were no differences in morbidity or hospital stay between the groups. This new method can be performed safely and is expected to minimize leakage from pancreaticojejunostomies. © 2012 Springer Japan.


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 | Ogawa M.,Kumamoto Regional Medical Center
JOP : Journal of the pancreas | Year: 2014

BACKGROUND: Pancreatectomy is the only effective treatment for cancers of the pancreas. Surgeons usually grasp tumors during pancreatectomy; however, this procedure may increase the risk of squeezing and shedding of the cancer cells into the portal vein, retroperitoneum, and/or peritoneal cavity. In an effort to overcome these problems, we have developed surgical techniques for no-touch pancreatectomy.METHODS: From April 2008 through September 2013, 52 patients have been operated on no-touch pancreatectomy for invasive ductal carcinoma of the pancreas by a single operator (M.H.). Among them, 40 received pancreatoduodenectomy (PD), and 12 did distal pancreatectomy (DP). Twenty two cases (42%) required SMV-PV resection. This is a study to see if pancreatectomy can be technically done using a no-touch surgical technique without deteriorating the post-operative prognosis. During the procedure, the pancreatic tumor is neither grasped nor squeezed by the surgeon. Furthermore, for improved dissection of the retroperitoneal tissue (leftward and posterior margins for PD and rightward and posterior margins for DP), we use a hanging and clamping maneuver and dissection behind Gerota fascia.RESULTS: Overall 2- and 5-year survival rates were 64 and 42% with mean follow-up periods of 34.4 months (range: 6-68 months). Recurrence free 2- and 5-year survival rates were 49 and 31%, respectively. The 5-year survival rates of patients with JPS-stage III and those with JPS-stage IV were 57 and 20%, respectively. The 5-year survival rates of patients with UICC-stage IIA and those with UICC- stage IIB were 49 and 39%, respectively. Patients with UICC-stage III or IV did not survive for more than 2 years.CONCLUSIONS: No-touch pancreatectomy has many theoretic advantages that merit further investigation in future randomized controlled trials.


Hashimoto D.,Kumamoto Regional Medical Center | Hirota M.,Kumamoto Regional Medical Center | Yagi Y.,Kumamoto Regional Medical Center | Baba H.,Kumamoto University
Surgery Today | Year: 2012

Purpose Hyaluronate carboxymethylcellulose-based bioresorbable membrane (HC membrane; Seprafilm) is used to prevent postoperative adhesion. We conducted this study to assess the effectiveness of the HC membrane in reducing the severity of adhesions in patients undergoing unplanned re-laparotomy. Methods Between February, 2002 and December, 2010, 123 patients underwent abdominal surgery followed by a re-laparotomy in Kumamoto Regional Medical Center. The HC membrane was placed under the first abdominal incision in 60 patients (HC membrane group), whereas it was not used in the other 63 patients (control group). We compared the medical and operative records of these two groups. Results At the second laparotomy, adhesion under the incision was severe in many of the control group patients, but was significantly reduced in the HC membrane group. Postoperative small-bowel obstruction was significantly less frequent in the HC membrane group. According to univariate analysis of the risk factors for adhesion, prolonged operation time, blood loss, and not using an HC membrane were significantly associated with severe adhesion. Multivariate analysis revealed that only not using the HC membrane was significant. Conclusion The HC membrane effectively reduces the severity of wound adhesion, making unplanned repeated laparotomy safer. © Springer 2012.


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.


Hirota M.,Kumamoto Regional Medical Center | Ogawa M.,Kaizuka City Hospital
Journal of the Pancreas | Year: 2014

Background Pancreatectomy is the only effective treatment for cancers of the pancreas. Surgeons usually grasp tumors during pancreatectomy, however, this procedure may increase the risk of squeezing and shedding of the cancer cells into the portal vein, retroperitoneum, and/or peritoneal cavity. In an effort to overcome these problems, we have developed surgical techniques for no-touch pancreatectomy. Methods From April 2008 through September 2013, 52 patients have been operated on no-touch pancreatectomy for invasive ductal carcinoma of the pancreas by a single operator (M.H.). Among them, 40 received pancreatoduodenectomy (PD), and 12 did distal pancreatectomy (DP). Twenty two cases (42%) required SMV-PV resection. This is a study to see if pancreatectomy can be technically done using a no-touch surgical technique without deteriorating the post-operative prognosis. During the procedure, the pancreatic tumor is neither grasped nor squeezed by the surgeon. Furthermore, for improved dissection of the retroperitoneal tissue (leftward and posterior margins for PD and rightward and posterior margins for DP), we use a hanging and clamping maneuver and dissection behind Gerota fascia. Results Overall 2- and 5-year survival rates were 64 and 42% with mean follow-up periods of 34.4 months (range: 6-68 months). Recurrence free 2- and 5-year survival rates were 49 and 31%, respectively. The 5-year survival rates of patients with JPS-stage III and those with JPS-stage IV were 57 and 20%, respectively. The 5-year survival rates of patients with UICC-stage IIA and those with UICCstage IIB were 49 and 39%, respectively. Patients with UICC-stage III or IV did not survive for more than 2 years. Conclusions No-touch pancreatectomy has many theoretic advantages that merit further investigation in future randomized controlled trials.

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