| 1.
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Itabashi, Yukihiro ; Baba, Toshiaki ; Kato, Satoru ; Hakamada, Kenichi
概要:
Forty patients with an average age of 64.6 years （range: 45-83） with early gastric cancer of cT1 （M,SM） underwent a cur
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ative-intended laparoscopy-assisted distal gastrectomy （LADG） where laparoscopic D1+αnodal clearance and extra-abdominal Billroth-I stapled anastomosis were performed. There was no conversionto open gastrectomy. The operation time for the 40 cases ranged 150 - 482 min （median: 285）, while that for thelatest 10 cases reduced to 154-278 min （median: 216）. The length of hospital stay of the patients varied 10-85 days（median: 17）. Postoperative complications encountered were anastomosis-related: 2 anastomotic bleeding and 2anastomotic passage disturbance（ 1 stricture and 1 temporary stenosis） occurred but no dehiscence. Four inaccuratepreoperative diagnoses of tumor invasion depth were revealed by postoperative pathology of the resected specimens.Thereafter the accuracy in the preoperative diagnosis was highly enhanced with implementation of endoscopicultrasound. Recurrence occurred in one patient with pT2（ SS） pN2, who died of pleural carcinomatosis 4 years and 3months after surgery. As the reduced operation time in LADG came closer to that in open distal gastrectomy, we will continuethis procedure for early gastric cancer. For this, the importance of an accurate preoperative diagnosis can’t beoveremphasized.
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| 2.
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Nodagashira, Tatsuya ; Odagiri, Hiroki ; Ikenaga, Shojiro-Kazunori ; Maruyama, Masateru ; Sato, Toshiyuki ; Hakamada, Kenichi
概要:
Tissue-specifi c promoter has been used for cancer-specifi c suicide gene therapy, but its transcriptionalactivity is r
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elatively low. For more effi cient gene therapy of HER2-expressing tumor, a double adenovirus infectionsystem was established, in which a ‘regulator’ vector carried Cre gene under the control of HER2 promoter and ‘target’vectors carried target genes activated by Cre. We constructed a Cre recombinase expression vector, AxHER2Cre, forthe ‘regulator’ vector. By the combination of this vector and AxCALNLZ, β-D-galactosidase was induced in 90% and70% of MKN7 and MDA-MB-453, HER2‒overexpressing cell lines, but only about 20% and 10% of MKN28 and MCF7,low HER2-expressing cell lines. By the quantifi cation analysis, the β-galactosidase activities induced by this systemwere comparable to those by the combination of AxCANCre and AxCALNLZ. These results indicated that Cre/loxP system under the regulation of HER2 promoter could induce effi cient gene expression, maintaining the HER2-expression specifi city. Breast cancer with HER2 overexpression is treated with trastuzumab. However, refractoryor resitance of HER2 positive breast cancer against trastuzumab becomes a severe clinical problem, recently. Thissystem seemed to be another therapeutic option.
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| 3.
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Maruyama, Masateru ; Odagiri, Hiroki ; Ikenaga, Shojiro-Kazunori ; Nodagashira, Tatsuya ; Sato, Toshiyuki ; Hakamada, Kenichi ; Munakata, Hirofumi
概要:
We examined the therapeutic efficacy for the suicide gene introduction using two recombinant adenovirusvectors with HER2
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promoter and Cre/loxP system in human gastric cancer cell lines, MKN-7 and MKN-28. HER2protein level was more expressed in MKN-7 than in MKN-28. Next, we constructed a Cre recombinae expressionvector in HER2-producing cell specifically, AxHER2NCre and AxCALNCD expressing cytosine deaminase （CD）gene under the control of the CAG promoter by the Cre switching system. Much higher CD messenger RNA （CDmRNA） and CD protein expression were induced in cells by the double infection method than by AxCALNCD only.Furthermore, CD mRNA and CD protein expression were induced higher in HER2-overexpressing cell line, MKN-7 than in MKN-28. We examined the efficacy of cell growth inhibition using 5-fluorocytosine （5-FC） as anti-tumorprodrug. Inhibition effect was dose-dependent at each cell line and rate was more in MKN-7 in comparison withMKN-28. This system can be applied for HER2-overexpressing cancer specific gene therapy.
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| 4.
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Sashinami, Hiroshi ; Hu, Dong-Liang ; Li, Sheng-Jun ; Mitsui, Toshihito ; Hakamada, Kenichi ; Ishiguro, Yoh ; Fukuda, Shinsaku ; Nakane, Akio
概要:
We investigated the eff ect of p60 that is one of virulence factors of Listeria monocytogenes on host immune response in
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vitro and in vivo. C57BL/6 mice immunized with p60 showed antigen-specifi c T-helper I type immune response. Mouse macrophage RAW264.7 cells produced tumor necrosis factor alpha （TNF-α）, interleukin-12 and interferon beta （IFN-β） in response to stimulation with recombinant p60. Administration of p60 prior to a sublethal infection with L. monocytogenes enhanced innate host resistance in naïve mice. TNF-α and IFN-β production from RAW264.7 cells and bone marrow-derived macrophages were Toll-like receptor 4 （TLR4）-dependent. The enhanced clearance of L. monocytogenes by p60 administration was not shown in C3H/HeJ mice. Our fi ndings demonstrated that p60 enhances host resistance against L. monocytngenes infection through both activation and attenuation of host innate immune response in the TLR4-dependent manner.
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| 5.
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Hasebe, Tatsuya ; Umeda, Takashi ; Danjo, Kazuma ; Takahashi, Ippei ; Matsuzaka, Masashi ; Kudo, Junko ; Sematoo, Mariko ; Saito, Yuriko ; Hisada, Takayoshi ; Benno, Yoshimi ; Nakaji, Shigeyuki ; Hakamada, Kenichi
概要:
Background and aim: The aim of this study is to investigate the relationship between methane production and gut microbio
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ta in a general population. Methods: Total of 697 subjects（58±13 years, 261 men and 436 women）have participated in this study. Their breath methane and hydrogen concentration were measured after an overnight fasting using gas chromatography,and their gut bacterial component was analyzed using T-RFLP（Terminal restriction fragment length polymorphism）method. All gut microbiota were divided into 28 operational taxonomic units（OTUs）according to its predominant bacterial groups. The breath methane concentration of above 10ppm and breath hydrogen concentration of above20ppm were considered positive. Subjects were divided into four groups;（1）Both negative: both methane and hydrogen were negative（2）CH₄only: only methane was positive（3）H₂only: only hydrogen was positive（4）Both positive: both hydrogen and methane were positive Results: OTU317（Prevotella）was significantly higher in CH₄only than both negative and H₂only. And OTU940（Clostridium subcluster XIVa and Enterobacteriales）was significantly lower in CH₄only than both negative and H₂only.Conclusions: OTU317 and OTU940 might affect the bacterial metabolism of methanogens.
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| 6.
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Morohashi, Hajime ; Murata, Akihiko ; Koyama, Motoi ; Sakamoto, Yoshiyuki ; Tsutsumi, shinji ; Yonaiyama, Shinnosuke ; Ogasawara, Hiroshi ; Yoshikawa, Toru ; Muroya, Takahiro ; Nakai, Makoto ; Ishido, Keinosuke ; Wajima, Naoki ; Hakamada, Kenichi
概要:
Introduction: The employment of laparoscopic resection for the treatment of colorectal cancer has beenexpanding rapidly.
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However, its indication is still on debate. We have been actively employing laparoscope-assisted colectomy （LAC） for patients with early colorectal cancer. Here we retrospectively review the 71 cases of early colorectal cancer treated with LAC and analyzed the initial institutional surgical outcome.Results: LAC was indicated as an additional surgical resection after endoscopic treatment in 27 cases, while it was employed as a definitive non-endoscopic treatment in 44 cases. Mean operative time was 163 min, and mean blood loss was 57 ml. Complications were encountered in 8 cases（ 11.3%）. Advanced lesions invading to the muscularis propria or the serosa were more included in the group initially treated with LAC alone（ p=0.04）. The reasons for additional LAC were the depth of submucosal invasion >1000 μm in 15 cases and lymphatic or microvascular invasion in 5 cases. Lymph node metastases were detected pathologically in 9 patients, in which one suffered relapse after surgery.Conclusion: Implementation of LAC for early colorectal cancer seems an acceptable strategy in terms of bothradicality and less invasiveness. Cooperation between endoscopists and laparoscopic surgeons is important to apply LAC appropriately for colorectal cancer.
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| 7.
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Wajima, Naoki ; Morohashi, Hajime ; Watanabe, Nobukazu ; Nakai, Makoto ; Miyamoto, Keiichi ; Kawasaki, Hitoshi ; Yonaiyama, Shinnosuke ; Ogasawara, Hiroshi ; Yoshikawa, Toru ; Muroya, Takahiro ; Yakoshi, Yuta ; Ishido, Keinosuke ; Sakamoto, Yoshiyuki ; Koyama, Motoi ; Murata, Akihiko ; Ohishi, Susumu ; Tateoka, Hiroshi ; Hakamada, Kenichi
概要:
INTRODUCTION: Pylorus-preserving gastrectomy （PPG）, which had been developed in 1960s, has been reappraised for years an
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d now accepted as a type of function-preserving compared with those of laparoscopy- ssisted distal gastrectomy （LADG）, which does not preserve the pylorus and involves resection of the suprapyloric lymph nodes.METHODS: Ninety six patients diagnosed as having gastric cancer of cT1N0 underwent either LADG （n=66） or LAPPG （n=30）. The patient demographics and the early surgical outcomes were evaluated retrospectively. The quality of lymph node dissection in LAPPG was also assessed pathologically.RESULTS: Among 96 patients preoperatively diagnosed as cT1, pT1 was 88 cases and pT2 in 8, 91.7 % of diagnostic accuracy. There were no differences in patient demographics, operative time, blood loss, the number of dissected lymph nodes, postoperative morbidity and length of hospitalization. Pathologically, the number of dissected lymph nodes at No. 3, 4, 6 were equal between the two groups. Among our LADG cases, 35（ 53%） were lesions confined to the mucosa with a distance between the pylorus and the anal margin of the tumor <4 cm.CONCLUSIONS: Our initial experience suggests that LAPPG can be performed with acceptable quality of lymph node dissection and early surgical outcome. Because LAPPG was thought to be applied for about a half of our LADG cases according to the new guideline, LAPPG is expected to be indicated for more cases with early gastric cancer as a function-preserving limited surgery.
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| 8.
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Narumi, Shunji ; Murakami, Reiichi ; Hatakeyama, Shingo ; Fujita, Tadashi ; Koie, Takuya ; Yoneyama, Takahiro ; Kudo, Shigemasa ; Kamimura, Noritaka ; Mori, Kazuyuki ; Shimada, Michiko ; Nakamura, Norio ; Umehara, Minoru ; Saito, Hisao ; Okumura, Ken ; Hakamada, Kenichi ; Ohyama, Chikara
概要:
Introduction Kidney transplantation has been widely accepted as a definitive therapy for patients with renal failure. Th
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e Hirosaki Kidney Transplant Unit was organized in June 2006 in conjunction with the Departments of Urology, Cardiology, Respiratory Medicine and Nephrology, and Gastrointestinal Surgery, from the Hirosaki University School of Medicine. Herein, we introduce our current results and discuss our future strategies. Patients and Methods From June 2006 to December 2011, 36 kidney transplants were performed with 31 living donors and 5 deceased donors. Immunosuppression therapy included an inductor treatment of anti-CD25 antibody andtriple therapy with calcineurin inhibitor, mycophenolate mofetil, and steroids. Results Recipients included 25 males and 11 females. The patients’ average age was 41.8 years. Nine living–pairs were ABO incompatible. Deceased donors were performed at Oyokyo Hospital. Median follow-up period was 27.6 months. Acute cellular rejection occurred in 8.3% of patients. Positive antigenemia for cytomegalovirus happened in 16.7% of patients, but none developed invasive diseases. All recipients are currently surviving. Graft survival rates at 1, 3, and 5 years are 100%, 94.7%, and 94.7%, respectively. Conclusion Successful kidney transplantations have been performed by a multidisciplinary unit at Hirosaki University. Our next step is a promotion to increase organ donation.
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| 9.
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Shibutani, Koichi ; Tsushima, Fumiyasu ; Kakehata, Shinya ; Miura, Hiroyuki ; Ono, Shuichi ; Seino, Hiroko ; Kakuta, Akihisa ; Tokuda, Toshihide ; Toyoki, Yoshikazu ; Hakamada, Kenichi ; Takai, Yoshihiro
概要:
Purpose: To evaluate the clinical efficacy and safety of preoperative percutaneous transhepatic portal vein embolization
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（PVE） with an ipsilateral approach, using microfibrillar collagen（MFC） as an embolic material for carcinomas of the biliary tract and liver metastases of colorectal carcinoma. Materials and methods: PVE using MFC was performed in 35 consecutive patients（ 29 men and 6 women; mean age 64 years, range 44–81 years） with small estimated future liver remnants （FLRs） after planned major hepatectomy. Patient malignancies included bile duct carcinoma（ n = 20）, gallbladder carcinoma（ n = 5）, and metastases of colorectal carcinoma （n = 8）. In one patient preoperatively diagnosed with gallbladder carcinoma, the pathological diagnosis of xanthogranulomatous cholecystitis was confirmed after resection. PVE was performed with ultrasound guidance （ipsilateral approach, 35; contralateral approach, 1）. Total liver volume （TLV） and FLR changes, hypertrophy ratio before and after PVE, and procedure-related complications were analyzed retrospectively. Results: PVE was successful in all patients. There were no major procedure-related complications. Mean absolute FLR volume increased significantly（ p < 0.001） from 434 to 524 cm3, as did the standardized FLR to TLV ratio（ p < 0.001）, from a mean of 37.9% to 46.1%. The mean ratio of standardized FLR increase was 8.2%. The hypertrophy ratio was 23%. In the group receiving selective embolization in a centripetal direction, the increase in FLR/TLV ratio was 9.5%, while the hypertrophy ratio was 27%. Neither puncture-related complications nor deterioration of liver function were observed. Conclusion: MFC was a safe and effective embolic material for preoperative PVE in patients with hepatobiliary malignancies, resulting in sufficient hypertrophy of FLRs.
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| 10.
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Kubo, Norihito ; Narumi, Shunji ; Hakamada, Kenichi ; Nakane, Akio
概要:
Stem cell therapy is one of the remarkable treatments for fatal diseases. Mesenchymal stem cells （MSCs） are adult stem c
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ells and detected in various tissues such as bone marrow, umbilical cord blood and adipose tissue. MSCs have some abilities to differentiate into multi-lineage mature cells, modify immune responses and play a role for tissue repairing. The purpose of the present study was to investigate the effect of adipose tissuederived mesenchymal stem cells（ ASCs） against fulminant hepatitis, a life threatening liver injury due to massive destruction of hepatocytes. BALB/c mice were sacrificed and adipose tissues were harvested. ASCs were purified from the tissues and confirmed by characterization of cell surface markers and induction of differentiation into multi-lineage mature cells. Concanavalin A （ConA）, a protein of jackbean, can induce fulminant hepatitis for mice. BALB/c mice were administered lethal or sublethal dose of ConA intravenously and treated by ASCs, phosphate buffered saline（ PBS） or splenocytes （SPLCs）. The survival rates, liver enzymes, cytokines, histopathological changes and localization of ASCs were investigated. ASCs could increase the survival rates, inhibit elevation of liver enzymes and cytokines, and attenuate necroses of hepatocytes compared to PBS or SPLCs. Fluorescent stained ASCs were detected in inflammatory liver, but not in normal liver. These findings suggest that ASCs have an ability to improve or attenuate fulminant hepatitis.
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| 11.
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Miura, Takuya ; Kimura, Norihisa ; Yamada, Toshiyuki ; Shimizu, Takeshi ; Nanashima, Naoki ; Yamana, Daisuke ; Hakamada, Kenichi ; Tsuchida, Shigeki
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Background/Aims: To clarify the mechanism of persistent cholestasis after massive hepatectomy, the relationship between
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such cholestasis and the expression and localization of organic anion transporters for bile acids was examined in a rat model.Methods: Male Sprague-Dawley rats were subjected to 90% hepatectomy, and tissues were harvested on 0, 1, 3, and 7 days for microarray analysis, the quantitative real-time polymerase chain reaction （RT-PCR）, Western blotting and immunohistochemistry to examine the expression of multidrug resistance protein 4 （Mrp4）, bile salt export pump（ Bsep） and sodium-dependent taurocholate cotransporting polypeptide（ Ntcp）.Results: Persistently elevated serum bile acids were observed on days 3 and 7. RT-PCR and Western blotting indicated that the expression of Mrp4, a bile acid export pump located in the basolateral membrane, was increased on day 3. Ntcp, a transporter used to uptake bile acids from the sinusoids, was significantly decreased throughout the period. Bsep, an export pump localized to the canalicular membrane, was unchanged. Immunohistochemistry revealed the localization of Mrp4 and Bsep in the basolateral and canalicular membranes, respectively. On the other hand, Ntcp was localized in the cytoplasm on days 3 and 7 and was hardly detected in the basolateral membrane.Conclusions: These results suggested that the sustained repression and translocation of Ntcp and the expression of Mrp4 at the basolateral membrane seemed to be responsible for the high blood bile acids levels after massive hepatectomy.
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| 12.
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Narumi, Shunji ; Umehara, Minoru ; Toyoki, Yoshikazu ; Ishido, Keinosuke ; Kudo, Daisuke ; Kimura, Norihisa ; Mori, Kazuyuki ; Ohyama, Chikara ; Hakamada, Kenichi
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［Introduction］In liver transplant, antibody mediated rejection is believed to occur less frequently and to lead less gra
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ft losses than in kidney transplant. So, liver transplant has been performed irrespective of positive lymphocyte crossmatch test. Nowadays, even in kidney transplant, both ABO incompatibility and cross-match positivity are being overcome with plasmapheresis, intravenous immunoglobulin, and improvement of immunosuppressive agents such as rituximab and IL-2 receptor antagonists. Retrospective analysis on living donor liver transplant recipient was performed focusing on cross-match positivity and posttransplant complications.［Patients and methods］Since 1994, 41 living-donor liver transplants were performed. Retrospective analysis was done in 33 patients, who were done pretransplant cross-match test. Immunosuppression was basically initiated with steroid and tacrolimus.［Results］Twelve patients （36.3%） were positive for lymphocyte cross-match. Acute rejection occurred in 13 cases（33.3％） within 180 post transplant days. One-year rejection-free survival were 42.3% in positive cases and 72.2% in negative cases （p<0.05）, but there was no significance in patient survival. Posttransplant complications including biliary stenosis, hepatic vein stenosis, and portal vein stenosis occurred more frequently in positive lymphocyte crossmatch transplant patietns（p<0.05）.［Conclusion］With improvement of immunosuppressive agents, liver transplant can be successfully performed with more favorable survival even in cross-match positive pair. Complications, however, happen more frequently in those recipients compared to cross-match negative ones. Posttransplant course should be carefully followed focusing on biliary and vascular complications. Screening of donor specific antigen by FACS cross-match test and LABScreen® would give us new information and strategy.
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| 13.
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Umehara, Minoru ; Narumi, Shunji ; Sugai, Michihiro ; Toyoki, Yoshikazu ; Ishido, Keinosuke ; Kudo, Daisuke ; Kimura, Norihisa ; Kobayashi, Tamotsu ; Hakamada, Kenichi
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Introduction We never knew how the liver function goes after splenectomy in case of huge splenomegaly because of the dramatic portal flow alteration. In this report, we will present a case of cryptogenic liver cirrhosis with huge
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splenomegaly.Case presentation A 14 years old male was admitted with huge splenemogaly and hepatomegaly. Computed tomography showed enlarged liver and huge spleen that occupied large volume of abdominal and pelvic cavity. His ADL was significantly deteriorated, and the patient could not stand up because of exertional dyspnea. Although the etiology of the patient was not determined in spite of several liver biopsies and laboratorial tests, we planned splenectomy to improve his ADL. Also, the progression of liver insufficiency was expected because the portal flow could be dramatically changed after the removal of the huge spleen. Therefore, we prepared for the living donor liver transplantation at first, and then splenectomy was performed. After the first operation, his general condition was improved and the liver function was not deteriorated for 6 months. Unfortunately, rapid progression of jaundice from his primary disease was occurred, and living donor liver transplantation using left lobe graft from his mother was performed 4 months later. The patient survived the two-stage liver transplantation procedure without major complications.Conclusion Our case suggests that we should consider the possibility of liver deterioration after splenectomy for the huge splenomegaly. In case of rapid deterioration of liver function, liver transplantation is the only feasible option.
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| 14.
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Sato, Orie ; Osanai, Yumiko ; Urushidate, Chie ; Yamaguchi, Tomoko ; Narumi, Shunji ; Umehara, Minoru ; Toyoki, Yoshikazu ; Sugai, Michihiro ; Hakamada, Kenichi ; Kimura, Toshiko
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［Introduction］ Liver transplant recipients suffer more complications than do patients undergoing other gastroenterologic
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al surgeries. Many factors inhibit ambulation in liver transplant patients, such as the level of restriction to bed rest and length of stay in the intensive care unit（ ICU）. Patients thus face ambulation difficulties. Support for ambulation is one of the major daily tasks of nurses. We reviewed the ambulation situations of patients who underwent living donor liver transplantation to investigate factors that contributed to ambulation and the nurse’s role therein.［Patients］ Ten recipients underwent living donor liver transplantation in our hospital between April 2009 and December 2010. Records of the 8 patients who survived were evaluated for this study.［Result］ According to the postoperative day of initiation of independent walking in the hospital ward, there were no significance difference among operation time, intraoperative bleeding, length of stay in ICU, bed rest level, complications, and rehabilitation intervention. However, the patients who received preoperative guidance were more highly motivated about ambulation than were patients who did not receive preoperative guidance.［Discussion］ Although initiation of independent walking in the hospital ward differed depending on the patient's general status, it was found that volition is also a strong factor in patient ambulation. Preoperative orientation helps patients to understand perioperative management and clinical course. Moreover, it is necessary to share information with the rehabilitation team and to assist in the activities of daily living for early ambulation.
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Kobayashi, Tamotsu ; Sugai, Michihiro ; Mori, Fumiaki ; Wakabayashi, Koichi ; Hakamada, Kenichi
概要:
ulmonary hypoplasia influences prognosis in congenital diaphragmatic hernia （CDH）. However, the abnormality of pulmonary
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innervation is not clearly understood. We immunohistochemically examined the lungs of CDH model rats, with special reference to sympathetic innervation. Pregnant rats were received nitrofen on gestational day 9 and the fetuses were recovered on gestational day 22. Control animals received only olive oil. Fetal lungs were dissected and the weight was measured. Whole mount sections at the level of main bronchus were immunostained using anti-tyrosine hydroxylase （TH） antibody as a sympathetic marker. The proportion of area of TH-immunoreactive nerve fi bers relative to the total lung area was calculated. The mean lung weight of CDH aff ected side was signifi cantly lower than that of ipsilateral side of controls. The percentage of TH-positive area of CDH affected side was significantly lower than that of unaffected side. The reduction of pulmonary sympathetic innervation may play an important role in respiratory morbidity in CDH.
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| 16.
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Yakoshi, Yuta ; Kudo, Daisuke ; Toyoki, Yoshikazu ; Ishido, Keinosuke ; Kimura, Norihisa ; Wakiya, Taiichi ; Sakuraba, Shingo ; Yoshizawa, Tadashi ; Sakamoto, Yoshiyuki ; Kijima, Hiroshi ; Hakamada, Kenichi
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Aim: Hepatic steatosis is a major cause of steatohepatitis and is observed in several diffuse liver diseases. We studied
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the efficacy of a novel ultrasound application, acoustic structure quantification （ASQ）, for analyzing the amount of fat deposition in the liver parenchyma. Methods: Forty-three patients who received a hepatectomy at our institution participated in this study. An ultrasound machine equipped with a software application for ASQ was used to detect steatosis prior to surgery. Non-tumoral liver parenchyma obtained by hepatectomy was pathologically evaluated according to the three-grade system. Results: Histopathologically, twenty-three patients did not present steatosis, seventeen presented grade 1, and the remaining three presented grade 2 steatosis. The median “focal disturbance ratio”（ FD-ratio）, a representative index obtained by ASQ, decreased with the steatosis grade, from 0.157（ range: 0.039-0.410） at steatosis grade 0, 0.085（ range: 0.021-0.159） at steatosis grade 1, and 0.039（ range: 0.021-0.048） at steatosis grade 2. There were significant differences in the FD-ratio between steatosis grades 0 and 1 and between steatosis grades 0 and 2 （p = 0.001 and p = 0.007, respectively）.Conclusions: ASQ can be useful during a quantitative examination of the fat accumulation in the liver parenchyma and offers a reliable marker for the early detection of liver injury.
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| 17.
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Sakuraba, Shingo ; Morohashi, Satoko ; Yoshizawa, Tadashi ; Tsutsumi, shinji ; Kimura, Norihisa ; Kudo, Daisuke ; Ishido, Keinosuke ; Toyoki, Yoshikazu ; Hakamada, Kenichi ; Kijima, Hiroshi
概要:
Both pancreas head ductal carcinoma（ PHDC） and distal bile duct carcinoma（ DBDC） are located within the pancreas head/in
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tra-pancreatic bile duct region, and are the most aggressive malignancies with poor patient prognosis. In the present study, we demonstrated clinicopathological features and patients prognosis of PHDC/DBDC. We examined total 87 surgically resected cases of PHDC （40 cases） and DBDC （47 cases）. PHDC showed frequent neural invasion （85.0%） and lymph node metastasis （77.5%）, compared with DBDC （57.4% and 40.4% respectively）, resulting in the poorer prognosis（ P=0.0219） than DBDC. In addition, PHDC expressed MUC2（ 10.0%）and MUC6 （25.0%） less frequently, compared with DBDC （36.2% and 55.3%, respectively）. MUC5AC-negative PHDC exhibited significantly poorer patient’s prognosis, compared with MUC5AC-positive PHDC （P=0.0111）, MUC5ACpositive DBDC （P=0.000162）, and MUC5AC-negative DBDC （P=0.00416）. In conclusion, MUC5AC-negative PHDC showed significantly poor patient’s prognosis.
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| 18.
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Morohashi, Hajime ; Sakamoto, Yoshiyuki ; Ichinohe, Daichi ; Jin, Hiroyuki ; Sato, Kentaro ; Yoshida, Tatsuya ; Miura, Takuya ; Akasaka, Harue ; Nagase, Hayato ; Okano, Kensuke ; Yoshida, Eri ; Aoki, Kazunori ; Watanabe, Nobukazu ; Takahashi, Seiji ; Hakamada, Kenichi
概要:
Backgroud: In Japan, the recommended standard surgical procedure for advanced lower rectal cancerincludes total mesorect
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al excision （TME） plus central D3 lymph node dissection and bilateral lateral lymph nodedissection （LLND）. Laparoscopic LLND is performed in the pelvis, which is an anatomically complex and smalloperative field and thus, requires an extremely high level of skill. Laparoscopic LLND has been introduced followingthe recent expansion in the application of laparoscopic surgery for advanced lower rectal cancer.Patients and methods: The subject sample comprised 79 patients who underwent lateral dissection, including 61patients who underwent laparotomic lateral dissection and 18 patients who underwent laparoscopic lateral dissection.Clinical characteristics and the oncological outcome were compared between groups.Results: The mean surgical duration in the laparoscopy group was 285 min, which was significantly longer than the165 min in the laparotomy group（ p < 0.001）. The mean blood loss amount was 131 g in the laparoscopy group, whichwas significantly less than the mean amount of 407 g in the laparotomy group （p < 0.001） There was no significantdifference in complications.Conclusion: The short-term outcomes of laparoscopic LLND were good, indicating that the procedure can be performed safely and is likely to be useful.
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| 19.
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Morohashi, Satoko ; Morohashi, Hajime ; Yoshizawa, Tadashi ; Tanaka, Masanori ; Mikami, Tatsuya ; Kagiya, Takuji ; Saito, Takeshi ; Hirai, Hideaki ; Haga, Toshihiro ; Wu, Yunyan ; Hakamada, Kenichi ; Kijima, Hiroshi
概要:
There are no reports on the degree of inflammation in the residual rectal mucosa inasymptomatic UC patients after an ope
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ration for ileal pouch anal canal anastomosis（ IACA）.Methods: We studied the residual rectal mucosal biopsies and rectal mucosa from the surgical specimens of 12asymptomatic postoperative UC cases. We analyzed the degree of inflammation, including crypt architecture andmucus content in the rectal mucosa.Results: Two pathological active cases （16.7%）, four resolving cases （33.3%）, and six remission cases （50%） wereobserved in the residual rectal mucosa. In terms of the degree of pathological inflammation in the residual rectalmucosa, one case （1/12, 8.3%） was upregulated, seven cases （7/12, 58.3%） were stable, and four cases （4/12, 33.3%）were downregulated compared with the rectal mucosa of the surgical specimens.Conclusions: We determined the natural history of the degree of inflammation on the residual rectal mucosa inpostoperative UC patients. Eight cases （8/12, 66.6%） of asymptomatic UC patients were associated with prolongedinflammation after an IACA operation in the residual rectal mucosa compared with that in the rectal mucosa of thesurgical specimens. Therefore, we could identify patients with prolonged inflammation in asymptomatic UC cases by a residual rectal mucosal biopsy.
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| 20.
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Hashimoto, Naoki ; Narumi, Shunji ; Itabashi, Yukihiro ; Hakamada, Kenichi ; Sasaki, Mutsuo
概要:
Background: We previously demonstrated that a high level of chimerism was induced by low dose of bone marrow cells (BMCs
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) combined with splenocytes (SPLCs), while the same dose of BMCs alone was insufficient for tolerance induction. In the present study, we investigated whether stable mixed chimerism and donor specific tolerance could be established in sublethally irradiated mice following intravenous injection of various dosages of fully allogeneic peripheral blood stem cells (PBSCs). In addition, validity of combination of donor splenocytes in the peripheral blood stem cell transplantation (PBSCT) as well as in bone marrow transplantation for tolerance induction were examined. Methods: Sublethally irradiated C57BL/6 recipient mice were injected 10×10^6 PBSCs mixed with various numbers of granulocyte-colony-stimulating factor (G-CSF)-mobilized SPLCs harvested from BALB/c donor mice. Three months later, the degree of chimerism in peripheral blood lymphocytes and in SPLCs was examined by FACS analysis. Mixed lymphocyte responses (MLR) and skin grafting were performed to confirm donor-specific tolerance. Results: Recipients receiving 10×10^6 PBSCs mixed with 30×10^6 G-CSF-mobilized SPLCs showed a higher level of chimerism. High percentage chimeric mice all showed donor specific tolerance in vitro, MLR and in vivo, and skin grafting. Conclusions: PBSCT mixed with SPLCs was proven to be useful for induction of donor-specific tolerance. Admixture of SPLCs reduces the amount of PBSCs needed for induction of tolerance.
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| 21.
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Kudo, Daisuke ; Suto, Akiko ; Hakamada, Kenichi
概要:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to
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intervention is currently considered to be caused by the desmoplastic change of the extracellular matrix (ECM) in PDAC tissues, which is characterized by the accumulation of cancer-associated fibroblasts, collagen, proteoglycan, and hyaluronan. Among these ECM components, hyaluronan has attracted interest because various studies have indicated that hyaluronan-rich PDAC is correlated with the progressive properties of cancer cells, both in experimental and clinical settings. Hence, the reduction of hyaluronan in cancer tissue may represent a novel therapeutic approach for PDAC. 4-methylumbelliferone (4-MU) is a derivative of coumarin that was reported to suppress the synthesis of hyaluronan in cultured human skin fibroblasts in 1995. As an additional study, our group firstly reported that 4-MU reduced the hyaluronan synthesis of mouse melanoma cells and exerted anti-cancer activity. Subsequently, we have showed that 4-MU inhibited liver metastasis in mice inoculated with human pancreatic cancer cells. Thereafter, 4-MU has been accepted as an effective agent for hyaluronan research and is expected to have clinical applications. This review provides an overview of the interaction between PDAC and hyaluronan, the properties of 4-MU as a suppressor of the synthesis of hyaluronan, and the perspectives of PDAC treatment targeting hyaluronan.
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| 22.
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Yoshizawa, Tadashi ; Ishido, Keinosuke ; Saitou, Kensuke ; Haga, Toshihiro ; Seino, Hiroko ; Wu, Yunyan ; Morohashi, Satoko ; Hakamada, Kenichi ; Kijima, Hiroshi
概要:
Extrahepatic bile duct carcinoma is a potentially malignant gastrointestinal lesion. Cancer cells spread via the lymphatic system to regional lymph nodes and help in tumor progression. However, there are no reports on the prognostic
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impact of extracapsular lymph node invasion and myofibroblastic activity in this cancer. Hence, we classified the histopathologic patterns of lymph nodes into 2 patterns: extracapsular lymph node invasion or not. Based on this, we investigated 32 cases of extrahepatic bile duct cancer with lymph node metastasis and classified 21 cases as positive and 11 cases as negative. The extracapsular lymph node invasion cases were associated with poor disease-free survival and overall survival. The myofibroblast density of the metastatic foci was significantly higher in the extracapsular lymph node invasion cases. This is the first study to demonstrate that extracapsular lymph node invasion cases were associated with poor prognosis and that the myofibroblast distribution contributed to malignancy.
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| 23.
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Kimura, Toshiro ; Imaizumi, Tadaatsu ; Yoshida, Tatsuya ; Shimada, Taku ; Hayakari, Ryo ; Kawaguchi, Shogo ; Yoshida, Hidemi ; Kobayashi, Tamotsu ; Hirabayashi, Takeshi ; Mizukami, Hiroki ; Kijima, Hiroshi ; Hakamada, Kenichi
概要:
Purpose: Retinoic acid-inducible gene-I （RIG-I） is a member of cytoplasmic viral sensors which plays an important role i
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n inflammation of biliary epithelial cells（ BECs）. The aim of this study is to examine if RIG-I and C-X-C motif chemokine 10（ CXCL10） are involved in the etiology of human biliary atresia（ BA）.Methods: Immunohistochemical study was performed on surgically resected tissues obtained（ June 1994 to March 2016）from 30 infants with BA and non-inflamed hepatic tissues from 7 infants with hepatoblastoma. A semiquantitative scoring system was designed to evaluate the staining with an antibodies to the RIG-I and CXCL10. The expression of RIG-I and CXCL10 in HuCCT1 cholangiocarcinoma cell line were studied by western blotting, ELISA and RT-PCR analyses.Results: Intense immunoreactivity for RIG-I and CXCL10 was detected in BECs in tissues resected from BA patients.The expression of RIG-I and CXCL10 in the hilar tissue was significantly stronger than in the hepatic tissue.Transfection of HuCCT1 cells with poly（I:C）, a synthetic analog of viral dsRNA, induced the expression of RIG-I, and knockdown of RIG-I inhibited the induction of CXCL10 in HuCCT1 cells transfected with poly（I:C）.Conclusion: These results suggest that RIG-I-CXCL10 cascade may be involved in the etiology of human BA.
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| 24.
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Saito, Kensuke ; Yoshizawa, Tadashi ; Morohashi, Satoko ; Seino, Hiroko ; Goto, Shintaro ; Muroya, Takahiro ; Yokoyama, Hiroshi ; Yoshida, Eri ; Miura, Hiroyuki ; Yu, Chen ; Kijima, Hiroshi ; Kakeda, Shingo ; Hakamada, Kenichi ; Sato, Atsushi
概要:
Background: Positron emission tomography（PET） is the standard method for metabolic and quantitative evaluation of therap
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eutic response to chemotherapy in solid tumors. This study determined the ability of PET parameters used in combination in predicting recurrence-free survival（RFS）after neoadjuvant chemotherapy （NAC）and operation for esophageal cancer.Methods: This single-center retrospective study included 96 patients who underwent 18F-fluorodeoxyglucose-PET/computed tomography before and after NAC. Maximum standardised uptake value（SUVmax）after NAC and the rate of change in SUVmax following NAC（ΔSUVmax）were determined to examine their relationship with postoperative recurrence and clinicopathological factors.Results: Receiver operating characteristic curves, with recurrence after NAC as the event, were used to determine optimal cut-off SUVmax and ΔSUVmax of 6.8 and 45.7, respectively. Using these cut-off values, the patients were classified into four groups: Group A, SUVmax > 6.8 and ΔSUVmax ≤ 45.7; Group B, SUVmax > 6.8 and ΔSUVmax > 45.7; Group C, SUVmax ≤ 6.8 and ΔSUVmax ≤ 45.7; and Group D, SUVmax ≤ 6.8 and ΔSUVmax > 45.7. Of the four groups, Group D had the longest RFS compared to the other groups.Conclusion: Combination of SUVmax with ΔSUVmax was useful for evaluating the effects of NAC in patients with esophageal cancer.
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