無症候性腎機能障害が膵頭十二指腸切除術後臨床経過に及ぼす影響

BACKGROUND: Although recent large-scale clinical studies have shown that preoperative renal insufficiency is associated with increased risk of postoperative complications after pancreatoduodenectomy (PD), it is unknown whether asymptomatic renal dysfunction has an impact on postoperative course after PD. METHODS: Two hundred and fifty-four patients who underwent PD between 2007 and 2013 were enrolled. Renal function was evaluated by the preoperative estimated glomerular filtration rate (eGFR). Patients were divided into two groups according to the cutoff value of 55 of eGFR. RESULTS: Thirty-five patients were classified as the low eGFR group, while 219 were classified as the normal group. There were differences between groups in age, comorbidity and pancreatic texture. The incidence of overall postoperative complication, grade B/C pancreatic fistula and severe complication in the low eGFR group was significantly higher than that in the normal group. Multivariate analysis identified low eGFR as an independent risk factor for severe postoperative complications and grade B/C pancreatic fistula after PD. However, there were no differences in mortality and survival between the low and normal eGFR groups. CONCLUSIONS: We have demonstrated for the first time that preoperative asymptomatic renal dysfunction may be a significant risk factor for severe morbidity and clinically relevant pancreatic fistula after PD.博士（医学）・乙第1394号・平成29年3月15日© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.This is the peer reviewed version of the following article: http://dx.doi.org/10.1002/jhbp.286, which has been published in final form at http://dx.doi.org/10.1002/jhbp.286. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving

ヒト膵癌におけるNectin-4発現の腫瘍増殖、血管新生に対する効果と臨床的意義

BACKGROUND: Nectin-4 belongs to the nectin family that has diverse physiological and pathological functions in humans. Recent studies have also suggested some roles for Nectin-4 in several human cancers. However, the precise roles and clinical relevance of Nectin-4 in tumors are largely unknown. METHODS: Nectin-4 expression was investigated in 123 patients with pancreatic cancer by immunohistochemistry. Furthermore, we investigated the association of Nectin-4 in pancreatic cancer with tumor proliferation, angiogenesis and immunity by using immunohistochemistry and siRNA interference method. RESULTS: Patients with high Nectin-4 expression had poorer postoperative prognosis than those with low expression. Importantly, multivariate analysis indicated that Nectin-4 expression had a significant independent prognostic value in pancreatic cancer (HR = 1.721, 1.085-2.730; P = 0.021). Tumor Nectin-4 expression was significantly correlated with Ki67 expression. In addition, siRNA-mediated gene silencing of Nectin-4 significantly inhibited the cell proliferation in human pancreatic cancer cells, Capan-2 and BxPC-3. Furthermore, Nectin-4 expression was also positively correlated with VEGF expression and intratumoral microvessel density. However, there were no significant correlations of tumor Nectin-4 expression with tumor-infiltrating T cells. CONCLUSION: Nectin-4 is a significant prognostic predictor, and may play a critical role in pancreatic cancer. Nectin-4 may be novel therapeutic target for pancreatic cancer.博士（医学）・乙第1400号・平成29年6月28日Copyright © Nishiwada et al.; licensee BioMed Central. 2015 : This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes

GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3′UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes

化学療法を施行した膵癌患者に対する喫煙の影響

OBJECTIVE: Smoking may affect pharmacokinetics of chemotherapeutic agents and hemodynamics of the smokers, thereby influencing adverse events and efficacy of chemotherapy in patients with pancreatic cancer (PC). The aim of this study was to clarify how smoking totally affected patients with PC receiving current chemotherapy. METHODS: We evaluated the impact of smoking status on the performance of chemotherapy and survival in 262 patients with PC including 158 resectable and 104 unresectable PC. RESULTS: There were more male and younger patients in current smokers than in nonsmokers. In unresectable PC, current smokers had more metastatic tumors than locally advanced tumors compared with nonsmokers. In current smokers receiving chemotherapy, the baseline white blood cell count, neutrophil count, and hemoglobin concentration were significantly higher in current smokers than in nonsmokers. Furthermore, grades 3 to 4 neutropenia was observed more often in nonsmokers than smokers. On the other hand, the performance and efficacy of the planned adjuvant chemotherapy were similar between smokers and nonsmokers. More importantly, there was no significant difference in overall prognosis between smokers and nonsmokers receiving chemotherapy. CONCLUSIONS: Smoking status has no significant impact on the efficacy of current chemotherapy for both resectable and unresectable PC.博士（医学）・乙第1393号・平成29年3月15日Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.This is a non-final version of an article published in final form in "http://dx.doi.org/10.1097/MPA.0000000000000395

80歳以上の高齢者膵癌に対する膵切除の意義

Background: There is increasing need to evaluate the surgical indication of pancreatic cancer in very elderly patients. However, the available clinical data are limited, and the optimal treatment is still controversial. The aim of this study was to evaluate the benefit of pancreatic resection in pancreatic cancer patients over the age of 80. Methods: Between 2005 and 2012, 26 octogenarian patients who received pancreatic resection and 20 who received chemotherapy for pancreatic cancer were retrospectively reviewed. Clinicopathological factors, chemotherapy administration status, and survival were compared. Univariate and multivariate analysis of prognostic factors for survival was performed. Results: Postoperative major complication rate was 8%, with no mortality. The one-year survival rate and median survival time of the surgery and chemotherapy groups were 50% and 45%, and 12.4 months and 11.7 months, respectively (P = 0.263). Of the 26 resected cases, 6 completed the planned adjuvant chemotherapy treatment course. The median survival time of those 6 completed cases was significantly longer than that of the 20 not completed cases (23.4 versus 10.0 months, P = 0.034). Furthermore, a multivariate analysis of the 26 resected cases showed that distant metastasis (HR 3.206, 95%CI 1.005-10.22, P = 0.049) and completion of the planned adjuvant therapy (HR 4.078, 95%CI 1.162-14.30, P = 0.028) were independent prognostic factors of surgical resection. Conclusions: Surgical resection was safe, but not superior to chemotherapy for pancreatic cancer in octogenarians. In the very elderly, only selected patients may benefit from pancreatic resection.博士（医学）・乙第1513号・令和3年12月21日Copyright © 2015 IAP and EPC. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved

Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report

Background: Ganciclovir is a therapeutic choice for extremely premature infants with severe postnatal cytomegalovirus disease, but little is known about its optimal dose size and dosing interval for them. Case presentation: We treated an extremely premature female infant with postnatal cytomegalovirus infection with intravenous administration of ganciclovir since 49 days of life (postmenstrual age of 31 weeks). After ganciclovir treatment was initiated at a dose of 5 mg/kg every 12 h, cytomegalovirus loads in the peripheral blood were markedly decreased. However, since plasma ganciclovir trough level was too high, the interval was extended to every 24 h. Subsequently, the trough level and the estimated 12-h area under the concentration-time curve (AUC0-12) were decreased from 3.5 mg/L to 0.3 mg/L and 53.9 mg ・ h/L to 19.2 mg ・ h/L, respectively, resulting in an exacerbation of viremia and clinical condition. Adjustment of dosing interval from 24 h to 12 h led to a peak level of 4.2 mg/L, trough level of 1.1 mg/L, and AUC0-12 of 31.8 mg ・ h/L, resulting in a marked suppression of viral load. Conclusions: Monitoring the therapeutic drug levels and cytomegalovirus loads is useful in obtaining a proper treatment effect and preventing overdosage during ganciclovir therapy in premature infants with postnatal cytomegalovirus infection

セロトニン受容体2A、2C活性化による脂肪細胞分化の制御--microRNA-448によるKLF5の抑制との関連

京都大学0048新制・課程博士博士(医学)甲第15714号医博第3502号新制||医||984(附属図書館)28259京都大学大学院医学研究科医学専攻(主査)教授 中尾 一和, 教授 野田 亮, 教授 稲垣 暢也学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA