Publications by authors named "Tsuyoshi Shimamura"

88 Publications

[Distribution of Luliconazole in Nail Plate by In Vitro Permeation and Efficacy by Zone of Inhibition Test after Treatment of Luliconazole Nail Solution].

Med Mycol J 2016 ;57(1):J19-25

R&D Laboratories, POLA PHARMA INC.

To clarify the character of luliconazole nail solution we have developed, we investigated luliconazole distribution and antifungal activity in nail plate. An in vitro permeation study which measured luliconazole concentration of sliced nail in the transverse direction after treatment of luliconazole nail solution was conducted to investigate for concentration dependency and the influences of nail thickness and treatment duration. When 0.2, 1, 3, 5, and 7.5% luliconazole nail solutions were used, luliconazole was detected in the all the layers of nail and there was a concentration gradient from the dorsal side to deep nail layers. The luliconazole concentration was almost same after 14-day treatment with 5% luliconazole nail solution when using nails of different thicknesses. And we confirmed that concentration of luliconazole into the nail was increased depending on the treatment duration. In zone of inhibition test after 14-day treatment, 5% luliconazole nail solution showed statistically high formation rate of zones of inhibition compared to 8% ciclopirox nail lacquer. Above all, these data suggested that 5% luliconazole nail solution has the potential to show high therapeutic effect for onychomycosis.
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http://dx.doi.org/10.3314/mmj.57.J19DOI Listing
December 2016

[Antifungal Activity of Luliconazole Nail Solution on in vitro and in vivo Onychomycosis Model].

Med Mycol J 2016 ;57(1):J13-8

R&D Laboratories, POLA PHARMA INC.

We evaluated luliconazole nail solution, originally generated formulation, for the topical treatment of onychomycosis by two infection models. First, a suspension of Trichophyton mentagrophytes was dropped onto the ventral layer of human nail plate and these nails were set in Franz diffusion cells. After 9-day culture, luliconazole nail solutions (1, 3, and 5%) were applied to the dorsal surface of the nails once a day for 7 days. After application, fungal viability was assessed by measuring the ATP contents of the samples. The dose-dependent efficacy was confirmed, with 3% and 5% luliconazole nail solutions producing significantly lower ATP levels at 7-day treatment. When 3% and 5% luliconazole nail solutions were evaluated in a rabbit model of onychomycosis, both concentrations completely inhibited the recovery of fungi on culture after 4-week treatment. We therefore think these results indicate that 5% luliconazole nail solution is sufficiently potent for treatment of onychomycosis.
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http://dx.doi.org/10.3314/mmj.57.J13DOI Listing
December 2016

A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis E in Liver Transplant Recipients in Japan.

EBioMedicine 2015 Nov;2(11):1607-12

Background: Recently, chronic hepatitis E has been increasingly reported in organ transplant recipients in European countries. In Japan, the prevalence of hepatitis E virus (HEV) infection after transplantation remains unclear, so we conducted a nationwide cross-sectional study to clarify the prevalence of chronic HEV infection in Japanese liver transplant recipients.

Methods: A total of 1893 liver transplant recipients in 17 university hospitals in Japan were examined for the presence of immunoglobulin G (IgG), IgM and IgA classes of anti-HEV antibodies, and HEV RNA in serum.

Findings: The prevalence of anti-HEV IgG, IgM and IgA class antibodies was 2.9% (54/1893), 0.05% (1/1893) and 0% (0/1893), respectively. Of 1651 patients tested for HEV RNA, two patients (0.12%) were found to be positive and developed chronic infection after liver transplantation. In both cases, HEV RNA was also detected in one of the blood products transfused at the perioperative period. Analysis of the HEV genomes revealed that the HEV isolates obtained from the recipients and the transfused blood products were identical in both cases, indicating transfusion-transmitted HEV infection.

Interpretation: The prevalence of HEV antibodies in liver transplant recipients was 2.9%, which is low compared with the healthy population in Japan and with organ transplant recipients in European countries; however, the present study found, for the first time, two Japanese patients with chronic HEV infection that was acquired via blood transfusion during or after liver transplantation.
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http://dx.doi.org/10.1016/j.ebiom.2015.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740318PMC
November 2015

A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation.

Hepatology 2016 08 10;64(2):632-43. Epub 2016 Mar 10.

Center for Allergy and Immunology, Juntendo University School of Medicine, Tokyo, Japan.

Unlabelled: Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy.

Conclusions: A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (Hepatology 2016;64:632-643).
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http://dx.doi.org/10.1002/hep.28459DOI Listing
August 2016

Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study).

BMJ Open 2015 Sep 29;5(9):e008356. Epub 2015 Sep 29.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Introduction: This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT).

Methods And Analysis: The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm.

Ethics And Dissemination: The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals.

Trial Registration Number: The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.
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http://dx.doi.org/10.1136/bmjopen-2015-008356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593153PMC
September 2015

Postoperative assessment of hepatic asialoglycoprotein receptor function with Tc-99m GSA: the safety margin of resection size in living donor liver transplantation.

Ann Transplant 2015 Jan 26;20:51-8. Epub 2015 Jan 26.

Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: Living liver donation is associated with size-dependent complications. The resectable size and its safety margin should be defined for the safety of donors. The purpose of the present study was to determine if the current partial hepatectomies are done under the safety margin of the resectable size, by measuring asialoglycoprotein receptor (ASGPR) function of donor's remnant liver.

Material And Methods: Seventy-four living donors (age 35±11 years) underwent Technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (Tc-99m GSA) scintigraphy at postoperative week 1. We evaluated the scintigraphic results using established parameters of GSA uptake (LHL15) and its clearance from the blood pool (HH15). Based on the literature, we consider HH15 <0.55 to indicate normal ASGPR function, and 0.55£ HH15 <0.65 to indicate mild impairment. In terms of the hepatic uptake, we consider LHL15>0.93 to indicate normal ASGPR function, and 0.87< LHL15 £0.93 to indicate mild impairment.

Results: The average resected size was 337±170 mL, corresponding to 28±12% of the original donor's whole liver volume. No donors showed 0.65≤ HH15 or LHL15 <0.87, suggesting moderate or severely impaired ASGPR function. However, larger resection size (35-53%) was positively associated with higher HH15 values (R=0.53, p<0.001). In the range of HH15 (0.35-0.64) among present donors, higher HH15 values did not affect the regeneration volume (R=0.03, p=NS).

Conclusions: Larger partial resection (≥35% of the original liver volume) may impair postsurgical ASGPR function, but smaller resection (<35%) was considered to be under the safety margin of the hepatectomy. Although mildly impaired postsurgical ASGPR function did not indicate poor prognosis, careful attention may be required for donors undergoing larger (³35%) partial resection.
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http://dx.doi.org/10.12659/AOT.892490DOI Listing
January 2015

A Post-Liver Transplant Girl With Recurrent Cramps in the Legs.

Glob Pediatr Health 2015 8;2:2333794X14566074. Epub 2015 Jan 8.

Hokkaido University Hospital, Sapporo, Japan.

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http://dx.doi.org/10.1177/2333794X14566074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784624PMC
June 2016

Multiplication of alpha-fetoprotein and protein induced by vitamin K absence-II is a powerful predictor of prognosis and recurrence in hepatocellular carcinoma patients after a hepatectomy.

Hepatol Res 2015 Oct 8;45(10):E21-31. Epub 2014 Dec 8.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Aim: To evaluate the oncological implications of multiplication of α-fetoprotein (AFP) and protein induced by vitamin K absence or antagonists-II (PIVKA-II) in patients with hepatocellular carcinoma (HCC).

Methods: Data were prospectively collected from 516 consecutive patients who underwent a curative primary hepatectomy for HCC between 1998 and 2010. The AP-factor (AFP × PIVKA-II) was evaluated in relation to 2-year survival outcomes by receiver-operator curve analysis to determine the cut-off values. Patient survival, recurrence-free survival and risk factors were analyzed in accordance with the preoperative AP-factor.

Results: The AP-factor was categorized into three groups depending on the serum concentrations of AFP and PIVKA-II as follows: AP1 (n = 206; AFP < 200 ng/mL and PIVKA-II < 100 mAU/mL), AP2 (n = 152; AFP × PIVKA-II < 10(5) ) and AP3 (n = 158; AFP × PIVKA-II ≥ 10(5) ). The AP-factor was found to be significantly related to pathological factors such as differentiation, portal vein invasion, hepatic vein invasion and intrahepatic metastasis. Multivariate analysis was performed to identify the risk factors for survival and recurrence. Albumin, AP-factor and pathological factors including portal vein invasion, hepatic vein invasion and intrahepatic metastasis are independent risk factors for survival. Tumor number, AP-factor, and a non-cancerous liver were determinants of recurrence.

Conclusion: The AP-factor is closely related to differentiation and microscopic vascular invasion, and was selected by multivariate analysis as an independent factor for survival and recurrence, in HCC. Patients hopeful of obtaining good outcomes after a hepatectomy could be selected by the AP-factor evaluation.
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http://dx.doi.org/10.1111/hepr.12451DOI Listing
October 2015

Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver.

Surg Today 2015 Jul 2;45(7):892-903. Epub 2014 Nov 2.

Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan.

Background And Purpose: Hydrogen sulfide (H2S) ameliorates hepatic ischemia and reperfusion injury (IRI), but the precise mechanism remains elusive. We investigated whether sodium hydrogen sulfide (NaHS), a soluble derivative of H2S, would ameliorate hepatic IRI, and if so, via what mechanism.

Methods: Mice were subjected to partial warm ischemia for 75 min followed by reperfusion. Either NaHS or saline was administered intravenously 10 min before reperfusion. The liver and serum were collected 3, 6, and 24 h after reperfusion.

Results: In the NaHS(-) group, severe IRI was apparent by the ALT leakage, tissue injury score, apoptosis, lipid peroxidation, and inflammation (higher plasma TNF-α, IL-6, IL-1β, IFN-γ, IL-23, IL-17, and CD40L), whereas IRI was significantly ameliorated in the NaHS(+) group. These effects could be explained by the augmented nuclear translocation of Nrf2, and the resulting up-regulation of HO-1 and thioredoxin-1. Phosphorylation of the PDK-1/Akt/mTOR/p70S6k axis, which is known to mediate pro-survival and anti-apoptotic signals, was significantly augmented in the NaHS(+) group, with a higher rate of PCNA-positive cells thereafter.

Conclusion: NaHS ameliorated hepatic IRI by direct and indirect anti-oxidant activities by augmenting pro-survival, anti-apoptotic, and anti-inflammatory signals via mechanisms involving Nrf-2, and by accelerating hepatic regeneration via mechanisms involving Akt-p70S6k.
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http://dx.doi.org/10.1007/s00595-014-1064-4DOI Listing
July 2015

A technique for orthotopic liver transplantation in cynomolgus monkeys.

Transplantation 2014 Sep;98(6):e58-60

1 Department of Transplant Surgery Graduate School of Medicine Hokkaido University Sapporo, Japan 2 Department of Gastroenterologic Surgery I Graduate School of Medicine Hokkaido University Sapporo, Japan 3 Division of Gastroenterologic and General Surgery Asahikawa Medical College Asahikawa, Japan 4 Division of Organ Transplantation Hokkaido University Hospital Sapporo, Japan.

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http://dx.doi.org/10.1097/TP.0000000000000359DOI Listing
September 2014

Small-for-size syndrome in living-donor liver transplantation using a left lobe graft.

Surg Today 2015 Jun 5;45(6):663-71. Epub 2014 Jun 5.

Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical College, 2-1 Midorigaoka-Higashi, Asahikawa, 078-8510, Japan,

In living-donor liver transplantation with a left lobe graft, which can reduce the burden on the donor compared to right lobe graft, the main problem is small-for-size (SFS) syndrome. SFS syndrome is a multifactorial disease that includes aspects related to the graft size, graft quality, recipient factors and even technical issues. The main pathophysiology of SFS syndrome is the sinusoidal microcirculatory disturbance induced by shear stress, which is caused by excessive portal inflow into the smaller graft. The donor age, the presence of steatosis of the graft and a poor recipient status are all risk factors for SFS syndrome. To resolve SFS syndrome, portal inflow modulation, splenectomy, splenic artery modulation and outflow modulation have been developed. It is important to establish strict criteria for managing SFS syndrome. Using pharmacological interventions and/or therapeutic approaches that promote liver regeneration could increase the adequate outcomes in SFS liver transplantation. Left lobe liver transplantation could be adopted in Western countries to help resolve the organ shortage.
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http://dx.doi.org/10.1007/s00595-014-0945-xDOI Listing
June 2015

[Impact of desensitization for ABO-blood barrier on living donor liver transplantation for hepatocellular carcinoma].

Nihon Shokakibyo Gakkai Zasshi 2014 May;111(5):892-8

Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University.

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May 2014

Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium.

World J Surg Oncol 2013 Oct 5;11:259. Epub 2013 Oct 5.

Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo, Japan.

Background: The prognosis for advanced hepatocellular carcinoma (HCC) with tumor thrombi in the inferior vena cava (IVC) or right atrium (RA) is poor, and there is no established effective treatment for this condition. Thus study aimed to evaluate the efficacy of surgical resection and prognosis after surgery for such cases.

Methods: Between January 1990 and December 2012, 891 patients underwent hepatectomy for HCC at our institution. Of these, 13 patients (1.5%) diagnosed with advanced HCC with tumor thrombi in the IVC or RA underwent hepatectomy and thrombectomy. Data detailing the surgical outcome were evaluated and recurrence-free and overall survival rates were calculated using the Kaplan-Meier method.

Results: Seven patients had an IVC thrombus and six had an RA thrombus. Extra-hepatic metastasis was diagnosed in 8 of 13 patients. Surgical procedures included three extended right lobectomies, three extended left lobectomies, five right lobectomies, and two sectionectomies. Right adrenal gland metastases were excised simultaneously in two patients. All IVC thrombi were removed under hepatic vascular exclusion and all RA thrombi were removed under cardiopulmonary bypass (CPB). Four patients (30.8%) experienced controllable postoperative complications, and there was no surgical mortality. The mean postoperative hospital stay for patients with IVC and RA thrombi was 23.6 ± 12.5 days and 21.2 ± 4.6 days, respectively. Curative resection was performed in 5 of 13 cases. The 1- and 3-year overall survival rates were 50.4%, and 21.0%, respectively, and the median survival duration was 15.3 months. The 1- and 3-year overall survival rates for patients who underwent curative surgical resection were 80.0% and 30.0%, respectively, with a median survival duration of 30.8 months. All patients who underwent curative resection developed postoperative recurrences, with a median recurrence-free survival duration of 3.8 months. The 1-year survival rate for patients who underwent noncurative surgery and had residual tumors was 29.2%, with a median survival duration of 10.5 months.

Conclusions: Aggressive surgical resection for HCC with tumor thrombi in the IVC or RA can be performed safely and may improve the prognoses of these patients. However, early recurrence and treatment for recurrent or metastatic tumors remain unresolved issues.
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http://dx.doi.org/10.1186/1477-7819-11-259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851861PMC
October 2013

Histopathological evaluation of the efficacy of antifungals for experimental Trichosporon bloodstream infection.

Jpn J Infect Dis 2013 ;66(2):133-9

Department of Surgical Pathology, Toho University Omori Medical Center, Tokyo 143-8541, Japan.

The efficacy of polyene macrolides to treat experimental Trichosporon bloodstream infection was evaluated by histopathological examination and viable cell counts in the kidneys of infected mice. Viable cell counts on the 5th day after infection confirmed that liposomal amphotericin B (L-AMB) is a more effective treatment than fluconazole (FLC) for mice infected with an azole-resistant strain of Trichosporon. Histological examination revealed that the administration of L-AMB induced a transformation from acute purulent inflammation caused by both azole-susceptible and -resistant strain infections to a chronic and subsiding form, whereas FLC failed to convert the acute inflammation induced by the azole-resistant strain to a subsiding form. Our results demonstrate that polyene macrolides can be used as an alternative therapy for infection of azole-resistant strains of Trichosporon and that histopathological evaluation is useful for elucidating the pathophysiology of an experimental Trichosporon infection.
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http://dx.doi.org/10.7883/yoken.66.133DOI Listing
September 2013

Reliability and validity of a new living liver donor quality of life scale.

Surg Today 2013 Jul 17;43(7):732-40. Epub 2013 Jan 17.

Division of Health Science, Osaka University, 1-7 Yamadaoka, Suita City, Osaka, 565-0871, Japan.

Purpose: To develop a living liver donor (LLD) quality of life (QOL) scale and test its reliability and validity.

Methods: We sent a draft questionnaire comprising 38 questions to 965 LLDs from five hospitals. To evaluate test-retest reliability, the questionnaire was re-sent 2 weeks later to some of the donors from one hospital.

Results: Of the 447 (54.5 %) donors who responded, 15 were excluded. Factor analysis of 26 items extracted 7 subscales; namely, damage from the operation, scarring, satisfaction, burden, after-effects, digestive symptoms, and lack of understanding of donor health. We analyzed construct validity on the basis of factor analysis and observed significant correlations among the seven subscales. Criterion-related validity was confirmed by significant correlation with the 36-item Short-Form Health Survey scores. None of the subscales showed unreasonable values. We evaluated the subscale reliability for internal consistency (α = 0.670-0.868, except for "digestive symptoms", α = 0.431) and test-retest reliability (r = 0.749-0.918). The factor "digestive symptoms" needs careful consideration because of low internal consistency.

Conclusion: The findings of this study confirmed the reliability and validity of the LLD QOL scale, which can be used for quantitatively evaluating the QOL of LLDs.
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http://dx.doi.org/10.1007/s00595-012-0476-2DOI Listing
July 2013

Animal model of dermatophytosis.

J Biomed Biotechnol 2012 29;2012:125384. Epub 2012 Apr 29.

R&D Laboratories, POLA Pharma Inc, 560 Kashio-cho, Totsuka-ku, Yokohama 244-0812, Japan.

Dermatophytosis is superficial fungal infection caused by dermatophytes that invade the keratinized tissue of humans and animals. Lesions from dermatophytosis exhibit an inflammatory reaction induced to eliminate the invading fungi by using the host's normal immune function. Many scientists have attempted to establish an experimental animal model to elucidate the pathogenesis of human dermatophytosis and evaluate drug efficacy. However, current animal models have several issues. In the present paper, we surveyed reports about the methodology of the dermatophytosis animal model for tinea corporis, tinea pedis, and tinea unguium and discussed future prospects.
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http://dx.doi.org/10.1155/2012/125384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350966PMC
December 2012

Three cases of acute or fulminant hepatitis E caused by ingestion of pork meat and entrails in Hokkaido, Japan: Zoonotic food-borne transmission of hepatitis E virus and public health concerns.

Hepatol Res 2012 Sep 9;42(9):870-8. Epub 2012 May 9.

Department of Gastroenterology, Abashiri Kosei General Hospital, Abashiri Center for Gastroenterology, Teine Keijinkai Hospital Department of Gastroenterology, Aiiku Hospital Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan.

Aim:   In developed countries including Japan, the transmission route of indigenous hepatitis E virus (HEV) infection is obscure. Accordingly, public health implications of indigenous HEV infection have not been well addressed. The aim of this study was to clarify the route of transmission of a small outbreak of acute hepatitis E and assess the public health implications of indigenous zoonotic HEV transmission.

Methods:   Three patients with non-A, B and C acute hepatitis, two of whom presented in a critical condition, were assessed for HEV infection using polymerase chain reaction and their route of infection; the genome sequences of the infecting HEV were also analyzed. A phylogenetic tree based on the full, or near full, HEV RNA sequences were constructed by neighbor-joining method.

Results:   All three patients ingested grilled pork meat and entrails at the same barbecue restaurant in Abashiri, Hokkaido, Japan. When comparing partial to entire, or nearly entire, nucleotide sequences of HEV detected in these patients, they were 99.9-100% identical to each other. These genotype 4 isolates had great resemblance to the genome sequences of the isolates from the mini-outbreak in 2004 in Kitami, a city adjacent to Abashiri. These Kitami/Abashiri strains were segregated into a single cluster on the phylogenetic tree of HEV genotype 4 indigenous to Japan.

Conclusion:   Indigenous HEV transmission via a zoonotic food-borne route has been demonstrated in Kitami and Abashiri via pork meat and entrails contaminated with virulent HEV strains. Because a similar outbreak can recur in the future, infection sources and distribution routes should be clarified rapidly for public health.
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http://dx.doi.org/10.1111/j.1872-034X.2012.01006.xDOI Listing
September 2012

Successful transplantation of rat hearts subjected to extended cold preservation with a novel preservation solution.

Transpl Int 2012 Jun 4;25(6):696-706. Epub 2012 Apr 4.

Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Since prolonged cold preservation of the heart deteriorates the outcome of heart transplantation, a more protective preservation solution is required. We therefore developed a new solution, named Dsol, and examined whether Dsol, in comparison to UW, could better inhibit myocardial injury resulting from prolonged cold preservation. Syngeneic heterotopic heart transplantation in Lewis rats was performed after cold preservation with UW or Dsol for 24 or 36 h. In addition to graft survival, myocardial injury, ATP content, and Ca(2+) -dependent proteases activity were assessed in the 24-h preservation group. The cytosolic Ca(2+) concentration of H9c2 cardiomyocytes after 24-h cold preservation was assessed. Dsol significantly improved 7-day graft survival after 36-h preservation. After 24-h preservation, Dsol was associated with significantly faster recovery of ATP content and less activation of calpain and caspase-3 after reperfusion. Dsol diminished graft injury significantly, as revealed by the lower levels of infarction, apoptosis, serum LDH and AST release, and graft fibrosis at 7-day. Dsol significantly inhibited Ca(2+) overload during cold preservation. Dsol inhibited myocardial injury and improved graft survival by suppressing Ca(2+) overload during the preservation and the activation of Ca(2+) -dependent proteases. Dsol is therefore considered a better alternative to UW to ameliorate the outcome of heart transplantation.
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http://dx.doi.org/10.1111/j.1432-2277.2012.01469.xDOI Listing
June 2012

Endoscopic naso-pancreatic drainage for the treatment of pancreatic fistula occurring after LDLT.

World J Gastroenterol 2011 Aug;17(30):3560-4

Department of General Surgery, Graduate School of Medicine, Hokkaido University, N-15 W-7, Kita-ku, 060-8638 Sapporo, Japan.

Pancreatic fistula is a quite rare complication in patients who undergo living donor liver transplantation (LDLT). However, in the cases that show pancreatic fistula, the limited volume of the graft and the resultant inadequate liver function may complicate the management of the fistula. As a result, the pancreatic fistula may result in the death of the patient. We present 2 cases in which endoscopic treatment was effective against pancreatic fistulas that developed after LDLT. In case 1, a 61-year-old woman underwent LDLT for primary biliary cirrhosis. Because of a portal venous thrombus caused by a splenorenal shunt, the patient underwent portal vein reconstruction, and a splenorenal shunt was ligated on postoperative day (POD) 7. The main pancreatic duct was injured during the manipulation to achieve hemostasis, thereby necessitating open drainage. However, discharge of pancreatic fluid continued even after POD 300. Endoscopic naso-pancreatic drainage (ENPD) was performed, and this procedure resulted in a remarkable decrease in drain output. The refractory pancreatic fistula healed on day 40 after ENPD. In case 2, a 58-year-old man underwent LDLT for cirrhosis caused by the hepatitis C virus. When the portal vein was exposed during thrombectomy, the pancreatic head was injured, which led to the formation of a pancreatic fistula. Conservative therapy was ineffective; therefore, ENPD was performed. The pancreatic fistula healed on day 38 after ENPD. The findings in these 2 cases show that endoscopic drainage of the main pancreatic duct is a less invasive and effective treatment for pancreatic fistulas that develop after LDLT.
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http://dx.doi.org/10.3748/wjg.v17.i30.3560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163256PMC
August 2011

[Comprehensive strategy for extermination of hepatocellular carcinoma--prevention, diagnosis and treatment].

Hokkaido Igaku Zasshi 2011 May;86(3):127-30

Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan.

In this symposium, we explained etiology, prevention and treatment for hepatocellular carcinoma (HCC). It has been revealed that the carcinogenesis in hepatocellular carcinoma is almost caused by the infection of hepatitis virus B and/or C. Therefore, the carcinogenesis in hepatocellular carcinoma is able to be prevented. Even if the carcinogenesis in hepatocellular carcinoma occurs, the diagnosis and treatment in the worldwide level; radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), hepatectomy, and liver transplantation will be offered to patients with HCC in Japan. We hope that this symposium would help the attendance to understand the prevention and treatment for HCC.
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May 2011

[Spontaneous disappearance of intracranial arteriovenous malformation after living-donor liver transplantation: a case report].

No Shinkei Geka 2011 Jun;39(6):589-94

Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

In this report, the authors describe a 35-year-old male whose intracranial arteriovenous malformation (AVM) spontaneously disappeared about 2 years after successful living-donor liver transplantation for alcohol-induced liver cirrhosis. Preoperative screening MRI revealed intracranial arteriovenous malformation (AVM) around the midbrain. Cerebral angiography demonstrated that the AVM was fed by the paramedian mesencephalic arteries and was drained via the vein of Galen. He successfully underwent living-donor liver transplantation, and his postoperative course was uneventful. Follow-up MRI and MRA revealed spontaneous disappearance of the AVM 27 months after surgery. The authors discuss precisely the underlying mechanism of this rare phenomenon, based on thorough literature review.
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June 2011

Establishment of a novel model of onychomycosis in rabbits for evaluation of antifungal agents.

Antimicrob Agents Chemother 2011 Jul 9;55(7):3150-5. Epub 2011 May 9.

R&D Laboratories, Pola Pharma Inc., 560 Kashio-cho, Totsuka-ku, Yokohama 244-0812, Japan.

We developed a novel model of onychomycosis in which we observed fungi in the deep layer of the nail, and we used the model to evaluate the efficacy of two topical antifungal drugs. To establish an experimental, in vivo model of onychomycosis, we applied Trichophyton mentagrophytes TIMM2789 to the nails of the hind limbs of rabbits that underwent steroid treatment. The nails were taken from the rabbits' feet at 0, 2, and 6 weeks after a 2-week infection. The localization of the fungi was evaluated histopathologically. Some fungi were seen to penetrate to the nail bed, and the infection rate in the sample at 0, 2, and 6 weeks after infection was 57, 87, and 93%, respectively. In addition, fungi proliferated and moved proximally into the nail plate in a manner that depended on the duration of infection. Second, using this model we evaluated antifungal efficacy both by the culture recovery method and histopathological examination. Two topical antifungal drugs, 8% ciclopirox nail lacquer and 5% amorolfine nail lacquer, were applied to the nail for 4 weeks in each group. On histopathological examination, two antifungal treatment groups showed no significant difference against the nontreated control group. However, there were a significantly low fungus-positive rate and intensity of the recovery of fungi on culture between antifungal treatment and nontreated control groups. We therefore suggest that we have established an in vivo model of onychomycosis that is useful for the evaluation of the efficacy of antifungal agents.
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http://dx.doi.org/10.1128/AAC.00399-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122464PMC
July 2011

Perioperative management of hepatic resection toward zero mortality and morbidity: analysis of 793 consecutive cases in a single institution.

J Am Coll Surg 2010 Oct 8;211(4):443-9. Epub 2010 Aug 8.

Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: The mortality rates associated with hepatectomy are still not zero. Our aim was to define the risk factors for complications and to evaluate our perioperative management.

Study Design: Between 2001 and 2008, 793 consecutive patients (547 men and 246 women; mean age ± SD, 56.1 ± 14.9 years) underwent hepatectomy without gastrointestinal resection and choledocojejunostomy at our center. Of these patients, 354 (44.6%) were positive for the hepatitis B virus surface antigen and/or the hepatitis C virus antibody. We categorized 783 (98.7%) patients as Child-Pugh class A. Major resection (sectionectomy, hemihepatectomy, and extended hemihepatectomy), was performed in 535 patients (67.5%) and re-resection in 81 patients (10.2%).

Results: The median operative time was 345.5 minutes and median blood loss was 360 mL. The rate of red blood cell transfusion was 6.8%. The morbidity rate was 15.6%. Reoperations were performed in 19 patients (2.4%). The mean postoperative hospital stay was 18.4 ± 10.4 days. The in-hospital mortality rate was 0.1% (1 of 793 patients; caused by hepatic failure). The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes, blood loss of more than 400 mL, and serum albumin levels of less than 3.5 g/dL, as determined using multivariate logistic regression analysis.

Conclusions: Shorter operative times and reduced blood loss were obtained by improving the surgical technique and using new surgical devices and intraoperative management, including anesthesia. Additionally, decision making using our algorithm and perioperative management according to CDC guidelines reduced the morbidity and mortality associated with hepatectomy.
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http://dx.doi.org/10.1016/j.jamcollsurg.2010.06.005DOI Listing
October 2010

Three-dimensional computed tomography scan analysis of hepatic vasculatures in the donor liver for living donor liver transplantation.

Liver Transpl 2010 Sep;16(9):1062-8

Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Because hepatic vasculatures exhibit variations, a preoperative evaluation of the vascular anatomy and an estimation of the volume of the liver graft are essential for successful adult living donor liver transplantation. Using 3-dimensional (3D) computed tomography (CT), we analyzed the volumetric and anatomical relationship of the hepatic vasculatures of liver grafts. The livers of 223 potential donors were analyzed by 3D CT. Volumetric analysis was performed for each hepatic vein and its tributaries. The anatomy of the portal vein and hepatic artery was assessed along with the biliary system via intraoperative cholangiography in 110 recipients. On the basis of the anatomical presentation of the inferior right hepatic vein (IRHV), the hepatic veins were classified as follows: in type I, the IRHV was absent; in type II, the IRHV was smaller than the right hepatic vein (RHV); and in type III, the IRHV was greater than or equal to the RHV in size. The drainage volume of the middle hepatic vein (MHV) and especially its tributaries in the right lobe increased with the size of the IRHV (P < 0.001). In type III hepatic veins with a large IRHV (17% of the donors), the MHV tributaries had the largest drainage volume in the right lobe (41.2% +/- 11.8%). Furthermore, type III hepatic veins typically exhibited biliary variations in 75% of the donors. No correlation was observed between variations in the hepatic artery and portal vein. In conclusion, a right lobe graft with a large IRHV is accompanied by a large drainage volume via the MHV and by bile duct variations in 17% of livers. Therefore, anatomical and volumetric analysis is important for preoperative evaluations.
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http://dx.doi.org/10.1002/lt.22109DOI Listing
September 2010

Risk factors for portal vein complications in pediatric living donor liver transplantation.

Clin Transplant 2010 Jul-Aug;24(4):550-6

Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Background: Portal vein (PV) complications in pediatric living donor liver transplantation (LDLT) are often asymptomatic in the early stages after transplantation and can be serious enough to lead to graft failure. There have been few reports on risk factors for PV complications in LDLT. The aim of this study is to investigate the influence of hepatic inflow upon PV complications and to predict patients at risk for these complications.

Material/method: From 1997 to 2008, 46 pediatric patients underwent LDLT at our center. Portal venous and hepatic arterial flows and PV diameter were analyzed.

Results: PV complications were identified in seven patients (15.2%) and occurred at a younger age and lower weight. As a result of appropriate treatment, none of the patients suffered graft failure. Analysis of the 46 patients and 27 patients under two yr of age identified smaller PV diameter in recipient and larger discrepancy of PV diameter as risk factors. Portal venous flow tended to be low, in contrast to hepatic arterial flow, which tended to be high.

Conclusion: PV size strongly influences PV complications. Other factors such as younger age, low portal venous flow, and high hepatic arterial flow may be risk factors for PV complications.
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http://dx.doi.org/10.1111/j.1399-0012.2009.01123.xDOI Listing
February 2011

Liver transplantation for hepatocellular carcinoma: the Japanese experience.

J Hepatobiliary Pancreat Sci 2010 Sep 18;17(5):533-8. Epub 2009 Sep 18.

Department of Organ Transplantation and Regenerative Medicine, Hokkaido University School of Medicine, N-15 W-7, Kitaku, Sapporo, 060-8648, Japan.

Despite the wide spectrum of selection criteria used by living donor liver transplantation (LDLT) centers in Japan, LDLT for hepatocellular carcinoma (HCC) can achieve an acceptable outcome comparable to the outcome for deceased donor liver transplantation (DDLT) for HCC. One of the most crucial considerations in liver transplantation for HCC is the advent of expanded criteria that allow more patients with HCC to receive the organs and offer similar or even better results compared to the Milan of UCSF criteria. Expanded criteria for HCC are proposed from three single-center and one multicenter study in Japan. These criteria are based on the independent predictors for outcome derived from the analyses of the pretransplant factors and explant pathology. The beneficial effect of those proposed criteria can be predicted by the inclusion rates of the patients compared to the Milan or UCSF criteria in the same cohort and the outcome for those included patients. While application of the UCSF criteria increases the inclusion rate compared to the Milan criteria by 5-10%, these proposed criteria increase the inclusion rates by 5-54% compared to the Milan criteria. The higher inclusion rates compared to the application of the Milan criteria are achieved by criteria including tumor markers, either AFP or PIVKA II or both. Inclusion of tumor markers in addition to parameters of tumor morphology might be the key to establish the best criteria for liver transplantation for HCC.
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http://dx.doi.org/10.1007/s00534-009-0168-5DOI Listing
September 2010

Recurrence patterns after hepatectomy of hepatocellular carcinoma: implication of Milan criteria utilization.

Ann Surg Oncol 2009 Jun 4;16(6):1560-71. Epub 2009 Mar 4.

Department of General Surgery, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.

Background: Bridge hepatectomy followed by salvage liver transplantation has been proposed for patients with hepatocellular carcinoma (HCC) and preserved liver function.

Methods: Data were prospectively collected for 501 consecutive patients who underwent curative primary hepatectomy for HCC between 1990 and 2006. Patient survival, disease-free survival (DFS), recurrence patterns, and risk factors were analyzed in patients classified according to the Milan criteria.

Results: Patients were divided into two groups on the basis of whether their disease was within the Milan criteria (group 1, n = 321) or not (group 2, n = 180). Group 1 patient survival and DFS rates were 73.6% and 40.6% at 5 years. Recurrence was observed in 160 group 1 patients (49.8%); in 42 (26.3%) of these 160 patients, the recurrence exceeded the Milan criteria. No recurrence was noted in 145 group 1 patients (45.2%). Group 2 patient survival and DFS rates were 52.2% and 23.2%, respectively, at 5 years. Recurrence was noted in 116 patients (64.4%); recurrence in 58 (50.0%) of these patients was within the Milan criteria. In group 2, no recurrence was noted in 55 patients (30.6%). In group 1, indocyanine green retention rate at 15 minutes of >15%, nonanatomical resection, and multiple tumors were statistically significant risk factors for survival; 10-year patient survival was 78.5% for patients with no risk factors and 64.9% for patients with a single risk factor.

Conclusions: The Milan criteria should be used to recommend hepatectomy for patients with HCC; however, it is important to consider the high recurrence rate after hepatectomy and the possible requirement of salvage transplantation.
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http://dx.doi.org/10.1245/s10434-009-0407-7DOI Listing
June 2009

Liquid chromatographic method for the determination of sirolimus in blood using electrochemical detection.

Biomed Chromatogr 2009 Mar;23(3):267-72

Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.

Therapeutic drug monitoring of sirolimus (rapamycin) is important for immunosuppressive therapy in solid organ transplantation. We have developed a simple and reliable method for determining blood concentrations of sirolimus using reversed-phase HPLC with electrochemical detection (ECD). The E(2) potential was set at +900 mV. The potential of guard cell was set at +950 mV and that of the E(1) cell at +400 mV. The method was linear for a concentration range of 1-50 ng/mL when 0.5 mL blood was used. The correlation coefficients of all standard curves were greater than or equal to 0.999. The limit of detection was 0.5 ng/mL. The inter-assay precision ranged from 3.22 to 7.48%, and the coefficient of variation (CV) for a quality control sample at 10 ng/mL was 7.48% with a bias of 8.4% from the target value. The intra-assay precision ranged from 0.72 to 3.71%, and the CV for a quality control sample at 10 ng/mL was 0.72% with a bias of 6.8% from the target value. In a solid organ transplant recipient, trough concentrations of sirolimus were well within the analytic range of the HPLC/ECD procedure. The method described here is suitable for management of sirolimus therapy in solid organ transplantation.
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http://dx.doi.org/10.1002/bmc.1109DOI Listing
March 2009

[Indication, management and problems of alcoholic liver diseases for liver transplantation: current status in Japan, US and Europe].

Nihon Arukoru Yakubutsu Igakkai Zasshi 2007 Dec;42(6):622-8

First Department of Surgery, Hokkaido University Hospital, North14 West5, Kita-ku, Sapporo 060-8648, Japan.

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December 2007
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