三木 厚

Background In small infants, left lateral segment grafts are sometimes too large to overcome the problems of large-for-size grafts in the abdominal compartment. To address this problem, we have developed a safe living donor graftectomy for neonates, a so-called "S2 monosegment graft" to minimize graft thickness. We reviewed our single-center experience to evaluate the feasibility of this technique for reducing graft size. Methods Eleven living-donor liver transplants using S2 monosegment grafts were performed between October 2008 and September 2014 at our institution. Medical records of both donors and recipients were reviewed and data collected retrospectively. Results The mean age of recipients at the time of transplantation was 125.3 days, including 3 neonates. The average S2 monosegment graft weight was 127.4 g, and the graft-to-recipient body weight ratio was successfully reduced to 3.5%. The graft livers were reduced to 4.1 cm in thickness. Two recipients with grafts larger than 5 cm could not undergo primary abdominal closure. Portal vein stenosis and biliary stenosis was observed in 1 recipient, and hepatic artery complications were seen in 2 recipients the clinical course for all donors were uneventful. Liver regeneration was seen in every patient. The graft and patient 1-year survival rate was 100%. Conclusions Living-donor liver transplantation using S2 monosegment grafts offers a safe and useful option for treating smaller infants. Here, we introduce our method of S2 monosegment graft emphasizing the donor harvest and graft thickness.

BACKGROUND: Urinary tract infection caused by human adenovirus (HAdV) after renal transplantation (RT) results in graft loss because of concomitant nephropathy and acute rejection and may result in death because of systemic dissemination. METHODS: We assessed the time period between RT and disease onset, symptoms, treatment details, disease duration, renal graft function, outcomes, and complications. RESULTS: HAdV infection of the urinary tract occurred in 8 of 170 renal transplant recipients. Symptoms were macrohematuria in all 8 patients, dysuria in 7, and fever in 5. The median period from RT to disease onset was 367 (range, 7-1763) days, and the median disease duration was 15 (range, 8-42) days. The mean serum creatinine (sCr) level prior to onset was 1.35 ± 0.48 mg/dL and the mean maximum sCr level during disease was 2.34 ± 1.95 mg/dL. These values were increased by ≥25% in 5 patients. The mean sCr levels when symptoms resolved was 1.54 ± 0.67 mg/dL, and no significant difference was seen before, during, or after disease onset (P = 0.069). Two patients were diagnosed with HAdV viremia and 1 with acute tubulointerstitial nephritis revealed on biopsy. In addition to a reduction in immunosuppressant dosage, 2 patients received gammaglobulins and 5 received ganciclovir. CONCLUSION: Symptoms of all patients were alleviated, although some patients developed nephritis or viremia. Hence, the possibility of exacerbation should always be considered. Adequate follow-up observation should be conducted, and diligent and aggressive therapeutic intervention is required to prevent the condition from worsening.

膵切除術を行った浸潤性膵管癌74例(男性46例、女性28例、平均66.6歳)を対象に、標記について検討した。膵体尾部癌は31例、膵頭部癌は43例で、臨床病期はStage Iが2例、Stage IIが8例、Stage IIIが40例、Stage IVaが24例であった。術後補助化学療法は50例に施行した。R0群の3年生存率は60.1%、R1群では41.0%であったが有意差は認められなかった。癌組織型では有意差はなく、T因子についてはT1〜T2群に対しT3〜T4群は有意に予後良好であった。リンパ節転移なし群に対し、あり群は有意に予後不良であった。多変量解析では、リンパ節転移の有無のみが独立した予後規定因子であった。リンパ節転移の有無(N)と癌遺残度(R)の検討では、R0N-群の3年生存率は85.8%、R0N+群では40.3%、R1N-群は50.0%、R1N+群は41.7%と、R0N-群で有意に予後良好であった。

当院では膵良性疾患に対して腹腔鏡下膵体尾部切除術(LDP)を施行しているが、視野確保が不十分な症例や高度癒着例、および膵切離面の状態からステイプラーによる切離閉鎖が困難な症例には、用手的補助下腹腔鏡下手術(HALS)や小切開手術(MIS)への移行が有用な場合がある。今回、LDPからHALSへ移行し、さらにMISへ移行することで確実な膵切離が行えた2例(61歳女、21歳女)を報告した。

We report a rare case of immunoglobulin G4 (IgG4)-related sclerosing cholangitis without other organ involvement. A 69-year-old-man was referred for the evaluation of jaundice. Computed tomography revealed thickening of the bile duct wall, compressing the right portal vein. Endoscopic retrograde cholangiopancreatography showed a lesion extending from the proximal confluence of the common bile duct to the left and right hepatic ducts. Intraductal ultrasonography showed a bile duct mass invading the portal vein. Hilar bile duct cancer was initially diagnosed and percutaneous transhepatic portal vein embolization was performed, preceding a planned right hepatectomy. Strictures persisted despite steroid therapy. Therefore, partial resection of the common bile duct following choledochojejunostomy was performed. Histologic examination showed diffuse and severe lymphoplasmacytic infiltration, and abundant plasma cells, which stained positive for anti-IgG4 antibody. The final diagnosis was IgG4 sclerosing cholangitis. Types 3 and 4 IgG4 sclerosing cholangitis remains a challenge to differentiate from cholangiocarcinoma. A histopathologic diagnosis obtained with a less invasive approach avoided unnecessary hepatectomy.

Chemotherapy-induced nausea and vomiting is a serious adverse side-effect of anthracycline-based chemotherapy regimens, in patients with breast cancer. A combination of three drugs, 5-hydroxytryptamine (5-HT3) receptor antagonist, aprepitant and dexamethasone, is recommended for antiemetic therapy. Palonosetron (PALO), a novel 5-HT3 receptor antagonist has been identified to be effective against delayed nausea and vomiting. In this study, the results of PALO for patients who received anthracycline-based chemotherapy were compared with that of granisetron (GRA) using a crossover study design. This study evaluated the efficacy of antiemetics in the first cycle of chemotherapy, as well as the second and third cycles. A total of 21 patients and 19 patients were assigned to PALO and GRA treatment groups during the first cycle of chemotherapy, respectively. The patients switched to the other antiemetic drug for the second chemotherapy cycle (PALO followed by GRA or GRA followed by PALO). The patients could select PALO or GRA antiemetics for the third cycle, according to their preference. A total of 21 patients selected PALO and 18 patients selected GRA in the third cycle, and one patient was withdrawn from the study as their third cycle questionnaire was not obtained. No significant differences between PALO and GRA were identified in first and second cycles. However, during the third cycle, a significant difference was observed in acute-phase complete control of emetic events between the PALO and GRA groups, which was defined as no emetic episode, no additional antiemetic treatment and no more than mild nausea, between PALO and GRA. These results demonstrated that changing antiemetics may affect the efficacy of antiemetics. This study indicates that alteration of antiemetic regimens, including drug combination and order, may improve the efficacy of antiemetic treatment.

OBJECTIVES: The effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture. METHODS: Methylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet cell transplantation. Islets were cultured for 24 hours with 3 different conditions (control, no additives; MP alone; and MP + EX). β-Cell fractional viability, cellular composition, multiple cytokine/chemokine production, multiple phosphorylation proteins, and glucose-induced insulin secretion were evaluated. RESULTS: Viable β-cell survival in MP and MP + EX group was significantly higher than in the control group. Exendin-4 prevented MP-induced reduction of insulin secretion. Methylprednisolone supplementation to the culture medium decreased cytokine and chemokine production. Moreover, extracellular signal-regulated kinase 1/2 phosphorylation was significantly increased by MP and MP + EX. CONCLUSIONS: Glucocorticoid supplementation into culture media significantly decreased the cytokine/chemokine production and increased the extracellular signal-regulated kinase 1/2 phosphorylation, resulting in the improvement of human β-cell survival. In addition, EX maintained the insulin secretion suppressed by MP. The supplementation of MP and EX together could be a useful strategy to create suitable human islets for transplantation.

アルコール摂取(多飲)は急性膵炎、慢性膵炎の成因として最も頻度が高い。他の成因と異なり、アルコール性膵炎は断酒・禁煙で発症・進展の予防が可能で、生活指導が重要な疾患である。その一方で「アルコール性」を規定するエタノール摂取量の明確な基準はなく、その発症・進展の機序についても不明な点が多い。慢性膵炎臨床診断基準2009では慢性膵炎をアルコール性と非アルコール性に分類し、発症前、発症早期に治療介入ができるように慢性膵炎疑診、早期慢性膵炎の診断基準を設定した。急性膵炎でも高リスク群であるアルコール多飲者の実際の発症率は低率で、遺伝子異常(SPINK1、PRSS1など)など、他の要因が深く関与していることが想定されている。アルコール性急性膵炎、慢性膵炎の診断・治療は、他の成因によるものと大きく変わるところはなく、介入治療は改訂アトランタ分類2012による膵炎局所合併症の新分類に応じた適切な時期・手技で行うことが推奨される。(著者抄録)

We report a 71-year-old man who had undergone pylorus-preserving pancreatoduodenectomy (PPPD) using PPPD-IV reconstruction for cholangiocarcinoma. For 6 years thereafter, he had suffered recurrent cholangitis, and also a right liver abscess (S5/8), which required percutaneous drainage at 9 years after PPPD. At 16 years after PPPD, he had been admitted to the other hospital because of acute purulent cholangitis. Although medical treatment resolved the cholangitis, the patient was referred to our hospital because of dilatation of the intrahepatic biliary duct (B2). Peroral double-balloon enteroscopy revealed that the diameter of the hepaticojejunostomy anastomosis was 12 mm, and cholangiography detected intrahepatic stones. Lithotripsy was performed using a basket catheter. At 1 year after lithotripsy procedure, the patient is doing well. Hepatobiliary scintigraphy at 60 minutes after intravenous injection demonstrated that deposit of the tracer still remained in the upper afferent loop jejunum. Therefore, we considered that the recurrent cholangitis, liver abscess, and intrahepatic lithiasis have been caused by biliary stasis due to nonobstructive afferent loop syndrome. Biliary retention due to nonobstructive afferent loop syndrome may cause recurrent cholangitis or liver abscess after hepaticojejunostomy, and double-balloon enteroscopy and hepatobiliary scintigraphy are useful for the diagnosis of nonobstructive afferent loop syndrome.

胆道手術におけるドレーン挿入の功罪を臨床試験の結果から検討した.膿瘍・穿孔などの合併症がない胆嚢摘出術では,開腹・腹腔鏡下ともにドレーンの挿入は創感染,呼吸器感染といった術後の合併症を増やし,それに見合う利点がないとされる.胆道切開や胆管切除・吻合でも同様に,ドレーンの利点が乏しいという結果が得られている.ルーチンワークとして行われがちなドレーンの挿入であるが,evidence-based medicine(EBM)に基づき再考すべきである.(著者抄録)

Anastomotic stricture of the choledochojejunostomy is a common complication after living donor liver transplantation. Most anastomotic strictures can be treated by percutaneous transhepatic cholangiodrainage and/or double balloon endoscopy. However, in severe cases and/or in small infants, neither of these is possible. Our new technique, cholangiography accompanied by cholangioscopy, enabled successful guidewire placement and balloon dilatation in cases with severe anastomotic stricture.

The luciferase reporter system is useful for the assessment of various biological processes in vivo. The transcription factor pancreatic and duodenal homeobox 1 (Pdx1) is critical for the formation and the function of pancreatic β-cells. A novel reporter system using secreted Gaussia princeps luciferase (GLuc) under the control of a Pdx1 promoter was generated and activated in rat and mouse β-cell lines. This Pdx1-GLuc construct was used as a transgene for the generation of reporter mice to monitor Pdx1 promoter activity in vivo via the measurement of secreted GLuc activity in a small aliquot of blood. Significantly increased plasma GLuc activity was observed in Pdx1-GLuc mice. Analysis of Pdx1-GLuc mice by bioluminescence imaging, GLuc reporter assays using homogenatesof various organs,andimmunohistochemistryrevealed thatGLucexpressionandactivity were exponentially higher in pancreatic β-cells than in pancreatic non-β-cells, the duodenum, and other organs. In addition, GLuc activity secreted into the culture medium from islets isolated from Pdx1-GLucmicecorrelatedwiththenumberofislets. ThetransplantationofPdx1-GLucisletsintosevere combined immunodeficiency mice elevated their plasma GLuc activity. Conversely, a partial pancreatectomy in Pdx1-GLuc mice reduced plasma GLuc activity. These results suggest that a secreted luciferase reporter system in vivo enables not only the monitoring of promoter activity but also a quantitative and minimally invasive assessment of physiological and pathological changes in small cell masses, such as pancreatic β-cells. Copyright © 2013 by The Endocrine Society.

A 64-year-old man received mFOLFOX6+bevacizumab chemotherapy for metastatic lung cancer after rectal cancer resection( Stage IV). After 28 courses, he had an abdominal pain with fever, and computed tomography showed pelvic abscess with stercolith of appendix. He was diagnosed as acute appendicitis with intra-abdominal abscess, and emergency appendectomy with drainage was performed. Two days after the operation, he was suspected to have a sutural leakage as was suggested from the properties of his drainage, therefore re-operation was performed. A small hole of the ileum, about 2mm in diameter, was observed. The margin of the hole showed neither inflammatory nor neoplastic change, and a suturing closure of the hole was performed. The post-operative course was uneventful. Histopathological findings of the resected appendix suggested that the perforation was caused by necrosis of metastatic cancer cells penetrating the appendiceal wall. This is a case of a bevacizumab-related metachronous perforation that occurred in different gastrointestinal origins within a very short term.

OBJECTIVE: The Lichtenstein inguinal hernia repair is commonly performed and suitable for teaching basic surgical skills. The objective of this study is to evaluate the feasibility of this procedure for surgical training, particularly in regard to patient outcomes. DESIGN: Retrospective case review after introduction of an integrated teaching program. SETTING: University teaching hospital. PARTICIPANTS: The Lichtenstein inguinal hernia repair is the standard procedure for adult primary unilateral inguinal hernia since 2003 at Jichi Medical University. We introduced an integrated teaching system of lectures, skill training, and videos to teach the skills for Lichtenstein inguinal hernia repair to residents and junior faculty in 2003. Cases were retrospectively divided into 4 groups. based on the experience of the operating surgeon; junior residents (PGY 1-2, group A), senior residents (PGY 3-5, group B), junior faculty (PGY 6-10, group C), and senior faculty (PGY 11 or more, group D). Background, perioperative factors, and outcomes were evaluated among the groups. RESULTS: A total of 246 elective inguinal hernia repairs (group A: 136, group B: 49, group C: 42, group D: 19) were performed. There was a significant difference in the frequeney of concomitant diseases (p = 0.012) and anticoagulant therapy (p = 0.031). Average operating time was 80.7 +/- 24.9, 72.6 +/- 20.8, 63.5 +/- 22.0, and 54.7 +/- 27.9 (min +/- SD) in groups A, B, C, and D, respectively, with a significant difference between groups A and D (p < 0.001). No significant differences were observed in estimated blood loss (p = 0.216) or morbidity (p = 0.294). CONCLUSIONS: The Lichtenstein inguinal hernia repair can be safely performed by residents and junior faculty with the appropriate supervision of senior faculty without any disadvantage to patients. This integrated teaching program for Lichtenstein inguinal hernia repair is effective and feasible for training residents and junior faculty. (J Surg 69:605-610. (C) 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

There is abundant evidence that immune cells infiltrating into a transplanted organ play a critical role for destructive inflammatory or regulatory immune reactions. Quantitative in situ analysis (i.e., in tissue sections) of immune cells remains challenging due to a lack of objective methodology. Laser scanning cytometry (LSC) is an imaging-based methodology that performs quantitative measurements on fluorescently and/ or chromatically stained tissue or cellular specimens at a single-cell level. In this study, we have developed a novel objective method for analysis of immune cells, including Foxp3(+) T regulatory cells (Tregs), on formalin-fixed /paraffin-embedded (FFPE) transplant biopsy sections using iCys® Research Imaging Cytometer. The development of multiple immunofluorescent staining was established using FFPE human tonsil sample. The CD4/CD8 ratio and the population of Tregs among CD4(+) cells were analyzed using iCys and compared with the results from conventional flow cytometry analysis (FCM). Our multiple immunofluorescent staining techniques allow obtaining clear staining on FFPE sections. The CD4/CD8 ratio analyzed by iCys was concordant with those obtained by FCM. This method was also applicable for liver, small intestine, kidney, pancreas, and heart transplant biopsy sections and provide an objective quantification of Tregs within the grafts.

OBJECTIVES: Recent studies demonstrated that prolactin (PRL) has beneficial effects on beta cells for islet transplantation. We examined the effect of human recombinant PRL (rhPRL) supplementation to the culture media to determine its potential use in the context of clinical islet transplantation. MATERIALS AND METHODS: Each human islet isolated from 14 deceased multiorgan donors was cultured in Miami modified media-1 supplemented with or without rhPRL (500 microg/L) for 48 hr. beta-Cell survival and proliferation (BrdU and Ki-67) were determined by laser scanning cytometry. The cytoprotective effects of rhPRL against noxious stimuli were assessed by flow cytometry (tetramethylrhodamine ethyl ester). Cytokine/chemokine and tissue factor productions were measured in vitro, and islet potency was assessed in vivo in diabetic immunodeficient mice. RESULTS: beta-Cell survival during culture was 37% higher in the rhPRL group than in control (P=0.029). rhPRL protected beta cells in vitro from cytokines, Nitric oxide donor, and H2O2. The exposure to rhPRL did not affect human beta-cell proliferation with our protocol. rhPRL treatment did not alter cytokine/chemokine and tissue factor production in vitro or affected human islet functionality in vivo: recipient mice achieved normoglycemia with a comparable tempo, whereas loss of graft function was observed in two of the seven mice in the control group and in none of the rhPRL group (p=n.s.). CONCLUSION: rhPRL supplementation to islet culture media improved human beta-cell-specific survival without altering islet quality. Addition of rhPRL to cultured islets may grant a more viable beta-cell mass in culture. The development of beta-cell cytoprotective strategies will be of assistance in improving islet transplantation outcomes.

Substantial amounts of nonendocrine cells are implanted as part of human islet grafts, and a possible influence of nonendocrine cells on clinical islet transplantation outcome has been postulated. There are currently no product release criteria specific for nonendocrine cells due to lack of available methods. The aims of this study were to develop a method for the evaluation of pancreatic ductal cells (PDCs) for clinical islet transplantation and to characterize them regarding phenotype, viability, and function. We assessed 161 human islet preparations using laser scanning cytometry (LSC/iCys) for phenotypic analysis of nonendocrine cells and flow cytometry (FACS) for PDC viability. PDC and beta-cells obtained from different density fractions during the islet cell purification were compared in terms of viability. Furthermore, we examined PDC ability to produce proinflammatory cytokines/chemokines, vascular endothelial growth factor (VEGF) and tissue factor (TF) relevant to islet graft outcome. Phenotypic analysis by LSC/iCys indicated that single staining for CK19 or CA19-9 was not enough for identifying PDCs, and that double staining for amylase and CK19 or CA19-9 allowed for quantitative evaluation of acinar cells and PDC content in human islet preparation. PDC showed a significantly higher viability than beta-cells (PDC vs beta-cell: 75.5+/-13.9 and 62.7+/-18.7%; P<0.0001). Although beta-cell viability was independent of its density, that of PDCs was higher as the density from which they were recovered increased. There was no correlation between PDCs and beta-cell viability (R(2)=0.0078). PDCs sorted from high-density fractions produced significantly higher amounts of proinflammatory mediators and VEGF, but not TF. We conclude that PDCs isolated from different fractions had different viability and functions. The precise characterization and assessment of these cells in addition to beta-cells in human islet cell products may be of assistance in understanding their contribution to islet engraftment and in developing strategies to enhance islet graft function.

BACKGROUND: Sirolimus plays a critical role in facilitating steroid-free immunosuppression, in conjunction with low dose tacrolimus, in current islet transplantation. Although several studies have investigated the effects of sirolimus on islet cells, conflicting results have been reported. In this study, we assessed the effects of sirolimus supplementation in culture media on human islet preparations, focusing on the anti-proinflammatory aspects. METHODS: Human islet preparations were divided into four groups: pure (purity >90%) sirolimus (30 ng/mL); pure control (0 ng/mL); impure (purity 40%-60%) sirolimus; and impure control. All groups were cultured for 3 days and assessed regarding glucose stimulated insulin release, fractional beta-cell viability, beta-cell, and macrophage content. Cytokine and chemokine production from islet preparations and sorted pancreatic ductal cells were also examined. RESULTS: Stimulated insulin release in the impure sirolimus group was significantly increased (P=0.024), as previously reported. Although fractional beta-cell viability showed no significant differences, beta-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-alpha and macrophage inflammatory protein-1beta production from sorted ductal cells significantly decreased in the sirolimus group (P<0.05). The number of macrophages contained in islet preparations significantly decreased in the impure sirolimus group when compared with the impure control group (P<0.05). CONCLUSIONS: Sirolimus improved not only stimulated insulin release, but also beta-cell survival during culture. The antiinflammatory effects of sirolimus also appear beneficial to islet cells in culture and may be a useful strategy in improving islet transplantation outcomes.

BACKGROUND: The quality and stability of enzyme blends used in islet cell processing are critical for successful human islet isolation. A wide variability in enzymatic activity among lots of Liberase HI has been reported. This study examines the interlot and intralot variability of Liberase HI and the over-time deterioration of enzyme quality based on the analysis of islet isolation outcomes. METHODS: The data of 169 human isolations processed for clinical islet transplantation, using five different lots of Liberase HI, were retrospectively analyzed. Inter- and intralot variables in the islet isolation were assessed over a 15-month period. RESULTS: The analysis revealed significant interlot differences in the digestion time, prepurification islet counts, percent recovery, viability, and glucose stimulation insulin index. Moreover, a significant decrease in the pre- and postpurification islet yield per pancreas weight (IEQ/g) in isolations processed by two different enzyme lots used over a 15-month period was observed, suggesting a progressive deterioration of enzyme quality. CONCLUSIONS: Our data demonstrate a significant lot-to-lot related variability in islet isolation outcomes. In addition, the over-time decline in isolation outcomes processed using a single enzyme lot was observed even when the enzyme blends were used within the expiration dating specified by the manufacturer.