佐久間 康成

BACKGROUND: Although congenital portosystemic shunts (CPSSs) are increasingly being recognized, the optimal treatment strategies and natural prognosis remain unclear, as individual CPSSs show different phenotypes. METHODS: The medical records of 122 patients who were diagnosed with CPSSs at 15 participating hospitals in Japan between 2000 and 2019 were collected for a retrospective analysis based on the state of portal vein (PV) visualization on imaging. RESULTS: Among the 122 patients, 75 (61.5%) showed PV on imaging. The median age at the diagnosis was 5 months. The main complications related to CPSS were hyperammonemia (85.2%), liver masses (25.4%), hepatopulmonary shunts (13.9%), and pulmonary hypertension (11.5%). The prevalence of complications was significantly higher in patients without PV visualization than in those with PV visualization (P < 0.001). Overall, 91 patients (74.6%) received treatment, including shunt closure by surgery or interventional radiology (n = 82) and liver transplantation (LT) or liver resection (n = 9). Over the past 20 years, there has been a decrease in the number of patients undergoing LT. Although most patients showed improvement or reduced progression of symptoms, liver masses and pulmonary hypertension were less likely to improve after shunt closure. Complications related to shunt closure were more likely to occur in patients without PV visualization (P = 0.001). In 25 patients (20.5%) without treatment, those without PV visualization were significantly more likely to develop complications related to CPSS than those with PV visualization (P = 0.011). CONCLUSION: Patients without PV visualization develop CPSS-related complications and, early treatment using prophylactic approaches should be considered, even if they are asymptomatic. LEVEL OF EVIDENCE: Level III.

Abstract Background Osteopenia reflects frailty and has been shown to be associated with outcomes in cancer patients. This study was undertaken to examine whether osteopenia is an independent prognostic factor in patients with esophageal cancer after resection. Methods A total of 214 patients who underwent surgery for esophageal cancer were analyzed retrospectively. Bone mineral density (BMD) of the 11th thoracic vertebra was measured by computed tomography scan, and patients classified into osteopenia and normal BMD groups with BMD &lt;160 Hounsfield units as the cutoff. Clinicopathological data and prognosis were analyzed. Results The 5‐year survival rate was 55.4% for the osteopenia group and 74.7% for the normal BMD group with a significantly worse prognosis in the osteopenia group (p = 0.0080). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.27–3.34, and p = 0.0151) along with R1/2 resection (HR 3.02, 95% CI 1.71–5.18, and p = 0.0002). Conclusion In patients with esophageal cancer undergoing resection, osteopenia may be a surrogate marker for frailty and an independent predictor of prognosis.

Background: Osteopenia is a well-known risk factor for survival in patients with hepatocellular carcinoma; however, it is unclear whether osteopenia can apply to both genders and how osteopenia is associated with cancer progression. The aim of this study was to elucidate whether osteopenia predicts reduced survival in regression models in both genders and whether osteopenia is associated with the pathological factors associated with reduced survival. Methods: This study included 188 consecutive patients who underwent hepatectomy. Bone mineral density was assessed using computed tomography (CT) scan images taken within 3 months before surgery. Non-contrast CT scan images at the level of the 11th thoracic vertebra were used. The cutoff value of osteopenia was calculated using a threshold value of 160 Hounsfield units. Overall survival (OS) curves and recurrence-free survival (RFS) were constructed using the Kaplan–Meier method, as was a log-rank test for survival. The hazard ratio and 95% confidence interval for overall survival were calculated using Cox’s proportional hazard model. Results: In the regression analysis, age predicted bone mineral density. The association in females was greater than that in males. The OS and RFS of osteopenia patients were shorter than those for non-osteopenia patients. According to univariate and multivariate analyses, osteopenia was an independent risk factor for OS and RFS. The sole pathological factor associated with osteopenia was microvascular portal vein invasion. Conclusion: Models suggest that osteopenia may predict decreased OS and RFS in patients undergoing resection of hepatocellular carcinoma due to the mechanisms mediated via microvascular portal vein invasion.

The liver and pancreas work together to recover homeostasis after hepatectomy. This study aimed to investigate the effect of liver resection volume on the pancreas. We collected clinical data from 336 living liver donors. They were categorized into left lateral sectionectomy (LLS), left lobectomy, and right lobectomy (RL) groups. Serum pancreatic enzymes were compared among the groups. Serum amylase values peaked on postoperative day (POD) 1. Though they quickly returned to preoperative levels on POD 3, 46% of cases showed abnormal values on POD 7 in the RL group. Serum lipase levels were highest at POD 7. Lipase values increased 5.7-fold on POD 7 in the RL group and 82% of cases showed abnormal values. The RL group's lipase was twice that of the LLS group. A negative correlation existed between the remnant liver volume and amylase (r = - 0.326)/lipase (r = - 0.367) on POD 7. Furthermore, a significant correlation was observed between POD 7 serum bilirubin and amylase (r = 0.379)/lipase (r = 0.381) levels, indicating cooccurrence with liver and pancreatic strain. Pancreatic strain due to hepatectomy occurs in a resection/remnant liver volume-dependent manner. It would be beneficial to closely monitor pancreatic function in patients undergoing a major hepatectomy.

Abstract Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.

Segmental grafts from living donors have advantages over grafts from deceased donors when used for small intestine transplantation. However, storage time for small intestine grafts can be extremely short and optimal graft preservation conditions for short-term storage remain undetermined. Secreted factors from mesenchymal stem cells (MSCs) that allow direct activation of preserved small intestine grafts. Freshly excised Luc-Tg LEW rat tissues were incubated in preservation solutions containing MSC-conditioned medium (MSC-CM). Preserved Luc-Tg rat-derived grafts were then transplanted to wild-type recipients, after which survival, injury score, and tight junction protein expression were examined. Luminance for each graft was determined using in vivo imaging. The findings indicated that 30-100 and 3-10 kDa fractions of MSC-CM have superior activating effects for small intestine preservation. Expression of the tight-junction proteins claudin-3, and zonula occludens-1 preserved for 24 h in University of Wisconsin (UW) solution containing MSC-CM with 50-100 kDa, as shown by immunostaining, also indicated effectiveness. Reflecting the improved graft preservation, MSC-CM preloading of grafts increased survival rate from 0% to 87%. This is the first report of successful transplantation of small intestine grafts preserved for more than 24 h using a rodent model to evaluate graft preservation conditions that mimic clinical conditions.

腸管重積型逆流防止弁付加手術を行った胆道閉鎖症(BA)において,挙上空腸狭窄が難治性胆管炎の契機となり,生体肝移植(LDLT)を施行した2例を報告する.【症例1】15歳女児.生後1ヵ月時にBAに対して肝門部空腸吻合術を施行したが,胆汁排泄不良で生後2ヵ月時に逆流防止弁付き再吻合術を施行した.術後15年時に挙上空腸狭窄による難治性胆管炎に対してイレウス管を留置したが,肝内胆管数珠状拡張と黄疸は改善せず,LDLTを施行した.【症例2】26歳男性.生後4ヵ月時にBAに対して逆流防止弁付き肝門部空腸吻合術を施行した.術後25年時に黄疸を伴う胆管炎が出現したため,挙上空腸狭窄に対してENBDチューブを留置したが,胆管炎は改善せず,LDLTを施行した.逆流防止弁は長期BAにおいて挙上空腸狭窄による難治性胆管炎の原因になることがある.(著者抄録)

Abstract It is important to assess the prognosis and intervene before and after surgery in patients with hepatocellular carcinoma. This study aims to elucidate the association of outcomes and residual liver function after hepatectomy. A total of 176 patients who underwent the initial resection for hepatocellular carcinoma between January 2011 and March 2021 at Jichi Medical University were included. Hepatic clearance of the remnant liver was measured using 99mTc-galactosyl serum albumin scintigraphy. The log-rank test was used to analyze survival using the Kaplan–Meier method. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival were calculated using Cox’s proportional hazard model. In multivariate analysis, microvascular invasion, intraoperative blood loss, and hepatic clearance of the remnant liver were independently associated with overall survival. Hepatic clearance of the remnant liver was independently associated with recurrence free survival. This is the first report to show that lower residual liver function is associated with shorter survival in patients with hepatocellular carcinoma undergoing hepatectomy. Preoperative determination of remnant liver function may allow assessment of prognosis in patients planned to undergo resection of hepatocellular carcinoma. Preservation of liver functional reserve may be crucial for improved long-term outcomes after hepatectomy.

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD. CASE REPORT: The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M. CONCLUSIONS: In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.

Background: The prognostic importance of osteopenia in patients with intrahepatic cholangiocarcinoma (ICC) undergoing hepatectomy is unclear. The aim of this study was to evaluate the impact of osteopenia on survival in patients with ICC. Methods: A total of 71 patients who underwent hepatectomy at Jichi Medical University between July 2008 and June 2022 were included in this study. Non-contrast computed tomography scan images at the eleventh thoracic vertebra were used to assess bone mineral density. The cutoff value was calculated using a threshold value of 160 Hounsfield units. Overall survival curves were made using the Kaplan–Meier method and the log-rank test was used to evaluate survival. The hazard ratio (HR) and 95% confidence interval (CI) for overall survival were calculated using Cox’s proportional hazard model. Results: In multivariable analysis, osteopenia (HR 3.66, 95%CI 1.16–14.1, p = 0.0258) and the platelet–lymphocyte ratio (HR 6.26, 95%CI 2.27–15.9, p = 0.0008) were significant independent factors associated with overall survival. There were no significant independent prognostic factors for recurrence-free survival. Conclusions: Preoperative osteopenia is significantly associated with postoperative survival in patients with ICC undergoing hepatectomy.

The success of islet transplantation in both basic research and clinical settings has proven that cell therapy has the potential to cure diabetes. Islets intended for transplantation are inevitably subjected to damage from a number of sources, including ischemic injury during removal and delivery of the donor pancreas, enzymatic digestion during islet isolation, and reperfusion injury after transplantation in the recipient. Here, we found that protein factors secreted by porcine adipose-tissue mesenchymal stem cells (AT-MSCs) were capable of activating preserved porcine islets. A conditioned medium was prepared from the supernatant obtained by culturing porcine AT-MSCs for 2 days in serum-free medium. Islets were preserved at 4°C in University of Wisconsin solution during transportation and then incubated at 37°C in RPMI-1620 medium with fractions of various molecular weights prepared from the conditioned medium. After treatment with certain fractions of the AT-MSC secretions, the intracellular ATP levels of the activated islets had increased to over 160% of their initial values after 4 days of incubation. Our novel system may be able to restore the condition of isolated islets after transportation or preservation and may help to improve the long-term outcome of islet transplantation.Abbreviations: AT-MSC, adipose-tissue mesenchymal stem cell; Cas-3, caspase-3; DAPI, 4,6-diamidino-2-phenylindole; DTZ, dithizone; ES cell, embryonic stem cell; FITC, fluorescein isothiocyanate; IEQ, islet equivalent; INS, insulin; iPS cell, induced pluripotent stem cell; Luc-Tg rat, luciferase-transgenic rat; PCNA, proliferating cell nuclear antigen; PDX1, pancreatic and duodenal homeobox protein-1; UW, University of Wisconsin; ZO1, zona occludens 1.

自己肝温存胆道閉鎖症の長期経過観察中に肝内胆管癌を認めた1例を報告する.25歳男性.日齢78にIII-a1-vの胆道閉鎖症に対して逆流防止弁付き肝門部空腸吻合術を施行した.21歳時に超音波検査で肝右葉に嚢状肝内胆管拡張を認め,bile lakeとして経過観察した.25歳時に黄疸を伴う胆管炎と肝膿瘍を疑う病変を認め,小腸内視鏡を施行し,逆流防止弁の狭窄解除を行ったが,肝門部空腸吻合部に到達できなかった.難治性胆管炎にて肝移植を考慮され,当科紹介となった.当科受診時のCA19-9が7,092U/mlと高値であり,肝右葉の腫瘍性病変に対して生検を施行し,肝内胆管癌stage IVB(腹膜播種)と診断した.門脈浸潤に対して経皮経肝的ステント留置を行い,化学療法を施行したが,化学療法開始11ヵ月時に十二指腸浸潤の消化管出血で死亡した.胆道閉鎖症の長期管理に悪性腫瘍のスクリーニングは必須である.(著者抄録)

対象は肝移植後外来フォロー中の2021年12月～2022年5月にCOVID-19陽性となった小児18例(男児8例、女児10例)で肝移植時年齢中央値0歳、感染時年齢中央値12歳、肝移植後感染時期は移植後131ヵ月であった。臨床症状は咳嗽12例(66.7%)、発熱10例(55.6%)、鼻汁8例(44.4%)、咽頭痛6例(33.3%)の順であり、重症度は全例軽症であった。COVID-19の移植医療における基本指針の第5版のガイドラインに基づき、ミコフェノール酸モフェチル(MMF)内服中の5例中2例にMMFを半量に減量する指示を行ったが、抗ウイルス薬を投与した症例はなく、全例後遺症なく治癒した。

BACKGROUND: Repeat liver transplantation (LT) for patients with the liver graft failure who underwent metallic stent placement in the previous graft hepatic vein (HV) for HV complications can be very difficult. We retrospectively reviewed the safer surgical procedures during repeat LT for patients with a metallic stent in the graft HV. CASE REPORTS: Patient 1 with biliary atresia who was treated with metallic stent placement for HV stenosis underwent a third LT form a deceased donor at the age 17 years. Patient 2 with ornithine transcarbamylase deficiency who was treated with metallic stent placement for refractory HV stenosis underwent a second LT form a deceased donor at age 9 years. In both patients, transection of the previous graft HV through an intraabdominal approach was difficult during repeat LT, and a supradiaphragmatic inferior vena cava (IVC) approach was introduced. Using a midline incision of the diaphragm, the pericardium was incised and the supradiaphragmatic IVC was encircled. After clamping the supradiaphragmatic IVC, graft hepatectomy was performed. The metallic stent was successfully removed breaking, and HV reconstruction was performed on the suprahepatic IVC. Both patients did well without serious HV complications after repeat LT. CONCLUSIONS: The surgical technique for the supradiaphragmatic IVC approach is useful to decrease the risk of fatal operative complications during repeat LT for patients with a metallic stent in the graft HV.

肝移植領域でのエベロリムス(EVR)の使用経験例は少ない。またEVRは移植臓器である肝臓で代謝されることに加えて、初期投与量設定に用いる指標がないため速やかに目標血中濃度に到達させるのが難しい現状がある。今回、タクロリムス(Tac)の薬物動態に基づいたEVRの初期投与量設計の可能性を見出すため、自治医科大学附属病院におけるEARとTacの薬物動態の相関関係を検討した。方法として、EVRとTacの血中濃度(ng/mL)を1日投与量(mg/day)で除したC/D比を算出し、相関関係を後方視的に検討した。結果は患者間でEVRの1日投与量と血中濃度の相関関係はなく(r=0.3615、p=0.169)、EARとTacのC/D比に正の相関関係が得られた(r=0.7472、p<0.001)。肝移植症例におけるTacとEVRの薬物動態には相関関係があるため、今後、EVR投与量設計の参考になると思われた。(著者抄録)

肝移植後胆道合併症は依然として発症率が高く、予後に影響する重要な合併症である。胆道合併症は胆管狭窄、胆汁瘻に大別されるが、肝内結石はまれであり、とくに小児肝移植後肝内結石の診断・治療は確立されていない。小児肝移植症例の胆道再建は胆管空腸吻合がほとんどであるため、胆道合併症に対する治療は経皮経肝的胆道ドレナージ(PTBD)下カテーテル治療か外科的治療に限られていた。近年、ダブルバルーン小腸内視鏡(DBE)の改良とデバイスの進歩により、小児肝移植後胆道合併症においてもDBE下カテーテル治療が可能になってきている。低侵襲治療であるDBE下治療により、小児肝移植後肝内結石に対しても早期発見治療が可能となり、今後長期予後の向上が期待できる。(著者抄録)

BACKGROUND: Osteopenia is defined as low bone mineral density (BMD) and has been shown to be associated with outcomes of patients with various cancers. The association between osteopenia and perihilar cholangiocarcinoma is unknown. The aim of this study was to evaluate osteopenia as a prognostic factor in patients with perihilar cholangiocarcinoma. METHODS: A total of 58 patients who underwent surgery for perihilar cholangiocarcinoma were retrospectively analyzed. The BMD at the 11th thoracic vertebra was measured using computed tomography scan within one month of surgery. Patients with a BMD &lt; 160 HU were considered to have osteopenia and b BMD ≥ 160 did not have osteopenia. The log-rank test was performed for survival using the Kaplan-Meier method. After adjusting for confounding factors, overall survival was assessed by Cox's proportional-hazards model. RESULTS: The osteopenia group had 27 (47%) more females than the non-osteopenia group (p = 0.036). Median survival in the osteopenia group was 37 months and in the non-osteopenia group was 61 months (p = 0.034). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival in patients with perihilar cholangiocarcinoma (hazard ratio 3.54, 95% confidence interval 1.09-11.54, p = 0.036), along with primary tumor stage. CONCLUSIONS: Osteopenia is associated with significantly shorter survival in patients with perihilar cholangiocarcinoma.