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Background: The aim of this study was to evaluate the effectiveness and safety of TJ-100 TSUMURA Daikenchuto (DKT) Extract Granules in preventing post-hepatectomy digestive symptoms and the effects on small intestinal mucosal atrophy. Methods: Eligible patients were randomly assigned to the DKT therapy and usual care groups in a 1:1 ratio. The DKT therapy group was administered DKT for 14 days after surgery or until the day of discharge if the patient left the hospital before 14 days, and the usual care group did not receive DKT. We used the numeric rating scale to measure abdominal pain and bloating after surgery and compared the results between the two groups to determine the efficiency of DKT. We also evaluated postoperative small intestinal mucosal atrophy using diamine oxidase (DAO) and glucagon-like peptide-2 (GLP-2) activities in the serum, and postoperative complications. Results: No adverse effects were observed in the DKT group. No significant difference was observed in the area under the curve for postoperative abdominal pain or bloating throughout the study period. No differences were observed in DAO2, GLP2, and other nutrition assessment indicators. Four postoperative infections were observed in three patients (two with intra-abdominal surgical site infections [SSIs] and two with pneumonia). All cases of infection occurred in the control group. Conclusions: Although DKT did not significantly improve postoperative symptoms, such as abdominal pain or bloating, it is widely used in Japan to improve bowel movement and is safely prescribed for patients undergoing hepatectomy with a tendency toward less postoperative infection.

Background & Aims: Polystyrene microplastics (PS-MPs) are pervasive in our daily life and can be ingested by the human body through bioaccumulation, causing organ damage, especially liver damage. However, the effect of PS-MPs bioaccumulation on human hepatotoxicity and their metabolism remains unclear. Recent studies have demonstrated that PS-MPs cause lipid and bile acid metabolism disorders. The human hepatobiliary organoids (HBOs) regenerated from chemically induced liver progenitor cells converted by mature hepatocytes and the bile duct provides a bioengineering model for liver disease and hepatic metabolism. Approach & Results: Exposure of HBOs to PS-MPs with a diameter of 1 µm for 48 h causes hepatotoxicity, hepatocyte damage, and changes in bile acid metabolism. PS-MPs could be accumulated into the bile ducts of HBOs, which can be promoted by ursodeoxycholic acid, increasing bile flow and volume by activating the bile transporter of BSEP in a dose-dependent manner along with MRP-2. The accumulation of PS-MPs in the bile duct was able to be inhibited by the bile transporter inhibitor of troglitazone that could inhibit the transporters of BSEP and MRP-2, which increased the hepatotoxicity caused by PS-MPs. Conclusions: This study provides insights into the metabolic pathways of PS-MPs in the liver and suggests potential therapeutic strategies to reduce MP-induced liver damage.

Abstract Background Liver disease imposes a significant medical burden that persists due to a shortage of liver donors and an incomplete understanding of liver disease progression. Hepatobiliary organoids (HBOs) could provide an in vitro mini-organ model to increase the understanding of the liver and may benefit the development of regenerative medicine. Methods In this study, we aimed to establish HBOs with bile duct (BD) structures and mature hepatocytes (MHs) using human chemically induced liver progenitor cells (hCLiPs). hCLiPs were induced in mature cryo-hepatocytes using a small-molecule cocktail of TGF-β inhibitor (A-83-01, A), GSK3 inhibitor (CHIR99021, C), and 10% FBS (FAC). HBOs were then formed by seeding hCLiPs into ultralow attachment plates and culturing them with a combination of small molecules of Rock-inhibitor (Y-27632) and AC (YAC). Results These HBOs exhibited bile canaliculi of MHs connected to BD structures, mimicking bile secretion and transportation functions of the liver. The organoids showed gene expression patterns consistent with both MHs and BD structures, and functional assays confirmed their ability to transport the bile analogs of rhodamine-123 and CLF. Functional patient-specific HBOs were also successfully created from hCLiPs sourced from cirrhotic liver tissues. Conclusions This study demonstrated the potential of human HBOs as an efficient model for studying hepatobiliary diseases, drug discovery, and personalized medicine.

Background. Patients undergoing liver transplantation are in a state of coagulopathy before surgery because of liver failure. Intraoperative hemorrhage, massive transfusions, and post–reperfusion syndrome further contribute to coagulopathy, acidosis, and hypothermia. In such situations, temporary cessation of surgery with open abdominal management and resuscitation in the intensive care unit (ICU), which is commonly used as a damage control strategy in trauma care, may be effective. We assessed the outcomes of open abdominal management in liver transplantation and the corresponding complication rates. Methods. We retrospectively reviewed the outcomes of patients undergoing open abdominal management among 250 consecutive liver transplantation cases performed at our institution from 2009 to 2022. Results. Open abdominal management was indicated in 16 patients. The open abdomen management group had higher Model for End-stage Liver Disease scores (24 versus 16, P

Abstract Background Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP). Methods This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP. Discussion If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy. Trial registration This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].

Abstract Background Thyroid storm can be complicated by liver dysfunction, which may occasionally progress to acute liver failure. We herein report a case of acute liver failure following thyroid storm that was treated with living donor liver transplantation after resuscitation from cardiopulmonary arrest. Case report The patient was a woman in her 40 s who had been diagnosed with an abnormal thyroid function. She suffered from fatigue and vomiting, and was found to have consciousness disorder, a fever, and tachycardia with a neck mass. She was diagnosed with thyroid storm and was referred to our hospital. After arrival, she went into cardiopulmonary arrest and veno-arterial extracorporeal membrane oxygenation was initiated. In addition to treatment for thyroid storm with antithyroid drugs, steroids, and plasma exchange, extracorporeal life support was required for 5 days. However, despite improvements in her thyroid function, her liver function deteriorated. We planned living donor liver transplantation for acute liver failure after ensuring the recovery and control of the thyroid function following total thyroidectomy. The donor was her husband who donated the right lobe of his liver. Although she experienced acute cellular rejection after surgery, and other complications—including intra-abdominal hemorrhaging and ischemic changes in the intestine—her liver function and general condition gradually improved. One year after living donor liver transplantation, the patient was in a good condition with a normal liver function. Conclusions To our knowledge, this is the first report of living donor liver transplantation in a patient with acute liver failure following thyroid storm. Liver transplantation should be recognized as an effective treatment for acute liver failure following thyroid storm.

We previously reported the efficacy of chemically induced liver progenitors (CLiP) as a source of cells for transplantation in patients with liver disease. This study aimed to characterize CLiP derived from steatotic livers using a pig model for future clinical applications. Livers were removed from miniature pigs with diet-induced steatosis and normal livers by laparoscopic hepatectomy. Mature hepatocytes (MH) isolated from the livers of each group were cultured in differentiation medium composed of Y-27632, A-83-01, and CHIR99021 (YAC medium). The characteristics of CLiP, including liver-specific function, proliferative capacity in vivo, and extracellular vesicles (EVs) production, were evaluated. Although CLiP in both groups expressed hepatic progenitor cell markers (Epithelial cell adhesion molecule and Trophoblast cell surface antigen 2), the proliferative potential was higher for the disease group than the healthy group. In contrast, markers of functional MH after re-differentiation were only detected in the healthy group. Both groups showed high cell viability and the ability to differentiate into albumin-positive cells in vivo. EVs counts were lower in disease-derived CLiP than in the normal group; however, there were no differences in microRNA expression within EVs. Using a pig model, CLiP was successfully produced from a liver that reproduced steatotic liver disease. Although there were slightly fewer EVs from CLiP in the disease group than in the normal liver group, the in vivo proliferative capacity of CLiP was high. Therefore, CLiP induced in the steatotic liver are a promising source for cell therapy in patients with liver disease.

Background Can Background be changed from bold to normal text?: Chemically-induced liver progenitors (CLiPs) have promising applications in liver regenerative medicine. We aimed to clarify the efficacy of CLiPs for ameliorating fibrosis in a diet-induced nonalcoholic steatohepatitis rat model, since nonalcoholic fatty liver disease is currently recognized as the most common form of chronic liver disease in developed countries. Methods: Primary mature hepatocytes were isolated from 7-week-old male Wistar rats. To establish CLiPs, isolated hepatocytes were cultured in differentiation medium composed of Y-27632, A-83-01, and CHIR99021 (YAC medium). As an animal model that reproduces NASH pathophysiology, 6-week-old severe combined immunodeficient (SCID) mice were carefully selected and prepared and fed with choline-deficient, L-amino acid-defined, high-fat diet (HFD). After 12 weeks’ HFD feeding, the mice were assigned to continue HFD with or without the administration of rat CLiPs (HFD + CLiPs and HFD-CLiPs, respectively). Rat CLiPs were administered from the spleen. Hepatic fibrosis was semi-quantitatively evaluated according to histology. Liver parenchyma and blood samples were collected for biochemical analyses. Results: Rat CLiPs were positive for CK19 and EpCAM were successfully delivered to the liver. At 8 weeks after CLiPs transplantation, the HFD + CLiPs group showed significantly less positive staining than the HFD-CLiPs group. Alanine aminotransferase significantly improved in the HFD + CLiPs group, as demonstrated by Azan staining and αSMA immunostaining. RT qPCR showed that the liver expression of MMP2 and 9 tended to be higher in the HFD + CLiPs group. Conclusions: The anti-fibrotic effect of CLiPs was demonstrated in the immunodeficient NASH animal model and may have therapeutic applications in humans.

Background: The intrahepatic bile ducts (BDs) play an important role in the modification and transport of bile, and the integration between the BD and hepatocytes is the basis of the liver function. However, the lack of a source of cholangiocytes limits in vitro research. The aim of the present study was to establish three-dimensional BDs combined with human mature hepatocytes (hMHs) in vitro using chemically induced human liver progenitor cells (hCLiPs) derived from hMHs.Methods: In this study, we formed functional BDs from hCLiPs using hepatocyte growth factor and extracellular matrix. BDs expressed the typical biliary markers CK-7, GGT1, CFTR and EpCAM and were able to transport the bile-like substance rhodamine 123 into the lumen. The established three-dimensional BDs were cocultured with hMHs. These cells were able to bind to the BDs, and the bile acid analog CLF was transported from the culture medium through the hMHs and accumulated in the lumen of the BDs. The BDs generated from the hCLiPs showed a BD function and a physiological system (e.g., the transport of bile within the liver) when they were connected to the hMHs.Conclusion: We present a novel in vitro three-dimensional BD combined with hMHs for study, drug screening and the therapeutic modulation of the cholangiocyte function.

Portal vein thrombosis following liver transplantation is generally managed by endovascular treatment. Although several techniques are available for portal venous access, trans-splenic access is of interest because it avoids damage to the liver graft. However, the spleen cannot be punctured to access the portal vein after splenectomy. We herein report a case of portal vein thrombosis following living donor liver transplantation with simultaneous splenectomy successfully treated by percutaneous intervention with direct puncture of the retropancreatic splenic vein. The splenic vein was punctured under computed tomography guidance in the prone position. Portal venography revealed a contrast defect due to a thrombus in the extrahepatic to intrahepatic portal vein. The portal vein was reopened after thrombectomy, and the portal vein thrombosis did not recur for 2 y. The technique and advantages of our approach are described.

Background and purposeSerum glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) is a marker of liver fibrosis and hepatocellular carcinoma (HCC). In this study, we aimed to evaluate the diagnostic ability of WFA+-M2BP for occult HCC, which current diagnostic imaging tests fail to detect.MethodsPatients who underwent hepatectomy for liver transplantation (LT) and whose whole liver could be sliced and subjected to histological examination between 2010 and 2018 were eligible for this study (n = 89). WFA+-M2BP levels were measured in samples collected before the LT. Comparison of the postoperative histological test results with the preoperative imaging data grouped the patients into histologically no group (N), histologically detected group (D), histologically increased group (I), and histologically decreased or same group (DS), and the results were compared with the WFA+-M2BP values. In addition, comparisons were made between each data with and without HCC, including occult HCC, and total tumor diameter.ResultsIrrespective of underlying hepatic disease conditions, there were 6 patients in the N group, 10 in the D group, 41 in the I group, and 32 in the DS group. The median of the serum WFA+-M2BP level for each group was as follows: N group, 8.05 (1.25-11.9); D group, 11.025 (1.01-18.21); I group, 9.67 (0.29-17.83); and DS group, 9.56 (0.28-19.44) confidence of interval. We found no significant differences between the pairings. Comparison of underlying hepatic diseases revealed that liver cirrhosis due to hepatitis B and C and non-B and -C liver cirrhosis had no significant differences. AFP levels, on the other hand, had significant relationships in comparison between the presence or absence of histological HCC, in correlation between total tumor diameter, and in the ROC analysis for the diagnosis of HCC including occult HCC.ConclusionSerum WFA+-M2BP cannot help diagnose occult HCC that is already undetected using imaging tests in decompensated liver cirrhosis patients requiring LT.

Background: It remains to be clarified whether combined hepatectomy and microwave ablation for multifocal hepatocellular carcinoma (HCC) is feasible. This aim of this study was to examine the perioperative and oncological outcomes after combined hepatectomy and microwave ablation for multifocal HCC. Methods: This retrospective study included 81 patients who underwent combined hepatectomy and microwave ablation for multifocal HCC in our institute between June 1998 and December 2017. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis. Results: Median follow-up time was 45.6 months for the entire cohort. OS rates were 1-year: 96%, 3-year: 72%, and 5-year: 54%; RFS rates were 1-year: 77%, 3-year: 37%, and 5-year: 22%. The major complication rate (Clavien–Dindo classification IIIa or above) after surgery was 10%, with one patient of in-hospital mortality. Multivariate analysis revealed that des-γ-carboxy prothrombin level >200 mAU/mL and >5 tumors were independent risk factors for OS, and des-γ-carboxy prothrombin level >200 mAU/mL, > 5 tumors, and maximum tumor size >5 cm were independent risk factors for RFS. Conclusions: Our results indicate that combined hepatectomy and microwave ablation is safe and feasible for selected patients with multifocal HCC.

Abstract Background Glomus tumors (GTs) are mesenchymal neoplastic lesions arising from the glomus bodies and generally occur in the fingers and toes. Gastrointestinal GTs are rare, and most of them originate from the stomach; however, GT arising from the duodenum is exceedingly rare. Case presentation A 68-year-old man was admitted due to abdominal pain. Endoscopy showed a round, smooth, elevated mass in the second portion of the duodenum with central ulceration. Abdominal contrast computed tomography showed a hypervascular tumor measuring 26 mm in diameter in the second portion of the duodenum, and pancreatic invasion was suspected. Endoscopic ultrasonography of the lesion confirmed a hypoechoic mass arising from the fourth layer of the duodenal wall. A biopsy was performed for central ulceration, and immunochemical studies showed positive results for smooth muscle actin (SMA) and negative results for S100, C-Kit, and CD34. Leiomyoma or gastrointestinal stromal tumor was suspected and pancreatoduodenectomy was performed. The specimen exhibited a vascular-rich tumor, 24 × 24 × 19 mm in size, with deep ulceration in the duodenum. Histological examination showed uniform small round cells with central nuclei and a pale cytoplasm (glomus cell) with perivascular proliferation. Immunochemical studies showed that the tumor was positive for SMA and collagen type IV, and negative for C-Kit, CD34, desmin, and S100. We diagnosed the tumor as a GT of the duodenum. Conclusion GTs of the duodenum are exceedingly rare, but should be considered in the differential diagnoses of duodenal submucosal lesions.

Abstract Background Gastroenteric neuroendocrine carcinomas (NECs) account for 6.2% of gastroenteric neuroendocrine tumors (NETs), and only 1% or less of gastroenteric NETs occur in the ampulla of Vater (AoV). Clinical features of NEC of the AoV remain obscure. Case presentation A 65-year-old man visited a general practitioner because of jaundice, and an abdominal contrast-enhanced computed tomography scan revealed a tumor of 11 mm in diameter, which was enhanced in the arterial phase at the duodenal papilla, with dilation of the upstream bile duct. Gastrointestinal scope revealed an unexposed tumor of the AoV. Based on a biopsy of the site, a moderately differentiated tubular adenocarcinoma was suspected, and pancreatoduodenectomy was performed. Histopathological examination revealed dysplasia and highly proliferative small tumor cells, with solid and nodular formation at the AoV. Histological analysis showed a high mitotic count, and immunohistochemical staining revealed a Ki-67 index of 40–50% and cells positive for synaptophysin, chromogranin A, and p53. Small cell-type NEC was finally diagnosed. Four months post pancreatoduodenectomy, multiple liver metastases developed, and systemic chemotherapy was administered. Salvage liver resection for liver metastases was performed 14 months after the pancreatoduodenectomy. Unfortunately, multiple liver metastases developed 2 months after liver resection, and the patient died 18 months after the pancreatoduodenectomy. Conclusions Neuroendocrine carcinoma originating from the bile duct is very rare; therefore, in this article, we provide a review of the literature and a case report.

A 73-year-old male was initially treated with sorafenib for advanced stage HCC. However, the disease progressed 2 months after starting sorafenib. Progressive disease (PD) was confirmed by radiological examination, which revealed mediastinal and abdominal lymph node metastasis, pulmonary metastasis, and intrahepatic recurrence. The patient was enrolled in the REACH-2 (NCT02435433) trial and randomized to receive ramucirumab (8 mg/kg div. every 2 weeks). The patient had a Child–Pugh score of 6A and his AFP level was found to be 1,256.8 ng/mL at initiation. Radiological examination revealed PD, 5 months after starting ramucirumab. Ramucirumab treatment was continued after the confirmation of radiological PD, not but clinical progression, as allowed by the study protocol. His AFP level increased after continuous ramucirumab treatment, however, it suddenly decreased from 7,653 ng/mL to within normal limits 10 months after initiation of ramucirumab treatment. Radiological evaluation revealed a significant decrease in the size of the tumors, which constituted a partial response (PR). We reported a rare case of advanced HCC with PR to a continuous ramucirumab treatment after radiological PD.

Abstract Background Schistosomiasis is prevalent in tropical and subtropical areas and rarely reported in developed countries. Schistosomiasis often occurs as a chronic illness, which can cause liver and intestinal damage. Appendicitis is an unusual complication of schistosomiasis. We herein present a case of acute appendicitis associated with the presence of schistosome eggs in a sailor from the Philippines. Case presentation A 34-year-old Filipino man who worked as a sailor presented to our hospital with a 2-day history of acute right lower quadrant abdominal pain and fever. A physical examination revealed right lower quadrant abdominal pain with signs of peritoneal irritation, including rebound tenderness. Computed tomography revealed thickening of the appendix associated with mural calcification and fluid collection around the cecum. Based on these findings, the preoperative diagnosis was acute appendicitis. Laparoscopic appendectomy was performed. Swelling of the appendix and contaminated ascites were observed intraoperatively, but there was no evidence of appendiceal perforation. A histopathological examination showed inflammation of the appendix wall and numerous ovoid bodies present within the submucosa, many of which were calcified. Severe infiltration of lymphocytes and fibrosis were recognized around the oval bodies. The numerous oval bodies were morphologically consistent with schistosomiasis. The final diagnosis was acute phlegmonous appendicitis associated with the presence of schistosome eggs. We examined the patient for signs of adult worm activity, but the results of stool ova and parasite examinations performed twice were negative. He was discharged and returned to his country on postoperative day 9. Conclusions The incidence of schistosomal appendicitis, which is seldom reported in developed countries, is expected to increase in Japan in the near future. Clinicians should suspect schistosome eggs as a cause of acute appendicitis in patients who have emigrated from or are traveling from endemic areas, and when mural calcification of the appendix is observed on imaging.

Background. Given the expected increase in the number of elderly recipients, details regarding how clinical factors influence the outcome in living donor liver transplantation (LDLT) for the elderly remain unclear. We examined the survival outcomes according to the results of donor age-based and graft volume–based analyses and assessed the impact of prognostic factors on the survival after LDLT for elderly recipients. Methods. The 198 adult recipients were classified into 2 groups: an elderly group (n = 70, E group; ≥ 60 years of age) and a younger group (n = 128, Y group;

We herein present a case of hepatic cysts causing obstructive jaundice that was treated with single-incision laparoscopic deroofing. A 72-year-old female patient was referred to hospital due to a large hepatic cyst that compressed the intrahepatic bile ducts. The patient was scheduled to undergo single-incision laparoscopic deroofing. The EZ ACCESS™ oval type (Hakko Co. Ltd.) was placed at the umbilicus using a 25-mm incision with two 5-mm trocars. An additional 12-mm port was placed at the left epigastric region. We unroofed and excised the cyst wall using a vessel sealing system in liver segment 4. After surgery, the patient was found to be asymptomatic. The unroofed cysts were completely diminished. Notably, the remnant liver had fairly regenerated. The estimated regeneration volume of the normal liver was 153 cm3. To prevent surgical complications, clinicians should perform adequate management and use of devices. To prevent postoperative recurrence of cysts, performing complete deroofing is essential. Single-incision laparoscopic deroofing contributes to improving the quality of life of patients and should be considered a standard treatment.

Recently, materials made of natural resources have been gaining attention. In particular, high expectations are placed on bamboo fiber. However, conventional bamboo fiber extraction techniques have problems, primarily involving quality, accuracy, and efficiency. To solve these problems, a new method of obtaining bamboo fibers with a machining center (MC) is proposed. NC programs are designed according to a cutting theory based on a geometrical tool path for cylindrical work. The experimental results verify that fiber shape can be controlled by adjusting the appropriate end-milling conditions with a spiral tool path. The fiber length is influenced by the axial depth of the cut, while the fiber diameter is influenced by the vascular bundle size, which is a component of bamboo. Therefore, considering the direction and size of the bamboo components, the desired bamboo fibers can be obtained with high quality and accuracy using end-milling with an MC.