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Purpose: To clarify whether the preoperative lymphocyte/C-reactive protein (CRP) ratio (LCR) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (IHCC), and investigate its mechanism via tumor-infiltrating lymphocytes., Methods: The subjects of this retrospective study were 42 patients who had undergone hepatectomy for IHCC. We divided the patients into low LCR and high LCR groups (cutoff value: 8780) and analyzed their overall survival (OS) and disease-free survival (DFS) with respect to LCR and other clinicopathological factors. We also investigated the levels of stromal tumor-infiltrating lymphocytes (TILs) and CD8 + TILs in surgical specimens, and the relationship between LCR and TILs., Results: A low LCR was identified in 21 patients and was significantly correlated with older age, a high CRP-albumin ratio, and advanced disease stage, and was a prognostic factor for OS and DFS. Multivariate analysis revealed that a low LCR was an independent prognostic factor for worse OS (HR 10.40, P = 0.0077). Although the LCR and levels of stromal TILs were not significantly related, LCR and levels of CD8 + TILs were significantly related (P = 0.0297)., Conclusion: The preoperative LCR may predict the postsurgical prognosis of patients with IHCC and reflect the CD8 + TILs., (© 2021. Springer Nature Singapore Pte Ltd.)

Purpose: Epigallocatechin 3-gallate (EGCG), a green tea polyphenol, has been shown to have anti-oxidant and anti-inflammatory effects in vitro and in vivo. The aim of this study was to investigate the effects and mechanism of EGCG on isolated pancreatic islets as pre-conditioning for pancreatic islet transplantation., Methods: The pancreatic islets were divided into two groups: an islet culture medium group (control) and an islet culture medium with EGCG (100 µM) group. We investigated the islet viability, Nrf2 expression, reactive oxygen species (ROS) production, and heme oxygenase-1 (HO-1) mRNA. Five hundred islet equivalents after 12 h of culture for the EGCG 100 µM and control group were transplanted under the kidney capsule of streptozotocin-induced diabetic ICR mice., Results: The cell viability and insulin secretion ability in the EGCG group were preserved, and the nuclear translocation of Nrf2 was increased in the EGCG group (p < 0.01). While the HO-1 mRNA levels were also higher in the EGCG group than in the control group (p < 0.05), the ROS production was lower (p < 0.01). An in vivo functional assessment showed that the blood glucose level had decreased in the EGCG group after transplantation (p < 0.01)., Conclusion: EGCG protects the viability and function of islets by suppressing ROS production via the Nrf2 pathway.

Purposes: The number of patients with nonalcoholic fatty liver disease (NAFLD) is increasing. Hepatic steatosis is a major risk factor for hepatic failure after ischemia-reperfusion (I/R) injury. Hydrolyzed whey peptide (HWP) is a functional liquid-type nutritional diet containing whey peptide, which has previously been shown to exert anti-inflammatory effects. In the present study, we examined the effects of HWP on the hepatic I/R injury in a rat NAFLD model., Methods: Rats fed a methionine/choline-deficient diet for 4 weeks were divided into two groups after 30 min of whole liver ischemia. In Group-M, HWP was given immediately after reperfusion and every 6 h thereafter. In Group-C, the vehicle was given in the same manner. The liver function tests and microscopic findings of the liver after reperfusion were compared between the two groups., Results: The serum transaminase levels in Group-M were significantly lower than those in Group-C after reperfusion. The gene expression levels of IL-6 and inducible nitric oxide synthase (iNOS) were significantly lower in Group-M compared to Group-C. The TNF-α and uncoupling protein-2 (UCP-2) expression levels were also markedly lower in Group-M. The hepatic necrotic areas in Group-M were significantly smaller than those in Group-C., Conclusion: The administration of a HWP diet ameliorated the hepatic I/R injury in rats with NAFLD.

Purpose: Laparoscopic liver surgery is widely performed around the world, and surgeons recognize its feasibility. We herein report the current status of laparoscopic liver surgery in Japan., Methods: A questionnaire survey was conducted at 761 hospitals, including 41 member hospitals of the Japanese Endoscopic Liver Surgery Study Group and 720 facilities certified by the Japanese Society of Gastroenterological Surgery. Four hundred ninety-one hospitals responded to the questionnaire (response rate: 64 %). The data collected from 2,259 patients in 124 hospitals that reported performing laparoscopic liver resection were used. The surgical procedures and intraoperative complications, including the rate of conversion to open surgery, and morbidity rates were analyzed., Results: Pure laparoscopic procedures were performed in 1,346 patients (59.6 %), hand-assisted procedures in 174 (7.7 %) and hybrid procedures in 739 (32.7 %). Laparoscopic hepatectomy was performed in 1,982 patients (87.7 %): hemihepatectomy in 141 (7.1 %), sectionectomy in 87 (4.4 %), left lateral sectionectomy in 208 (10.5 %), segmentectomy in 91 (4.6 %) and non-anatomical partial resection in 1,248 (63.0 %). A total of 45 procedures (2.3 %) were converted to conventional open surgery. Postoperative complications occurred in 91 patients (4.6 %)., Conclusions: Laparoscopic liver surgery is a safe, feasible procedure for treating liver disease in carefully selected patients.

Background and Aims: Whey protein, a protein complex derived from milk is well known as a functional food with a number of health benefits. MEIN(®) (Meiji Dairies Co., Tokyo Japan) is a functional liquid-type nutritional diet containing whey-hydrolyzed peptide. In this study, we examined the effects of MEIN(®) on postoperative liver dysfunction in patients who underwent living donor-related liver transplantation (LDLT)., Methods: Sixteen adult patients transplanted between 2005 and 2011 at our institute were evaluated retrospectively. In MEIN group (n = 8), administration of MEIN(®) was started around 14 days after liver transplantation when serum liver enzymes were re-elevated, while MEIN(®) was not administered in the control group (n = 8) who did not have postoperative liver dysfunction., Results: In the preoperative clinical characteristics, the model for end-stage liver disease score in the MEIN group was significantly lower than that in the control group. The graft-to-recipient body weight ratio in the MEIN group was lower than that in the control group. Elevation of enzymes in the liver function tests such as alanine aminotransferase and total bilirubin, and C-reactive protein in the MEIN group had significantly improved, and became almost normal values which were the same as those in the control group., Conclusion: These findings suggest that administration of whey-hydrolyzed peptide attenuates the post-transplant liver dysfunction and may avoid an unnecessary liver biopsy.

Purpose: Cholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tumor. It is thought to originate from the ductules and/or canals of Hering, where hepatic stem cells (HpSC) are located, but there are few reports on cancer stem cell markers in CLC. Thus, we evaluated the significance of cancer stem cell markers, including CD133, CD44, and EpCAM, in CLC., Methods: The subjects of this study were three patients with CLC and one patient with an intermediate type of combined hepatocellular cholangiocarcinoma (CHC). The cancer cell markers, CK7, CK19, and EMA, were evaluated immunohistochemically., Results: Histological examination of the CLC revealed morphologically cholangiolar features and immunohistochemical examination revealed positivity for CD133, CD44, and EpCAM. On the other hand, in the intermediate type of CHC, only CD44 was positive, whereas CD133 and EpCAM were negative., Conclusion: CLC may have stronger features derived from HpSCs than an intermediate type of CHC.

Purpose: The function of regulatory T cells (Foxp3(+)CD4(+)CD25(+) T cells: Treg) after surgery remains unspecified. We investigated the potential role of Treg as a new stress marker for various operations., Methods: Thirty-three patients who underwent various operations at our department were divided into the following three groups based on the invasiveness of their surgery: Group A, those who underwent massively invasive surgery; Group B, those who underwent moderately invasive surgery; and Group C, those who underwent minimally invasive surgery. We measured Treg levels in the peripheral blood by flow cytometry and labeling with anti-CD4, CD25, and Foxp3 antibodies on preoperative day 1 and then on postoperative days (PODs) 1 and 6. Treg subpopulations in each group on the 3 days were compared., Results: Treg subpopulations were significantly higher on POD 6 than on preoperative day 1 in all patients. In Group B, Treg subpopulations varied according to the operative procedures undertaken. For example, there were marked differences between open and laparoscopic abdominal surgery. In Group A, the Treg subpopulations tended to be increased on POD 6, although those on POD 1 were lower than those on preoperative day 1., Conclusions: These findings suggest that Treg is an efficient biomarker, indicative of the degree of surgical stress and its impact on immunological status.

Purpose: To clarify the functional involvement of hedgehog signaling, especially sonic hedgehog (Shh) and glioma-associated oncogene (Gli)-1 which are known to play an important role in embryonic development and cancer, in the regeneration of a hepatectomized rat liver., Methods: Six-week-old male Wistar rats were subjected to 70 or 90 % hepatectomy (Hx). Animals were killed at 24, 48 and 72 h after Hx. The liver/body weight ratio was measured as an index of regeneration. Formalin-fixed liver samples were embedded in paraffin, stained for immunohistochemistry with proliferating cell nuclear antigen (PCNA) antibody, and the labeling index was calculated. Immunohistochemistry was also performed with Shh and Gli-1 antibodies., Results: The liver/body weight ratio gradually increased in both the 70 and 90 % Hx, groups. The hepatocytes were strongly stained for PCNA at 24 h after Hx. Non-parenchymal cells were gradually stained by PCNA from 24 to 72 h after Hx. Shh and Gli-1 expression in hepatocytes was higher after 24 h than at other times and then gradually decreased. Shh and Gli-1 expression in non-parenchymal cells increased gradually, and was found mainly in liver zone I at 72 h after 70 and 90 % Hx., Conclusions: The expression of both markers suggested that Shh signaling contributes to tissue reconstruction after Hx.

Purpose: To assess the safety and feasibility of pancreatoduodenectomy (PD) in elderly patients, we investigated the clinical characteristics of patients aged ≥75 years, who underwent this procedure at our hospital., Methods: Between November 2005 and December 2010, 84 patients underwent PD at Tokushima University Hospital. We analyzed the clinicopathological data and outcomes after PD in patients aged ≥75 years compared with those in patients <75 years., Results: The preoperative characteristics of the elderly group (n = 28) were similar to those of the younger group (n = 56). The hemoglobin and albumin levels were significantly lower in the elderly patients (P < 0.05), who also had a higher rate of preoperative pulmonary dysfunction (P < 0.05). The operation time and intraoperative blood loss did not differ significantly between the groups, but the incidence of pneumonia was higher in the elderly group (P < 0.05). The overall survival rate did not differ significantly between the groups., Conclusion: Advanced age alone does not have an adverse effect on surgical outcomes, including postoperative complications and long-term prognosis. Therefore, PD may be justified for selected elderly patients.

Purpose: The liver-hanging maneuver (LHM) is a useful technique in major hepatectomy. We made modifications to this technique with special reference to the ligamentum venosum for performing a left hepatectomy (LH). The aim of this study was to clarify the usefulness of our new technique., Methods: Between August 2007 and May 2009, five patients underwent LH using our modified LHM and 12 patients underwent LH using a conventional procedure. The two groups were compared in terms of the patient characteristics, preoperative hepatic functions, surgical records, and outcomes., Results: The characteristics and preoperative hepatic function tests were similar between the modified LHM and non-LHM groups. Intraoperative blood loss was significantly reduced in the modified LHM group compared with the non-LHM group (193 ± 133 vs. 375 ± 167 ml, P < 0.05). The lengths of the operations and time required to perform a parenchymal transection did not differ significantly between the two groups (duration of operations 273 ± 37 vs. 337 ± 70 min; transection times 29 ± 10 vs. 28 ± 13 min). The postoperative complications and hospital stays did not differ significantly between the two groups., Conclusion: Our modified LHM can reduce the intraoperative blood loss during LH, and our results have shown the usefulness of this modified technique for LH.

Purpose: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in the metabolism of 5-fluorouracil, which have been examined as possible predictive markers. We conducted this study to clarify the role of TS and DPD expressions in gallbladder carcinoma (GBC)., Methods: The subjects were 28 patients who underwent surgical resection of GBC. We examined intratumoral TS and DPD mRNA expressions, using the Danenberg tumor profile method. The expression levels were classified into two groups, based on median values. Clinicopathological variables, including prognosis, were then compared between the high and low expression groups., Results: There was a significant difference in the incidence of lymph node metastasis between the high and low TS expression groups. The incidence of advanced clinical stage was higher in the low TS expression group than in the high TS expression group. However, no clear correlation was observed between the DPD mRNA expression and any clinicopathological variable. There was no significant difference in the postoperative survival rates between the groups, in accordance with the expression of TS or DPD genes., Conclusion: Low TS mRNA was correlated with a high incidence of lymph node metastasis and advanced clinical stage. Therefore, TS gene expression may help identify patients at increased risk of the progression of GBC.

Purpose: To investigate the prognostic factors of peripheral-type intrahepatic cholangiocarcinoma (PP-IHCC) and evaluate the surgical outcomes according to surgical strategy alterations., Methods: Twenty-two patients were divided into two groups according to the surgical strategy: an extended surgery group (Ex group: n = 10), composed of those who underwent hepatic lobectomy combined with lymph node (LN) dissection and bile duct resection; and a customized surgery group (Cx group: n = 12), composed of those who underwent hepatectomy and bile duct resection according to tumor spread. LN dissection was not performed in patients without LN metastasis., Results: Multivariate analysis revealed that R2 resection, LN metastasis, and intrahepatic metastasis were independent prognostic factors. LN dissection was significantly infrequent in the Cx group. Survival after curative resection was similar in the two groups (3-year survival: 42.9 vs. 57.1%). Liver metastasis was the most frequent primary recurrence, occurring in more than 80% of patients from both groups., Conclusions: Curative surgery might improve the prognosis of patients with PP-IHCC, but routine LN dissection is not recommended, particularly for patients without LN metastasis. Surgery alone, including LN dissection, cannot control this type of tumor, and additional treatment should be given.

Purpose: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in the metabolism of 5-fluorouracil and possible predictive markers. We conducted this study to clarify if TS and DPD gene expressions are a prognostic indicator for intrahepatic cholangiocarcinoma (IHCC)., Methods: The subjects of this study were 21 patients with IHCC who had undergone surgical resection. Intratumoral TS and DPD mRNA expressions were examined using the Danenberg tumor profile method and classified into two groups according to the median value of each. We then compared the clinicopathological variables, including prognosis, between the high and low expression groups., Results: Low DPD expression was correlated with macroscopic type, namely, mass-forming + infiltrative (P = 0.08). Postoperative survival rates in the low DPD expression group were significantly lower than those in the high DPD expression group. Multivariate analysis revealed macroscopic type to be an independent prognostic factor, whereas TS mRNA expression did not correlate with any clinicopathological variables, including prognosis., Conclusions: Low DPD mRNA expression was related to macroscopic type and associated with poor prognosis. DPD mRNA expression in tumor cells is suggested to be an important regulator of malignant behavior in IHCC.

Purpose: We describe a new technique of ultrasound (US)-guided microwave coagulation (MC) of the Glissonean pedicle, performed before transection to control the inflow and select the resection area. This report introduces our procedure and evaluates the outcomes of patients treated using this technique., Methods: The Glissonean pedicles feeding the segment or cone unit were coagulated by US-guided MC, after which transection was performed. We used this US-guided MC technique to perform anatomical resections in 12 patients with hepatocellular carcinoma (MC group). We compared the outcomes of this group with those of a historical group of 10 patients who underwent conventional hepatectomy (control group). The two groups were well matched for age, tumor size, location, and type of hepatectomy., Results: The mean operative times were similar, but the mean blood loss was significantly lower the in MC group than in the control group. Recurrence developed in four patients from the MC group, but local recurrence was not observed. Bile leakage occurred in one patient from the MC group, but the incidences of postoperative complications did not differ between the groups., Conclusions: Our procedure allows anatomical resection to be performed safely and easily, and helps prevent intrahepatic metastasis via portal flow during the transection.

Patients who undergo organ transplantation are now known to be at increased risk of the development of de novo malignant tumors. This is primarily a consequence of immunosuppression, which may promote tumor development and progression by a variety of mechanisms. It was also reported recently that the relative ratio of lung tumors developing in orthotopic liver transplantation patients was 3.7 times greater than in the general population. We report a case of de novo lung cancer diagnosed in a 65-year-old man 32 months after he underwent liver transplantation for hepatocellular carcinoma secondary to hepatitis C virus cirrhosis. He had received tacrolimus as immunosuppressive therapy after the liver transplantation. The tumor was resected, and he remains well almost 3 years later. Previous reports provide evidence that immunosuppressive therapy is a risk factor for de novo lung cancer; thus, it is important to reduce immunosuppression for orthotropic liver transplantation patients, and to screen them carefully to detect the tumor at an early stage.

Regenerative medicine is emerging as a rapidly evolving field of research and therapeutics. Stem cells hold great promise for future translational research and clinical applications in many fields. Much research has focused on mesenchymal stem cells isolated from bone marrow in vitro and in vivo; however, bone marrow procurement causes considerable discomfort to the patient and yields a relatively small number of harvested cells. By contrast, adipose tissue represents an abundant and easily accessible source of adult stem cells, termed adipose-derived stem cells (ADSCs), with the ability to equally differentiate along multiple lineage pathways. These stem cells have angiogenic properties, possibly because of their secretion of cytokines. They may also play a role in healing acute and chronic tissue damage. Subsequently, they have a wide range of potential clinical implications. This article reviews the potential preclinical and clinical applications of mesenchymal stem cells, especially ADSCs, in surgery.

It is difficult to make an accurate radiological diagnosis of a pancreatic tumor because of its location and anatomical characteristics. Mass-forming pancreatitis and pancreatic cancer are particularly difficult to differentiate. New diagnostic technology, which includes diffusion-weighted imaging-magnetic resonance imaging (DWI-MRI) and 2-[(18)F]-fluoro-2-deoxy-Dglucose positron emission tomography (FDG-PET), offers hope for the detection of classical pancreatic cancer. Few studies have been conducted on FDG-PET and DWI-MRI as tools used to distinguish between mass-forming pancreatitis and pancreatic cancers. Furthermore, positive findings of mass-forming pancreatitis on DWI-MRI and FDG-PET have yet to be documented. We report a case of a pancreatic head tumor, present on FDG-PET and DWI-MRI which, on closer examination, revealed benign mass-forming pancreatitis. We discuss the utility of FDG-PET and DWI-MRI as preoperative diagnostic tools.

The extended application of living donor liver transplantation (LDLT) has revealed the problem of graft size mismatching called "small-for-size (SFS) graft syndrome." The initial trials to resolve this problem involved increasing the procured graft size, from left to right, and even extension to include a right lobe graft. Clinical cases of living right lobe donations have been reported since then, drawing attention to the risks of increasing the liver volume procured from a living donor. However, not only other modes of increasing graft volume such as auxiliary or dual liver transplantation, but also control of the increased portal pressure caused by an SFS graft, such as a portosystemic shunt or splenectomy, have been trialed with some positive results. To establish an effective strategy for transplanting SFS grafts and preventing SFS graft syndrome, it is essential to have precise knowledge and tactics to evaluate graft quality and graft volume, when performing these LDLTs with portal pressure control. We reviewed the updated literature on the pathogenesis of and strategies for using SFS grafts.