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Cumulative exposure to environmental factors and chemicals can be damaging to human health. A new concept called the exposome refers to the totality of exposures and their impact on health. Professor Yukiko Minamiyama, Food Hygiene and Environmental Health Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, is exploring how lifestyle factors could reduce exposure and maintain human health and also how certain lifestyle changes could control or avoid chronic oxidative stress. She and her team are delving deeper into the concept of the exposome and chronic oxidative stress to enhance understanding and facilitate informed, beneficial changes for humankind. Minamiyama is collaborating with a leading researcher on oxidative stress Dr Toshikazu Yoshikawa, Dr Hiroshi Ichikawa of Doshisha University School of Life and Medical Sciences and Dr Shigekazu Takemura of Osaka Metropolitan University Graduate School of Medicine. Minamiyama and the team believe controlling free radicals and reactive oxygen species (ROS) can prevent or improve diseases. Although food additives are unavoidable, Minamiyama believes that consuming antioxidants could help reduce oxidative stress and disease. In one study , the researchers investigated the in vitro and in vivo effects of food additives on the male rat brain and sperm/testes, with an emphasis on oxidative stress and found that the food additive stevioside induced ROS production in sperm and resulted in sperm dysfunction. They also discovered that treatment with the antioxidant alpha-tocopherol significantly improved oxidative stress.

Pancreaticobiliary maljunction (PBM) is a congenital malformation. The reflux of pancreatic juice into the biliary tract caused by PBM plays a significant role in the development of biliary tract cancers (BTCs), such as gallbladder cancer and cholangiocarcinoma. Previous studies have demonstrated a high incidence of BTC in patients with PBM. However, there are only a few reports of patients who developed BTC after a diagnosis of PBM. We report the cases of two patients who developed gallbladder cancer after being diagnosed with PBM. They had refused treatment and were being managed with follow-up observation alone after the diagnosis of PBM and developed gallbladder cancer after several years of observation. Thus, surgical treatment should be recommended for all patients with PBM in order to prevent the development of BTC. Moreover, long-term, close, regular follow-up is necessary to facilitate the early diagnosis of subsequent BTC in patients with untreated PBM.

AIM We investigated effects of direct-acting antiviral (DAA)-induced sustained virological response (SVR) after liver resection in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) for postoperative recurrence and survival. METHODS Surgical outcomes in 18 patients with postoperative DAA-induced SVR (HCC-DAA group) were compared with those in 23 patients with preoperative DAA-induced SVR (DAA-HCC group) and those in 10 patients who did not receive DAA therapy (control group). Patients who received DAA therapy >1 year after surgery and those with recurrence

Aim This study aimed to evaluate the indications of laparoscopic repeat liver resection (LRLR) for recurrent hepatocellular carcinoma from the viewpoint of its difficulty. Methods One hundred and one patients who underwent LRLR and 59 patients who underwent open repeat liver resection (ORLR) were included. The difficulty was classified according to the preoperative predictive factors for difficult LRLR, including an open approach during previous liver resection, history of two or more previous liver resections, history of previous major liver resection, tumor near the resected site of the previous liver resection, and intermediate or high difficulty with the difficulty scoring system. We compared the surgical outcomes between the LRLR and ORLR groups based on the difficulty class (low‐ or intermediate difficiulty class, 0 to 3 predictive factors; high difficiulty class, 4 or 5 factors). Results In the low‐ or intermediate difficiulty class, intraoperative blood loss and the proportion of patients with postoperative complications were significantly lower in LRLR than in ORLR, and the duration of the postoperative hospital stay was significantly shorter in LRLR than in ORLR. In the high difficiulty class, total operative time and operative time before starting hepatic parenchymal resection were significantly longer in LRLR than in ORLR, and there were no significant differences in other surgical outcomes between the two groups. Conclusion LRLR is recommended for patients in the low or intermediate difficulty class. However, LRLR does not have an advantage with longer operative time for patients in the high difficulty class compared with ORLR., Laparoscopic repeat liver resection (LRLR) is recommended for patients in our suggested low or intermediate difficulty class. On the other hands, LRLR does not have an advantage with longer operative time for patients in the high difficulty class, compared with open repeat liver resection.

Despite the recently increasing number of elderly patients undergoing liver resection, the impact of advancing age on postoperative infections (PIs) incidence and risk remains unclear. This study aimed to investigate the impact of advancing age on PIs incidence and status. This retrospective study included 744 patients undergoing liver resection without biliary reconstruction or combined resection of other organs. Multivariable analysis with a restricted cubic spline was used to evaluate the impact of advancing age on PIs and to determine its association with PIs risk in patients undergoing open and laparoscopic liver resection (OLR and LLR, respectively). Multivariable analysis demonstrated that advancing age was significantly associated with increased PIs risk (P = 0.017). The spline curve showed that the odds ratio for PIs sharply increased starting approximately at 65 years of age. Unadjusted restricted cubic splines assessing the subcategories of PIs demonstrated that advancing age was associated with increased risks of organ/space surgical site infection and sepsis (P = 0,064 and 0.048, respectively). Multivariable analysis revealed that LLR was associated with the lower PIs risk compared with OLR (P = 0.025), whereas the lower PIs risk with LLR was not significantly obscured by advancing age (P = 0.29). Advancing age was associated with increased risk of PIs, including organ/space surgical site infections and sepsis, after liver resection especially in patients aged ≥ 65 years.

Few studies compared the oncological and biological characteristics between ampullary carcinoma (AC) and cancer of the second portion of the duodenum (DC-II), although both tumors arise from anatomically close locations.To elucidate differences in clinicopathological characteristics, especially the patterns of lymph node metastasis (LNM), between AC and DC-II.This was a retrospective cohort study of 80 patients with AC and 27 patients with DC-II who underwent pancreaticoduodenectomy between January 1998 and December 2018 in two institutions. Clinicopathological factors, LNM patterns, and prognosis were compared between the two groups.The patients with AC and DC-II did not exhibit significant differences in 5-year overall survival (66.0% and 67.1%, respectively) and 5-year relapse-free survival (63.5% and 62.2%, respectively). Compared to the patients with DC-II, the rate of preoperative biliary drainage was higher (Although there were no significant differences in the prognosis and recurrence rates between the two groups, metastases to N-He and N-Py were more frequent in patients with DC-II than in those with AC.

Background Extrahepatic recurrence and early intrahepatic recurrence of hepatocellular carcinoma after hepatic resection are indicative of poor prognoses. We aimed to develop nomograms to predict extrahepatic recurrence and early intrahepatic recurrence after hepatic resection. Methods The participants of this study were 1,206 patients who underwent initial and curative hepatic resection for hepatocellular carcinoma. Multivariate logistic regression analyses using the Akaike information criterion were used to construct nomograms to predict extrahepatic recurrence and early intrahepatic recurrence (within 1 year of surgery) at the first recurrence sites after hepatic resection. Performance of each nomogram was evaluated by calibration plots with bootstrapping. Results Extrahepatic recurrence was identified in 95 patients (7.9%) and early intrahepatic recurrence in 296 patients (24.5%). Three predictive factors, α-fetoprotein >200 ng/mL, tumor size (3–5 cm or >5 cm vs ≤3 cm), and image-diagnosed venous invasion by computed tomography, were adopted in the final model of the extrahepatic recurrence nomogram with a concordance index of 0.75. Tumor size and 2 additional predictors (ie, multiple tumors and image-diagnosed portal invasion) were adopted in the final model of the early intrahepatic recurrence nomogram with a concordance index of 0.67. The calibration plots showed good agreement between the nomogram predictions of extrahepatic recurrence and early intrahepatic recurrence and the actual observations of extrahepatic recurrence and early intrahepatic recurrence, respectively. Conclusion We have developed reliable nomograms to predict extrahepatic recurrence and early intrahepatic recurrence of hepatocellular carcinoma after hepatic resection. These are useful for the diagnostic prediction of extrahepatic recurrence and early intrahepatic recurrence and could guide the surgeon’s selection of treatment strategies for hepatocellular carcinoma patients.

研究グループは、肝細胞癌の腫瘍分化度による予後不良リスクは腫瘍サイズとともに増大することを明らかにしました。近年国内でも増加している生活習慣病などが原因となって発症する肝細胞癌ですが、肝細胞癌における腫瘍分化度と予後との関連性は一定の見解が得られておらず、欧州肝臓学会のガイドラインでも「結論に至っていない」と示されています。今回1,107例の肝細胞癌肝切除症例を対象に検討したところ、低分化型は術後予後不良因子であり、腫瘍サイズ5cmまでは予後不良リスクが急激に上昇することが分かりました。腫瘍サイズを, Introduction: The present study aimed to evaluate the effect of poor differentiation and tumor size on survival outcome after hepatic resection of hepatocellular carcinoma (HCC). / Methods: A total of 1,107 patients who underwent initial and curative hepatic resection for HCC without macroscopic vascular invasion participated in the study. Using the multivariable Cox proportional hazards regression model, we evaluated changes in hazard ratios (HRs) for the association between tumor differentiation and survival based on tumor size....

Tanaka et al. previously reported a case in which nivolumab for recurrent occupational cholangiocarcinoma resulted in complete response persisting for 26 months after discontinuation. Afterward, in that clinical trial, nivolumab was administered to two patients for recurrence. Both patients achieved complete response, suggesting that nivolumab is effective for occupational cholangiocarcinoma.

Background Cholangiocarcinoma and secondary biliary cirrhosis can develop after liver resection for hepatolithiasis and are causes of hepatolithiasis-related death. We determined potential risk factors for hepatolithiasis-related death and subsequent cholangiocarcinoma, including precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct, in patients undergoing liver resection for hepatolithiasis. Methods The study cohort included 62 patients who underwent liver resection for hepatolithiasis without concomitant cholangiocarcinoma and had surgical specimens available for pathological examination. Univariate and multivariate analyses were conducted to examine risk factors associated with subsequent cholangiocarcinoma after hepatolithiasis and hepatolithiasis-related death. In 28 patients with BilIN lesions, the specimens were immunohistochemically stained for γ-H2AX and S100P. Results In the study cohort, the causes of death were subsequent cholangiocarcinoma, biliary cirrhosis, and other diseases in 5, 3, and 7 patients, respectively. Liver atrophy, precancerous lesions, postoperative repeated cholangitis, and jaundice for ≥1 week during the follow-up period were risk factors for hepatolithiasis-related death. Multivariate analysis showed that liver atrophy and precancerous lesions were independent risk factors for hepatolithiasis-related death. Liver atrophy or precancerous lesions were also risk factors for subsequent cholangiocarcinoma by univariate analysis. The positive expression of γ-H2AX and S100P was observed in 18 and 14 of the 28 BilIN lesions, respectively. Conclusions Liver atrophy and precancerous lesions with malignant transformation were risk factors not only for subsequent cholangiocarcinoma but also hepatolithiasis-related death after liver resection for hepatolithiasis, indicating that long-term follow-up is necessary even after liver resection in patients harboring these risk factors. .

Background:Hepatic resection (HR) is not recommended for intermediate-stage hepatocellular carcinoma (HCC) by the Barcelona Clinic Liver Cancer criteria. We examined the prognostic factors of HR for intermediate-stage HCC and developed new HR criteria for intermediate-stage HCC., Methods:A total of 110 patients who underwent HR without any prior treatment for intermediate-stage HCC between January 2007 and December 2012 were enrolled at eight university hospitals. The outcomes and prognostic factors of HR were evaluated to develop new HR criteria., Results:In terms of tumor size and number, the most significant prognostic factors were within the up-to-seven criteria. Furthermore, serum albumin level ≥35 g/L and serum alpha-fetoprotein (AFP) level.

Background/purpose Aeromonas hydrophila can cause lethal infectious complications after surgery. There have been no large cohort studies of this specific to the hepato-biliary-pancreatic (HBP) field. We investigate the postoperative influence of A hydrophila infection after HBP surgery. Methods We retrospectively reviewed patients who underwent HBP surgery between 2008 and 2017 at eight university hospitals. Patients with A hydrophila isolation during perioperative management were extracted, and their postoperative courses were investigated. Results Bacterial culture examination of 10 074 patients was performed as perioperative management. Among them, 76 patients (0.75%) had A hydrophila isolation, most of whom underwent pancreatoduodenectomy (n = 38) or hepatectomy with biliary reconstruction (n = 14). There were seven mortalities after these two procedures (13.5%), five within 3 days after the onset of infection. Bile (n = 48) and abdominal drainage fluid (n = 29) were major sites of A hydrophila isolation. Typical prophylactic antibiotics, cefazolin or flomoxef, were mostly resistant. There was no mortality among patients that received sensitive antibiotics prophylactically. Conclusions Isolation of A hydrophila was low in our cases of HBP surgery, but the condition of some patients deteriorated rapidly by this infection. Although there could be several bacterial infections during management of HBP surgery, A hydrophila should not be overlooked. Preparation of appropriate prophylactic antibiotics may prevent or reduce mortality.

Objective: The present study aimed to investigate the impact of preoperative C-reactive protein to albumin (CRP/Alb) ratio on the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC). Methods: 82 patients who underwent hepatic resection for mass-forming type of ICC were evaluated. The relationship between preoperative CRP/Alb ratio and survival outcomes was investigated. Results: The optimal cutoff value of CRP/Alb ratio for assessing overall survival (OS) was determined as 0.089. Univariate analysis for recurrence-free survival (RFS) showed that CRP/Alb ratio >0.089, carbohydrate antigen 19-9 (CA 19-9) >37 U/mL, lymph node metastasis, vascular invasion, and multiple tumors were significantly associated with postoperative recurrence. On multivariate analysis, the independent prognostic factors identified were CRP/Alb ratio >0.089 (p < 0.001), lymph node metastasis (p = 0.006), and multiple tumors (p < 0.001). Univariate analysis for OS showed that CRP/Alb ratio >0.089, CA 19-9 >37 U/mL, lymph node metastasis, vascular invasion, multiple tumors, and positive surgical margin were significantly associated with overall death. On multivariate analysis, the independent prognostic factors identified were CRP/Alb ratio >0.089 (p < 0.001), lymph node metastasis (p = 0.01), and multiple tumors (p = 0.005). Conclusion: Preoperative CRP/Alb ratio may predict poor long-term outcomes after hepatic resection in patients with ICC.

Background Occupational cholangiocarcinoma (CCA) was first described in patients who were working at a printing company in Osaka, Japan. Recently, the therapeutic efficacy and safety of a PD1 inhibitor nivolumab are being evaluated in patients with occupational CCA in an investigator-initiated clinical trial. The therapeutic effects of immune checkpoint inhibitors are closely associated with immune cells. Methods Immunohistochemical analysis was performed to characterize immune cells in the tumor microenvironment of occupational CCA. The status of mismatch repair (MMR)/microsatellite instability (MSI) was also examined. Results The tumor stroma of occupational CCA was characterized by abundant infiltration of immune cells expressing CD3, CD4, CD8, CD163, FOXP3, and granzyme B. Additionally, lymphocytes expressing immune checkpoint receptors, such as PD1, CTLA4, LAG3, TIM3, and TIGIT, were frequently infiltrated. The loss of immunohistochemical expression of the MMR proteins (MLH1, MSH2, PMS2, and MSH6) was not observed in cases of occupational CCA, and MSI was not detected. Conclusions The tumor microenvironment of occupational CCA had features of immunosuppression, and the occurrence of T-cell dysfunction or exhaustion was suggested. The results provide supportive evidence for the efficacy of immune checkpoint inhibitor therapy for this disease.

This study is aimed to compare the occurrence of postoperative infections between patients with hepatocellular carcinoma (HCC) undergoing laparoscopic liver resection (LLR) and those undergoing open liver resection (OLR).This study included 446 patients who underwent initial curative liver resection for HCC 5 cm or less in size without macroscopic vascular invasion. To adjust for confounding factors between the LLR and OLR groups, propensity score matching and inverse probability weighting (IPW) analysis were performed. The incidence rates of postoperative infection, including incisional surgical site infection (SSI), organ/space SSI, and remote infection (RI), were compared between the two groups.An imbalance in several confounding variables, including period of surgery, extent of liver resection, difficult location, proximity to a major vessel, tumor size ≥ 3 cm, and multiple tumors, was observed between the two groups in the original cohort. After matching and weighting, the imbalance between the two groups significantly decreased. Compared with OLR, LLR was associated with a lower volume of intraoperative blood loss (140 vs. 350 mL, P 0.001 in the matched cohort; 120 vs. 320 mL, P 0.001 in the weighted cohort) and reduced risk of postoperative infection (2.0% vs. 12%, P = 0.015 in the matched cohort; 2.9% vs. 14%, P = 0.005 in the weighted cohort). Of the types of postoperative infections, organ/space SSI and RI were less frequently observed in the LLR group than in the OLR group in the matched cohort (1.0% vs. 6.0%, P = 0.091 for organ/space SSI; 0% vs. 6.0%, P 0.001 for RI) and in the weighted cohort (1.2% vs. 7.8%, P 0.001 for organ/space SSI; 0.3% vs. 5.1%, P = 0.009 for RI).Compared with OLR, LLR for HCC might reduce postoperative infections, including organ/space SSI and RI.

We aimed to investigate the difference in engraftment rates depending on the transplant site for a patient-derived xenograft (PDX) of pancreatic ductal adenocarcinoma (PDAC) and the effects of the microenvironment on engraftment.Frozen cancer tissues from PDAC tumors were used, and tumor fragments were directly implanted into the subcutaneous, orthotopic pancreas, peritoneum, and liver of X-linked severe combined immunodeficiency (XSCID) rats. We assessed the success of engraftment in each organ. Additionally, to evaluate the effect of the microenvironment in each organ, we performed immunohistochemical analysis.Subcutaneous transplantation was successful in 8 of 10 PDAC cases (16 of 30 rats). This was a higher rate than for other organ transplants. The vascular endothelial cells in the stroma were replaced with those from rats instead of humans. Vascular endothelial growth factor-A (VEGF-A) and cluster of differentiation-31 (CD31) was significantly more strongly expressed in the subcutaneous transplantation model (VEGF-A: p0.001, CD31: p=0.0036).The engraftment rate was significantly higher for the subcutaneous PDX model than for the orthotopic pancreatic, peritoneal, and liver PDX models. Blood vessels of the PDX stroma had been replaced by rat-derived vessels instead of the original human vessels, suggesting that angiogenesis in the PDX microenvironment may be a major factor in engraftment.

This study aimed to determine the risk factors for severe postoperative complications in patients undergoing pure laparoscopic liver resection (LLR) for tumors in the right posterosuperior (PS) segments.The study included 289 patients who underwent parenchyma-sparing pure LLR for tumors in the right PS segments at eight treatment centers between January 2009 and December 2019.Multivariate analysis revealed tumor size ≥3 cm (P = .016), segmentectomy (P = .044), and liver cirrhosis (P = .029) as independent risk factors for severe postoperative complications. The severe complication rates (2.7% vs 12.1%, P = .0025), median intraoperative blood loss (100 mL vs 150 mL, P = .001), and median operation time (248 minutes vs 299.5 minutes, P = .0013) were lower in the patients without all these three risk factors than those with at least one risk factor. The median length of postoperative hospital stay was shorter in patients with no risk factors than those with at least one risk factor (9 days vs. 10 days, P = .001).Tumor size ≥3 cm, segmentectomy, and liver cirrhosis were the risk factors for severe postoperative complications after parenchyma-sparing pure LLR for tumors in the right PS segments. Patients without these three risk factors would be appropriate candidates for safely performing parenchyma-sparing pure LLR in the right PS segments at the outset.

The incidence of postoperative adhesions is directly correlated with the difficulty level of repeat hepatectomies. However, the incidence, location, and severity of postoperative adhesions in relation to hepatectomy-related operative procedures are yet unclear.First hepatectomy-induced hard dense adhesions were evaluated from the surgical records and/or videos of 168 patients who underwent second hepatectomies.The incidence of postoperative hard dense adhesions around the liver was significantly associated with locations, such as the hepatic cut surface, dissected areas around the liver, and peri-incision peritoneum, and hepatectomy-related operative procedures, such as Pringle maneuver and cholecystectomy. The incidence of hard dense adhesions after dissection was higher around the right liver than in the left infraphrenic space. Further, the incidence of hard dense adhesions around the hepatoduodenal ligament or Morison pouch was greater than 30% even in patients who did not undergo Pringle maneuver, cholecystectomy, or hepatorenal ligament dissection. Although the incidence of hard dense adhesions of the peritoneum around the incision was higher after open hepatectomy than after laparoscopic hepatectomy, adhesion barrier use reduced the incidence of such adhesions in patients after open hepatectomy.Hepatectomy-related operative procedures such as peri-hepatic dissection, Pringle maneuver and cholecystectomy are directly associated with postoperative hard dense adhesions. However, the incidence of postoperative hard dense adhesions around the hepatoduodenal ligament and Morison pouch was high even when the above-mentioned operative procedures were not performed. These findings may help inform clinical decisions regarding the indications and sites for adhesion barrier use during hepatectomies.

Purpose We aimed to elucidate the effects of biliary stents on the survival in patients with advanced pancreatic cancer treated with modified FOLFIRINOX (mFFX). Methods We retrospectively reviewed the medical charts of patients with advanced pancreatic cancer treated with mFFX between January 2014 and April 2020. In the analysis, we compared the overall survival (OS) of patients with and those without biliary stent during the mFFX treatment, and examined the independent effect on mortality by means of propensity score-matching. Results Overall, we included 89 patients (stent group, n = 24; non-stent group, n = 65). The proportion of patients with pancreatic head cancer was significantly higher in the stent group than in the non-stent group (p

The effectiveness and extent of regional lymph node dissection in primary duodenal cancer (DC) remains unclear. This study aimed to analyze the prognostic factors and lymph node metastasis (LNM) patterns in DC. Fifty-three patients who underwent surgical resection for DC between January 1998 and December 2018 at two institutions were retrospectively analyzed. Univariate and multivariate analyses were performed on the prognostic factors of resected DC. Moreover, the relationships between depth of tumor invasion and incidence of LNM and between tumor location and LNM stations were analyzed. The five-year survival rate of the study population was 68.9%. Multivariate survival analysis demonstrated that histologic grade G2–G4, presence of LNM, pT3–4, and elevated preoperative CA19-9 were the independent poor prognostic factors. No patient with pTis–T2 had LNM. On the other hand, LNM was found in 70% of patients with pT3–4. Among 36 patients who underwent pancreaticoduodenectomy (PD), LNM around the pancreatic head was observed, regardless of the duodenal cancer site, including the duodenal bulb and the third to the fourth portion. Histologic grade G2–G4, presence of LNM, pT3–T4, and elevated preoperative CA19-9 were the independent poor prognostic factors in patients with resected DC. Our results suggested that lymph node dissection could be omitted for DC Tis–T1a. Moreover, based on the high frequency of LNM in T3–4 cases, PD with lymph node dissection in the pancreatic head region was considered necessary for T3–4 DC at any site.

Background This study aimed to evaluate the prognostic impact of alcohol abstinence on survival after hepatic resection for hepatocellular carcinoma (HCC) in patients with alcohol-related liver disease (ALD). Patients and methods In total, 92 patients with ALD-HCC who underwent initial and curative hepatic resection were identified, including 56 and 36 patients with and without alcohol abstinence, respectively. Results The 3-, 5-, and 7-year recurrence-free survival (RFS) were 46%, 43%, and 37% in the abstinence group, and 61%, 36%, and 36% in the non-abstinence group, respectively (p = 0.71). The 3-, 5-, and 7-year overall survival (OS) were 91%, 76%, and 66% in the abstinence group, and 87%, 57%, and 44% in the non-abstinence group, respectively (p = 0.023). Multivariate analysis revealed that non-abstinence was an independent prognostic factor for OS (P = 0.026). The incidence rate of liver-related death including HCC-specific death, liver failure, and renal failure in cirrhosis (hepatorenal syndrome) between the non-abstinence and abstinence groups were 41.7% vs. 19.6% (p = 0.032). Worsening of the Child–Pugh grade at intrahepatic recurrence was more frequently observed in the non-abstinence (33.3%) than that in the abstinence group (6.5%) (p = 0.039). Conclusions Alcohol abstinence might improve the long-term survival of patients with ALD-HCC undergoing hepatic resection., Highlights • Non-abstinence after surgery was an independent prognostic factor for overall survival with a 2.2-fold increased risk. • Worsening of Child–Pugh grade at intrahepatic recurrence was less frequently observed in the abstinent patients. • Hepatic resection tended to be more frequently performed for the treatment of HCC recurrence in the abstinent patients. • The incidence rate of liver-related death was significantly lower in the abstinent patients.

Introduction We conducted a retrospective study to investigate the progress of the operative outcome after laparoscopic splenectomy (LS), with a special reference to the administration of prophylactic antibiotics (PA). Methods The study included 123 patients who underwent elective LS. Operative outcomes before and after the operative procedure was standardized and the impact of treatment with PA on surgical-site infection were investigated. Results With regard to complications, wound infection developed in one (0.8%), portal trunk thrombosis in one (0.8%), pancreatic fistula in one (0.8%), postoperative bleeding in two (1.6%), pleural effusion in one (0.8%), and reoperation because of bowel injury in one (0.8%). Although morbidity did not differ between patients in the early (until the end of 2010) and late (after the beginning of 2011) periods, intraoperative blood loss was lower in patients in the late period. During the late period, no patients required conversion to open surgery. The proportion of patients with surgical-site infection did not differ between those who received PA 1 h before the start of surgery and every 3 h during surgery and those who received PA 1 h before the start of surgery, every 3 h during surgery, and twice a day for 24-72 h after surgery. Conclusion Operative outcomes after LS improved after the standardization of the operative procedure. The administration of PA 1 h before surgery and every 3 h during surgery seems to be sufficient to prevent surgical-site infection during LS.

Introduction This study aimed to investigate the predictive factors and classifications for difficulty of laparoscopic repeated liver resection (LRLR) in patients with recurrent hepatocellular carcinoma. Methods Sixty patients who underwent LRLR were included. Potential predictive factors for difficult LRLR included the approach of the previous liver resection (laparoscopic or open), the number of previous liver resections, a history of cholecystectomy in previous liver resection, the operative procedure of previous liver resection, whether the tumor was near the resected site of the previous liver resection, non-surgical treatments before the present surgery, and the difficulty scoring system for laparoscopic liver resection. The relationship between these factors and perioperative outcomes were evaluated to investigate the predictive factor for difficult LRLR. Results Univariate and multivariate analyses demonstrated that an open approach during previous liver resection, two or more previous liver resections, a history of previous liver resection with not less than sectionectomy, tumor near the resected site of the previous liver resection, and intermediate or high difficulty in the difficulty scoring system were independent risk factors for prolonged operative time and/or severe adhesion of LRLR. Three difficulty classifications were then suggested based on the number of these five predictive factors. The difficulty classification reflected operative time, intraoperative blood loss, and incidence of postoperative complication. Conclusion The difficulty of LRLR may be predicted by three difficulty classifications using five preoperative predictive factors.

Introduction We investigated the indications for laparoscopic liver resection (LLR) of mass-forming intrahepatic cholangiocarcinoma (MF-ICC), including the need for lymph node dissection for improved postoperative prognosis. Methods This study involved 36 patients who underwent surgery for solitary peripheral MF-ICC. Fifteen patients underwent LLR, and 21 underwent open liver resection (OLR). Surgical outcomes and prognostic factors were investigated to determine the indications for LLR. Results No significant differences were observed in perioperative outcomes between patients who underwent LLR and OLR. A significantly worse disease-free survival (DFS) rate was observed in patients who preoperatively had a tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) levels. A significantly worse overall survival (OS) rate was observed in patients with a tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum CA19-9 levels. Therefore, a tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum CA19-9 and CEA levels were determined to be preoperative prognostic factors. DFS and OS rates were significantly better in patients without these factors. Moreover, in six patients without these factors who underwent LLR, neither lymph node metastasis nor postoperative recurrence was observed. Conclusion A tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum CA19-9 and CEA levels are preoperative prognostic factors for peripheral MF-ICC. LLR is indicated for patients without these factors.

Aim Pancreaticobiliary maljunction (PBM) with or without congenital biliary dilatation (CBD) is a risk factor for biliary tract cancer. We investigated long‐term outcomes after biliary diversion operation with special reference to types of CBD. Methods Subjects comprised 40 adult patients who underwent biliary diversion operation for PBM without biliary tract cancer. Group A comprised 20 patients with type Ia or Ic CBD, or non‐dilated bile ducts, while group B comprised 20 patients with type IV‐A CBD. The clinical findings and postoperative outcomes were compared between groups. Results Of 40 patients, nine patients suffered from repeated cholangitis and eight of these nine patients suffered from hepatolithiasis after biliary diversion operation. Biliary tract cancer or pancreatic cancer was detected in four patients at 3 years and 2 months to 24 years after the operation. In three of these four patients, the serum concentration of carbohydrate antigen 19‐9 increased before detection of carcinoma. One patient died of hepatic failure due to repeated cholangitis. The proportions of patients with repeated cholangitis, hepatolithiasis, and re‐operation, and patients who died of biliary tract cancer, pancreatic cancer, or hepatic failure, were significantly higher in group B than in group A. The survival rate was significantly worse in group B than in group A. Conclusions Careful long‐term follow‐up with measurement of serum tumor markers is necessary after biliary diversion operation for PBM, especially in patients with type IV‐A CBD or repeated cholangitis., This study showed that careful long‐term follow‐up with measurement of serum tumor markers is necessary after biliary diversion operation for PBM, especially in patients with type IV‐A CBD who were found to have significantly less favorable outcomes.

Laparoscopic liver resection for hepatic lesions is increasingly performed worldwide. However, parenchyma-sparing laparoscopic liver resection for hepatic lesions in the right posterosuperior segments is very technically demanding. This study aimed to compare postoperative outcomes between patients undergoing laparoscopic liver resection and open liver resection for hepatic lesions in the right posterosuperior segments.In total, 617 patients who underwent liver resection of hepatic lesions in the right posterosuperior segments (segment Ⅶ or Ⅷ) at 8 centers were included in this study. We lessened the impact of confounders through propensity score matching, inverse probability weighting, and double/debiased machine learning estimations.After matching and weighting, the imbalance between the 2 groups significantly decreased. Compared with open liver resection, laparoscopic liver resection was associated with a lower volume of intraoperative blood loss and incidence of postoperative complications in the matched and weighted cohorts. After surgery, the incidence of pulmonary complication and cardiac disease was lower in the laparoscopic liver resection group than in the open liver resection group in both the matched and weighted cohorts. The odds ratios of laparoscopic liver resection for postoperative complications in the matched and weighted cohorts were 0.49 (95% confidence interval, 0.29-0.83) and 0.40 (95% confidence interval, 0.25%-0.64%), respectively. The double/debiased machine learning risk difference estimator for postoperative complications of laparoscopic liver resection was -19.8% (95% confidence interval, -26.8% to -13.4%).Parenchyma-sparing laparoscopic liver resection for hepatic lesions in the right posterosuperior segments had clinical benefits, including lower volume of intraoperative blood loss and incidence of postoperative complications.

Introduction Pancreaticobiliary maljunction (PBM) is a congenital anomaly wherein the persistent reflux of the pancreatic juice into the biliary tract induces biliary tract cancer. The prediction criteria for gallbladder carcinogenesis have been reported previously through results obtained from examining carcinogenic and non-carcinogenic cases with the parameters that classified each confluent form in PBM. This study aimed to validate these previous study results and provide new recommendations for gallbladder carcinogenesis prevention. Methods Twenty-four patients with PBM underwent hepaticojejunostomy. The prediction criteria for gallbladder carcinogenesis consist of three elements. The confluent forms that satisfied none or one of the three criteria were defined as a low score group, and those that satisfied two or three were defined as the high score group. Immunohistology and pathological search were performed on the gallbladders' sections in both groups to evaluate chronic inflammation. Results The cases with dysplasia, positive Ki67 labeling index, and gallbladder cancer were more common in the high score group and tended to have more lymphocyte infiltration. These findings indicate that the degree of inflammation and cell proliferation might be more severe in the high score group than in the low score group. Conclusions There is a close relationship between the confluent form and the histopathological findings of the gallbladder in patients with PBM. The confluent forms observed in the high score group might have an additional correlation with increased proliferation activity and subsequent malignant transformation of the gallbladder epithelium., Highlights • Pancreaticobiliary maljunction (PBM) may induce biliary tract cancer. • This is the first report showing a correlation between the form in PBM and pathological findings of the gallbladder. • We were able to show that PBM has a group with confluent forms with a strong carcinogenic tendency.

Although it has recently been reported that immune checkpoint inhibitors (ICIs) constitute effective treatment for solid tumors, the success rate in patients with intrahepatic cholangiocarcinoma is limited. We administered pembrolizumab to a patient as treatment for liver and lymph node metastases of intrahepatic cholangiocarcinoma. The patient had abundant infiltration of programmed death ligand 1-positive macrophages, cytotoxic T cells (CD8-positive lymphocytes), and programmed death 1-positive lymphocytes as well as a high combined positive score of 33.1, high-frequency microsatellite instability, and mismatch repair deficiency. These characteristics are predictive biomarkers of the efficacy of ICIs. After pembrolizumab was administered four times (triweekly administration), the carbohydrate antigen 19-9 serum level fell within the normal range, and computed tomography revealed that the size of the metastatic liver tumors and enlarged hilar lymph node had markedly decreased. However, the patient developed pruritus and exanthema on the trunk and limbs after 14 administrations and was diagnosed with bullous pemphigoid. We discontinued pembrolizumab therapy and started treatment for bullous pemphigoid. Nine months after discontinuation of pembrolizumab therapy, the patient remains alive without tumor relapse. This patient had durable response even after discontinuation of pembrolizumab therapy for multiple metastases of intrahepatic cholangiocarcinoma.

Idiopathic pulmonary fibrosis, a chronic and progressive lung disease with poor prognosis, presents with acute exacerbation. Pathophysiology and treatments for this acute exacerbation, and an appropriate animal model to perform such examinations, have not established yet. We presented a rat model for assessing acute exacerbation in cases of idiopathic pulmonary fibrosis. Wistar rats were intratracheally administered bleomycin (3 mg/kg) to induce pulmonary fibrosis. After 7 days, lipopolysaccharide (0, 0.05, or 0.15 mg/kg) was administered. In the bleomycin or lipopolysaccharide group, there were almost no change in the oxygen partial pressure, arterial blood gas (PaO

Background Vascular invasion involving a tumor thrombus in the inferior vena cava and/or right atrium is an unfavorable prognostic factor after intrahepatic cholangiocarcinoma resection. We report an intrahepatic cholangiocarcinoma case with a tumor thrombus extending from the left hepatic vein via the inferior vena cava to the right atrium. Case presentation A 58-year-old man with epigastralgia was referred to our hospital after an emergent transcatheter arterial embolization was done following the radiological diagnosis of a ruptured hepatic tumor. The serum concentrations of carcinoembryonic antigen, carbohydrate 19-9, duke pancreatic monoclonal antigen type 2, and cytokeratin-19 fragments were elevated; meanwhile those of alfa-fetoprotein and des-γ-carboxy prothrombin were within normal ranges. A contrast-enhanced computed tomography scan showed a heterogeneously enhanced tumor, 13 cm in diameter, in the left lobe of the liver, enlarged lymph nodes along the lesser curvature of the stomach, and a tumor thrombus extending from the left hepatic vein via the inferior vena cava to the right atrium. We performed a left hemihepatectomy and tumor thrombectomy under total hepatic vascular exclusion to reduce the risk of sudden death. After dissection of the liver parenchyma along the left side of the middle hepatic vein, except for the left hepatic vein, the inferior vena cava just below the right atrium could be clamped by pulling down the left lobe of the liver toward the caudal side. The thrombus could be removed by incising the inferior vena cava under total hepatic vascular exclusion. Microscopic examination showed a tubular adenocarcinoma. Immunohistochemical staining was positive for cytokeratin-7, cytokeratin-19, and epithelial membrane antigen, but negative for arginase-1, glypican-3, and hepatocyte. The patient was pathologically diagnosed with an intrahepatic cholangiocarcinoma with a tumor thrombus in the inferior vena cava. Adjuvant chemotherapy with tegafur/gimeracil/oteracil was administered for 1 year. The patient remained in good health without cancer recurrence for over 4 years after the operation. Conclusion An aggressive surgical approach may be indicated for intrahepatic cholangiocarcinoma with a tumor thrombus in the inferior vena cava and/or right atrium to avoid the risk of impending death.

As currently defined, the exposome represents the lifetime exposure measure of an individual to all potential external genetic influences and their impact on health. Although intentionally added chemicals (e.g., food additives) and food contact materials (e.g., packaging, pesticides) have been assessed for safety to some degree, the full extent to which they can affect health and reproduction has not been reported. The aim of this study was to determine the in vitro and in vivo effects of food additives on the male rat brain and sperm/testes, particularly through oxidative stress. Results from our in vitro study demonstrated that the administration of the common food additive, stevioside, a major component of the common sweetener stevia, as well as the preservatives, diphenyl and orthophenyl phenol (OPP), induced reactive oxygen species (ROS) production in sperm, and led to sperm dysfunction. These effects were inhibited by the addition of the antioxidant α-tocopherol. Moreover, OPP treatment (1/10,000 of no observed adverse effect) induced ROS production in sperm and lipid peroxidation in the epididymis and hippocampus after two weeks in vivo. Furthermore, 4-hydroxynonenal-positive cells, indicating ROS-generated protein modifications, were detected in spermatocytes in the testes and granular cell layer of the dentate gyrus in the brain. Treatment with α-tocopherol significantly improved oxidative stress. Our study suggests that certain food additives may affect sperm function and induce oxidative stress in the testes and brain, resulting in infertility and short-term memory loss, and some antioxidants may improve these dysfunctions.

This study aimed to evaluate the impact of the age-adjusted Charlson comorbidity index (ACCI) on outcomes after hepatic resection for hepatocellular carcinoma (HCC). We assessed 763 patients who underwent hepatic resection for HCC. The ACCI scores were categorized as follows: ACCI ≤ 5, ACCI = 6, and ACCI ≥ 7. A multivariate analysis showed that the odds ratios for postoperative complications in ACCI = 6 and ACCI ≥ 7 groups, with reference to ACCI ≤ 5 group, were 0.71 (p = 0.41) and 4.15 (p

Background This study aimed to evaluate the prognostic impact of the 5-5-500 rule in patients after hepatic resection for the intermediate stage of hepatocellular carcinoma (HCC; The Barcelona Clinic Liver Cancer classification [BCLC] B). Methods 177 patients had hepatic resection for BCLC-B HCC. The 5-5-500 rule was defined by tumor size ≤5 cm in diameter, tumor number ≤5, and α-fetoprotein ≤500 ng/mL. Results The 3-, 5-, and 7-year recurrence-free survival rates were 22%, 14%, and 11% in patients within the 5-5-500 rule, and 16%, 10%, and 10% in patients beyond the 5-5-500 rule, respectively (P = .015). The 3-, 5-, and 7-year overall survival rates were 72%, 47%, and 34% in patients within the 5-5-500 rule, and 52%, 31%, and 25% in patients beyond the 5-5-500 rule, respectively (P = .035). Being beyond the 5-5-500 rule and liver cirrhosis were independent prognostic factors for recurrence-free survival. For overall survival, being beyond the 5-5-500 rule, age ≥65 years, Child-Pugh class B, and anti-hepatitis C antibody positive were identified as independent prognostic factors. Conclusions The 5-5-500 rule could predict prognosis in BCLC-B patients with hepatic resection. Hepatic resection might provide survival benefit for selected patients with BCLC-B HCC within the 5-5-500 rule.

We investigated the effect of bisphenol A (BPA) on oxidative stress and tau-related proteins in adult rat brains. BPA (10 mg/L) was administered to rats for eight weeks through their drinking water. The reactive oxygen species (ROS) scavenging capacity for hydroxyl radicals in the plasma was reduced after two weeks. In the hippocampus, four and eight weeks of BPA increased the ratio of oxidized DJ-1/DJ-1 (PARK7). The ratio of phosphorylated-GSK3&beta, /GSK3&beta, and phosphorylated-AKT/AKT increased after one week of BPA treatment. The ratio of phosphorylated JNK/JNK and phosphorylated-ERK/ERK increased after eight weeks of BPA, the elevation could be related to tau phosphorylation. Protein phosphatase 2A (PP2A) in the hippocampus decreased after eight weeks of BPA treatment. At that time, SOD1 was significantly induced, but no changes in SOD2 expression were apparent in the hippocampus. Furthermore, the ratio of phosphorylated-tau (PHF-1, Ser396/ Ser404) to total tau level did not change. However, PHF-1 or other sites of tau could be phosphorylated after eight weeks in the hippocampi of rats. BPA induced systemic oxidative stress and could change ROS-induced signaling pathways in the brain. These results suggest that mitochondrial dysfunction possibly is not responsible for oxidative stress and neurodegeneration due to low doses of BPA.

Pirfenidone is a representative medication to treat interstitial pulmonary fibrosis. Researchers reported pirfenidone (>100 µg/ml) significantly suppressed fibroblast growth in vitro. However, clinically, the maximum concentration of pirfenidone in the blood is approximately 10 µg/ml. We hypothesized there might be an additional mechanism of pirfenidone to fibroblasts indirectly. Macrophages are known to control the activation of fibroblasts via the regulation of inflammatory M1 and suppressive M2 polarization. The aim of this study was to investigate the effects of pirfenidone on alveolar macrophage polarization. Rat alveolar macrophages (NR8383) were stimulated in vitro with lipopolysaccharide (LPS) + interferon (IFN)-γ, or interleukin (IL)-4 + IL-13. Expression of M1 and M2 markers and supernatant's levels of TGF-β1 were assessed after pirfenidone treatment (0-100 µg/ml). Treatment with LPS + INF-γ or IL-4 + IL-13 significantly increased the expression of M1 and M2 markers, respectively. In macrophage polarization assays, pirfenidone significantly reduced the expression of M2 markers at concentrations greater than 10 µg/ml but had no effect on the expression of M1 markers. At these concentrations, pirfenidone significantly reduced TGF-β1 levels in NR8383 culture supernatants. In rat lung fibroblasts treated with NR8383 culture supernatants, pirfenidone significantly suppressed proliferation, and the collagen mRNA and protein levels. In conclusion, our results demonstrated that pirfenidone suppressed polarization to M2 macrophages at clinically relevant concentrations and suppressed the rat lung fibroblasts fibrogenic activity.