Early Prediction of a Serious Postoperative Course in Perihilar Cholangiocarcinoma: Trajectory Analysis of the Comprehensive Complication Index.

OBJECTIVE: The aim of this study was to visualize the postoperative clinical course using the comprehensive complication index (CCI) and to propose an early alarming sign for subsequent serious outcomes in perihilar cholangiocarcinoma. BACKGROUND: Surgery for this disease carries a high risk of morbidity and mortality. The developmental course of the overall morbidity burden and its clinical utility are unknown. METHODS: Patients who underwent major hepatectomy for perihilar cholan-giocarcinoma between 2010 and 2019 were reviewed retrospectively. All postoperative complications were evaluated according to the Clavien-Dindo classification (CDC), and the CCI was calculated on a daily basis until postoperative day 14 to construct an accumulating graph as a trajectory. Group-based trajectory modeling was conducted to categorize the trajectory into clinically distinct patterns and the predictive power of early CCI for a subsequent serious course was assessed. RESULTS: A total of 4230 complications occurred in the 484 study patients (CDC grade I, n = 27; II, n = 132; IlIa, n = 290; IIIb, n = 4; IVa, n = 21; IVb, n = 1; and V, n = 9). The trajectory was categorized into 3 patterns: mild (n = 209), moderate (n = 235), and severe (n = 40) morbidity courses. The 90-day mortality rate significantly differed among the courses: 0%, 0.9%, and 17.5%, respectively (P<0.001). The cutoff values of the CCI on postoperative days 1, 4, and 7 for predicting a severe morbidity course were 15.0, 28.5, and 40.6 with areas under the curves of 0.780, 0.924, and 0.984, respectively. CONCLUSIONS: The CCI could depict the chronological increase in the overall morbidity burden, categorized into 3 patterns. Early CCI potentially predicted sequential progression to serious outcomes.

Efficacy of Extended Modification in Left Hemihepatectomy for Advanced Perihilar Cholangiocarcinoma: Comparison Between H12345'8'-B-MHV and H1234-B.

OBJECTIVE: The aim of this study was to verify the prognostic impact of the tumor exposure at the liver transection margin (LTM) in left-sided perihilar cholangiocarcinoma and the impact of middle hepatic vein (MHV) resection on this exposure. BACKGROUND: In perihilar cholangiocarcinoma, tumors are unexpectedly exposed at the LTM during left hemihepatectomy (LH). METHODS: Patients who underwent LH for perihilar cholangiocarcinoma during 2002 to 2018 were retrospectively evaluated. LH was classified into conventional and extended types, which preserved and resected the MHVs, respectively. Positive LTM was defined as the involvement of invasive carcinoma at the liver transection plane and/or the adjacent Glissonean pedicle exposed. The clinicopathologic features and survival outcomes were compared between procedures. RESULTS: Among 236 patients, conventional and extended LHs were performed in 198 and 38 patients, respectively. The LTM was positive in 31 (13%) patients, with an incidence of 14% versus 8% ( P = 0.432) and 24% versus 0% in advanced tumors ( P = 0.011). Tumor size ≥ 18 mm ( P = 0.041), portal vein invasion ( P = 0.009), and conventional LH ( P = 0.028) independently predicted positive LTM. In patients with negative LTM, the survival was comparable between the two groups: 60.4% versus 59.2% at 3 years ( P = 0.206), which surpassed 17.7% for those with positive LTM in the conventional group ( P < 0.001). Multivariable analysis demonstrated that LTM status was an independent prognostic factor ( P = 0.009) along with ductal margin status ( P = 0.030). CONCLUSIONS: The LTM status is an important prognostic factor in perihilar cholangiocarcinoma. Extended LH reduced the risk of tumor exposure at the LTM with a subsequent improvement in the survival, particularly in advanced tumors.

Trefoil factor 1 inhibits the development of esophageal adenocarcinoma from Barrett's epithelium.

Trefoil factor family 1 (TFF1) is one of three members of the trefoil factor family that are abundantly expressed in the gastrointestinal mucosal epithelium. Recent studies have shown that TFF1 acts as a tumor suppressor in gastric, pancreatic and hepatocellular carcinogenesis; however, little is known about its function in esophageal carcinogenesis, especially in esophageal adenocarcinoma (EAC). Barrett's epithelium is the metaplastic columnar epithelium of the esophagus and a known premalignant lesion of EAC. To investigate the role of TFF1 in EAC development, a mouse model of Barrett's epithelium was employed, and human specimens of EAC were assessed by immunohistochemistry (IHC) and methylation-specific PCR. Wild-type (WT) mice underwent gastrojejunostomy on the forestomach, resulting in the development of Barrett's epithelium-like (BE-like) epithelium adjacent to the anastomotic site. BE-like epithelium in these mice expressed TFF1, indicating the association of TFF1 with esophageal adenocarcinoma. TFF1-knockout (TFF1KO) mice underwent the same procedure as well, revealing that a deficiency in TFF1 resulted in the development of adenocarcinoma in the anastomotic site, presumably from BE-like epithelium. IHC of human samples revealed strong TFF1 expression in Barrett's epithelium, which was lost in some EACs, confirming the association between TFF1 and EAC development. Aberrant DNA hypermethylation in TFF1 promoter lesions was detected in TFF1-negative human EAC samples, further confirming not only the role of TFF1 in EAC but also the underlying mechanisms of TFF1 regulation. In addition, IHC revealed the nuclear translocation of ß-catenin in human and mouse EAC, suggesting that activation of the Wnt/ß-catenin pathway was induced by the loss of TFF1. In conclusion, these results indicate that TFF1 functions as a tumor suppressor to inhibit the development of esophageal carcinogenesis from Barrett's epithelium.

Combined Vascular Resection for Locally Advanced Perihilar Cholangiocarcinoma.

OBJECTIVE: To evaluate the efficacy and safety of combined vascular resection (VR) in advanced perihilar cholangiocarcinoma (PHC). SUMMARY OF BACKGROUND DATA: Hepatectomy combined with portal vein resection (PVR) and/or hepatic artery resection (HAR) is technically demanding but an option only for tumor eradication against PHC involving the hilar hepatic inflow vessels; however, its efficacy and safety have not been well evaluated. METHODS: Patients diagnosed with PHC during 2001-2018 were included. Patients who underwent resection were divided according to combined VR. Patients undergoing VR were subdivided according to type of VR. Postoperative outcomes and OS were compared between patient groups. RESULTS: Among the 1055 consecutive patients, 787 (75%) underwent resection (without VR: n = 484, PVR: n = 157, HAR: n = 146). The incidences of postoperative complications and mortality were 49% (without VR vs with VR, 48% vs 50%; P= 0.715) and 2.1% (without VR vs with VR, 1.2% vs 3.6%; P= 0.040), respectively. The OS of patients who underwent resection with VR (median, 30 months) was shorter than that of those who underwent resection without VR (median, 61 months; P < 0.0001); however, it was longer than that of those who did not undergo resection (median, 10 months; P < 0.0001). OS was not significantly different between those who underwent PVR and those who underwent HAR (median, 29 months vs 34 months; P = 0.517). CONCLUSION: VR salvages a large number of patients from having locally advanced PHC that is otherwise unresectable and is recommended if the hilar hepatic inflow vessels are reconstructable, providing acceptable surgical outcomes and substantial survival benefits.

Mild Prognostic Impact of Postoperative Complications on Long-term Survival of Perihilar Cholangiocarcinoma.

OBJECTIVE: To evaluate the impact of complications on long-term survival in patients with perihilar cholangiocarcinoma. BACKGROUND: Surgical resection for perihilar cholangiocarcinoma is vulnerable to postoperative complications. The prognostic impact of complications in patients with this disease is unknown. METHODS: The medical records of patients who underwent curative-intent hepatectomy for perihilar cholangiocarcinoma between 2010 and 2017 were reviewed retrospectively. The comprehensive complication index (CCI) was calculated based on all postoperative complications, which were graded by the Clavien-Dindo classification (CDC). Patients were divided into high and low CCI groups by the median score, and survival was compared between the 2 groups. RESULTS: Excluding 8 patients who died in hospital, 369 patients were analyzed. The CDC grade was I in 20 (5.4%), II in 108 (29.3%), III in 224 (60.7%), and IV in 17 (4.6%) patients. The CCI increased with increasing CDC grade; the median was 42.9 (range, 15.0-98.9). Overall survival differed significantly between the high (n = 187) and low (n = 182) CCI groups (41.2% vs 47.9% at 5 years; P = 0.041). However, multivariable analyses demonstrated that traditional clinicopathological factors were independent predictors of survival and that the dichotomized CCI was not. In addition, the CCI score as a continuous variable was not an independent prognostic factor for overall survival in the multivariable analyses (hazard ratio per 1 CCI score: 1.00, 95% confidence interval: 0.99-1.01, P = 0.775). CONCLUSIONS: Cumulative postoperative complications after resection of perihilar cholangiocarcinoma only moderately deteriorate long-term survival, and should not be an argument to deny surgery in this high-risk population.

Results of a Phase II Study on the Use of Neoadjuvant Chemotherapy (FOLFIRINOX or GEM/nab-PTX) for Borderline-resectable Pancreatic Cancer (NUPAT-01).

OBJECTIVE: Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified. SUMMARY OF BACKGROUND DATA: Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial. METHODS: Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate. RESULTS: Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups. CONCLUSIONS: These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis.

Neoadjuvant S-1 With Concurrent Radiotherapy Followed by Surgery for Borderline Resectable Pancreatic Cancer: A Phase II Open-label Multicenter Prospective Trial (JASPAC05).

OBJECTIVE: This study assessed whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate in BRPC. SUMMARY OF BACKGROUND DATA: Although a multidisciplinary approach that includes neoadjuvant treatment has been shown to be a better strategy for BRPC than upfront resection, a standard treatment for BRPC has not been established. METHODS: A multicenter, single-arm, phase II study was performed. Patients who fulfilled the criteria for BRPC received S-1 (40 mg/m 2 bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery. The primary endpoint was the R0 resection rate. At least 40 patients were required, with a 1-sided α = 0.05 and ß = 0.05 and expected and threshold values for the primary endpoint of 30% and 10%, respectively. RESULTS: Fifty-two patients were eligible, and 41 were confirmed to have definitive BRPC by a central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% among the 52 eligible patients and 63% among the 41 patients who were centrally confirmed to have BRPC. Postoperative grade III/IV adverse events according to the Clavien-Dindo classification were observed in 7.5%. Among the 41 centrally confirmed BRPC patients, the 2-year overall survival rate and median overall survival duration were 58% and 30.8 months, respectively. CONCLUSIONS: S-1 and concurrent radiotherapy seem to be feasible and effective at increasing the R0 resection rate and improving survival in patients with BRPC. TRIAL REGISTRATION: UMIN000009172.

Prognostic Significance of Intraoperative Peritoneal Lavage Cytology in Patients with Pancreatic Ductal Adenocarcinoma: A Single-Center Experience and Systematic Review of the Literature.

BACKGROUND: The prognostic significance of peritoneal lavage cytology (PLC) in patients with pancreatic ductal adenocarcinoma (PDAC) remains controversial. The purpose of this study was to evaluate the prognostic impact of PLC status in PDAC patients. METHODS: Patients intending to undergo resection for PDAC between 2007 and 2020 were included. Survival was compared among patients who underwent resection with negative or positive PLC status and those who did not undergo resection. Univariable and multivariable analyses were conducted to evaluate the prognostic impact of positive PLC status. A systematic literature review was performed to evaluate the correlation between prognosis and the positive PLC rate. RESULTS: A total of 480 patients formed the study cohort and were divided as follows: 438 in the negative PLC group, 18 in the positive PLC group, and 24 in the no resection group. Although the median survival time significantly differed between the negative and positive PLC groups (35.7 vs. 13.6 months, P < 0.001), it did not significantly differ between the positive PLC and no resection groups (13.6 vs. 12.2 months, P = 0.605). Multivariable analyses demonstrated that positive PLC status (hazard ratio = 3.54, 95% confidence interval = 1.97-6.38, P < 0.001) was the strongest poor prognostic factor. Based on statistical analyses for the systematic review, the prognostic impact of positive PLC status weakened significantly as the institutional positive PLC rate increased (P = 0.044). CONCLUSIONS: Resection did not improve the prognosis of patients with positive PLC status in our cohort. The institutional positive PLC rate may be a good reference for surgical indication in these patients.

Predicting Inchinkoto efficacy, in patients with obstructive jaundice associated with malignant tumors, through pharmacomicrobiomics.

Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.

Impact of pancreatic fat infiltration on postoperative pancreatic fistula occurrence in patients undergoing invagination pancreaticojejunostomy.

BACKGROUND: No studies to date have determined the impact of pancreatic fat infiltration on postoperative pancreatic fistula (POPF) occurrence in patients undergoing invagination pancreaticojejunostomy (IV-PJ). METHODS: The medical records of patients with a soft pancreas who underwent pancreatoduodenectomy followed by IV-PJ were reviewed . The pancreatic fat ratio on computed tomography (CT) images (I-PFR) was determined using preoperative CT and verified by histologic examination. The relationship between the I-PFR and POPF occurrence was determined. Patients were classified into 2 groups based on I-PFR value (fatty and non-fatty pancreas). Postoperative outcomes were compared between the two groups, and specifically among patients who developed POPF. RESULTS: Of 221 patients, POPF occurred in 67 (30.3%). I-PFR was positively correlated with histologic-calculated fat ratio (ρ = 0.517, p < 0.001). This index was shown to be an independent predictor of POPF. Based on an I-PFR cut-off value of 3.2%, 92 patients were classified in the fatty pancreas group. Subgroup analysis of the patients who developed POPF showed that incidence of abscess formation and hemorrhage tended to be higher in patients with fatty pancreas than in those with non-fatty pancreas. CONCLUSIONS: Pancreatic fat infiltration is highly associated with POPF and possibly causes subsequent serious complications in patients undergoing IV-PJ.

Trefoil factor family 2 inhibits cholangiocarcinogenesis by regulating the PTEN pathway in mice.

Trefoil factor family 2 (TFF2) is one of three trefoil factor family proteins and is expressed abundantly in the gastrointestinal epithelium. Recent studies have shown that TFF2 acts as a tumor suppressor in gastric and pancreatic carcinogenesis; however, little is known about its function in cholangiocarcinogenesis. To investigate the function of TFF2 in cholangiocellular carcinoma (CCC), immunohistochemistry of surgically resected human CCC samples was performed. TFF2 expression was upregulated in the early stage and lost in the late stage of cholangiocarcinogenesis, suggesting the association of TFF2 and CCC. A TFF2 expression vector was then transfected into a CCC cell line (HuCCT1) in vitro, revealing that TFF2 functions as a tumor suppressor not only by inhibiting proliferation and invasion but also by promoting the apoptosis of cancer cells. In addition, PTEN signaling activity was downregulated by TFF2, suggesting an association between TFF2 and PTEN. Next, hepatic carcinogenesis model mice (KC; albumin-Cre/Lox-Stop-Lox KRASG12D) were bred with TFF2-knockout mice to generate a TFF2-deficient mouse model (KC/TFF2-/-). Although the incidence of hepatocellular carcinoma was not different between KC/TFF2-/- mice and control mice, biliary intraepithelial neoplasm (BilIN), the precursor of CCC, was frequently found in the biliary epithelium of KC/TFF2-/- mice. Immunohistochemistry revealed that BilIN samples from these mice did not express PTEN. In addition, two KC/TFF2-/- mice developed CCC adjacent to BilIN, suggesting that TFF2 functions to inhibit the development of CCC in vivo. These results indicate that TFF2 acts as a tumor suppressor to inhibit the development of CCC by regulating PTEN activity.

A Study on Radial Margin Status in Resected Perihilar Cholangiocarcinoma.

OBJECTIVE: To investigate radial margin (RM) status in resected perihilar cholangiocarcinoma (PHCC) and to evaluate the incidence of positive RM and its effect on survival. BACKGROUND: Although numerous studies have reported on ductal margin (DM) status in resected PHCC, no studies have addressed RM status. METHODS: Patients who underwent hepatectomy for PHCC between 2001 and 2014 were retrospectively reviewed. After formalin fixation, resected specimens were serially sectioned at 5-mm intervals. All serial sections were color-copied, and RMs and DMs were identified and indicated on the color copies. RESULTS: Among 478 patients, 85 (17.8%) had positive surgical margins (R1 resection); of the 85 patients, 37 had positive RM alone, 33 had positive DM alone, and the remaining 15 had both positive RM and positive DM. Overall, 52 (61.2%) patients had positive RM. The sites of positive RM included the liver transection plane (n = 20) and the dissection plane in the hepatoduodenal ligament (n = 32). RM positivity on the liver transection plane was higher in left hepatectomy than in other hepatectomies (9.2% vs 1.9%, P < 0.001). RM positivity in the hepatoduodenal ligament was higher in left-sided hepatectomy than in right-sided hepatectomy (8.7% vs 3.6%, P = 0.031). The survival of the patients with positive RM was poorer than that of R0 patients (MST 2.1 vs 4.9 yrs, P < 0.001) and was similar to that of patients with positive DM. Multivariate analysis identified positive RM as one of the independent prognostic factors. CONCLUSIONS: Positive RM was the most common cause of R1 resection of PHCC and had similarly negative effects on survival as positive DM. Meticulous handling of the resected specimen is important to accurately evaluate RM status together with DM status.

Trefoil Factor Family 1 Inhibits the Development of Hepatocellular Carcinoma by Regulating ß-Catenin Activation.

BACKGROUND AND AIMS: Recent studies have suggested that trefoil factor family 1 (TFF1) functions as a tumor suppressor in gastric and pancreatic carcinogenesis. APPROACH AND RESULTS: To investigate the role of TFF1 in hepatocarcinogenesis, we performed immunohistochemical staining of surgically resected human liver samples, transfected a TFF1 expression vector into hepatocellular carcinoma (HCC) cell lines, and employed a mouse model of spontaneous HCC development (albumin-cyclization recombination/Lox-Stop-Lox sequence-Kirsten rat sarcoma viral oncogene homologG12D [KC]); the model mouse strain was bred with a TFF1-knockout mouse strain to generate a TFF1-deficient HCC mouse model (KC/TFF1-/- ). TFF1 expression was found in some human samples with HCC. Interestingly, TFF1-positive cancer cells showed a staining pattern contradictory to that of proliferating cell nuclear antigen, and aberrant DNA hypermethylation in TFF1 promoter lesions was detected in HCC samples, indicating the tumor-suppressive role of TFF1. In vitro, induction of TFF1 expression resulted in impaired proliferative activity and enhanced apoptosis in HCC cell lines (HuH7, HepG2, and HLE). These anticancer effects of TFF1 were accompanied by the loss of nuclear ß-catenin expression, indicating inactivation of the ß-catenin signaling pathway by TFF1. In vivo, TFF1 deficiency in KC mice accelerated the early development and growth of HCC, resulting in poor survival rates. In addition, immunohistochemistry revealed that the amount of nuclear-localized ß-catenin was significantly higher in KC/TFF1-/- mice than in KC mice and that human HCC tissue showed contradictory expression patterns for ß-catenin and TFF1, confirming the in vitro observations. CONCLUSIONS: TFF1 might function as a tumor suppressor that inhibits the development of HCC by regulating ß-catenin activity.

Impact of Qualitative and Quantitative Biliary Contamination Status on the Incidence of Postoperative Infection Complications in Patients Undergoing Pancreatoduodenectomy.

BACKGROUND: Bacterial contamination status may differ under different biliary drainage conditions. The purpose of this study was to determine the impact of qualitative and quantitative biliary bacterial contamination on the incidence of infection complications in patients undergoing pancreatoduodenectomy. METHODS: Patients undergoing pancreatoduodenectomy for periampullary diseases with different biliary drainage conditions, such as external drainage (ED), internal drainage (ID), and no drainage (ND), were included. Bile was collected intraoperatively, and biliary contamination status was qualified and quantified using bacterium-specific ribosomal RNA-targeted reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The impact of biliary contamination status on infection complications was analyzed. RESULTS: A total of 152 patients were included (38 with ED, 40 with ID, and 74 with ND). The positive rate of microorganisms in bile was higher in the ID group (98%) compared with the ED group (82%, p = 0.021) and the ND group (65%, p < 0.001). The number of microorganisms detected in bile samples was higher in the ID group compared with the ED group (median 489,788 vs. 5375 bacteria/mL of bile, p < 0.001). With multivariate analysis, soft pancreas, intraoperative bleeding (> 600 mL), and biliary contamination by Atopobium cluster were identified as independent risk factors for infection complications. Biliary contamination by Atopobium cluster was significantly higher in the ID group compared with the other groups. CONCLUSIONS: Biliary bacterial contamination is more frequently induced by ID than either ED or ND. In addition to the previously known risk factors, biliary contamination with Atopobium cluster may be one of the risk factors of infection complications following pancreatoduodenectomy.

Oncologic Reappraisal of Bile Duct Resection for Middle-Third Cholangiocarcinoma.

BACKGROUND: Although bile duct resection (BDR) in addition to pancreaticoduodenectomy (PD) is considered a surgical approach in patients with middle-third cholangiocarcinoma (MCC), available prognostic information after BDR remains very limited. The aim of this study was to reappraise BDR from the viewpoint of surgical oncology. METHODS: Patients who underwent BDR or PD for MCC between 2001 and 2010 at 32 Japanese hospitals were included. Clinicopathological factors were retrospectively compared according to surgical procedure to identify a subset cohort who benefited most from BDR. RESULTS: During the study, 92 patients underwent BDR (n = 38) or PD (n = 54). BDR was characterized by a shorter operation time, less blood loss, less frequent complications, and lower mortality, than PD. The incidence of positive surgical margins was 26.3% versus 5.6% (P = 0.007). The survival rate after BDR was significantly worse than that after PD: 38.8% versus 54.8% at 5 years (P = 0.035), and BDR was independently associated with deteriorated survival [hazard ratio (HR), 1.76; P = 0.023] by multivariable analysis. In the BDR group, tumor length < 15 mm (HR, 3.38; P = 0.017) and ductal margin length ≥ 10 mm (HR, 2.54; P = 0.018) were independent positive prognostic factors. Stratified by these two favorable factors, the 5-year survival rate was 63.0% in patients with 1/2 factors and 6.7% in those with 0 factors (P < 0.001). CONCLUSION: In patients with MCC, BDR provided a better short-term and a worse long-term outcome than PD. However, patient selection using tumor length and ductal margin length may allow a favorable survival probability even after BDR.

Impact of Perioperative Steroid Administration in Patients Undergoing Major Hepatectomy with Extrahepatic Bile Duct Resection: A Randomized Controlled Trial.

BACKGROUND: To date, five randomized controlled trials have assessed the clinical benefit of perioperative steroid administration in hepatectomy; however, all of these studies involved a substantial number of 'minor' hepatectomies. The benefit of steroid administration for patients undergoing 'complex' hepatectomy, such as major hepatectomy with extrahepatic bile duct resection, is still unclear. This study aimed to evaluate the clinical benefit of perioperative steroid administration for complex major hepatectomy. METHODS: Patients with suspected hilar malignancy scheduled to undergo major hepatectomy with extrahepatic bile duct resection were randomized into either the control or steroid groups. The steroid group received hydrocortisone 500 mg immediately before hepatic pedicle clamping, followed by hydrocortisone 300 mg on postoperative day (POD) 1, 200 mg on POD 2, and 100 mg on POD 3. The control group received only physiologic saline. The primary endpoint was the incidence of postoperative liver failure. RESULTS: A total of 94 patients were randomized to either the control (n = 46) or steroid (n = 48) groups. The two groups had similar baseline characteristics; however, there were no significant differences between the groups in the incidence of grade B/C postoperative liver failure (control group, n = 8, 17%; steroid group, n = 4, 8%; p = 0.188) and other complications. Serum bilirubin levels on PODs 2 and 3 were significantly lower in the steroid group than those in the control group; however, these median values were within normal limits in both groups. CONCLUSION: Perioperative steroid administration did not reduce the risk of postoperative complications, including liver failure following major hepatectomy with extrahepatic bile duct resection.

Comprehensive metabolome analysis for the pharmacological action of inchinkoto, a hepatoprotective herbal medicine.

INTRODUCTION: The precise pharmacological action of inchinkoto (ICKT, Yin-Chen-Hao-Tang in Chinese), a hepatoprotective herbal medicine, on total metabolic pathways has not been well investigated. OBJECTIVES: The aim of this study was to explore the serum metabolites reflecting the pharmacological activity of ICKT, and mechanism of action of ICKT using serum metabolome analysis. METHODS: 54 patients with obstructive jaundice due to malignancies were included in this study. ICKT was administered for 3 days. Serum and bile samples were collected before and 1 h after ICKT administration on days 1 and 4. Serum metabolome analysis including ICKT components were performed. RESULTS: The levels of total/direct bilirubin, C-reactive protein, γ-glutamyl transpeptidase, and albumin in the serum were significantly improved after ICKT administration. In the serum metabolome analysis, inosine was the only elevated metabolite on days 1 and 4. Most of the metabolites which were significantly changed after ICKT administration were lipid mediators, and all decreased on day 1. Notably, the levels of many lipid mediators were increased on day 4. The difference in serum aspartic acid 1 h after ICKT administration was significantly correlated with a decrease in the levels of total bilirubin in the serum on day 4. CONCLUSIONS: Using metabolome analysis, we demonstrated several metabolic changes that may be associated with the pharmacological mechanisms of ICKT. The biological implications of these metabolites should be further investigated in basic research studies.

Differential Effect of Polymorphisms on Body Mass Index Across the Life Course of Japanese: The Japan Multi-Institutional Collaborative Cohort Study.

BACKGROUND: Obesity is a reported risk factor for various health problems. Genome-wide association studies (GWASs) have identified numerous independent loci associated with body mass index (BMI). However, most of these have been focused on Europeans, and little evidence is available on the genetic effects across the life course of other ethnicities. METHODS: We conducted a cross-sectional study to examine the associations of 282 GWAS-identified single nucleotide polymorphisms with three BMI-related traits, current BMI, BMI at 20 years old (BMI at 20), and change in BMI (BMI change), among 11,586 Japanese individuals enrolled in the Japan Multi-Institutional Collaborative Cohort study. Associations were examined using multivariable linear regression models. RESULTS: We found a significant association (P < 0.05/282 = 1.77 × 10-4) between BMI and 11 polymorphisms in or near FTO, BDNF, TMEM18, HS6ST3, and BORCS7. The trend was similar between current BMI and BMI change, but differed from that of the BMI at 20. Among the significant variants, those on FTO were associated with all BMI traits, whereas those on TMEM18 and HS6SR3 were only associated with BMI at 20. The association of FTO loci with BMI remained, even after additional adjustment for dietary energy intake. CONCLUSIONS: Previously reported BMI-associated loci discovered in Europeans were also identified in the Japanese population. Additionally, our results suggest that the effects of each loci on BMI may vary across the life course and that this variation may be caused by the differential effects of individual genes on BMI via different pathways.

The significance of the time to arterial perfusion in intraoperative ICG angiography during colorectal surgery.

BACKGROUND: Intraoperative indocyanine green angiography (ICG-A) is a promising tool to confirm blood supply; however, the assessment is difficult without clear demarcation. In this study, the clinical impact of the time to arterial perfusion (TAP) on anastomotic leakage (AL) was evaluated, especially in patients without ICG demarcation. METHODS: The TAP was assessed using ICG-A during colorectal surgery in 110 patients. ICG demarcation required changing the transection line, and the TAP was measured at the new stump. The patients were divided into marginal flow (MF) and direct flow (DF) groups according to the arterial route. Delayed TAP was defined as the third quartile or slower TAP in each group. RESULTS: Sixty-six patients (60%) were classified into the MF group, including 64 patients who underwent rectal or sigmoid resection with high ligation of the inferior mesenteric artery. The cut-off value of the delayed TAP in the MF group was significantly slower than that in the DF group (30 and 22 s, respectively, p < 0.001). In the entire cohort, the transection line was changed in 2 patients, resulting in no AL. Nevertheless, AL still developed in 6 patients (5.4%), 5 of whom were in the MF group, and delayed TAP was found in 5 of 6 patients. Delayed TAP was significantly associated with AL in the MF group (p = 0.046). CONCLUSIONS: In patients without ICG demarcation, delayed TAP might be helpful for predicting the high-risk patients with AL in the MF group; however, performing diverting stoma or strictly careful observation might be a realistic reaction.

Long-term oncological outcomes of laparoscopic versus open transhiatal resection for patients with Siewert type II adenocarcinoma of the esophagogastric junction.

BACKGROUND: Insufficient information is available about the long-term outcomes of patients with Siewert type II adenocarcinoma of the esophagogastric junction (AEG) who undergo laparoscopic transhiatal approach (LTH). Here we evaluated the oncological safety of LTH for patients with Siewert type II AEG compared with the open transhiatal approach (OTH). METHODS: Subjects included 79 patients with Siewert type II AEG who underwent gastrectomy combined with lower esophagectomy from 2008 to 2018 at our institution. Overall survival (OS), recurrence-free survival (RFS), status of adjuvant chemotherapy, late-phase complications, and recurrence patterns were compared between the OTH (n = 29) and LTH groups (n = 43). RESULTS: The median observation periods were 60 months (6-120 months) and 36 months (1-88) for the OTH and LTH groups, respectively. The 5-year OS rates were significantly different: 74% (95% CI 71-77%) and 98% (95% CI 97-99) in the OTH and LTH groups (HR 0.10, 95% CI 0.01-0.83), respectively, though the OTH group included more patients with advanced disease. After stratification, according to pathological stage to adjust for selection bias, the 5-year OS and RFS rates were longer, but not significantly different among patients in the LTH group with pStage III (HR 0.42, 95% CI 0.05-3.47; HR 0.47, 95% CI 0.10-2.12, respectively). Recurrence patterns were similar in the both groups. CONCLUSIONS: Long-term outcomes of the LTH group were not inferior to those of the OTH group, suggesting the possibility of LTH as a treatment option for selected patients with Siewert type II AEG.