Tumor immune microenvironment and clinical outcomes in stage IV urothelial cancer: YODO study.

BACKGROUND: Bladder cancer is the 10th most common cancer globally, with a growing incidence in Japan. Evaluation of molecular, genetic, and cellular biomarkers that predict treatment response and prognosis in patients with metastatic urothelial carcinoma (mUC) may help optimize sequential treatment strategies with chemotherapy and immune checkpoint inhibitors (ICIs). METHODS: This multicenter, retrospective cohort study, evaluated programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and cancer-immune phenotype as predictive prognostic biomarkers following first-/second-line treatment in Japanese adult patients with mUC. The primary endpoint was prevalence of PD-L1 expression. Secondary endpoints were TMB, overall survival (OS), and progression-free survival (PFS) from initiation of first-line treatment, and exploratory endpoints were cancer-immune phenotype, OS, PFS, and treatment response according to potential biomarker status. RESULTS: Of the 143 patients included (mean age 71.7 years), PD-L1 expression was high in 29.4% of patients. Non-synonymous TMB was high in 33.6% and low in 66.4%. Cancer-immune phenotype was immune-desert in 62.9%, immune-excluded in 30.8%, and inflamed in 6.3%. Median OS and PFS following first-line treatment were 18.2 and 7.4 months, respectively. Overall response to second-line treatment was slightly better with high versus low/negative PD-L1 expression. PD-L1 expression and TMB were non-significant predictors of OS or PFS, whereas immune-excluded phenotype was associated with better OS in comparison with immune-desert phenotype. CONCLUSION: PD-L1 expression and TMB were non-significant predictors of prognosis after first-line treatment in Japanese patients with mUC, but cancer-immune phenotype may be an important prognostic factor in chemotherapy-ICI sequential treatment strategies. Clinical trial registration number UMIN000037727.

Real-world treatment patterns and clinical outcomes of Japanese patients with non-muscle invasive bladder cancer receiving intravesical bacillus Calmette-Guérin treatment.

OBJECTIVES: To investigate current patterns and outcomes of intravesical bacillus Calmette-Guérin treatment in Japanese patients with bladder cancer, including the proportion of patients completing induction therapy, and time to subsequent treatments. METHODS: This retrospective cohort study utilized administrative claims data from the Medical Data Vision Co., Ltd. database to identify patients with a diagnosis of bladder cancer who had received ≥1 prescription of intravesical bacillus Calmette-Guérin between April 2008 and September 2015, and had ≥1 database record dated ≥12 weeks after the initial bacillus Calmette-Guérin dose. Patients were followed until September 2018, the last date of available data, or in-hospital death. Patients receiving six doses of bacillus Calmette-Guérin at intervals of <21 days were considered to have completed induction according to guidelines. Time from initial bacillus Calmette-Guérin dose to subsequent bladder cancer treatment after the end of treatment was defined as the recurrence-free duration. RESULTS: Of 6140 patients identified (median age 73.0 years; 83.4% males), 4588 (74.7%) completed induction and 1552 (25.3%) did not. Median recurrence-free duration was 64.4, 77.7, and 31.6 months in the overall, complete-induction and incomplete-induction cohorts, respectively. Corresponding 3-year recurrence-free rate was 56.3%, 59.0%, and 48.2% in these groups. The rate of cystectomy was approximately 6% at 5 years in all cohorts. CONCLUSIONS: Approximately 75% of Japanese patients who undergo intravesical bacillus Calmette-Guérin treatment receive a guideline-compliant induction regimen, but outcomes were not satisfactory, highlighting the need for more effective treatments for non-muscle invasive bladder cancer.

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.

BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.

Interaction of the hepatitis B virus X protein with the lysine methyltransferase SET and MYND domain-containing 3 induces activator protein 1 activation.

Hepatitis B virus (HBV) is a widespread human pathogen that often causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The detailed mechanisms underlying HBV pathogenesis remain poorly understood. The HBV X protein (HBx) is a multifunctional regulator that modulates viral replication and host cell functions, such as cell cycle progression, apoptosis and protein degradation through interaction with a variety of host factors. Recently, the nonstructural protein 5A (NS5A) of hepatitis C virus has been reported to interact with methyltransferase SET and MYND domain-containing 3 (SMYD3), which is implicated in chromatin modification and development of cancer. Because HBx shares fundamental regulatory functions concerning viral replication and pathogenesis with NS5A, it was decided to examine whether HBx interacts with SMYD3. In the present study, it was demonstrated by co-immunoprecipitation analysis that HBx interacts with both ectopically and endogenously expressed SMYD3 in Huh-7.5 cells. Deletion mutation analysis revealed that the C-terminal region of HBx (amino acids [aa] 131-154) and an internal region of SMYD3 (aa 269-288) are responsible for their interaction. Immunofluorescence and proximity ligation assays showed that HBx and SMYD3 co-localize predominantly in the cytoplasm. Luciferase reporter assay demonstrated that the interaction between HBx and SMYD3 activates activator protein 1 (AP-1) signaling, but not that of nuclear factor-kappa B (NF-κB). On the other hand, neither overexpression nor knockdown of SMYD3 altered production of HBV transcripts and HBV surface antigen (HBsAg). In conclusion, a novel HBx-interacting protein, SMYD3, was identified, leading to proposal of a novel mechanism of AP-1 activation in HBV-infected cells.

Anatomical variations of liver blood supply in patients with pancreaticobiliary maljunction.

PURPOSE: Pancreaticobiliary maljunction (PBM) arises from a developmental abnormality during the embryonic period; thus, these patients may have anatomical variations of the liver blood supply, including aberrant vessels and unusual locations. METHODS: We reviewed retrospectively the vascular anatomy of 52 patients with PBM, who were seen between 1998 and 2013. RESULTS: There were 11 male patients and 41 female patients. Sixteen patients had bile duct type (C-P type) PBM, 35 had pancreatic duct type (P-C type) PBM, and one had complex type PBM. Thirty-three patients had biliary dilatation. Nine (17.3 %) patients had an aberrant (replaced or accessory) hepatic artery and 2 (3.8 %) had an aberrant portal vein. Among 39 patients evaluated by contrast-enhanced computed tomography, 8 (20.5 %) had their right hepatic artery positioned on the ventral side of the common bile duct. The presence of aberrant hepatic vessels was not related to the type of confluence, biliary dilatation, type of Todani classification, or associated biliary malignancies. CONCLUSIONS: The incidence of the right hepatic artery being located on the ventral side of the common bile duct may be higher in patients with PBM than the naturally occurring incidence of about 10 % in the general Japanese population.

[Resection of Initially Unresectable Gallbladder Cancer with Multiple Liver Metastases after Chemotherapy with Gemcitabine plus Cisplatin].

A 61-year-old woman was referred to our hospital for surgery for gallstones. She was diagnosed as having gallbladder cancer after a detailed radiologic examination. At the first laparotomy, gallbladder cancer with bulky invasion to the liver and multiple liver metastases were observed. Gemcitabine plus cisplatin (GC) administration was chosen. After 7 administration of GC, we changed GC to gemcitabine alone due to blood toxicity. After 7 months of chemotherapy, although CT findings showed regression of the liver invasion and the liver metastases, the serum CA19-9 level gradually increased. Because there were no obvious distant metastases on detailed radiologic examination, we performed surgery for the primary lesion after obtaining informed consent. Pathological examination demonstrated fibrosis without viable cancer cells in the metastatic liver tumor. Gemcitabine was administered as post-operative adjuvant chemotherapy. Twelve months after surgery, there was no sign of recurrence.

Curative resection of hilar cholangiocarcinoma in a 25-year-old woman: report of a case.

A 25-year-old woman was referred to our hospital with persistent upper abdominal pain. Preoperative imaging studies revealed a hilar bile duct stricture with portal venous encasement, and the patient underwent curative resection involving extended left hepatectomy and segmental portal vein resection. The pathological findings demonstrated a well-differentiated tubular adenocarcinoma of the bile duct with regional lymph node metastasis (stage IIIB according to the UICC TNM classification), as well as the overexpression of p53 proteins and the K-ras gene mutation in tumor cells. The patient has shown no evidence of recurrence in the 10 months since the operation. Although there are several reports of relatively young adults with cholangiocarcinoma, the majority of such patients demonstrate either an anomalous arrangement of the pancreaticobiliary duct system or primary sclerosing cholangitis. The absence of any morphological abnormalities in this patient's biliary system implicates de novo carcinogenesis as the most likely cause of the cholangiocarcinoma.

[Long-term survivor of unresectable bile duct cancer complicated with sclerosing cholangitis treated with chemotherapy].

A 70-year-old woman was admitted to a near by hospital with complaints of epigastric pain and fever. Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) revealed stenosis of the hilar bile duct and multiple stenoses in the intrahepatic bile duct; bile cytological analysis indicated adenocarcinoma. The levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were within normal limits. It was very difficult to evaluate the extent of tumor invasion; therefore, we concluded that the tumor was unresectable. The patient underwent systemic chemotherapy with gemcitabine. After 5 years, she developed obstructive jaundice and cholangitis. The patient underwent endoscopic retrograde biliary drainage (ERBD), with 3 incidents of cholangitis recurrence. Although systemic chemotherapy with gemcitabine was performed for a long time, she died 6 years after the initiation of chemotherapy. Gemcitabine was administered 140 times in total, with a total dose of 203.744 g.

[Re-resection for recurrent intrahepatic cholangiocarcinoma].

INTRODUCTION: The benefits of re-resection for recurrent intrahepatic cholangiocarcinoma (IHC) are unknown. PATIENTS AND METHODS: We evaluated the comparative efficacy of different treatment schema for recurrent IHC following curative resection. RESULTS: Among 46 patients, 26 underwent R0 resection, while 20 underwent R1 resection. There were 13 cases of recurrence in R1 patients (65%), and 19 in R0 patients (61%). Recurrent IHC cases were divided into 3 groups based on the treatment received after recurrence: re-resection (n=5), chemotherapy (n=13), and best supportive care (BSC) (n=8). Survival times were evaluated for each group; median survival times (MSTs) after recurrence were 26, 14, and 4 months for the re-resection, chemotherapy, and BSC groups, respectively (p=0.030). Next, we examined the patients who only had intrahepatic recurrence; MSTs after recurrence for re-resection, chemotherapy, and BSC groups were 26, 14, and 5 months, respectively (p=0.0018). CONCLUSION: In recurrent IHC, survival time improves with re-resection or chemotherapy, when compared to BSC. In patients with intrahepatic recurrence only, re-resection is especially effective in prolonging survival.

Real-world evidence of systemic treatment practices for biliary tract cancer in Japan: Results of a database study.

PURPOSE: To describe the real-world treatment patterns of systemic therapies for biliary tract cancer (BTC) and to examine the frequency and management of biliary infection in Japan. METHODS: Patients diagnosed with BTC and prescribed systemic therapy between January 2011 and September 2020 were retrieved from the Japanese Medical Data Vision database. The look-back period was set to 5 years. Patient characteristics, treatment patterns, and biliary infection-induced treatment interruption were analyzed. RESULTS: The full analysis set comprised 22 742 patients with a mean age of 71.0 years and 61.6% were male. The most common BTC type was extrahepatic cholangiocarcinoma (44.6%). The three most common first-line regimens were S-1 monotherapy (33.0%), gemcitabine+cisplatin (32.5%), and gemcitabine monotherapy (18.7%) over the entire observation period (January 2011-September 2021). Patients who received monotherapies tended to be older. Biliary infection-induced treatment interruption occurred in 29.5% of patients, with a median time to onset of 64.0 (interquartile range 29.0-145.0) days. The median duration of intravenous antibiotics was 12.0 (interquartile range 4.0-92.0) days. CONCLUSIONS: These results demonstrated potential challenges of BTC in Japanese clinical practice particularly use of multiple regimens, commonly monotherapies, which are not recommended as first-line treatment, and the management of biliary infections during systemic therapy.

[A case involving long-term survival following bile duct cancer with para-aortic lymph node metastasis that was treated by multidisciplinary therapy].

Complete resection of advanced bile duct cancer is difficult due to the anatomical location of the tumor and invasion into other organs. Even if a complete resection is achieved, the survival rates of patients with bile duct cancer after surgery are lower as compared to those associated with other gastrointestinal tumors. Certain cases with para-aortic lymph node metastasis have a poor prognosis. In the present report, we describe a case involving long-term survival following bile duct cancer that was treated by multidisciplinary therapy (particle radiotherapy, surgical resection, chemotherapy). In the present case, we detected lymph node (LN) metastasis only in LN#16, but not in LN#13 or LN#17. We believe that particle radiotherapy, consisting of proton and carbon-ion, can be used to control the lymphatic metastasis around the pancreas head and hepatoduodenal ligament. Our findings suggest that particle radiotherapy can be a standard neoadjuvant therapy for bile duct cancer.

[A case of initially unresectable gallbladder cancer with surgical resection after chemotherapy with gemcitabine].

A 75-year-old woman was admitted to our hospital with elevated serum hepatic enzyme levels. After evaluation with imaging studies, she was diagnosed as having gallbladder cancer, which had invaded the liver and hepatic artery, with lymph node metastases. The tumor was considered unresectable, and the patient received chemotherapy with gemcitabine (GEM)alone. Six months later, computed tomography(CT)indicated shrinkage of the gallbladder tumor and disappearance of lymph node metastases. Surgical resection was planned. However, liver metastasis was suspected on the basis of macroscopic findings, and the patient underwent gallbladder bed resection. Pathological examination indicated that almost all of the tumor cells in the gallbladder were viable; however, there were no tumor cells in the liver nodule and lymph node. The postoperative course was uneventful. The patient received adjuvant chemotherapy with GEM and was alive without recurrence 17 months after tumor resection. Immunohistochemical analysis showed that 80.9% of the tumor cells were positive for CD133, a cancer stem cell marker. This case illustrates a possible relationship between cancer stem cells and chemoresistance.

The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration-resistant prostate cancer in real-world clinical practice: The multi-institutional observational ZENSHIN study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC. METHODS: This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS). RESULTS: Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations. CONCLUSIONS: In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease.

[Long-term survival in 2 cases with unresectable hilar bile duct cancer and sclerosing cholangitis].

Case 1: A 69-year-old man was admitted to a nearby clinic due to upper abdominal pain. Computed tomography revealed stenosis of the hilar bile duct and dilation of the intrahepatic bile duct in both lobes of the liver. A percutaneous transhepatic biliary drainage tube was inserted in the right anterior segment branch, and an endoscopic naso-biliary drainage tube was inserted in the left hepatic duct. He was referred to our hospital because of suspected hilar bile duct cancer. Radiographic examination showed severe stenosis of the hepatic hilar duct and tapering of the entire intrahepatic bile duct. The extent of invasion could not be evaluated and we concluded that the tumor was unresectable. Although systemic chemotherapy with gemcitabine was performed, the patient died at 37 months after the start of chemotherapy. Case 2: A 70- year-old woman was admitted to a nearby hospital due to epigastric pain and fever. Endoscopic retrograde cholangiopancreatography revealed stenosis of the hilar bile duct and a wide range of multiple stenosis in the intrahepatic bile duct. Bile cytology showed adenocarcinoma. Therefore, we decided the tumor was unresectable. Systemic chemotherapy with gemcitabine was started. She is in good health 57 months after the start of chemotherapy.

[Three cases of recurrent bile duct cancer diagnosed and treated by double-balloon endoscopy].

Local recurrences often develop after the resection of bile duct cancer. Imaging modalities do not have sufficient sensitivity or specificity to enable the definite diagnosis of recurrent bile duct cancer, and it may be difficult to decide when to start chemotherapeutic treatment. It is difficult to obtain specimens by conventional endoscopy after Roux-Y biliary reconstruction. The double-balloon endoscope(DBE) has 2 balloons: one at the tip of the endoscope and the other at the over- tube. The 2 balloons are inflated alternately and the endoscope can move through the small intestine in a caterpillar-like manner. DBE simplifies the approach to Roux-Y choledochojejunostomy and to obtaining a pathological specimen. Moreover, endoscopic biliary drainage and cholangiography can be performed with the DBE. Recently, the DBE has enabled systemic chemotherapy to be started after obtaining pathological evidence of malignancy, as well as biliary drainage instead of percutaneous transhepatic biliary drainage in cases with recurrent bile duct cancers. Here, we present 3 cases of recurrent bile duct cancer diagnosed and treated by a DBE.

Risk factors for occult metastasis detected by inflammation-based prognostic scores and tumor markers in biliary tract cancer.

BACKGROUND: Radiological detection of small liver metastasis or peritoneal metastasis is still difficult, and some patients with biliary tract cancer (BTC) are unresectable after laparotomy. Staging laparoscopy may help avoid unnecessary laparotomy. However, which category of BTC is amenable with staging laparoscopy remains unclear. AIM: To clarify the risk factors for occult metastasis in patients with BTC. METHODS: Medical records of patients with BTC who underwent surgery at our institution between January 2008 and June 2014 were retrospectively reviewed. The patients were divided into two groups, according to resection or exploratory laparotomy (EL). Preoperative laboratory data, including inflammation-based prognostic scores and tumor markers, were compared between the two groups. Prognostic importance of detected risk factors was also evaluated. RESULTS: A total of 236 patients were enrolled in this study. Twenty-six (11%) patients underwent EL. Among the EL patients, there were 16 cases of occult metastasis (7 liver metastases and 9 abdominal disseminations). Serum carcinoembryonic antigen level, carbohydrate antigen 19-9 level, neutrophil-lymphocyte ratio and modified Glasgow prognostic score were significantly higher in the EL group than in the resected group, and these factors were prognostic. Among these factors, carcinoembryonic antigen > 7 ng/mL was the most useful to predict occult metastasis in BTC. When patients have more than three of these positive factors, the rate of occult metastasis increases. CONCLUSION: Inflammation-based prognostic scores and tumor markers are useful in detecting occult metastasis in BTC; based on these factors, staging laparoscopy may reduce the rate of EL.

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

BACKGROUND & AIMS: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC. METHODS: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle. RESULTS: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]). CONCLUSIONS: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade. LAY SUMMARY: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.

Preoperative Cholangitis Affects Survival Outcome in Patients with Extrahepatic Bile Duct Cancer.

BACKGROUND: It remains controversial whether preoperative cholangitis affects long-term outcomes after resection in patients with extrahepatic bile duct cancer. METHODS: A total of 107 patients with extrahepatic bile duct cancer who underwent resection with curative intent from 2008 to 2014 were retrospectively reviewed. Patients were categorized into two groups according to the presence or absence of preoperative cholangitis. Clinicopathological variables and long-term outcomes were compared in the two groups. RESULTS: In the preoperative cholangitis group, the rate of preoperative biliary drainage, the number of tube changes and/or additions, and the rate of lymph node metastasis were higher compared to the no-cholangitis group. Overall survival and disease-free survival were significantly worse in the cholangitis group compared to the no-cholangitis group (p = 0.022, p = 0.007). A poorer prognosis was not observed with an increasing grade of cholangitis in Tokyo Guidelines 2013 (p = 0.09). A multivariate logistic regression analysis revealed that the preoperative cholangitis was an independent prognostic factor for extrahepatic bile duct cancer. CONCLUSION: Preoperative cholangitis is an independent prognostic factor in patients with extrahepatic bile duct cancer regardless of the severity of the cholangitis.

Clinical significance of bile reflux into the pancreatic duct without pancreaticobiliary maljunction assessed by intraoperative cholangiography.

INTRODUCTION: Bile reflux into the pancreatic duct (BRPD) is sometimes demonstrated during intraoperative cholangiography (IOC) even in patients without pancreaticobiliary maljunction. However, the clinical significance of this finding in laparoscopic and open cholecystectomy is unclear. METHODS: Among 484 patients who underwent cholecystectomy (372 laparoscopic, 112 open), patients whose pancreatic duct was depicted in IOC were selected. The value of pancreatic amylase (p-amylase) of the gallbladder bile, histological changes, and the immunohistochemical expression of proliferating cell nuclear antigen (PCNA) in the gallbladder mucosa were analyzed in patients with BRPD. The data were then compared to those in patients without BRPD whose gallbladder bile p-amylase was measured (control group, n = 20). RESULTS: The success rate of IOC was 93.6%. The rate of BRPD in laparoscopic and open cholecystectomy was 5.2% and 5.7%, respectively. The value of gallbladder bile p-amylase in patients with BRPD was significantly higher than in the control group (790.5 vs 14.0 IU/L, P = 0.034). The value of the PCNA labeling index in patients with BRPD was significantly higher than that of the control group (15.4% vs 4.1%, P = 0.0026). Among the 24 patients with BRPD, pathological changes in the gallbladder mucosa were detected in five (two hyperplasia, three metaplasia), but there was no correlation between the presence of pathological change and PCNA labeling index or gallbladder bile p-amylase. CONCLUSIONS: IOC could detect BRPD both in laparoscopic and open cholecystectomy at a similar rate. Patients with BRPD had high levels of gallbladder bile p-amylase and PCNA labeling index, findings similar to those in patients with pancreaticobiliary maljunction.

Preoperative bile replacement improves immune function for jaundiced patients treated with external biliary drainage.

BACKGROUND: Although preoperative biliary drainage in jaundiced patients is controversial, external biliary drainage (EBD) is beneficial for infection control in patients with biliary cancers. When EBD is performed, additional bile replacement (BR) has the benefit of improving impaired intestinal barrier function, but the detailed mechanism remains unknown. We examined the effect of bile replacement on immune functions over the duration of BR in jaundiced patients. METHODS: Fifteen patients were enrolled into this prospective study. BR was started soon after the total serum bilirubin concentration reached 5.0 mg/dl and was continued for 14 days. Drained bile was given two times orally (2 × 100 ml/day). Concanavalin A (Con A)- and phytohemagglutinin (PHA)-stimulated lymphocyte proliferation and serum diamine oxidase (DAO) activity were measured before starting and during BR. Twenty patients with EBD and no BR were analyzed as a control group. RESULTS: Serum liver enzymes, prothrombin time-international normalized ratio (PT-INR), and responses to Con A and PHA gradually improved over the 14 days of BR, but percentages of lymphocytes and DAO levels did not. PT-INR, and Con A and PHA responses did not improve during EBD in the control group. PT-INR significantly decreased in patients with a greater fraction of their drained bile replaced. CONCLUSIONS: Our results indicate that preoperative BR using as large a quantity of bile as possible is useful for improving blood coagulability and cellular immunity in patients with EBD.