Transmembrane serine protease 4 expression in the prognosis of radical resection for biliary tract cancer

BACKGROUND Recent advancements in biliary tract cancer(BTC)treatment have expanded beyond surgery to include adjuvant therapy,yet the prognosis remains poor.Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC.AIM To determine transmembrane serine protease 4(TMPRSS4)utility as a prognostic biomarker of radical resection for BTC.METHODS Medical records of patients who underwent radical resection for BTC,excluding intrahepatic cholangiocarcinoma,were retrospectively reviewed.The associations between TMPRSS4 expression and clinicopathological factors,overall survival,and recurrence-free survival were analyzed.RESULTS Among the 85 patients undergoing radical resection for BTC,46(54%)were TMPRSS4-positive.The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9(CA19-9)values and greater lymphatic invasion than the TMPRSS4-negative group(P=0.019 and 0.039,respectively).Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group(median survival time:25.3 months vs not reached,P<0.001;median survival time:28.7 months vs not reached,P=0.043,respectively).Multivariate overall survival analysis indicated TMPRSS4 positivity,pT3/T4,and resection status R1 were independently associated with poor prognosis(P=0.032,0.035 and 0.030,respectively).TMPRSS4 positivity correlated with preoperative CA19-9 values≥37 U/mL and pathological tumor size≥30 mm(P=0.016 and 0.038,respectively).CONCLUSION TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.

Current status of the biliary tract malformation

The choledochal cyst(CC)can be better termed as biliary tract malformation because of the close association of embryology and etiology in the causation of CC.Contrary to Babbitt's postulation of reflux,damage and dilatation,reflux was not demonstrable as the causative factor in all varieties of CC.High pressure in the biliary system,otherwise termed ductal hypertension,is put forth as an alternative to explain the evolution of CC.The forme fruste type,which does not find a place in the standard classification,typifies the ductal hypertension hypothesis.Hence a closer,in-depth review would be able to highlight this apt terminology of biliary tract malformation.

Practical Use of Gemcitabine and Cisplatin Combination Therapy as First-Line Treatment for Japanese Patients with Advanced Biliary Tract Cancer

Gemcitabine and cisplatin combination therapy (GC) is accepted as a standard treatment for advanced biliary tract cancer (BTC). However, little information is available regarding such treatment in the clinical practice setting in Japan. We retrospectively examined the clinical data of patients with unresectable or recurrent BTC who received GC as first-line treatment. The regimen consisted of cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8 of repeated 3-week cycles. Twenty patients were analyzed. A total of 148 cycles of GC was administered, with a median of 8 and a range of 1 to 18 cycles. Treatment delay and dose reduction were noted in 35 (24%) and 41 (28%) of the 148 cycles, respectively. The major adverse events of grade 3 or 4 included neutropenia (50%), leukopenia (45%), anemia (30%), and thrombocytopenia (15%). Nonhematologic toxicities included nausea (10%), appetite loss (10%), and fatigue (10%). Median progression-free and overall survival times were 6.9 and 12.3 months, respectively. Gallbladder cancer showed a significantly higher response rate than did other types of BTC (chi-squaretest, P = 0.002). GC was thus effective and well tolerated as first-line chemotherapy for Japanese patients with advanced BTC in the clinical practice setting.

Epidemiology of biliary tract cancer in China:A narrative review

Biliary tract cancer(BTC)is a group of rare malignancies that affect the gallbladder and bile ducts.Although rare,BTC is becoming a significant public health burden in China,particularly among males and older individuals.The increasing trends in BTC incidence and mortality in China are influenced by various demographic,environmental,and lifestyle factors.In this review,we examine available epidemiological data on the incidence,mortality,prognosis,and trends of different BTC subtypes in China.We also discuss the challenges and opportunities for improving the prevention,diagnosis,and management of BTC in China,and identify areas for further research and intervention.The article aims to provide a better understanding of the epidemiological features of BTC in China and to inform public health strategies and clinical practice.

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers:An open-label,non-randomized,phase II clinical trial

BACKGROUND Biliary tract cancers(BTCs)are a heterogeneous group of tumors with high malignancy,poor prognosis,and limited treatment options.AIM To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs.METHODS This open-label,non-randomized,double-center,phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University.Eligible patients were administered nab-paclitaxel(150 mg/m^(2),day 1)and capecitabine(2000 mg/m^(2),twice daily,days 1-7)in 14-day cycles until experiencing intolerable toxicity or disease progression.The primary outcome was the objective response rate(ORR).The secondary outcomes included the disease control rate(DCR),overall survival(OS),progression-free survival(PFS),and safety.RESULTS A total of 44 patients successfully completed the trial,with a median age of 64.00 years(interquartile range,35.00-76.00),and 26(59.09%)were females.Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage.Among the remaining 43 patients undergoing at least one imaging assessment,the ORR was 23.26%[95%confidence interval(CI):11.80%-38.60%],and the DCR was 69.77%(95%CI:53.90%-82.80%).The median OS was 14.1 months(95%CI:8.3-19.9),and the median PFS was 4.4 months(95%CI:2.5-6.3).A total of 41 patients(93.18%)experienced at least one adverse event(AE),with 10 patients(22.73%)encountering grade≥3 AEs,and the most frequent AEs of any grade were alopecia(79.50%),leukopenia(54.55%),neutropenia(52.27%),and liver dysfunction(40.91%),and no treatment-related deaths were documented.CONCLUSION Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas

BACKGROUND Despite advances in detection and treatments,biliary tract cancers continue to have poor survival outcomes.Currently,there is limited data investigating the significance of socioeconomic status,race/ethnicity,and environmental factors in biliary tract cancer survival.Data from the Surveillance,Epidemiology,and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016.Socioe-conomic data included smoking,poverty level,education,adjusted household income,and percentage of foreign-born persons and urban population.Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis.RESULTS Our study included 15883 gallbladder,11466 intrahepatic biliary,12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases.When analyzing county-specific demographics,patients from counties with higher incomes were associated with higher survival rates[hazard ratio(HR)=0.97,P<0.05].Similarly,counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates(HR=0.96,P=0.002 and HR=0.97,P=0.004,respectively).CONCLUSION Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

Impact of open hepatectomy on postoperative bile leakage in patients with biliary tract cancer

BACKGROUND Bile leakage is a common and serious complication of open hepatectomy for the treatment of biliary tract cancer.AIM To evaluate the incidence,risk factors,and management of bile leakage after open hepatectomy in patients with biliary tract cancer.METHODS We retrospectively analyzed 120 patients who underwent open hepatectomy for biliary tract cancer from February 2018 to February 2023.Bile leak was defined as bile drainage from the surgical site or drain or the presence of a biloma on imaging.The incidence,severity,timing,location,and treatment of the bile leaks were recorded.The risk factors for bile leakage were analyzed using univariate and multivariate logistic regression analyses.RESULTS The incidence of bile leak was 16.7%(20/120),and most cases were grade A(75%,15/20)according to the International Study Group of Liver Surgery classification.The median time of onset was 5 d(range,1-14 d),and the median duration was 7 d(range,2-28 d).The most common location of bile leakage was the cut surface of the liver(70%,14/20),followed by the anastomosis site(25%,5/20)and the cystic duct stump(5%,1/20).Most bile leaks were treated conservatively with drainage,antibiotics,and nutritional support(85%,17/20),whereas some required endoscopic retrograde cholangiopancreatography with stenting(10%,2/20)or percutaneous transhepatic cholangiography with drainage(5%,1/20).Risk factors for bile leakage include male sex,hepatocellular carcinoma,major hepatectomy,blood loss,and blood transfusion.CONCLUSION Bile leakage is a frequent complication of open hepatectomy for biliary tract cancer.However,most cases are mild and can be conservatively managed.Male sex,hepatocellular carcinoma,major hepatectomy,blood loss,and blood transfusion were associated with an increased risk of bile leak.

Reduction of the ages at diagnosis and operation of biliary atresia in Taiwan: A 15-year population-based cohort study

AIM: To describe the ages at diagnosis and operation of biliary atresia(BA) and its incidence over a 15-year period in Taiwan.METHODS: This was a population-based cohort study. BA cases were identified from the Taiwan National Health Insurance Research Database based on the International Classification of Diseases,Ninth Revision(ICD-9) code of BA 751.61 plus Kasai operation(ICD-9 procedure code 51.37) or liver transplantation(LT,ICD-9 procedure code 50.5). The patients' characteristics including sex,age at diagnosis,age at receiving Kasai operation and age at receiving LT were compared among three birth cohorts:(1) 1997 to 2001;(2) 2002 to 2006; and(3) 2007 to 2011.RESULTS: There were a total of 540 BA cases(275 females) with an incidence of 1.62 per 10000 live births. No seasonality of BA was noted. The mean ages at diagnosis of three cohorts were 57.9,55.6 and 52.6 d.A linear regression model demonstrated a decreasing trend of the mean age at diagnosis(1.27 d per year). The proportion of BA cases that received the Kasai operation within 60 d of age increased from 76% to 81%. A total of 189(35%) BA patients underwent LT. The mean age at LT was reduced from 3-year-old to 1-year-old. The rates of LT were 25.6% and 32.3% in patients who received the Kasai operation within 60 d or after 60 d of age,respectively. All patients who did not undergo a Kasai operation eventually required LT.CONCLUSION: The ages at diagnosis and operation in BA cases have decreased over time. Kasai operation performed at younger age reduces the need for LT. The incidence of BA in Taiwan fluctuates,but without certain trend.

Baseline and early dynamic changes in inflammatory and nutritional status can predict survival in patients with advanced biliary tract carcinoma receiving immunotherapy:A retrospective cohort study

Background:Inflammatory and nutritional indicators are established prognostic factors in patients with various types of solid tumors.However,it remains unclear whether differences in the baseline and early dynamic changes in these factors can predict the prognosis of immunotherapy in patients with advanced biliary tract carcinoma(aBTC).Methods:Data were retrospectively collected from 74 consecutive patients who were diagnosed with aBTC and received immunother-apy.Peripheral blood cell counts and other laboratory tests were performed at baseline and after two cycles of immunotherapy.The skeletal muscle index was measured using computed tomography/magnetic resonance imaging scans.Analyses of the relationship be-tween clinicopathological characteristics and survival outcomes were conducted using Kaplan-Meier curves and Cox regression models.Results:Seventy-four patients were enrolled in the study,with 42(56.8%)being male.The median age at diagnosis for all participants was 61 years(range,35–77 years).In the univariate analysis,six baseline indices were associated with survival,namely,lactate dehy-drogenase(LDH),carbohydrate antigen 199,neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio,Prognostic Nutritional Index,and Controlling Nutritional Status score.In the multivariable analysis,an elevated baseline NLR(HR:3.363,95%CI:1.600–7.070,P=0.001)and elevated baseline LDH(HR:2.030,95%CI:1.122–3.670,P=0.019)were independent risk factors for a shorter overall survival.Sarcopenia was not correlated with the overall survival(P>0.05).A persistently high NLR,platelet-to-lymphocyte ratio,and Controlling Nutritional Status score and low Prognostic Nutritional Index indicated a worse prognosis.Conclusions:Elevated baseline NLR and LDH values are independent negative prognostic factors in patients with aBTC receiving im-munotherapy.Patients with persistently high inflammation and poor nutritional status experience a poorer prognosis.

Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer:A meta-analysis

AIM: To investigate the efficacy and safety of gemcitabine (Gem)-based combination chemotherapies for the treatment of advanced biliary tract cancer.

The efficacy of fluoropyrimidine.based adjuvant chemotherapy on biliary tract cancer after R0 resection

Background: The optimal treatment strategy for biliary tract cancer(BTC) after curative?intent resection remains con?troversial. The purpose of this study was to evaluate the efficacy of fluoropyrimidine?based adjuvant chemotherapy for BTC patients undergoing microscopically margin?negative(R0) resection.Methods: We retrospectively analyzed the clinical data of BTC patients who underwent curative?intent R0 resection. Patients were eligible if they received either fluoropyrimidine?based adjuvant chemotherapy or observation after R0 resection.Results: A total of 153 patients were included. In the entire patient cohort, no significant differences were observed in 5?year overall survival(OS) rates(48.4% vs. 39.6%, P = 0.439) or 3?year recurrence?free survival(RFS) rates(49.1% vs. 39.5%, P = 0.299) between patients who received fluoropyrimidine?based adjuvant chemotherapy or observation. However, for patients with stages Ⅱ and Ⅲ BTC, chemotherapy significantly improved 5?year OS rate(52.4% vs. 35.6%, P = 0.002) and 3?year RFS rate(55.5% vs. 39.1%, P = 0.021) compared with observation.Conclusion: Fluoropyrimidine?based adjuvant chemotherapy may prolong the survival of patients with stages Ⅱ and Ⅲ BTC after R0 resection.

Optimum chemotherapy for the management of advanced biliary tract cancer

Biliary tract cancers(BTCs) are highly fatal malignancies, which are often diagnosed at an advanced stage and have relatively poor prognosis.The treatment of patients with advanced BTC is systemic, based on chemotherapy or best supportive care, depending on their performance status.Despite clinical trials studyingmany chemotherapeutic regimens and targeted therapies for the treatment of BTC, the standard of care for advanced BTC remains the combination of gemcitabine with cisplatin.Many new molecules targeting proliferation and survival pathways, the immune response and angiogenesis are currently undergoing phase Ⅰ and Ⅱ trials for the treatment of advanced BTC with promising results.

Inhibition of histone deacetylase for the treatment of biliary tract cancer:A new effective pharmacological approach

AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.

Primary malignant melanoma of the biliary tract: A case report and literature review

BACKGROUND Primary malignant melanoma of the biliary tract (MBT) is a rare condition whose diagnosis requires excluding a primary origin in another location.This paper reviews the most important characteristics of MBT cases published in the literature and reports a new case.The patient reported here is the first case of primary malignant melanoma of the biliary tract with pulmonary metastasis treated with immunotherapy.This patient remains disease-free 36 mo after the treatment of metastatic lung lesions.CASE SUMMARY A 51-year-old man was admitted to the gastrointestinal department to study obstructive jaundice of a 1 wk clinical course.Magnetic resonance cholangiopancreatography revealed dilatation of the intrahepatic biliary tract and stenosis of the common hepatic duct.Given the suspicion of biliary tract neoplasia,cholecystectomy and resection of the common hepatic duct were performed with hepatic jejunostomy free of complications.Anatomo-pathological diagnosis was melanoma.After intervention,the patient was referred to the Department of Medical Oncology,where a primary origin was excluded in the skin,mucosa,and eyes.This confirmed diagnosis of primary biliary tract melanoma.Computed tomography was performed 12 mo after the procedure revealed several subcentimetric lung nodules.Wedge resection was performed.After confirming the diagnosis of pulmonary metastasis of primary melanoma of the biliary tract,the patient was started on immunotherapy with nivolumab.Tolerance to treatment was excellent.The patient remains disease-free 36 mo after the treatment of metastatic lung lesions.CONCLUSION The patient reported here is the first case of primary malignant melanoma of the biliary tract with lung metastases successfully treated with immunotherapy.

Re-expression of RASSF1A by 5-Aza-CdR Induced Demethylation of the Promoter Region in Human Biliary Tract Carcinoma Cells

Hypermethylation of the promoter region is an important mean for the transcriptional repression of a number of cancer-associated genes, and over-expression and/or increased activity of DNA methyltransferase are considered to be the main cause of promoter hypermethylation. In order to further explore the epigenetic mechanism of tumor suppressor gene RASSF1A inactivation, 5-aza-2’-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, was used to treat the human biliary tract carcinoma cell line QBC-939 at the concentration of 5 μmol/L for 24 h in this study. Af- ter the chemical intervention with 5-Aza-CdR, the methylation status in the promoter region of RASSF1A gene was detected by methylation specific PCR (MS-PCR), and the expression alteration of RASSF1A mRNA and protein were observed by RT-PCR and Western Blot respectively. Following the treatment with 5-Aza-CdR, methylaiton status in the promoter region of RASSF1A gene was re- versed from methylation to unmethylation. A 280 bp DNA band which represented RASS1FA expres- sion at transcriptional level and a 40 kDa (1kDa=0.9921 ku) protein band which represented RASSF1A expression at protein level were detected by RT-PCR and Western Blot respectively in the experimental group cells and there were no corresponding bands in the control group cells. The ex- perimental results suggest that 5-Aza-CdR can induce demethylation in the promoter region of RASSF1A. It can also reverse epigenetic transcriptional silencing caused by DNA methylation and induce the re-expression of RASSF1A in QBC-939. This study also suggest that the mechanism of RASSF1A inactivation is very closely related to the methylation of the promoter region, which may provide a new epigenetic understanding for tumor related gene inactivation and the pathogenesis of biliary tract carcinoma.

Targeted medical therapy of biliary tract cancer:Recent advances and future perspectives

The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.

Phase Ⅰ trial of combination chemotherapy with gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer

AIM: To evaluate the dose-limiting toxicities(DLTs)and determine the maximum-tolerated dose(MTD) and recommended dose(RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer.METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine(mg/m2), cisplatin(mg/m2), and S-1(mg/m2 per day) were as follows: level-1, 800/20/60;level 0, 800/25/60; level 1, 1000/25/60; and level 2,1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15,and S-1 was administered orally twice daily on days 1to 7 and days 15 to 21, every 4 wk.RESULTS: Twelve patients were enrolled, and level0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs(grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1.We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase Ⅱ study.CONCLUSION: The RD was defined as gemcitabine1000 mg/m2(days 1, 15), cisplatin 25 mg/m2(days1, 15), and S-1 80 mg/m2 per day(days 1-7, 15-21),every 4 weeks. A phase Ⅱ study is planned to evaluate the effectiveness of combination chemotherapy withgemcitabine, cisplatin, and S-1 in advanced biliary tract cancer.

Treatment outcomes of chemotherapy between unresectable and recurrent biliary tract cancer

AIM: To evaluate the differences in the treatment outcomes between the unresectable and recurrent biliary tract cancer patients who received chemotherapy.

Effect of antisense DNMT3b gene eukaryotic expression plasmid on expression of the DNMT3b gene in human biliary tract carcinoma cells

BACKGROUND: Hypermethylation of the promoter region is one of the major mechanisms of tumor suppressor gene inactivation. DNA methyltransferase 3b (DNMT3b), an enzyme that participates in the establishment of de novo methylation patterns, is highly expressed in many tumor cells and tissues, and it is closely associated with hypermethylation of the promoter of tumor suppressor genes. The aim of this study was to explore the effect of transfection with antisense DNMT3b gene eukaryotic expression plasmid on the expression of the DNMT3b gene in human biliary tract carcinoma cell. METHODS: The constructed antisense DNMT3b gene eukaryotic expression plasmid was transfected into the human biliary tract carcinoma cell line QBC-939 with lipofectamine transfection reagent, and positive cell clones were formed using G418 selection after transfection. The constructed recombinant plasmid was transfected into QBC-939 cells successfully and was confirmed by amplification of the exogenous neo^R gene with the polymerase chain reaction method. The expression of DNMT3b gene mRNA and protein was detected by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and flow cytometry respectively. RESULTS: Following transfection, the mRNA level of the DNMT3b gene decreased from 0.956±0.053 to 0.209±0.023, and the protein level of the DNMT3b gene also decreased from (75.38±3.22)% to (29.87±3.46)%. Very significant differences were observed both at the transcription and posttranscription levels in the expression of the DNMT3b gene between the non-tranfection group and the antisense DN- MT3b gene eukaryotic expression plasmid transfection group (P<0.01). CONCLUSIONS: Transfection with the antisense DNMT3b gene eukaryotic expression plasmid can significantly reduce the expression level of the DNMT3b gene in the human biliary tract carcinoma cell line QBC-939. This study may provide a valid method to investigate the function of the DNMT3b gene and its role in biliary tract carcinoma.

Comparison of 4-Weekly vs 3-Weekly Gemcitabine as Adjuvant Chemotherapy Following Curative Resection for Biliary Tract Cancer: A Prospective Randomized Controlled Trial

Background: Surgery for biliary tract cancer, including pancreatoduodenectomy and major hepatectomy, is too aggressive and does not allow postoperative gemcitabine to be administered by the usual dosage protocol. We hypothesized that the feasibility of 3-weekly protocol (days 1 and 8, every 3 weeks) of adjuvant gemcitabine therapy may be superior to the usual 4-weekly protocol (days 1, 8, and 15 every 4 weeks). Method: We compared the outcomes of 6 cycles of the 4-weekly protocol and 9 cycles of the 3-weekly protocol in a prospective randomized setting. The primary endpoint was the completion rate, and the secondary endpoints were the adverse events and the recurrence-free survival rate. Results: Totally, 27 patients were enrolled. The protocol could be completed without any omittances and/or dose modifications in two patients (14%) of the 4-weekly protocol, and three patients (23%) of the 3-weekly protocol (p = 0.8099);grade 3/4 neutropenia occurred in almost all the remaining (70%) patients. The relative dose intensity was 72% in the 4-weekly protocol and 78% in the 3-weekly protocol. There was no significant difference in the recurrence-free survival rate. Conclusion: The 3-weekly protocol did not yield superior completion, adverse events or recurrence-free survival rates as compared to the 4-week protocol. Trial Registration: UMIN-CTR, UMIN000001020.