Morbidity and Mortality in Patients with Perioperative COVID-19 Infection: Prospective Cohort in General, Gastroesophagic, Hepatobiliary, and Colorectal Surgery.

BACKGROUND: Severe acute respiratory syndrome due to coronavirus 2 has rapidly spread worldwide in an unprecedented pandemic. Patients with an ongoing COVID-19 infection requiring surgery have higher risk of mortality and complications. This study describes the mortality and morbidity in patients with perioperative COVID-19 infection undergoing elective and emergency surgeries. METHODS: Prospective cohort of consecutive patients who required a general, gastroesophageal, hepatobiliary, colorectal, or emergency surgery during COVID-19 pandemic at an academic teaching hospital. The primary outcome was 30-day mortality and major complications. Secondary outcomes were specific respiratory mortality and complications. RESULTS: A total of 701 patients underwent surgery, 39 (5.6%) with a perioperative COVID-19 infection. 30-day mortality was 12.8% and 1.4% in patients with and without COVID-19 infection, respectively (p < 0.001). Major surgical complications occurred in 25.6% and 6.8% in patients with and without COVID-19 infection, respectively (p < 0.001). Respiratory complications occurred in 30.8% and 1.4% in patients with and without COVID-19 infection, respectively (p < 0.001). Mortality due to a respiratory complication was 100% and 11.1% in patients with and without COVID-19 infection, respectively (p < 0.006). CONCLUSIONS: 30-day mortality and surgical complications are higher in patients with perioperative COVID-19 infection. Indications for elective surgery need to be reserved for non-deferrable procedures in order to avoid unnecessary risks of non-urgent procedures.

Transductal versus transcystic laparoscopic common bile duct exploration: an institutional review of over four hundred cases.

BACKGROUND: Many studies have failed to demonstrate significant differences between single- and two-staged approaches for the management of choledocholithiasis with concomitant gallstones in terms of post-operative morbidity. However, none of these studies paid specific attention to the differences between the methods of accessing the bile duct during laparoscopy. The aim of this study was to report outcomes of transcystic versus transductal laparoscopic common bile duct exploration (LCBDE) from our experience of over four hundred cases. METHODS: Retrospective review of 416 consecutive patients who underwent LCBDE at a single-centre between 1998 and 2018 was performed. Data collected included pre-operative demographic information, medical co-morbidity, pre-operative investigations, intra-operative findings (including negative choledochoscopy rates, use of holmium laser lithotripsy and operative time) and post-operative outcomes. RESULTS: Transductal LCBDE via choledochotomy was achieved in 242 patients (58.2%), whereas 174 patients (41.8%) underwent transcystic LCBDE. Stone clearance rates, conversion to open surgery and mortality were similar between the two groups. Overall morbidity as well as minor and major post-operative complications were significantly higher in the transductal group. The main surgery-related complications were bile leak (5.8% vs 1.1%, p = 0.0181) and pancreatitis (7.4% vs 0.6%, p = 0.0005). Median length of post-operative stay was also significantly greater in the transductal group. CONCLUSION: This study represents the largest single study to date comparing outcomes from transcystic and transductal LCBDE. Where possibly, the transcystic route should be used for LCBDE and this approach can be augmented with various techniques to increase successful stone clearance and reduce the need for choledochotomy.

Failure to administer multimodality therapy leads to sub-optimal outcomes for patients with node-positive biliary tract cancers in the United States.

BACKGROUND: Lymph node-positive biliary tract cancers have poor overall survival. Surgical resection followed by systemic chemotherapy is the mainstay of treatment. We sought to assess the delivery of multimodality therapy in the United States. METHODS: The Surveillance, Epidemiology, and End Results program database was used to identify patients with node-positive biliary tract cancers without distant metastases from 2000 to 2014. Patients were stratified by disease subtype (gallbladder cancer, intrahepatic, extrahepatic, or hilar cholangiocarcinoma) and treatment received (surgery alone, chemotherapy alone, or surgery + chemotherapy). Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard modeling. RESULTS: A total of 3226 patients with node-positive biliary tract cancers were identified. Of 2837 patients who underwent surgical resection, 1386 (49%) received no systemic chemotherapy following surgery, while 1451 (51%) received surgery + chemotherapy. A total of 389 patients (12%) received chemotherapy alone. Median overall survival was longer for patients who underwent surgery + chemotherapy (19 months, p < 0.0001). There was no difference in survival for those who received surgery alone versus chemotherapy alone (10 months for both, p = NS). Receipt of surgery + chemotherapy was independently associated with survival on Cox proportional hazard ratio modeling compared to surgery alone (HR for mortality 1.71, 95% CI 1.56-1.87, p < 0.0001) or chemotherapy alone (HR 1.68, 95% CI 1.46-1.92, p < 0.0001). These trends were consistent across all disease subtypes. DISCUSSION: Optimal survival for node-positive biliary tract cancers depends on multimodality therapy. Following surgery, a substantial proportion of patients do not receive guideline recommended adjuvant therapy.

Role of cholangitis in predicting survival in patients with carcinoma of the ampulla of vater.

BACKGROUND: There have been strong suggestions that acute inflammation promotes tumour growth, and has a tendency for increased invasiveness, leading to poor survival after surgery. When cholangitis coexists with ampulla of vater cancer, the patient's prognosis may be influenced by the acute inflammatory status of the bile duct. We evaluated the relationship between the severity of acute cholangitis, preoperative CRP levels and survival. METHODS: We retrospectively analysed 154 patients who underwent surgical resection for AOV cancer between January 2003 and November 2018. Cholangitis was graded according to Tokyo Guidelines 2018. Patients were categorised into two groups based on their CRP levels: CRP > 1 mg/L and CRP ≤ 1 mg/L. Relationship of cholangitis grade and CRP >1 mg/L with survival was assessed. RESULTS: The mean age of the patients was 65.8 years. Preoperative cholangitis was present in 40 (25.9%) patients, of which 28 (18.2%) had mild cholangitis, 11 (7.1%) had moderate cholangitis, and one (0.6%) had severe cholangitis. CRP was elevated preoperatively in 56 (36.4%) patients. The median follow-up period was 33.5 months. Severity of cholangitis significantly affected the overall survival (P < 0.001) and disease-free survival (P < 0.001). Patients with mild cholangitis had a median overall survival of 43 months compared to 14 months in those with moderate cholangitis. A preoperative CRP level of >1 mg/L was significantly associated with poor overall survival (P = 0.023) but not with disease-free survival (P = 0.128), although it was associated with a trend towards poorer survival. The survival rate of patients with CRP ≤1 mg/L was 77.4%, whereas that of patients with CRP >1 mg/L was 56.7%. In multivariable analysis, age >65 years (P = 0.015), cholangitis grade (P = 0.050), CRP > 1 mg/L (P = 0.045), venous invasion (P = 0.005), and perineural invasion (P = 0.034) were independent prognostic factors for overall survival while cholangitis grade (P = 0.049) and perineural invasion (P = 0.004) were independent prognostic factors for disease-free survival. CONCLUSION: Acute inflammation when associated with cancer can have a negative effect on patient's survival. Patients with higher grades of cholangitis should be adequately treated to improve the inflammatory status.

Outcome of interventional radiology for delayed postoperative hemorrhage in hepatobiliary and pancreatic surgery.

BACKGROUND AND AIM: Postoperative hemorrhage is a rare but potentially lethal complication of hepatobiliary and pancreatic surgeries. This study aimed to retrospectively evaluate the clinical outcome of patients with delayed postoperative hemorrhage and compare the results according to the surgical procedure. METHODS: Overall, 4220 patients underwent surgery for hepatobiliary and pancreatic diseases. Delayed postoperative hemorrhage (observed more than 24 h postoperatively) occurred in 62 patients. Of these, 61 underwent interventional radiology to achieve hemostasis. Patients' clinical data were analyzed retrospectively. The chi-squared or Fisher's exact test was used in data analysis. RESULTS: A total of 62 patients (1.5%) developed delayed postoperative hemorrhage; 61 (1.4%) of them underwent interventional radiology to achieve hemostasis. Median duration from surgery to interventional radiology was 19 days (range: 5-252 days). Sentinel bleeding was detected in 31 patients; Clinical success was achieved in 54 patients (88.5%) by interventional radiology. Overall mortality rate was 26.2%. Causes of 16 in-hospital deaths were uncontrollable hemorrhage (n = 4) and worsening of general condition after hemostasis (n = 12). Mortality rates were 50.0% (11/22) and 12.8% (5/39) after hepatobiliary surgery and pancreatic resection, respectively. Mortality rate was significantly higher after hepatobiliary surgery than after pancreatic surgery (P = 0.002). CONCLUSIONS: Interventional radiology can be successfully performed to achieve hemostasis for delayed hemorrhage after hepatobiliary and pancreatic surgeries. Because successful interventional radiology does not necessarily lead to survival, particularly after hepatobiliary surgery, meticulous attention to prevent surgical complications and intensive treatments before and after interventional radiology are required to improve outcomes.

Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma: A cohort study.

CONTEXT: Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA). AIMS: This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA. SETTINGS AND DESIGN: We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013. MATERIALS AND METHODS: Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group. STATISTICAL ANALYSIS USED: The Kaplan-Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model. RESULTS: There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival. CONCLUSIONS: Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA.

Six-month Survival of Patients with Malignant Distal Biliary Stricture Following Endoscopic Biliary Stent Procedure and Its Associated Factors.

BACKGROUND: unresectable malignant distal biliary stricture patients require endoscopic biliary stent placement procedure. The survival rate and its associated factors in Indonesia are unknown. OBJECTIVES: To identify 6-month survival of patients with malignant distal biliary stricture following endoscopic biliary stent procedure and its associated factors. METHODS: a retrospective cohort study was conducted using medical records of patients with unresectable malignant distal biliary stricture, which involved caput of pancreas, ampulla of Vater or distal cholangiocarcinoma following endoscopic biliary stent procedure between June 2015 and August 2017 at Cipto Mangunkusumo National Central General Hospital. The cumulative survival was defined by using the Kaplan-Meier curve. Bivariate and multivariate analyses were performed using Cox regression of some factors including failure of biliary stent insertion, bleeding, sepsis, comorbidities, malnutrition, and serum albumin levels. RESULTS: out of total 120 subjects, 85 subjects died within 6 months following the stent procedure with a proportion of 180-day survival of 24% and a median survival of 81 days (CI 95%: 56-106 days). In bivariate analysis, factors of comorbidities, sepsis, malnutrition and albumin levels ≤ 3.0 g/dL had p values of < 0.25; while the subsequent multivariate analysis showed that albumin level of ≤ 3.0 g/dL had HR of 2.73 (CI 95%: 1.48 - 5.05; p = 0.001). CONCLUSION: the 6-month survival following endoscopic biliary stent procedure is 24% with a median survival of 81 days. Albumin level of ≤ 3.0 g/dL has a 2.73 times greater risk for 6-month mortality rate.

Surgical Strategies for the Treatment of Bismuth Type I and II Hilar Cholangiocarcinoma: Bile Duct Resection with or Without Hepatectomy?

BACKGROUND: The role of hepatic resection in the treatment of type I and II hilar cholangiocarcinoma (HCCA) remains controversial. In the present study, we aimed to identify whether hepatic resection was necessary for type I and II HCCA. METHODS: A total of 23 patients classified as type I and II HCCA undergoing surgical resection were included in this study. The patients were divided into two groups: bile duct resection (BDR) group (n = 15) and hepatic resection (HR) group (n = 8). Systematic review and meta-analysis were performed to compare the R0 resection and long-term survival between BDR and HR for Bismuth type I and II HCCA. A total of 7 studies with 260 cases were included in this meta-analysis. RESULTS: In our cohort, the R0 resection rate was 73.3% in BDR group and 87.5% in HR group. The HR group had a higher number of postoperative complications than the BDR group (P = 0.002). There was no difference in long-term survival (P = 0.544) and recurrence (P = 0.846) between BDR and HR in Bismuth type I and II HCCA. The meta-analysis showed that HR was associated with better R0 resection rate (RR 4.45, 95% CI 2.34-8.48) and overall survival (HR 2.15, 95% CI 1.34-3.44) compared with BDR group. There was no publication bias and undue influence of any single study. CONCLUSIONS: The meta-analysis showed that HR was associated with better R0 resection rate and overall survival compared with BDR for type I and II HCCA patients. More aggressive surgical strategies should be increasingly considered for the treatment of type I and II HCCA patients.

Does high-grade dysplasia/carcinoma in situ of the biliary duct margin affect the prognosis of extrahepatic cholangiocarcinoma? A meta-analysis.

BACKGROUND: High-grade dysplasia/carcinoma in situ (HGD/CIS) of the biliary duct margin was found to not affect the prognosis of patients with extrahepatic cholangiocarcinoma by recent studies, but it has not yet reached a conclusion. METHODS: Eligible studies were searched by PubMed, PMC, MedLine, Embase, the Cochrane Library, and Web of Science, from Jan. 1, 2000 to Jun. 30, 2019, investigating the influences of surgical margin status of biliary duct on the prognosis of patients with resectable extrahepatic cholangiocarcinoma. Overall survival (OS) and local recurrence were evaluated by odds ratio (OR) with 95% confidence interval (CI). RESULTS: A total of 11 studies were enrolled in this meta-analysis, including 1734 patients in the R0 group, 194 patients in the HGD/CIS group, and 229 patients in the invasive carcinoma (INV) group. The pooled OR for the 1-, 2-, and 3-year OS rate between HGD/CIS group and R0 group was 0.98 (95% CI 0.65~1.50), 1.01 (95% CI 0.73~1.41), and 0.98 (95% CI 0.72~1.34), respectively. The pooled OR for the 1-, 2-, and 3-year OS rate between HGD/CIS group and INV group was 1.83 (95% CI 1.09~3.06), 4.52 (95% CI 2.20~9.26), and 3.74 (95% CI 2.34~5.96), respectively. Subgroup analysis of extrahepatic cholangiocarcinoma at early stage showed that the pooled OR for the 1-, 2-, and 3-year OS rate between HGD/CIS group and R0 group was 0.54 (95% CI 0.21~1.36), 0.75 (95% CI 0.35~1.58), and 0.74 (95% CI 0.40~1.37), respectively, and the pooled OR for the 1-, 2-, and 3-year OS rate between HGD/CIS group and INV group was 3.47 (95% CI 1.09~11.02), 9.12 (95% CI 2.98~27.93), and 9.17 (95% CI 2.95~28.55), respectively. However, the pooled OR for the incidence of local recurrence between HGD/CIS group and R0 group was 3.54 (95% CI 1.66~7.53), and the pooled OR for the incidence of local recurrence between HGD/CIS group and INV group was 0.93 (95% CI 0.50~1.74). CONCLUSION: With the current data, we concluded that HGD/CIS would increase the risk of local recurrence compared with R0, although it did not affect the prognosis of patients with extrahepatic cholangiocarcinoma regardless of TNM stage. However, the conclusion needs to be furtherly confirmed.

Resultados iniciales de un programa de cirugía hepato-bilio-pancreática laparoscópica en el Hospital Regional de Talca / Initial results of a laparoscopic hepato-biliary-pancreatic surgery program at the Regional Hospital of Talca

Resumen Introducción: La cirugía laparoscópica es la vía de abordaje de elección para el tratamiento de múltiples patologías abdominales, sin embargo, su desarrollo en la cirugía hepato-bilio-pancreática (HBP) ha sido más lento y heterogéneo. Objetivo: Presentar los resultados de la implementación y desarrollo de un programa de cirugía HBP laparoscópica en el Hospital de Regional de Talca. Materiales y Método: Estudio de serie de casos que incluye a todos los pacientes operados por una patología HBP por vía laparoscópica como acceso a la cavidad abdominal en el Hospital Regional de Talca entre el 1 de junio de 2014 y el 30 de junio de 2016. Resultados: Fueron 42 pacientes, 25 (59,5%) de sexo femenino. La mediana de edad fue 58 años (IQ25-75 38-64 años). 22 (52,4%) tuvo una cirugía abdominal previa en la mayoría de ellos por vía abierta. 22 (52,4%) pacientes fueron intervenidos por patología maligna. La indicación más frecuente fue la cirugía radical por cáncer de vesícula biliar en 10 (23,8%) casos y la hidatidosis hepática (HH) en 7 (16,7%). 1 (2,4%) paciente portador de una HH requirió de una conversión a laparotomía. 5 (11,9%) presentaron alguna morbilidad posoperatoria, 2 de ellos > III de Clavien. La mediana de recuperación funcional fue de 1 día (1-2) y la de estadía posoperatoria de 3 días (3-4). No hubo mortalidad a 90 días. Con una mediana de seguimiento de 26,5 (18-33) meses, 4 (19%) de los 21 pacientes oncológicos intervenidos con intención curativa presentaron recurrencia de la enfermedad, la mayoría de ellos sistémica y el 95% está libre de recurrencia a los 24 meses. Conclusiones: La implementación y el desarrollo de la cirugía hepato-bilio-pancreática (HBP) por vía laparoscópica puede efectuarse en hospitales de referencia regional con los mismos estándares y resultados internacionales.

Introduction: Laparoscopic surgery is the preference access for the treatment of various abdominal pathologies, however, its development in hepato-biliary-pancreatic (HBP) surgery has been slower and heterogeneous. Aim: Present the results of the implementation and development of a laparoscopic HBP surgery program at the Regional Hospital of Talca. Materials and Method: Case series study in which were included all patients submitted to laparoscopic surgery for treatment of HPB pathology as access to the abdominal cavity in the Regional Hospital of Talca between June 1, 2014 and June 30, 2016. Results: There were 42 patients, 25 (59.5%) female. The median age was 58 years (IQ25-75 38-64 years). 22 (52.4%) had previous abdominal surgery in most of them by open route. 22 (52.4%) patients were operated on for malignant pathology. The most frequent indication was radical surgery for gallbladder cancer in 10 (23.8%) cases and hepatic hydatidosis (HH) in 7 (16.7%). 1 (2.4%) patient carrying a HH required a conversion to laparotomy. 5 (11.9%) presented some postoperative morbidity, 2 of them > Clavien III. The median functional recovery was 1 day (1-2) and the postoperative stay was 3 days (3-4). There was no mortality at 90 days. With a median follow-up of 26.5 (18-33) months, 4 (19%) of the 21 oncological patients operated on with curative intent presented recurrence of the disease, most of them systemic and 95% free from recurrence at 24 months. Conclusions: Implementation and development of HBP surgery by laparoscopy is feasible and it can be performed in regional referral hospitals with the same international standards and results.

Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker.

PURPOSE: In biliary tract cancer (BTC), standard chemotherapy has limited benefit and no molecular targeted agents have been approved. This study investigated the genetic profile of BTC to identify potential new therapeutic targets and predictive biomarkers. METHODS: Targeted exome sequencing was performed for 124 patients with BTC [gallbladder cancer (GBC), 25; intrahepatic cholangiocarcinoma (ICC), 55; extrahepatic cholangiocarcinoma (ECC), 44]. Survival analysis was performed in 112 patients who received palliative chemotherapy for locally unresectable or metastatic disease. RESULTS: Genetic alterations were observed in 104 patients (83.8%); the most commonly mutated genes were TP53 (44.4%), KRAS (29.0%), ARID1A (12.1%) and IDH1 (9.7%). IDH1/2 mutations appeared more frequently in ICC (23.6%, P = 0.0002) than in GBC (4.0%) or ECC (2.3%), while ERBB2/3 mutations were found only in GBC (20.0%) and ECC (11.4%). Patients harbouring TP53 mutations had shorter overall survival (OS; median 15.2 vs. 37.8 months, P = 0.018), while IDH1 mutations showed a tendency for longer progression-free survival (PFS; 10.6 vs. 6.1 months, P = 0.124). Potentially actionable genetic alterations were found in 54.8%, and 7.1% received appropriate molecular targeted therapy in the clinical trial setting. Germline or somatic mutations in DNA damage repair (DDR) genes were found in 63.5% of patients and were significantly associated with longer PFS (6.9 vs. 5.7 months, P = 0.013) and OS (21.0 vs. 13.3 months, P = 0.009) in patients who received first-line platinum-containing chemotherapies (n = 88). CONCLUSIONS: A subgroup of patients with BTC may benefit from targeted therapy by the aid of genetic information. In particular, DDR alterations may be a predictive biomarker for response to platinum-containing chemotherapy in patients with BTC.

Percutaneous transpapillary biliary stent placement for distal malignant biliary obstruction: Outcomes and survival analysis.

BACKGROUND/AIMS: For distal malignant biliary obstruction (MBO), a percutaneous metal stent is usually inserted by the transpapillary method. However, stent-related complications and recurrent biliary obstruction following transpapillary stent placement are concerns, and survival analysis of patients with distal MBO has rarely been done. MATERIALS AND METHODS: From January 2012 to March 2016, 104 patients underwent transpapillary uncovered metal stent placement for distal MBO at our institution. Clinical success, complications, recurrent biliary obstruction rates, and predictors of survival were analyzed. RESULTS: Of the total 104 patients, clinical success after stent insertion was achieved in 93 patients (90.3%). Major complications were observed in 24 patients (23.1%), which were as follows: cholangitis in 19 patients; pancreatitis in four patients; and biloma in one patient. Recurrent biliary occlusion was observed in 28 patients (26.9%). The median overall survival period was 162 days. The 3-, 6-, and 12-month overall survival rates after stent insertion were 64.4%, 41.3%, and 10.6%, respectively. Results of multivariate analysis indicated that metastatic carcinoma compared with ampullary carcinoma (HR=3.82; 95% CI, 1.30-11.24; p=0.015) and longer biliary stricture (HR=1.04; 95% CI, 1.02-1.06; p<0.001) were independent risk factors for worse survival after metal stent insertion. CONCLUSION: Transpapillary stent placement was found to be effective with acceptable complication rates for treating distal MBO. Primary tumor and length of biliary stricture were found to be statistically significant independent prognostic factors for survival.

Long-term Survival after resection for perihilar cholangiocarcinoma: Impact of UICC staging and surgical procedure.

BACKGROUND/AIMS: Perihilar cholangiocarcinoma is a rare disease with unfavorable prognosis resulting in low survival rates. This study aims to retrospectively assess the beneficial histopathological features and surgical procedures in long-term survivors (i.e., patients surviving perihilar cholangiocarcinoma for at least 2 y). MATERIAL AND METHODS: In total, 322 patients with perihilar cholangiocarcinoma underwent surgery at our center. The follow-up ended in 2017; 76 patients survived for >2 y. The type of resection, UICC stage, and histopathological features were compared between three survival groups (>2-3, >3-5, and >5 y). RESULTS: The >5-year-survival rate in our selected study cohort was 43.4% (>3-5 y,31.6% and >2-3 y, 25.0%), and 14.5% of the patients survived for >10 y after surgery. Patients with non-regional lymph node positive tumors and/or distant metastasis (i.e., UICC stage IVb; p=0.0112), R2 status (p=0.0288), and exploratory laparotomy only (p=0.0157) showed the poorest survival rates. Perineural invasion had no significant impact on the overall survival. However, 29.0% patients surviving for >5 y displayed the lowest perineural infiltration prevalence. Interestingly, Bismuth-Corlette stage IIIa (p=0.0467), especially caudate lobectomy (p=0.0034), was associated with disease-specific overall survival of >5y. CONCLUSION: Complete/extended tumor resection with additional caudate lobe resection is strongly associated with long-term survival. Perineural infiltration as a negative prognostic marker for prolonged survival needs to be evaluated in larger study cohorts.

Usefulness of serum microRNA as a predictive marker of recurrence and prognosis in biliary tract cancer after radical surgery.

Biliary tract cancer (BTC) is an aggressive type of malignant tumour. Even after radical resection, the risk of recurrence is still high, resulting in a poor prognosis. Here, we investigated the usefulness of serum miRNAs as predictive markers of recurrence and prognosis for patients with BTC after radical surgery using 66 serum samples that were collected at three time points from 22 patients with BTC who underwent radical surgery. Using microarray analysis, we successfully identified six specific miRNAs (miR-1225-3p, miR-1234-3p, miR1260b, miR-1470, miR-6834-3p, and miR-6875-5p) associated with recurrence and prognosis of BTC after radical surgery. In addition, using a combination of these miRNAs, we developed a recurrence predictive index to predict recurrence in patients with BTC after operation with high accuracy. Patients having higher index scores (≥ cut-off) had significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with lower index scores (

Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.

BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING: Cancer Research UK and Roche.

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.

PURPOSE: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

Inflammation-based prognostic scores in patients with extrahepatic bile duct lesions treated by percutaneous transhepatic biliary stenting combined with 125I seeds intracavitary irradiation.

PURPOSE: This study aimed at investigating the efficacy of percutaneous transhepatic biliary stenting (PTBS) combined with 125I seeds intracavitary irradiation in the treatment of extrahepatic cholangiocarcinoma (EHC) and to preliminarily explore the prognostic values of inflammation-based scores in these patients. METHODS: A total of 113 clinically/pathologically diagnosed cases of EHC who received PTBS combined with 125I seeds implantation were retrospectively analyzed. The postoperative changes of clinical symptoms and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total serum bilirubin (TBIL), direct bilirubin (DBIL), and albumin (ALB) were observed. Preoperative clinical data were extracted to calculate inflammation-based scores, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelets-to-lymphocyte ratio (PLR). Kaplan-Meier survival curves and Cox regression analyses were used to evaluate the prognostic significance of inflammation-based scores. RESULTS: After operation, clinical symptoms such as jaundice and fever significantly improved in all patients. At 1 month and 3 months postoperatively, serum levels of ALT, AST, ALP, TBIL, and DBIL significantly reduced, and ALB significantly increased, compared with preoperative values. The median survival time of the patients was 12 months and the 1-year survival rate was 56.8%. Univariate analysis revealed that factors related to overall survival were CA19-9, TBIL, ALB, SII, and NLR. Multivariate analysis further identified SII and NLR as independent prognostic models. CONCLUSION: The combination of PTBS and 125I seeds intracavitary irradiation is an effective palliative treatment for advanced EHC. Elevated SII and NLR can be used to predict poor survival.

Surgical technique and results of intrapancreatic bile duct resection for hilar malignancy (with video).

BACKGROUND: Hilar malignancy can occasionally be associated with high grade dysplasia (HGD) adjacent to invasive malignancy. For patients with HGD extending into the intrapancreatic bile duct, the authors adopted intrapancreatic bile duct resection (IP-BDR). The aims of this study were to compare the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF), distal R0 resection and local recurrence within the distal bile duct remnant for patients undergoing extrahepatic bile duct resection without pancreaticoduodenectomy (with or without IP-BDR). METHODS: Patients who presented with hilar malignancy and underwent extrahepatic bile duct resection without pancreaticoduodenectomy between January 2005 and December 2016 were identified and the outcomes retrospectively evaluated. RESULTS: Of 217 patients who met the inclusion criteria 62 (29%) patients underwent IP-BDR. There was a significant difference between patients undergoing standard resection vs. IP-BDR in terms of CR-POPF (5% (8/155) patients: vs 18% (11/62), p < 0.001). There were no significant differences between two groups of R0 status on distal margin (5% (8/155) patients: vs 10% (6/62), p = 0.359). No patient developed recurrence within the residual intrapancreatic bile duct. DISCUSSION: The incidence of CR-POPF after IP-BDR for hilar malignancies was 18%. IP-BDR was associated with CR-POF, but does not appear to alter survival or local recurrence rate.

Assessment of clinical outcomes of advanced hilar cholangiocarcinoma.

BACKGROUND: Low resectability and poor survival outcome are common for hilar cholangiocarcinoma (HCCA), especially in advanced stages. The present study was to assess the clinical outcome of advanced HCCA, focusing on therapeutic modalities, survival analysis and prognostic assessment. METHODS: Clinical data of 176 advanced HCCA patients who had been treated in our hospital between January 2013 and December 2015 were analyzed retrospectively. Prognostic effects of clinicopathological factors were explored by univariate and multivariate analysis. Survival predictors were evaluated by the receiver operating characteristic (ROC) curve. RESULTS: The 3-year overall survival rate was 13% for patients with advanced HCCA. Preoperative total bilirubin (P = 0.009), hepatic artery invasion (P = 0.014) and treatment modalities (P = 0.020) were independent prognostic factors on overall survival. A model combining these independent prognostic factors (area under ROC curve: 0.748; 95% CI: 0.678-0.811; sensitivity: 82.3%, specificity: 53.5%) was highly predictive of tumor death. After R0 resection, the 3-year overall survival was up to 38%. Preoperative total bilirubin was still an independent negative factor, but not for hepatic artery invasion. CONCLUSIONS: Surgery is still the best treatment for advanced HCCA. Preoperative biliary drainage should be performed in highly-jaundiced patients to improve survival. Prediction of survival is improved significantly by a model that incorporates preoperative total bilirubin, hepatic artery invasion and treatment modalities.

Impact of preoperative endoscopic cholangiography and biliary drainage in Ampulla of Vater cancer.

BACKGROUND: Ampulla of Vater (AOV) carcinoma is a rare malignancy but has a relatively good prognosis. The aims of this study were to determine the clinicopathologic factors associated with survival and disease recurrence in patients with AOV cancer, focusing on the impact of preoperative endoscopic retrograde cholangiopancreatography (ERCP) and type of biliary drainage (endoscopic retrograde biliary drainage [ERBD] or percutaneous transhepatic biliary drainage [PTBD]). METHODS: We retrospectively reviewed the medical records of 80 patients who underwent curative resection for AOV cancer at a single institution between 1995 and 2015. The clinicopathologic factors associated with survival and disease recurrence were analyzed using univariate and multivariable tests. RESULTS: The 5-year disease-free and overall actuarial survival rates were 39.3% and 51.3%, respectively. Moderate or poor differentiation, preoperative ERCP, advanced T stage, lymph node metastases, advanced stage and lymphovascular invasion were associated with disease-free survival in univariate analyses. The prognosis was worse in patients who underwent ERBD than in patients who underwent PTBD or no biliary drainage. Multivariable analysis showed that advanced AJCC stage and preoperative ERCP were independent risk factors for recurrence. Patient who underwent preoperative ERCP had a significantly higher rate of early distant metastasis within 1 year, especially in patients with early stage AOV cancer. CONCLUSIONS: Preoperative ERCP was an independent risk factor for postoperative recurrence in patients with AOV cancer, and is characterized by early distant metastasis in early stage cancer. Therefore, unnecessary ERCP should be avoided in patients with AOV cancer. If biliary drainage is necessary, PTBD may be preferred to ERBD in AOV cancer.