Extrahepatic Bile Duct Carcinoma Research Articles

Total lesion glycolysis by 18F-fluorodeoxyglucose positron emission tomography predicts tumor aggressiveness in patients with extrahepatic bile duct carcinoma.

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) parameters are prognostic factors in multiple malignancies. However, the prognostic value in bile duct carcinoma is unclear. We evaluated the impact of metabolic parameters of 18F-FDG-PET/CT in resectable extrahepatic bile duct carcinoma. We retrospectively reviewed the records of 100 patients with extrahepatic bile duct carcinoma who had undergone 18F-FDG-PET/CT and subsequent surgical resection between January 2017 and January 2023. We calculated maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and investigated their prognostic significance. The optimal cutoff values of SUVmax, MTV, and TLG for predicting overall survival (OS) after surgery were 3.88, 3.55 and 7.55, respectively. In multivariate analysis, each metabolic parameter influenced both OS and recurrence-free survival (RFS). TLG showed the lowest Akaike information criteria statistic value, indicating that it had the best ability to predict OS and RFS. High TLG was significantly associated with the number of lymph node metastases and poorly differentiated type. Patients with high TLG showed poorer RFS and OS, which were significantly worse than in those with low TLG. Tumor TLG predicted tumor malignancy potential and could be a useful prognostic predictor for extrahepatic bile duct carcinoma.

Prognostic Significance of Intratumoral and Peritumoral Budding in Distal Extrahepatic Bile Duct Carcinoma

Introduction: Although tumor budding (TB) has been recognized as a representative adverse prognosticator in gastrointestinal malignancies, it is not well elucidated in distal extrahepatic bile duct carcinoma (DBDC). Herein, we investigated the prognostic significance of peritumoral (PTB) and intratumoral (ITB) budding according to the modified DBDC staging of the 8th edition of the American Joint Committee on Cancer. Methods: PTB and ITB were independently evaluated in a cohort of DBDC patients (n = 410) based on the 2016 International Tumor Budding Consensus Conference. Results: High levels of PTB (PTBHigh, ≥ grade-2) and ITB (ITBHigh, ≥ grade-3) were identified in 316 (77%) and 238 (58%) cases, respectively. In univariate analysis, PTBHigh and ITBHigh, larger size and sclerosing tumor growth pattern, higher histologic grade, extrapancreatic location, adenocarcinomas unrelated to intraductal papillary neoplasm of the bile duct, pancreatic, duodenal, and lymphovascular invasion, perineural invasion, cancer involvement of the bile duct resection margin, nodal metastasis, and higher T and N categories and disease stages were associated with shorter patient overall survival (OS) times. In multivariate analysis, PTBHigh and ITBHigh remained poor independent prognostic indicators of OS in DBDC patients. Specifically, ITBHigh could predict poor prognosis in patients with stage I (T1N0) DBDC. Conclusions: Both PTBHigh and ITBHigh were strong prognostic indicators in patients with DBDC. Thus, ITB could be used to predict worse prognoses in patients with DBDC, in which PTB is difficult to assess, especially for patients with stage I (T1N0) DBDC.

127P Prognostic significance of intratumoral and peritumoral budding in distal extrahepatic bile duct carcinoma

127P Prognostic significance of intratumoral and peritumoral budding in distal extrahepatic bile duct carcinoma

Phytochemical research of the anticancer potential of Aloe turkanensis

Abstract. Adem FA, Yenessew A, Yusuf AO, Wanjohi JM. 2022. Phytochemical research of the anticancer potential of Aloe turkanensis. Asian J Nat Prod Biochem 20: 75-88. The number of people diagnosed with cancer is rising worldwide, particularly in Sub-Saharan Africa. The search for new cancer treatments continues to benefit greatly from nature as a rich supply of promising chemicals. The anticancer effects of quinones have made them a popular medicinal class among natural chemicals (e.g., daunomycin and doxorubicin). Aloe turkanensis Christian, like other members of the genus Aloe, is a good place to get quinones. Dried and powdered A. turkanensis rhizomes and leaves were cold percolated in a mixture of dichloromethane and methanol (1:1). The crude extracts significantly decreased the viability of the human extrahepatic bile duct cancer cell line (TFK-1). Twelve chemicals were isolated from the crude extracts through chromatographic separations on silica gel, Sephadex LH-20, and preparative TLC. Spectroscopic techniques such as UV, 1H, and 13C NMR, COSY, NOESY, HMBC, and HSQC were used to determine the structures of the isolated compounds. Two naphthoquinones [3,5,8-trihydroxy-2-methylnaphthalene-1,4-dione (1) and 5,8-dihydroxy-3-methoxy-2-methylnaphthalene-1,4-dione (2)], seven anthraquinones [chrysophanol (3), aloesaponarin I (4), aloesaponarin II (5), laccaic acid D methyl ester (6) helminthosporin (8) aloe-emodin (10) and ?-L-11-O-rhamnopyranosylaloe-emodin (11)], a pre-anthraquinone [aloesaponol I (7)] a pyrone derivative [feralolide (9)] and a benzoic acid derivative [3,4-dihydroxybenzoic acid (12)] were the chemicals that made up these substances. This study reported again that the Aloe genus produced the naphthoquinones [3,5,8-trihydroxy-2-methylnaphthalene-1,4-dione (1) and 5,8-dihydroxy-2-methoxy-2-methylnaphthalene-1,4-dione (2)]. In addition, this study made the first report of 3,5,8-trihydroxy-2-methylnaphthalene-1,4-dione (1) from the Asphodelaceae family. Human extrahepatic bile duct carcinoma (TFK-1) and liver cancer (HuH7) cell lines were used to test the extracted compounds for in-vitro anticancer activity. The anthraquinone aloe-emodin (10) and the naphthoquinone 5,8-dihydroxy-3-methoxy-2-methylnaphthalene-1,4-dione (2) showed significant inhibition against TFK-1 cell lines using the 3- [4,5-dimethylthiazol-2-yl]-2-,5-diphenyltetrazolium bromide (MTT) assay, with IC50 values of 6.0 and Aloesaponol I (7), a pre-anthraquinone, inhibited the development of TFK-1 cells with IC50 values of 10.0 µg/mL and HuH7 cells with 88.0 µg/mL. Both ?-L-11-O- rhamnopyranosyl aloe-emodin (11) and aloesaponarin II (4), an anthraquinone, decreased TKF-1 cell line viability with IC50 values of 23.0 and 34.0 µg/mL, and HuH7 cell line viability with IC50 values of 47.0 and 55.0 µg/mL, respectively. IC50 values of 46.0 µg/mL for helminthosporin (8) showed considerable inhibition of TFK-1 cell growth, although it did not affect HuH7 cells at those concentrations. Extrahepatic bile duct (TFK-1) and liver (HuH7) cancer cell lines are sensitive to these chemicals identified here for the first time. Before these chemicals can be established as potentially effective anticancer medicines, more research on normal cell lines and their mechanism of action is required.

Prognostic implications of immune classification using IDO1 expression in extrahepatic bile duct carcinoma.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme that catalyzes the degradation of tryptophan to kynurenine and induces immune tolerance in tumor cells. The effects of IDO1 on extrahepatic bile duct carcinoma (EHBDC) are poorly understood. Therefore, the present study aimed to investigate the expression and prognostic significance of IDO1 in EHBDC. An immunohistochemical microarray analysis of IDO1 expression was performed for 76 surgically resected cases of EHBDC. CD8+ tumor infiltrating lymphocytes (TILs) were also investigated through a combination analysis with IDO1 expression. IDO1 was highly expressed in 25 of 76 (32.9%) cases. High expression of IDO1 was associated with decreased numbers of CD8+ TILs (P=0.008), a higher pN category (P=0.007), an advanced overall stage (P=0.001) and frequent recurrence (P=0.018). When IDO1 expression was further stratified with CD8+ TIL state, the IDO1high/CD8low subgroup was decreased in terms of overall survival (P=0.025) and disease-free survival (P=0.015) compared with IDO1high/CD8high, IDO1low/CD8high and IDO1low/CD8low subgroups. High IDO1 expression was associated with a decreased number of CD8+ TILs and associated with a poor prognosis. As IDO1 may be a new target of immunotherapy applications, IDO1/CD8+ TIL subgrouping can be a useful prognostic and predictive tool in patients with EHBDC.

The T Category of Distal Extrahepatic Bile Duct Carcinoma: A Comparative Analysis With Invasive Tumor Thickness.

The T category of distal extrahepatic bile duct carcinoma (DBDC) is based on invasion depth from the basal lamina to the deepest infiltrating tumor cells. Recently, invasive tumor thickness (ITT) was proposed, defined as maximal vertical distance of invasive tumor components regardless of the basal lamina. We compared the predictive value of T category, and ITT grading in 424 surgically resected DBDCs. DBDCs were categorized as 6 Tis (1.4%), 134 T1 (<5 mm; 31.6%), 204 T2 (5 to 12 mm; 48.1%), and 80 T3 (>12 mm; 18.9%). With ITT, there were 6 G0 (no invasion; 1.4%), 3 G1 (<1 mm; 0.7%), 90 G2 (≥1 and <5 mm; 21.2%), 188 G3 (≥5 and <10 mm; 44.4%), and 137 G4 (≥10 mm; 32.3%). The 5-year survival rates of T1, T2, and T3 were 58.9%, 44.2%, and 18.2%, and those of ITT G1, G2, G3, and G4 were 33.3%, 54.1%, 51.6%, and 26.7%, respectively. The T category discriminated patient survival by overall (P<0.001) and pairwise (T1 vs. T2, P=0.007; T2 vs. T3, P<0.001) comparisons. ITT grading distinguished survival by overall and between G3-G4 (both P<0.001), with no survival differences observed between G1-G2 and G2-G3 comparisons. The T category more accurately discriminated patient survival than ITT grading. To determine the T category for DBDCs, (1) longitudinal sectioning on gross examination, especially for DBDCs with large papillary or nodular growth patterns; (2) evaluation of serial sections or alternative hematoxylin and eosin slides; (3) use of a straight or curved baseline depending on the shape of the peritumoral normal bile duct wall and/or the basal lamina of the peritumoral normal biliary epithelia/biliary intraepithelial neoplasias are recommended.

Bile cytology diagnosis in challenging cases: Validation of diagnostic bile cytology criteria and extensive study for immunocytochemical markers.

Bile cytology is useful in diagnosing biliary tract lesions, albeit often challenging due to equivocal findings. To achieve better diagnoses for clinical decisions, we conducted cytomorphological and immunocytochemical studies of bile cytology cases. We re-evaluated 40 bile cytology cases with initial equivocal diagnoses, taken from the cytology records of Jichi Medical University Hospital, including 1778 bile cytology specimens. First, we assessed the cases by the diagnostic bile cytology criteria of the Japanese Society of Clinical Cytology. Second, we searched for useful immunocytochemical markers by extensive immunohistochemical analyses using tissue microarray for 10 antibodies: S100P, IMP3, GLUT1, p53, S100A4, Mapsin, MUC17, CD10, MDM2, and SMAD4. Microarrays were from 257 extrahepatic bile duct carcinoma cases. To elucidate the utility of immunocytochemistry, we applied selected markers to immunocytochemical evaluation of the equivocal cases after cell transfer. The criteria indicated a sensitivity 60%, specificity 87%, and accuracy 70%. Irregularly overlapping (88%), arranged (96%), and shaped (76%) nuclei were more common in malignant cases, while enlarged nuclei were more frequent in benign cases (67% vs. 28%). We applied S100P and IMP3, which showed higher accuracy (88% and 77%) in tissue microarray, to immunocytochemistry. The sensitivity of S100P and IMP3 were 69% and 70%, respectively. The specificity of S100P and IMP3 were 50% and 100%, respectively. The criteria showed a certain effectiveness even in challenging cases, and some pitfalls associated with reactive changes of benign cells. Although comprehensive diagnosis including cytomorphology seems preferable, S100P and IMP3 are promising immunocytochemical markers.

Genetic Screens Identify a Context-Specific PI3K/p27Kip1 Node Driving Extrahepatic Biliary Cancer.

We used the first genetically engineered mouse model for extrahepatic bile duct carcinoma to identify cancer genes by genome-wide transposon-based mutagenesis screening. Thereby, we show that PI3K signaling output strength and p27Kip1 function are critical determinants for context-specific ECC formation. This article is highlighted in the In This Issue feature, p. 2945.

Different role of MSLN and CA125 co-expression as a prognostic predictor between perihilar and distal bile duct carcinoma.

Recent studies have suggested that the interaction of mesothelin (MSLN) and cancer antigen 125 (CA125) enhances tumor metastases. The aim of the present study was to clarify the impact of MSLN and CA125 co-expression on the prognosis of patients with extrahepatic bile duct carcinoma (BDC). Tissue samples from patients who underwent surgical resection between 2007 and 2015 for perihilar or distal BDC were immunohistochemically examined. The expression levels of MSLN and CA125 in tumor cells were analyzed. The expression in <50% and ≥50% of the total tumor cells were defined as low- and high-level expression, respectively. Tissue samples were obtained from 31 patients with perihilar BDC and 43 patients with distal BDC. Lymph node metastases were associated with MSLN and CA125 co-expression in patients with perihilar BDC (P=0.002), while there was no association between lymph node metastasis and co-expression in patients with distal BDC (P=0.362). MSLN and CA125 co-expression was associated with a worse overall survival rate in patients with perihilar BDC (5-year overall survival rate, co-expression positive vs. negative, 24 vs. 63%; P=0.038). To the best of our knowledge, the present study is the first to report an association between co-expression of MSLN and CA125 with a poor prognosis in patients with perihilar BDC. The current findings suggested that the significance of co-expression differed according to the BDC location.

Cholangiocarcinoma miscoding in hepatobiliary centres

IntroductionCholangiocarcinoma (CCA) are sub-divided into intrahepatic (iCCA) or extrahepatic (eCCA). eCCA are further subdivided into perihilar (pCCA) and distal (dCCA). Current and previous versions of the WHO International Coding of Disease and Oncology classifications (ICD) have separate topography codes for iCCA and eCCA, but none for pCCA. Over recent decades, multiple studies report rising incidence rates of iCCA with declining rates of eCCA, without reference to pCCA. We hypothesised the lack of a specific code for pCCA has led to errors CCA coding, specifically with miscoding of pCCA as iCCA. MethodsClinical notes of cases coded as hepatobiliary carcinoma using ICD-10 criteria (C22.1/Intrahepatic Bile Duct carcinoma, C24.0/Extrahepatic Bile Duct carcinoma, C23X/Malignant Neoplasm Gall Bladder, C22.0/Malignant Neoplasm Liver Cell Carcinoma) over a 2 year period (2015–2017), were reviewed by two independent clinicians at three independent UK regional HepatoPancreatoBiliary centres. The agreed final diagnosis was compared to the originally allocated ICD-10 code. ResultsOf the 625 CCA cases fully reviewed, 226 were coded as C22.1/iCCA. 98 (43%) of these were true iCCA and coded correctly, while 76 cases (34%) were actually pCCA. 92% all pCCA cases were incorrectly coded as iCCA. ConclusionCCA coding misclassification in UK HPB centres is common, particularly the miscoding of pCCA, which is extrahepatic and the commonest form of CCA, as iCCA. This may be contributing to apparent rising incidence rates of iCCA. Our findings confirm the need to implement distinct topographical codes for iCCA, pCCA and dCCA in future iterations of ICD.

Primary congenital choledochal cyst with squamous cell carcinoma: a case report

Cases of extrahepatic bile duct carcinoma are mostly adenocarcinomas and extrahepatic bile duct squamous cell carcinomas are rare. We report here a case of choledochal squamous cell carcinoma in a young woman who underwent surgery and chemotherapy. The woman presented with abdominal discomfort. A physical examination showed tenderness in the upper abdomen. Laboratory tests showed elevated direct bilirubin, total bilirubin, and C-reactive protein levels. Abdominal computed tomography and magnetic resonance imaging showed a cystic-solid mixed soft tissue mass in the common bile duct. Pain symptoms in the patient were not relieved and surgical treatment was performed. Postoperative pathological results showed a choledochal cyst complicated by squamous cell carcinoma. The patient was treated by biliary intestinal anastomosis followed by chemotherapy. However, the patient developed liver metastasis and recurrence at a 6-month follow-up. Primary congenital bile duct cysts with squamous cell carcinoma are extremely rare. Surgical resection is the main treatment option for choledochal squamous cell carcinoma. Postoperative chemoradiotherapy can be used, but the efficacy is poor and chemotherapy does not significantly prolong the patient’s survival.

Hepatitis B virus infection and the risk of cancer among the Chinese population.

The relationship between hepatitis B virus (HBV) and nonhepatocellular cancers remains inconclusive. This large case-control study aimed to assess the associations between HBV infection status and multiple cancers. Cases (n = 50 392) and controls (n = 11 361) were consecutively recruited from 2008 to 2016 at the First Affiliated Hospital of Nanjing Medical University. Multivariable adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression by adjusting age and gender. A meta-analysis based on published studies was also performed to verify the associations. Of these, 12.1% of cases and 5.5% of controls were hepatitis B surface antigen (HBsAg) seropositive. We observed significant associations between HBsAg seropositivity and esophagus cancer (aOR [95% CI] = 1.32 [1.13-1.54]), stomach cancer (1.46 [1.30-1.65]), hepatocellular carcinoma (HCC; 39.11 [35.08-43.59]), intrahepatic and extrahepatic bile duct carcinoma (ICC and ECC; 3.83 [2.58-5.67] and 1.72 [1.28-2.31]), pancreatic cancer (PaC; 1.37 [1.13-1.65]), non-Hodgkin lymphoma (NHL; 1.88 [1.61-2.20]) and leukemia (11.48 [4.05-32.56]). Additionally, compared to participants with HBsAg-/anti-HBs-/anti-HBc-, participants with HBsAg-/anti-HBs-/anti-HBc+, indicating past HBV-infected, had an increased risk of esophagus cancer (aOR [95% CI] = 1.46 [1.24-1.73]), stomach cancer (1.20 [1.04-1.39]), HCC (4.80 [3.95-5.84]) and leukemia (15.62 [2.05-119.17]). Then the overall meta-analysis also verified that HBsAg seropositivity was significantly associated with stomach cancer (OR [95% CI] = 1.23 [1.14-1.33]), ICC (4.05 [2.78-5.90]), ECC (1.73 [1.30-2.30]), PaC (1.26 [1.09-1.46]), NHL (1.95 [1.55-2.44]) and leukemia (1.54 [1.26-1.88]). In conclusion, both our case-control study and meta-analysis confirmed the significant association of HBsAg seropositivity with stomach cancer, ICC, ECC, PaC, NHL and leukemia. Of note, our findings also suggested that the risk of stomach cancer elevated for people whoever exposed to HBV.

Clinicopathological significance of olfactomedin-4 in extrahepatic bile duct carcinoma

The clinicopathological and prognostic significance of olfactomedin-4 (OLFM4) expression has not yet been elucidated in extrahepatic bile duct carcinomas (EBDCs). Immunohistochemical analysis of OLFM4 expression in 31 normal biliary epithelia, 33 biliary intraepithelial neoplasias (BilINs), and 180 surgically resected EBDCs (54 perihilar and 126 distal) was performed and was used to analyze clinicopathological variables including patient survival. The expression of OLFM4 showed a progressive increase from normal biliary epithelia (0.2 ± 0.4) to BilINs (2.8 ± 3.2) to EBDCs (4.6 ± 4.2; P < 0.001). OLFM4 was highly expressed in 26.1% (47/180) of the EBDC cases, and high OLFM4 levels were more frequently observed in tumors with nodular growth (P = 0.029), well differentiation (P = 0.011), and lower T-category (P = 0.025) and stage grouping (P = 0.013). Patients with EBDC having high expression of OLFM4 had better survival than those with low expression of OLFM4 (median, 43.3 vs. 29.2 months; P = 0.037). OLFM4 might play an important role in carcinogenesis and in the progression from BilINs to EBDCs. High OLFM4 expression predicted less aggressive clinical behavior in patients with EBDC.

Influence of bile contamination for patients who undergo pancreaticoduodenectomy after biliary drainage.

BACKGROUNDThe influence of bile contamination on the infectious complications of patients undergoing pancreaticoduodenectomy (PD) has not been thoroughly evaluated.AIMTo evaluate the effect of preoperative biliary drainage and bile contamination on the outcomes of patients who undergo PD.METHODSThe database of 4101 patients who underwent PD was reviewed. Preoperative biliary drainage was performed in 1964 patients (47.9%), and bile contamination was confirmed in 606 patients (14.8%).RESULTSThe incidence of postoperative infectious complications was 37.9% in patients with preoperative biliary drainage and 42.4% in patients with biliary contamination, respectively. Patients with extrahepatic bile duct carcinoma, ampulla of Vater carcinoma, and pancreatic carcinoma had a high frequency of preoperative biliary drainage (82.9%, 54.6%, and 50.8%) and bile contamination (34.3%, 26.2%, and 20.2%). Bile contamination was associated with postoperative pancreatic fistula (POPF) Grade B/C, wound infection, and catheter infection. A multivariate logistic regression analysis revealed that biliary contamination (odds ratio 1.33, P = 0.027) was the independent risk factor for POPF Grade B/C. The three most commonly cultured microorganisms from bile (Enterococcus, Klebsiella, and Enterobacter) were identical to those isolated from organ spaces.CONCLUSIONIn patients undergoing PD, bile contamination is related to postoperative infectious complication including POPF Grade B/C. The management of biliary contamination should be standardised for patients who require preoperative biliary drainage for PD, as the main microorganisms are identical in both organ spaces and bile.

Evaluation of preoperative risk factors for postpancreatectomy hemorrhage

PurposeTo investigate the risk factors for post-pancreatectomy hemorrhage (PPH).MethodsThe incidence, outcome, and risk factors for PPH were evaluated in 1169 patients who underwent pancreatectomy.ResultsThe incidence and mortality rates of PPH were 3% and 11% in all pancreatectomies, 4% and 11% in pancreatoduodenectomy, 1% and 20% in distal pancreatectomy, and 3% and 0% in total pancreatectomy, respectively. Male sex [odds ratio (OR) 2.32], body mass index (BMI) ≥ 25 kg/m2 (OR 3.70), absence of diabetes mellitus (DM; HbA1c ≤ 6.2%; OR 3.62), and pancreatoduodenectomy (OR 3.06) were risk factors for PPH after all pancreatectomies. The PPH incidence was 0%, 1%, 2%, 6%, and 20% in patients with risk scores of 0 (n = 65), 1 (n = 325), 2 (n = 455), 3 (n = 299), and 4 (n = 25), respectively. The differences between risk-score groups 0–2 (2%) and 3–4 (7%) were significant (P < 0.05, OR 4.7). In patients who had undergone pancreatoduodenectomy, postoperative pancreatic fistula (POPF; OR 31.7) and absence of DM (OR 3.45) were risk factors for PPH. There was no significant association between POPF and PPH after distal pancreatectomy (P = 0.28). The incidence of POPF post-pancreatoduodenectomy was 20%. BMI ≥ 25 kg/m2 (OR 3.17), serum albumin < 3.5 g/dl (OR 1.77), absence of DM (OR 1.75), distal extrahepatic bile duct carcinoma (OR 4.05), and carcinoma of the papilla of Vater (OR 5.19) were risk factors for POPF post-pancreatoduodenectomy.ConclusionOur study clarified the preoperative risk factors for PPH and recommends using a risk scoring system that includes “absence of DM” for predicting PPH.

Hospitalization outcomes between intrahepatic bile duct carcinoma versus extrahepatic biliary cholangiocarcinoma

Background: Cholangiocarcinoma is an uncommon cancer with a very bad prognosis despite advances made in treatment. The location of the tumor (intrahepatic versus extrahepatic) determines surgical options. In our study, we examine variations in outcomes between patients admitted to the hospital with intrahepatic versus extrahepatic disease. Methods: Data from the NIS, a database developed for the healthcare Cost and Utilization project (HCUP) was used for our analysis. We identified patients who were 18 years and older with intrahepatic or extrahepatic biliary duct carcinoma who underwent a procedure (biliary stent, resection, bypass, pancreatic resection, liver resection and transplantation) during a hospitalization. Our primary aim was to describe outcomes in terms of inpatient mortality, length of stay and hospitalization cost based on tumor location. We used multivariable logistic regression to calculate adjusted odd ratios and mean differences for each cohort. We controlled for patient level characteristics (age, race, sex, comorbidity burden), hospital level characteristics (hospital region, size and teaching status), insurance type and procedure received during hospitalization using multivariable analysis. Results: We identified a total of 18,840 admissions in 2014 with a discharge diagnosis of cholangiocarcinoma (intrahepatic or extrahepatic). Of these, 13,930 (73.1%) were intrahepatic while 4,930 (26.1%) were extrahepatic. Inpatient mortality amongst patents with extrahepatic bile duct carcinoma was 5.5% while that for intrahepatic bile duct carcinoma was 7.69%. After controlling for confounders, including treatment received during hospitalization, patients with extrahepatic disease were 30% less likely (Adjusted Odds Ratio 0.70, 95 % CI 0.512-0.966) to die during hospitalization compared to patients admitted for intrahepatic bile duct carcinoma. Length of stay was similar between the two groups (Adjusted Mean Difference -0.10, 95 % CI -0.64 -0.44) as was average cost of hospitalization (Adjusted Mean Difference. -4126, 95% CI -1.0986.5 - 2733.16). Conclusion: The location of biliary duct carcinoma predicts inpatient mortality, even after controlling for treatment received. Intrahepatic cholangiocarcinoma has a worse prognosis than extrahepatic tumors, although length of stay and average cost of hospitalization are similar across the two cohorts. The two carcinomas have different histology, molecular characteristics, and associated genetic abnormalities. Intrahepatic cholangiocarcinoma is more likely to be associated with cirrhosis due to underlying viral hepatitis or non alcoholic fatty liver disease. It is unclear if these pathological characteristics or underlying chronic inflammation influence outcomes. We recommend prospective studies to better understand reasons for variation in hospitalization mortality seen in patients with intrahepatic cholangiocarcinoma.

A Case Report of Intraoperatively Diagnosed Cholangiocarcinoma after Unsuccessful Conservative Treatment of ERCP Complicated with Hemorrhage

[full article, abstract in English; abstract in Lithuanian] Background Cholangiocarcinoma is a malignant tumor arising from the epithelium of the bile ducts. Most of these tumors are adenocarcinomas [1]. Intrahepatic cholangiocarcinoma accounts for 10% of all cholangiocarcinomas, hilar cholangiocarcinoma for 25%, and extrahepatic cholangiocarcinoma for 65% [2, 3]. Cholangiocarcinoma can develop in any part of the extrahepatic duct, occurring in 50–75% of reported cases in the upper third of the duct including the hepatic hilum, in 10–25% in the middle third, and in 10–20% in the lower third [4–6]. Approximately 95% of cases show extrahepatic obstruction at the time of diagnosis [7]. In a meta-analysis of 21 prospective trials, the rate of hemorrhage as a complication of ERCP was 1.3% (95% CI, 1.2%–1.5%) with 70% of the bleeding episodes classified as mild [8]. Hemorrhagic complications may be immediate or delayed, with recognition of occurring up to 2 weeks after the procedure. The risk of severe hemorrhage (ie, requiring >5 units of blood, surgery or angiography) is estimated to occur in fewer than1 per 1 000 sphincterotomies [9]. Despite new and advanced diagnostic methods, sometimes this type of tumor is finally diagnosed from pathological findings on excised tissue. Case report We present one case with cholangiocarcinoma diagnosed after surgical treatment of hemorrhage as post procedural complication from ERCP. With MRCP intraluminal stenosis of the upper part of common bile duct has been noticed and suspicious presence of substrate with consecutive dilatation of the upper billiary tract. ERCP was performed and sphincterotomy have been made without evacuation of any intraluminal substrate from common bile duct. Insufficient ERCP cholangiography was made and biopsy of the part with stenosis could not be taken due to permanent bleeding from performed sphincterotomy. Despite all attempts for conservative treatment of the hemorrhage, patient was still with permanent decreases of hemoglobin levels and with persistent hemorrhagic anemia. With decision from medical council the patient has been transferred to the Department of abdominal surgery for further immediate surgical treatment. Conclusion Patient with extrahepatic bile duct carcinoma initially diagnosed as a calculus in the common bile duct. Looking back, the patient had symptoms which differential diagnosis for bile duct cholangiocarcinoma should be established. Clinical symptoms such as right hypochondrium pain, itchy skin, vomiting and diarrhea. The laboratory findings showed constantly elevated bilirubin and liver enzymes also elevated tumor markers as CA19-9 and CEA. Hemorrhage that occurs after ERCP sphincterotomy and attempt for biopsy could not been controlled with conservative measures. Patient with consequently caused hemorrhagic anemia has been transferred for surgical treatment, which stopped the bleeding, made final diagnosis and treatment of proximal stenosis of common bile duct.

Progress of hepatic-biliary-pancreatic surgery in the 118th annual congress of Japan Surgical Society

The annual congress of Japan Surgical Society is a famous academic event in the field of surgery, and the participants can learn from the latest research results of all the major surgical disciplines. The authors selected topics of the 118th annual congress in 2018, including the latest research results and progresses of laparoscopic hepatectomy, liver transplantation, extrahepatic bile duct carcinoma and pancreatic surgery. The purpose of this study is to provide new information and reference for optimizing the diagnosis and treatment of hepatobiliary and pancreatic diseases. Key words: Hepatic neoplasms; Intrahepatic cho-langiocarcinoma; Pancreatic neoplasms; Liver transplantation; Hepatectomy; Laparoscopy; Translational medicine; Japan Surgical Society

Tumor-infiltrating mast cells predict prognosis and gemcitabine-based adjuvant chemotherapeutic benefit in biliary tract cancer patients

BackgroundRecent studies have reported TIMs play an important role in tumors progression or regression, but the effect of TIMs in biliary tract cancer remains unclear. The aim of this study is to investigate the prognostic value of tumor infiltrating mast cells (TIMs) and its influence on gemcitabine-based adjuvant chemotherapy (ACT) benefits in biliary tract cancer patients after surgery.MethodsTIMs were evaluated by immunohistochemical staining of tryptase in 250 patients with resected gallbladder carcinoma (GBC) or extrahepatic bile duct carcinoma (EBDC) from Zhongshan Hospital. The relationships between TIMs and clinicopathological factors and postoperative prognosis were analyzed respectively.ResultsHigh TIMs infiltration was significantly correlated with prolonged overall survival (OS). Furthermore, multivariate analysis indicated TNM stage and TIMs as independent prognostic factors for OS. Patients with high TIMs infiltration appeared to significantly benefit from Gemcitabine-based ACT in the discovery and validation cohorts. Spearman analysis identified that TIMs infiltration were positively correlated with anti-tumor CD8+ T cells.ConclusionTIMs infiltration is an independent favorable prognostic factor in GBC and EBDC patients, which could better stratify patients with different prognosis and predict benefit from gemcitabine-based ACT.

Combination of Kras activation and PTEN deletion contributes to murine hepatopancreatic ductal malignancy

Kras mutations are among the most common genetic abnormalities in human neoplasms, including cholangiocarcinomas, pancreatic cancer and colon cancer. PTEN has previously been associated with cholangiocarcinoma development in murine models. Here, we have established novel mouse models of neoplasms by liver-specific and biliary-pancreatic Kras activation and PTEN deletion. By liver-specific disruption of PTEN and activation of Kras in mice caused rapid development of intrahepatic biliary epithelial proliferative lesions (Intrahepatic cholangiocarcinoma, ICC), which progress through dysplasia to invasive carcinoma. In contrast, Kras activation in combination with heterozygous PTEN deletion induced mixed carcinomas of liver (both ICC and hepatocellular carcinoma, HCC), whereas Kras activation alone did not induce biliary tract neoplasm. Use of Sox9-Cre-LoxP-based approach to coordinately delete PTEN and activate Kras in the adult mouse resulted in not only development of low-grade biliary lesions (ICC and extrahepatic bile duct carcinoma, ECC) but also pancreatic carcinomas. Our data provide a functional link between PTEN gene status, hepatobiliary cell fate, and HCC, biliary carcinoma, pancreatic cancer pathogenesis, and present novel genetically engineered mouse models of PTEN loss-driven malignancy.