Extrahepatic Bile Duct Cancer Research Articles

Practice guidelines for managing extrahepatic biliary tract cancers.

Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.

There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer. Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p=0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p=0.004). Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Preoperative CT and MRI assessment of the longitudinal tumor extent of extrahepatic bile duct cancer after biliary drainage.

To examine the diagnostic performance for the longitudinal extent of extrahepatic bile duct (EHD) cancer on computed tomography (CT) after biliary drainage (BD) and investigate the appropriate timing of magnetic resonance imaging (MRI) acquisition. This retrospective study included patients who underwent curative-intent surgery for EHD cancer and CT pre- and post-BD between November 2005 and June 2021. The biliary segment-wise longitudinal tumor extent was evaluated according to the 2019 Korean Society of Abdominal Radiology consensus recommendations, with pre-BD CT, post-BD CT, and both pre- and post-BD CT. The performance for tumor detectability was compared using GEEs. When preoperative MRI was performed, patients were divided into two subgroups according to the timing of MRI with respect to BD, and the performance of MRI obtained pre- and post-BD was compared. In 105 patients (mean age: 67 ± 8 years; 74 men and 31 women), the performance for tumor detectability was superior using both CT scans compared with using post-BD CT alone (reader 1: sensitivity, 72.6% vs. 64.6%, P < 0.001; specificity, 96.9% vs. 94.8%, P = 0.063; reader 2: sensitivity, 77.2% vs. 72.9%, P = 0.126; specificity, 97.5% vs. 94.2%, P = 0.003), and it was comparable with using pre-BD CT alone. In biliary segments with a catheter, higher sensitivity and specificity were observed using both CT scans than using post-BD CT (reader 1: sensitivity, 74.4% vs. 67.5%, P = 0.006; specificity, 92.4% vs. 88.0%, P = 0.068; reader 2: sensitivity, 80.5% vs. 74.4%, P = 0.013; specificity, 94.3% vs. 88.0%, P = 0.016). Post-BD MRI (n = 30) exhibited a comparable performance to pre-BD MRI (n = 55) (reader 1: sensitivity, 77.9% vs. 75.0%, P = 0.605; specificity, 97.2% vs. 94.9%, P = 0.256; reader 2: sensitivity, 73.2% vs. 72.6%, P = 0.926; specificity, 98.4% vs. 94.9%, P = 0.068). Pre-BD CT provided better diagnostic performance in the preoperative evaluation of EHD cancer. The longitudinal tumor extent could be accurately assessed with post-BD MRI, which was similar to pre-BD MRI. The acquisition of pre-BD CT could be beneficial for the preoperative evaluation of EHD cancer when BD is planned. Post-BD MRI would not be significantly affected by BD in terms of the diagnostic performance of the longitudinal tumor extent.

Comparative dosimetric study of spot-scanning proton therapy versus volumetric-modulated radiation therapy for extrahepatic bile duct cancer

This study aimed to compare the dose distributions and clarify the dosimetric characteristics of spot-scanning proton therapy (SSPT) and photon volumetric modulated arc therapy (VMAT) for extrahepatic bile duct cancer (EBDC). This retrospective study included 10 patients with EBDC treated with real-time image-gated SSPT. Using the simultaneous integrated boost technique, the 2 prescription dose levels for planning target volumes were 72.6 and 44 Gy, delivered in 22 fractions. Plan quality comparisons were conducted by analyzing various parameters, including homogeneity, conformity, dose to organs at risk, and normal tissue complication probability (NTCP) for radiation-induced liver damage (RILD). The target dose distributions using SSPT were almost equivalent to those achieved using photon VMAT. There was a significant reduction in all liver dose parameters, the NTCP value for RILD, and kidney dose (mean, V12 Gy, and V18 Gy) in SSPT than in photon VMAT. No significant differences were observed in the intestinal doses in the high-dose area. Thus, compared with photon VMAT, SSPT for EBDC significantly reduced radiation doses to the liver and kidneys and has shown potential clinical benefits of reduced radiation-induced toxicity.

Osteosarcopenia is a significant predictor of recurrence and the prognosis after resection for extrahepatic bile duct cancer.

This study examined the impact of osteosarcopenia on recurrence and the prognosis after resection for extrahepatic biliary tract cancer (EBTC). We retrospectively analyzed 138 patients after resection for perihilar cholangiocarcinoma (11), distal cholangiocarcinoma (54), gallbladder carcinoma (30), or ampullary carcinoma (43). Osteosarcopenia is defined as the concomitant occurrence of osteopenia and sarcopenia. We investigated the relationship between osteosarcopenia and the overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analyses. Osteosarcopenia was identified in 38 patients (27.5%) before propensity score (PS) matching. In the multivariate analysis, the independent recurrence factors were the prognostic nutrition index (p = 0.015), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.004), perineural invasion (p = 0.002), and non-curability (p = 0.008), whereas the independent prognostic factors were prognostic nutrition index (p = 0.030), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.007), lymphatic invasion (p = 0.018), and non-curability (p = 0.004). After PS matching, there was no significant difference in the variables between the patients with and without osteosarcopenia (n = 34 each). The 5-year DFS and OS after PS matching in patients with osteosarcopenia were significantly worse than in patients without osteosarcopenia (17.6% vs. 38.8%, p = 0.013 and 20.6% vs. 57.4%, p = 0.0005, respectively). Preoperative osteosarcopenia could predict the DFS and OS of patients after resection for EBTC.

Adjuvant chemoradiotherapy vs chemotherapy for resectable biliary tract cancer: a propensity score matching analysis based on the SEER database

BackgroundAlthough the role of adjuvant chemotherapy (CT) for resectable biliary tract cancer (BTC) is gradually recognized, the benefit of adjuvant chemoradiotherapy (CRT) is still controversial. Our study is designed to compare the prognosis of CRT versus CT in BCT patients.MethodsClinicopathologic characteristics of patients with operable gallbladder cancer (GBCA), intrahepatic bile duct cancer (IHBDC), or extrahepatic bile duct cancer (EHBDC) were obtained from the Surveillance, Epidemiology and End Results (SEER) database (2004–2015). Univariate and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Selection bias were reduced by propensity-score matching (PSM). Kaplan–Meier analysis was used to estimate the survival time.ResultsWithin 922 patients, 53.9% received adjuvant CRT, and 46.1% received adjuvant CT. Multivariate analysis showed age, primary tumor site, T stage, N stage, tumor size, number of removed lymph nodes, and treatment were independent risk factors for OS. Similar improvement of CRT on survival was identified by PSM in the matched cohort compared with CT (28.0 months vs. 25.0 months, p = 0.033), particularly in GBCA cohort (25.0 months vs. 19.0 months, p = 0.003). Subgroup analysis indicated CRT improved outcomes of patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases.ConclusionAdjuvant CRT correlated with improved survival in patients with resected BTC compared with adjuvant CT, particularly in GBCAs. In addition, patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases may receive more benefits from adjuvant CRT.

The Demographic and Clinicopathological Characteristics of Hepatopancreatobiliary Cancers From a Specialized Center in India.

Introduction Hepatopancreatobiliary (HPB) cancers are a distinct group requiring specialized multidisciplinary care. The present study was an analysis of HPB cancers. Methods The institutional data for two years from 2017 to 2018 was retrieved from the hospital-based cancer registry (HBCR) database in Excel format (Microsoft® Corp., Redmond, WA). The demographic details, method of diagnosis, tumor characteristics, and disease extent of the patients with HPB primary sites were retrospectively analyzed. Results Out of the 1417 patients with HPB malignancies, 1193 were analyzed. Most of the patients at our center hailed from North India. The distribution of HPB cancers was as follows: hepatocellular carcinoma (HCC) (n=717, 60.1%), gallbladder (GB) (n=230, 19.3%), periampullarycarcinoma (n=76, 6.37%), head of the pancreas (HOP) (n=55, 4.61%), extrahepatic bile duct (EBD) (n=53, 4.44%), intrahepatic bile duct (IBD) (n=32, 2.68%), and body of the pancreas (BOP) (n=30, 2.52%). The most common disease presentation of HPB cancers was in the seventh and sixth decades of life. Male predominance was seen in all HPB cancers except in GB with a higher incidence in females. The predominant cause of chronic liver disease (CLD) with HCC was viral-related (53.7%) with hepatitis B virus (HBV) (34.3%) higher than hepatitis C virus (HCV) (19.2%)followed by non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) (24.8%) and then alcohol. Adenocarcinoma was the most common morphology in pancreatobiliary malignancies. The disease presentation was locoregional in 63.4% of HCC, 69.7% of periampullary carcinoma, and 50.9% of HOP cases. The patients with EBD and IBD cancers presented commonly with locoregional disease extent in 60.4% and 62.5%, respectively. Perihilar subsite was more commonly detected (71.7%) as compared to the distal one in the patients with EBD cancers. The patients with GB cancers (GBC) presented with distant metastases in 53.5% and locoregional disease in 33%. Distant metastases were present in 76.7% of the patients with BOP cancers. The liver was a common site of distant metastases in GB, periampullary, and pancreatic cancers. Conclusions The present study highlights the characteristics and the variations in disease presentation in different primary tumor sites of HPB cancers. In view of the common locoregionally advanced disease presentation of HCC, the patients with CLD need surveillance for the early detection of lesions. As the patients with HPB cancers show advanced disease presentation, effective locoregional and systemic therapies are needed.

Risk Factors for Distant Metastasis in Extrahepatic Bile Duct Cancer after Curative Resection (KROG 1814).

Risk factors predicting distant metastasis (DM) in extrahepatic bile duct cancer (EHBDC) patients treated with curative resection were investigated. Medical records of 1,418 EHBDC patients undergoing curative resection between Jan 2000 and Dec 2015 from 14 institutions were reviewed. After resection, 924 patients (67.6%) were surveilled without adjuvant therapy, 297 (21.7%) were treated with concurrent chemoradiotherapy (CCRT) and 148 (10.8%) with CCRT followed by chemotherapy. To exclude the treatment effect from innate confounders, patients not treated with adjuvant therapy were evaluated. After a median follow-up of 36.7 months (range, 2.7 to 213.2 months), the 5-year distant metastasis-free survival (DMFS) rate was 57.7%. On multivariate analysis, perihilar or diffuse tumor (hazard ratio [HR], 1.391; p=0.004), poorly differentiated histology (HR, 2.014; p < 0.001), presence of perineural invasion (HR, 1.768; p < 0.001), positive nodal metastasis (HR, 2.670; p < 0.001) and preoperative carbohydrate antigen (CA) 19-9 ≥ 37 U/mL (HR, 1.353; p < 0.001) were significantly associated with inferior DMFS. The DMFS rates significantly differed according to the number of these risk factors. For validation, patients who underwent adjuvant therapy were evaluated. In patients with ≥ 3 factors, additional chemotherapy after CCRT resulted in a superior DMFS compared with CCRT alone (5-year rate, 47.6% vs. 27.7%; p=0.001), but the benefit of additional chemotherapy was not observed in patients with 0-2 risk factors. Tumor location, histologic differentiation, perineural invasion, lymph node metastasis, and preoperative CA 19-9 level predicted DM risk in resected EHBDC. These risk factors might help identifying a subset of patients who could benefit from additional chemotherapy after resection.

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts.

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.

Incidence, Mortality, and Survival Trends in Cancer of the Gallbladder and Extrahepatic Bile Ducts in Lithuania.

Background and Objectives: Gallbladder cancer is a rare type of cancer, with aggressive clinical behavior. Limited treatment options provide poor survival prognosis. We aimed to investigate the incidence, mortality trends, and survival of gallbladder and extrahepatic bile duct cancer in Lithuania between 1998 and 2017. Materials and Methods: The study was based on the Lithuanian Cancer Registry database. The study included all cases of cancer of the gallbladder and extrahepatic bile ducts reported to the Registry in the period 1998-2017. Age-specific and age-standardized incidence rates were calculated. In addition, 95% confidence intervals for APC (Annual Percent Change) were calculated. Changes were considered statistically significant if p was <0.05. Relative survival estimates were calculated using period analysis according to the Ederer II method. Results: Age-standardized rates for gallbladder cancer and extrahepatic bile duct cancer among females decreased from 3.91 to 1.93 cases per 100.000 individuals between 1998 and 2017, and from 2.32 to 1.59 cases per 100.000 individuals between 1998 and 2017 among males. The highest incidence rates were found in the 85+ group with 27.5/100,000 individuals in females and 26.8/100,000 individuals in males. The 1-year as well as 5-year relative survival rates of both genders were 34.29% (95% CI 32.12-36.48) and 16.29% (95% CI 14.40-18.27), respectively. Conclusions: Incidence and mortality from gallbladder and extrahepatic bile duct cancer decreased in both sexes in Lithuania. Incidence and mortality rates were higher in females than in males. Relative 1-year and 5-year survival rates showed a steady increase during the study period among males and females.

Effect of local treatment in patients with oligo-recurrence after surgery of distal bile duct cancer: A bi-institutional study.

Distal extrahepatic bile duct (EHBD) cancer is highly recurrent. More than 50% of patients suffer from disease relapse after curative resection. Some patients present with oligo-recurrence which could be a single loco-regional mass or lesions limited to a single solid organ. The aim of this study was to examine the effect of local control (surgical resection or radiofrequency ablation) on survival outcomes in patients with oligo-recurrent distal EHBD cancer. Data of 1219 patients who underwent surgery for distal EHBD cancer from 2000 to 2018 were retrospectively reviewed. Clinicopathological characteristics and survival outcomes of patients with recurrence were investigated. Post-recurrence survival (PRS) was analyzed according to modalities of re-treatment (local treatment or systemic therapy alone). Among 654 patients with recurrence, 90 patients who had oligo-recurrence showed better recurrence-free and overall survival than patients with non-oligo-recurrent disease. Lymph node ratio and perineural invasion at initial pathology, timing of recurrence, and platelet-to-lymphocyte ratio at recurrence were independent risk factors for PRS in the oligo-recurrent group. Patients with local treatment for oligo-recurrence had better 3- and 5-year PRS than those with systemic treatment alone (38.3% vs. 14.1%, p=0.04; 28.3% vs. 7.1%, p=0.04, respectively). Recurrence within 24 months after initial surgery was the only significant factor for PRS in the local treatment group. In patients with oligo-recurrence after resection of distal EHBD cancer, post-recurrence local treatment could improve survival outcomes, particularly for those with recurrence more than 2 years after initial resection.

Habitually Skipping Breakfast Is Associated with the Risk of Gastrointestinal Cancers: Evidence from the Kailuan Cohort Study

BackgroundHabitually skipping breakfast may promote the initiation and progression of gastrointestinal (GI) cancers, which have never been systematically explored in large-scale prospective studies.MethodsWe prospectively examined the effects of breakfast frequency on the occurrence of GI cancers among 62,746 participants. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of GI cancers were calculated by Cox regression. The CAUSALMED procedure was used to perform the mediation analyses.ResultsDuring a median follow-up of 5.61 (5.18 ~ 6.08) years, 369 incident GI cancer cases were identified. Participants who consumed 1–2 times breakfasts per week exhibited an increased risk of stomach (HR = 3.45, 95% CI: 1.06–11.20) and liver cancer (HR = 3.42, 95% CI: 1.22–9.53). Participants who did not eat breakfast had an elevated risk of esophageal (HR = 2.72, 95% CI: 1.05–7.03), colorectal (HR = 2.32, 95% CI: 1.34–4.01), liver (HR = 2.41, 95% CI: 1.23–4.71), gallbladder, and extrahepatic bile duct cancer (HR = 5.43, 95% CI: 1.34–21.93). In the mediation effect analyses, BMI, CRP, and TyG (fasting triglyceride-glucose) index did not mediate the association between breakfast frequency and the risk of GI cancer incidence (all P for mediation effect > 0.05).ConclusionsHabitually skipping breakfast was associated with a greater risk of GI cancers including esophageal, gastric, colorectal, liver, gallbladder, and extrahepatic bile duct cancer.Trial RegistrationKailuan study, ChiCTR–TNRC–11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050

18F‑fluorodeoxyglucose positron emission tomography predicts recurrence and histological grade of extrahepatic bile duct cancer.

Malignant tumors in cholangiocarcinoma are diagnosed and staged using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and clinical analysis. However, comprehensive analysis, including pathological analysis, has not yet been sufficiently performed. In the present study, the maximum standardized uptake value (SUVmax) was calculated using FDG-PET and its relationship with clinicopathological factors was analyzed. The present study included 86 patients who underwent preoperative FDG-PET/computed tomography (CT) and did not receive chemotherapy among 331 patients with hilar and distal cholangiocarcinoma. Receiver operating characteristic analysis with recurrence events was used to determine the SUVmax cutoff of 4.9. Immunohistochemical staining of glucose transporter 1 (Glut1), hypoxia-inducible factor-1α and Ki-67 was performed for pathological analysis. The standardized uptake value (SUV)-high group (SUVmax ≥4.9) had a higher postoperative recurrence rate (P<0.046) and higher Glut1 and Ki-67 expression rates (P<0.05 and P<0.0001, respectively). Furthermore, SUVmax and Glut1 expression (r=0.298; P<0.01) and SUVmax and Ki-67 expression rates (r=0.527; P<0.0001) were positively correlated. The preoperative measurement of SUVmax by PET-CT is useful in predicting recurrence as well as cancer malignancy.

A multicenter, single-arm, phase II study of nivolumab in patients with biliary tract cancer with a PD-L1 combined positive score ≥ 1.

533 Background: Patients with advanced biliary tract cancer (BTC) have a poor prognosis, and high unmet medical needs still exist for the treatment of this disease. Nivolumab has shown its effectiveness against multiple cancer types, especially those with PD-L1 expression. This study assessed the efficacy and safety of nivolumab in BTC patients with a combined positive score (CPS) ≥ 1 who were refractory or intolerant to the standard of care (SOC): gemcitabine, cisplatin and tegafur/gimeracil/oteracil (S-1). Methods: This was a single-arm, multicenter, open-label, prospective phase II study. Key eligibility criteria were as follows: having unresectable or recurrent BTC (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer); being refractory or intolerant to SOC; having adequate hepatic, renal and hematological function; and having a CPS ≥ 1 in central assessment. Patients received nivolumab (480 mg, every 4 weeks) until disease progression, clinical deterioration, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the central review according to RECIST 1.1. The secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled between Mar 11, 2020 and Mar 15, 2021, of them 12 received one regimen and 72 received two or more regimens. The median follow-up period was 6.90 months. ORR per central assessment was 10.7% (CR: 3.6%, PR: 7.1%), and ORR per investigator assessment was 15.5% (CR: 2.4%, PR: 13.1%). The median PFS per central and investigator assessment was 1.02 (95% CI 0.95–1.77) months and 2.48 (95% CI 1.87–2.83) months, respectively. The median OS was 6.90 (95% CI 5.26–9.20) months. The median duration of response per central and investigator assessment was not reached (range 2.8–13.0+) and 10.15 (range 2.0–12.8+) months, respectively. The 1-year survival rate was 25.3% (95% CI 15.4–36.4). The most frequent treatment-related adverse events were pyrexia (19.0%), pruritus (16.7%), and decreased appetite (13.1%). Conclusions: Nivolumab may have some activity with a durable response and a manageable safety profile in heavily treated BTC patients with CPS ≥ 1. Clinical trial information: JapicCTI-205097 .

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.

New approach to the treatment of cancer of large duodenal papilla and extrahepatic bile ducts with photodynamic therapy

The study is based on the treatment of 79 patients with adenocarcinoma of large duodenal papilla and extrahepatic bile ducts. 29 patients received palliative bile drainage operations with PDT. 50 patients in the group of chronological control only palliative bile drainage operations had been performed. Patients in research group received from 1 to 3 PDT courses in a year. In total 29 patients received 52 PDT courses. Outcomes were assessed by determining the median survival. The treatment was well-tolerated by the patients. The median survival time was 18 months (11–60 months). In patients who had only one PDT session during the year median survival was 12,5 months; in patients who had two or more PDT sessions median survival was 29 months (15–60 months). Results of PDT treatment for cancer of this localization are comparable with the results of radical surgeries and overcome palliative surgeries. Decrease of tumor growth rate and longer survival period in patients after PDT are determined by vascular mechanisms produced by PDT (vascular thrombosis and impaired tumor blood supply), these factors provide long-term process stabilization. Repeated PDT courses signifi cantly improve treatment results.

Oncological outcome of proximal and middle extrahepatic bile duct cancer according to surgical extent (Is hilar resection oncologically acceptable in proximal and middle extrahepatic bile duct cancer?)

BackgroundFor proximal to middle bile duct cancer, it is controversial whether bile duct resection alone is sufficient, or whether hepatic or pancreatic resection should be accompanied by initial planning. This study aimed to determine the optimal surgical extent based on oncological outcomes in patients with proximal to middle bile duct cancer. MethodsPatients who underwent surgery for proximal to middle extrahepatic bile duct cancer, hilar resection, or combined resection of other organs were included. Clinicopathological characteristics and survival analyses were compared according to operation type. ResultsAmong 156 patients in total, R0 rate was 56.7% for hilar resection and 82.7% for other organ resection. Although hilar resection was associated with shorter hospital stay and fewer overall complications, operation type did not affect overall survival (p = 0.259) and disease-free-survival (p = 0.774). Overall survival differed according to R status (5YSR 49.8 vs. 27.1%; p = 0.012). ConclusionIn proximal to middle extrahepatic bile duct cancer, surgery should be tailored to achieve R0 resection according to the extent of the disease rather than uniformly resecting extensively with other organ resections. Hilar resection could be selected if R0 resection is feasible, considering the lower morbidity with similar long-term survival.

Surgery of extrahepatic bile duct cancer - current evidence and recommendations.

Extrahepatic cholangiocarcinoma is a rare disease with poor prognosis, requiring comprehensive multidisciplinary management. Only radical resection gives hope for long-term survival. Most patients have either an unresectable disease or their condition does not allow for radical surgery. The method of choice for resectable perihilar cholangiocarcinoma is en-block liver resection including the extrahepatic bile duct, or pancreatoduodenectomy for distal cholangiocarcinoma. Hepatopancreatoduodenectomy can be performed in selected patients if the entire hepato-choledochus is affected. Liver transplantation after neoadjuvant treatment can be also considered in highly selected patients with unresectable perihilar cholangiocarcinoma. These procedures are technically demanding, are associated with high morbidity and relevant mortality, and must be concentrated in tertiary hepatobiliary centers. Preoperative optimization (bile duct drainage, nutrition, portal venous embolization, etc.) plays a crucial role in reducing postoperative morbidity and mortality.

Prognostic value of functional SMAD4 localization in extrahepatic bile duct cancer

BackgroundSMAD4 is a key mediator of TGFβ signaling and one of the mutated genes in extrahepatic bile duct cancer (eBDC). It has been also reported that SMAD4 has dual functions, in carcinogenesis via silencing and in tumor invasion/metastasis via signaling, depending on tumor stage. We previously visualized more nuclear transitioning functional SMAD4 at the tumor invasion front than the central lesion. So, we investigated the localization of functional SMAD4 (e.g., invasion area or metastasis lesion) and its association with chemotherapy and chemo-radiation therapy.MethodsWe performed SMAD4 immunostaining on 98 resected eBDC specimens and evaluated the presence of the functional form of nuclear SMAD4 at the central lesion, invasion front, and metastatic lymph node. We also examined the influence on chemotherapy after recurrence (n = 33) and neoadjuvant chemo-radiation therapy (NAC-RT, n = 21) and the prognostic value of using retrospective data.ResultsIn 73 patients without NAC-RT, 8.2% had loss of SMAD4 expression and 23.3% had heterogeneous expression. Patients without SMAD4 expression at any site had significantly poorer overall survival (OS) than other patients (P = 0.014). Expression of SMAD4 at the invasion front was related to better survival (recurrence-free survival [RFS] P = 0.033; OS P = 0.047), and no SMAD4 expression at the metastatic lymph node was related to poorer OS (P = 0.011). The patients who had high SMAD4 expression had poorer prognosis after recurrence (RFS P = 0.011; OS P = 0.056). At the residual cancer in the resected specimen, SMAD4 was highly expressed after NAC-RT (P = 0.039).ConclusionsLoss of SMAD4 protein expression was a poor prognostic factor in eBDC at resectable stage. However, the intensity of functional SMAD4 in eBDC is a marker of resistance to chemo-radiotherapy and malignant potential at advanced stages.

Variation in clinical target volume delineation in postoperative radiotherapy for biliary tract cancer.

We aimed to evaluate the inter-clinician variability in the clinical target volume (CTV) for postoperative radiotherapy (PORT) for biliary tract cancer (BTC) including extrahepatic bile duct cancer (EBDC) and gallbladder cancer (GBC). Nine experienced radiation oncologists delineated PORT CTVs for distal EBDC (pT2N1), proximal EBDC (pT2bN1) and GBC (pT2bN1) patients. The expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) was used to quantify expert agreements. We generated volumes with a confidence level of 80% to compare the maximum distance to each CTV in six directions. The degree of agreement was moderate; overall kappa values were 0.573 for distal EBDC, 0.513 for proximal EBDC, and 0.511 for GBC. In the distal EBDC, a larger variation was noted in the right, post, and inferior direction. In the proximal EBDC, all borders except the right and left direction showed a larger variation. In the GBC, a larger variation was found in the anterior, posterior, and inferior direction. The posterior and inferior borders were the common area having discrepancies, associated with the insufficient coverage of the paraaortic node. A consensus guideline is needed to reduce inter-clinician variability in the CTVs and adequate coverage of regional lymph node area.