[Application and challenge of radiomics technique in the era of precision medicine for hepatobiliary disease].

Radiomics, as an emerging technique of omics, shows the pathophysiological information of images via extracting innumerable quantitative features from digital medical images. In recent years, it has been an exponential increase in the number of radiomics studies. The applications of radiomics in hepatobiliary diseases at present include: assessment of liver fibrosis, discrimination of malignant from benign tumors, prediction of biological behavior, assessment of therapeutic response, and prognosis. Integrating radiomics analysis with machine learning algorithms has emerged as a non-invasive method for predicting liver fibrosis stages, microvascular invasion and post-resection recurrence in liver cancers, lymph node metastasis in biliary tract cancers as well as treatment response in colorectal liver metastasis, with high performance. Although the challenges remain in the clinical transformation of this technique, radiomics will have a broad application prospect in promoting the precision diagnosis and treatment of hepatobiliary diseases, backed by multi-center study with large sample size or multi-omics study.

Problems and needs in patients with incurable esophageal and pancreaticobiliary cancer: a descriptive study.

Patients with incurable esophageal cancer (EC) or pancreaticobiliary cancer (PBC) often have multiple symptoms and their quality of life is poor. We investigated which problems these patients experience and how often care is expected for these problems to provide optimal professional care. Fifty-seven patients with incurable EC (N = 24) or PBC (N = 33) from our outpatient clinic completed the validated "Problems and Needs for Palliative Care" (PNPC) questionnaire and two disease-specific quality of life questionnaires, European Organization for Research and Treatment in Cancer (EORTC). Although patients in general had several problems, physical, emotional, and loss of autonomy (LOA) problems were most common. For these physical and emotional problems, patients also expected professional care, although to a lesser extent for LOA problems. Inadequate care was received for fatigue, fear, frustration, and uncertainty. We conclude that an individualized approach based on problems related to physical, emotional, and LOA issues and anticipated problems with healthcare providers has priority in the follow-up policy of patients with incurable upper gastrointestinal cancer. Caregivers should be alert to discuss needs for fatigue, feelings of fear, frustration, and uncertainty.

Expression of anterior gradient 2 is decreased with the progression of human biliary tract cancer.

Biliary tract cancers include cancers of the gallbladder and extrahepatic bile ducts, and its prognosis is poor. The anterior gradient 2 (AGR2) is a protein disulfide isomerase and is highly expressed in various human cancers, such as breast, prostate and pancreas cancers. AGR2 is expressed in normal cholangiocytes and its expression is maintained during biliary carcinogenesis. However, the clinical significance of AGR2 expression in biliary tract cancer has not yet been assessed. Thus, we examined the expression of AGR2 protein in biliary tract tumors using immunohistochemistry and its association with various clinicopathologic parameters. This study included 100 patients who underwent surgery for biliary tract cancers: 46 men and 54 women with a mean and median age of 64.2 and 65.0 years, respectively. AGR2 expression was detected in ductal epithelial cells of the normal biliary tract and in 95% of biliary tract cancer tissues. While the AGR2 expression was not associated with cancer location, patient age, patient sex, degree of regional lymph node metastasis (N-status), or residual status, the AGR2 expression level was decreased with increased tumor size (T-status, p = 0.006) and progression of tumor stage (p = 0.009). Moreover, well-differentiated cancers tended to show higher AGR2 expression than poorly differentiated cancers (p = 0.068); in fact, AGR2 expression was not associated with patient survival (Kaplan-Meier analysis, p = 0.415). Thus, AGR2 is of limited value as a prognostic marker for biliary tract cancer. In conclusion, the expression of AGR2 is decreased with the progression of biliary tract cancer.

Surgical management of biliary cystadenoma and cystadenocarcinoma of the liver.

Biliary cystadenoma (BCA) and biliary cystadenocarcinoma (BCAC) are rare biliary duct neoplasms. This study investigated reasonable management strategies of cystic neoplasms in the liver. Charts of 39 BCA/BCAC patients (9 males, 30 female; median age 53.74 ± 14.50 years) who underwent surgery from January 1999 to December 2009 were reviewed retrospectively. Cyst fluid samples of 32 BCA/BCAC patients and 40 simple hepatic cyst patients were examined for the tumor markers carbohydrate associated antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). The most frequent symptoms were abdominal pain (N = 10), abdominal mass (N = 7), abdominal distension (N = 4), jaundice (N = 2), and fever (N = 3); the remaining patients showed no clinical symptoms. Liver resection (N = 17) or enucleation (N = 22) was performed in the 39 patients. Ultimately, 35 patients were diagnosed with intrahepatic BCA and four patients were diagnosed with BCAC. The median CA19-9 level was significantly higher in BCA/BCAC patients than in simple hepatic cyst patients. The median CEA levels in BCA/BCAC patients and controls were 6.83 ± 2.43 and 4.21 ± 2.91 mg/L, respectively. All symptoms were resolved after surgery, and only one BCAC patient showed recurrence. The incidence of intrahepatic cystic lesions was 1.7%. Increased CA19-9 levels in the cyst fluid is a helpful marker for distinguishing BCA/BCAC from common simple cysts. The presence of coarse calcifications is suggestive of BCAC. Complete surgical removal of these lesions yielded satisfying long-term outcomes with a very low recurrence rate.

Body composition assessment and sarcopenia in patients with biliary tract cancer: A systematic review and meta-analysis.

BACKGROUND: Sarcopenia, as assessed by body composition, can affect morbidity and survival in several gastrointestinal cancer. However, the impact of sarcopenia, referring to both quantity and quality of skeletal muscle, in biliary tract cancer (BTC) is debatable. We aimed to investigate the impact of sarcopenia on morbidity and mortality in patients with BTC. METHODS: Electronic databases and trial registries were searched through July 2021 to perform random-effects meta-analyses. Study selection, data abstraction and quality assessment were independently performed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Twenty-nine studies (4443 patients) were included; 28 used computed tomography and one used dual-energy X-ray absorptiometry to assess body composition. Eighteen studies reported the impact of pre-operative sarcopenia on postoperative outcomes; namely, sarcopenia increased postoperative complications (risk ratio = 1.23, 95% confidence interval [CI] = 1.07 to 1.41; I2 = 2%), and decreased recurrence-free survival (hazard ratio [HR] = 2.20, 95% CI = 1.75 to 2.75; I2 = 0%) in multivariable analyses. Low muscle quantity (HR = 2.26, 95% CI = 1.75 to 2.92; I2 = 66%) and quality (HR = 1.75, 95% CI = 1.33 to 2.29; I2 = 50%) decreased overall survival in multivariable analyses. The certainty of the evidence was low because of heterogeneity and imprecision. CONCLUSIONS: In sarcopenia, low muscle quantity and quality by body composition conferred an independent risk of morbidity and mortality in patients with BTC. Further studies are needed to confirm these findings and mitigate risk.

A phase I study of S-1 treatment with a 3 week schedule in advanced biliary cancer patients with or without hepatic dysfunction.

PURPOSE: A 3 week treatment schedule consisting of 2 weeks of S-1 therapy and 1 week of no therapy was introduced to reduce the toxicity and increase the convenience of combination chemotherapy. Hepatic dysfunction (HD) is common in patients with biliary tract cancer. A phase I study was conducted to assess the effects of a 3 week treatment schedule in Asian patients with or without HD. METHODS: Forty-six patients were stratified into four groups, according to the HD criteria of the National Cancer Institute Organ Dysfunction Working Group. A three dose escalation schema was used. RESULTS: In the normal hepatic function group, two dose-limiting toxicity (DLT) events occurred among 12 patients at the prespecified maximal dose of 100 mg/m²/day. This dose was thereby established as the maximal tolerable dose (MTD). No DLT events were observed at the predefined maximal dose of 80 mg/m²/day in the mild HD group. In the moderate HD group, two DLT events occurred among five patients treated with 80 mg/m²/day, and the MTD was defined as 70 mg/m²/day. Two of six subjects in the severe HD group experienced DLT events at doses of 60 mg/m²/day and none developed DLT events at 50 mg/m²/day. CONCLUSIONS: The MTDs for a 3 week schedule of S-1 treatment were defined in patients with or without hepatic dysfunction. A 3 week treatment regimen of S-1 might be a platform for combination with newer cytotoxic agents or biologics.

Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study).

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. METHODS: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. RESULTS: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). CONCLUSIONS: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.

Intraductal papillary mucinous neoplasm of the biliary tract with cardiac metastasis: A case report.

INTRODUCTION: Intraductal papillary mucinous neoplasm of the biliary tract (IPNB) is a rare, low-grade neoplasm limited to the bile duct mucosa. The malignant transformation rate is low, and there have been limited reports of metastasis to other organs. Herein, we presented a rare case of a patient who was diagnosed with IPNB concurrent with invasive adenocarcinoma after surgery and was diagnosed with cardiac metastasis 6 months later. PATIENT CONCERNS: A 61-year-old male patient presented with abdominal pain to a local clinic. He was diagnosed with intrahepatic cholangiocarcinoma with pancreatitis and transferred to our hospital. DIAGNOSIS: Diagnostic testing (magnetic resonance imaging, endoscopic retrograde cholangiopancreatography, positron emission tomography-computed tomography) revealed a papillary neoplasm and invasive adenocarcinoma with papillary neoplasm in the periampullary lesion. INTERVENTIONS: Pancreaticoduodenectomy, right hemihepatectomy, and left lateral sectionectomy of the liver were performed. After surgery, we planned gemcitabine-based adjuvant chemotherapy. OUTCOMES: Upon completion of the sixth gemcitabine chemotherapy cycle, a hyperechoic, oval-shaped mass (1.3 × 2.6 cm) was found on the outer wall of the right atrium. Resection of a cardiac tumor in the right atrium and patch repair were performed. CONCLUSION: To our knowledge, no other case of cardiac metastasis found during observation after surgery for an IPNB has been described. IPNBs are known to be less aggressive and to have a lower metastasis rate than intraductal papillary mucinous neoplasms; therefore, the number of case reports describing metastasis after surgery is relatively low. Our case suggests that close observation is necessary in patients diagnosed with an IPNB.

Chemotherapy Improves Survival After Percutaneous Biliary Drainage in Patients With Pancreatic or Biliary Tract Cancer With Biliary Obstruction.

BACKGROUND: The survival benefit of chemotherapy compared to best supportive care (BSC) after percutaneous transhepatic biliary drainage (PTBD) was evaluated in patients with pancreatic or biliary tract cancer. PATIENTS AND METHODS: A retrospective registry study was conducted at a tertiary-level university hospital. The endpoint was survival measured from the PTBD and the initiation of chemotherapy. RESULTS: Among 158 patients (mean age=74 years, range=43-93 years; 51.9% women), 82 (51.9%) had pancreatic cancer and 76 (48.1%) had biliary tract cancer. After PTBD, 32 (20.3%) patients received chemotherapy and had a median survival of 11.7 months; 126 (79.7%) patients received only BSC resulting in a median survival of 1.7 months. The hazard ratio for survival at 1 year for patients who received chemotherapy compared to BSC was 0.22 (95% confidence interval=0.12-0.41, p<0.001). CONCLUSION: After PTBD, patients with pancreatic or biliary tract cancer should be critically evaluated by an oncologist to determine whether chemotherapy is possible, as it seems to significantly improve survival compared to BSC.

Value of indocyanine green clearance of the future liver remnant in predicting outcome after resection for biliary cancer.

BACKGROUND: It is difficult to predict hepatic functional reserve accurately before major hepatectomy. The aim of this study was to analyse the usefulness of the future liver remnant plasma clearance rate of indocyanine green (ICGK-F, calculated as plasma clearance rate of indocyanine green (ICGK) x proportion of the future liver remnant) in predicting death after major hepatectomy. METHODS: Data on ICGK and ICGK-F were collected prospectively and analysed retrospectively for 274 patients who underwent right hepatectomy, right trisectionectomy or left trisectionectomy for biliary cancer between 1991 and 2008. The mortality rate and incidence of postoperative complications were analysed. Patients were separated into two groups according to year of operation (85 patients operated on between 1991 and 2000; 189 from 2001 to 2008). RESULTS: In multiple logistic regression analyses, an ICGK-F less than 0.05 had the strongest impact on the incidence of postoperative mortality (odds ratio 8.06; P < 0.001). The postoperative mortality rate was significantly lower in the later period (P < 0.001). In patients with an ICGK-F value between 0.040 and 0.049, the mortality rate in the early period was 30 per cent, whereas it was only 8 per cent in the later period. CONCLUSION: An ICGK-F of 0.05 is a useful cut-off value for predicting mortality and morbidity. With careful perioperative patient management in an experienced institution, this cut-off value can be lowered further.

Uptake and phototoxicity of meso-tetrahydroxyphenyl chlorine are highly variable in human biliary tract cancer cell lines and correlate with markers of differentiation and proliferation.

Photodynamic therapy (PDT) using Photofrin and, recently, Foscan has gained broad acceptance for palliative treatment of non-resectable cholangiocarcinoma (CC). No information, however, is available whether the phenotype of CC tumour cells has an effect on the efficiency of the treatment. Using a well-characterised set of n = 9 biliary tract cancer cell lines this study investigated the uptake, phototoxicity, and release of meso-tetrahydroxyphenyl chlorine (mTHPC, Foscan) after incubation with 200 or 400 ng ml(-1) mTHPC. For uptake of mTHPC we found great variations between the individual cell lines (up to a factor 2), resulting in even more pronounced differences in phototoxicity. Based on statistical classification by hierarchical cluster analysis, two groups of cell lines can be distinguished which are characterised by either high or low susceptibility towards mTHPC-based photodynamic treatment. Correlation analysis with previously established immunochemical parameters showed that cells with a low cytokeratin-19 (ductal differentiation), high vimentin (mesenchymal marker), and high proliferative phenotype preferentially show higher uptake of mTHPC and subsequent phototoxicity. These results demonstrate high variability of biliary tract cancer cells when subjected to mTHPC-based photodynamic treatment and identify possible markers that could be used in the clinical setting in order to predict the efficiency of PDT and adjust the dose for complete tumour elimination.

The Hippo Pathway and YAP Signaling: Emerging Concepts in Regulation, Signaling, and Experimental Targeting Strategies With Implications for Hepatobiliary Malignancies.

The Hippo pathway and its effector protein YAP (a transcriptional coactivator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila, the understanding of the mammalian YAP signaling and its regulation continues to expand. In its "on" function, the canonical regulatory Hippo pathway, a well-described serine/threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm. In contrast, when the Hippo pathway is "off," YAP translocates to the nucleus and drives cotranscriptional activity. Given the role of Hippo/YAP signaling in hepatic malignancies, investigators have sought to target these molecules; however, standard approaches have not been successful based on the pathways' negative regulatory role. More recently, additional regulatory mechanisms, such as tyrosine phosphorylation, of YAP have been described. These represent positive regulatory events that may be targetable. Additionally, several groups have identified potentiating feed-forward signaling for YAP in multiple contexts, suggesting other experimental therapeutic approaches to interrupt these signaling loops. Herein we explore the current data supporting alternative YAP regulatory pathways, review the described feed-forward signaling cascades that are YAP dependent, and explore targeting strategies that have been employed in preclinical models of hepatic malignancies.

Pain management for hepatobiliary cancer.

OPINION STATEMENT: Although many options exist to address hepatobiliary cancer-induced pain, it remains undertreated and has an adverse impact on quality of life. Fortunately, if addressed appropriately, the majority of patients can be treated successfully. This pain may be nociceptive, neuropathic, or a combination of the two. A multimodality approach including oral and intravenous opioid and non-opioid medications, and interventional approaches including celiac plexus blocks and implantation of drug delivery systems for intrathecal delivery of opioids can be considered and utilized as appropriate. We review the pathophysiology of pain, the approach to correctly diagnosing the different types of pain, the appropriate treatment recommendations, and how to avoid and address the common side effects resulting from these treatments.

Systematic review of the psychometric properties of disease-specific, quality-of-life questionnaires for patients with hepatobiliary or pancreatic cancers.

AIM: To systematically review the quality of the psychometric properties of disease-specific quality-of-life questionnaires for patients with hepatobiliary or pancreatic cancers in order to help researchers and clinicians to select the most appropriate health-related quality-of-life (HRQoL) instruments. METHODS: MEDLINE from 1950, CINAHL from 1960, EMBASE from 1980, and PsycINFO from 1967, as well as additional sources were searched. The quality of the psychometric properties of the included instruments was evaluated by using the quality criteria for measurement properties of health status questionnaires. RESULTS: Ten studies that examined seven instruments were identified. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Biliary Cancer, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Liver Metastases of Colorectal Cancer, the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire, and the Quality of Life for Patients with Liver Cancer Instrument achieved satisfactory results in relation to the quality of their psychometric properties. CONCLUSION: Several well-validated instruments exist to adequately assess disease-specific HRQoL in patients with hepatobiliary or pancreatic cancers. Further improvement of the already-existing, promising measures is recommended.

The impact of skeletal muscle mass on survival outcome in biliary tract cancer patients.

Low skeletal muscle mass is frequently observed in cancer patients and is known to be a poor prognostic factor for survival outcomes. The purposes of our study were to determine the prevalence of sarcopenia and its relation to mortality in biliary tract cancer. Body composition measurements (skeletal muscle index, total fat mass, bone mineral content) were evaluated by using dual-energy x-ray absorptiometry in 75 biliary tract cancer patients before chemotherapy. Muscle strength was measured by handgrip strength and gait speed. Overall survival and its associated factors were determined. The mean appendicular muscle mass was 17.8±2.7 kg in men and 14.0±2.1 kg in women (p < 0.05). Sarcopenia was diagnosed in 46 patients (61.3%) and higher proportion of men was classified as sarcopenia than women (69.0% vs 35.3%, p < 0.05). Multivariable analysis adjusted for chemotherapy regimen and age revealed that high appendicular muscle mass independently predicted better survival outcomes (HR 0.40; 95% CI, 0.18 to 0.88; p = 0.023). Sarcopenia is common in biliary tract cancer patients and low appendicular muscle mass was associated with poor survival outcome.

Occupational exposure to endocrine-disrupting compounds and biliary tract cancer among men.

OBJECTIVES: This study investigated the association between cancer of the extrahepatic biliary tract and exposure to endocrine-disrupting compounds. METHODS: Altogether 183 men with histologically confirmed carcinoma of the extrahepatic biliary tract and 1938 matched controls were interviewed between 1995 and 1997 in the frame of an international multicenter case-control study in six European countries (Denmark, France, Germany, Italy, Spain, and Sweden). Self-reported job descriptions were converted to semiquantitative variables (intensity, probability, and duration of exposure) for 14 endocrine-disrupting compounds. The cases were compared with 1421 population controls and 517 colon adenocarcinoma patients. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained with unconditional logistic regression and adjusted for age, country, and gallstones. RESULTS: Occupational exposure to endocrine-disrupting compounds resulted in an OR of 1.4 (95% CI 1.0-2.1) with no dose-effect relationship for cumulative exposure (low: OR 1.3, 95% CI 0.6-3.0; medium: OR 1.5, 95% CI 0.8-2.7; high: OR 1.4, 95% CI 0.9-2.4) (only index participants). The elevated risk was restricted to extrahepatic bile ducts and ampulla Vateri (OR 1.7, 95% CI 1.0-2.6). The adjusted OR for cancer of the extrahepatic biliary tract after exposure to polychlorinated biphenyls was 2.8 (95% CI 1.3-5.9, only index participants). CONCLUSIONS: The data show some associations between exposure to endocrine-disrupting compounds in the workplace and the risk for cancer of the extrahepatic biliary tract among men, particularly for the extrahepatic bile duct and ampulla of Vater. Polychlorinated biphenyls could possibly be a strong risk factor.

Presence of CCK-A, B receptors and effect of gastrin and cholecystokinin on growth of pancreatobiliary cancer cell lines.

AIM: To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines. METHODS: Five pancreatic and 6 biliary cancer cell lines with 2 conrtol cells were used in this study. Cell proliferation study was done using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines. RESULTS: SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260 for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA. CONCLUSION: Gastrin and CCK exert a trophic action on some of the biliary tract cancers.

Clinical significance of hepatocyte growth factor and c-Met expression in extrahepatic biliary tract cancers.

Hepatocyte growth factor (HGF)/c-Met expression is known to be correlated with poor prognosis in several cancers. We investigated HGF/c-Met immunoreactivity and its correlation with clinical features in 51 patients with curatively resected extrahepatic biliary tract carcinoma. c-Met showed significant correlations with tumor location, T category, stage, perineural invasion and local recurrence. Overall survival in patients with HGF and c-Met immunopositivity was significantly worse than in those who were negative. Our findings suggest that HGF/c-Met play some roles in tumor development and that HGF/c-Met immunoreactivity could be a predictor of the mode of recurrence and poor prognosis.