Hepatolithiasis: Epidemiology, presentation, classification and management of a complex disease.

The term hepatolithiasis describes the presence of biliary stones within the intrahepatic bile ducts, above the hilar confluence of the hepatic ducts. The disease is more prevalent in Asia, mainly owing to socioeconomic and dietary factors, as well as the prevalence of biliary parasites. In the last century, owing to migration, its global incidence has increased. The main pathophysiological mechanisms involve cholangitis, bile infection and biliary strictures, creating a self-sustaining cycle that perpetuates the disease, frequently characterised by recurrent episodes of bacterial infection referred to as syndrome of "recurrent pyogenic cholangitis". Furthermore, long-standing hepatolithiasis is a known risk factor for development of intrahepatic cholangiocarcinoma. Various classifications have aimed at providing useful insight of clinically relevant aspects and guidance for treatment. The management of symptomatic patients and those with complications can be complex, and relies upon a multidisciplinary team of hepatologists, endoscopists, interventional radiologists and hepatobiliary surgeons, with the main goal being to offer relief from the clinical presentations and prevent the development of more serious complications. This comprehensive review provides insight on various aspects of hepatolithiasis, with a focus on epidemiology, new evidence on pathophysiology, most important clinical aspects, different classification systems and contemporary management.

Impact of socio-economic environment on incidence of primary liver cancer in France between 2006 and 2016.

BACKGROUND AND AIMS: To measure the impact of socio-economic environment on the incidence of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). METHOD: The study used data from the French Network of Cancer Registries (FRANCIM) between 2006 and 2016. Classification of patients into HCC and iCCA was performed according to the topographical and morphological codes of the 3rd edition of the International Classification of Diseases for Oncology. Patient addresses were geolocalized and assigned to an IRIS, the smallest French geographic unit. Socio-economic environment was assessed by the European Deprivation Index (EDI). Sex- and age-standardized incidence rates with 95% confidence intervals (CI) were estimated per 100 000 inhabitants, by national quintiles, for each IRIS, sex and age group. Quintile 1 (Q1) characterized the most affluent areas. A Poisson regression was performed to model the impact of deprivation. RESULTS: We included 22 249 cases (79.64% HCC, 16.97% iCCA). Incidence rates were 11.46 and 2.39 per 100 000 person-years for HCC and iCCA, respectively. There was an over-incidence of HCC in quintiles 2, 3, 4 and 5 compared to quintile 1: Q1 10.28 [9.9-10.66] per 100 000 person-years, Q2 11.43 [10.48-12.47] (p < .0001), Q3 11.81 [10.82-12.89] (p < .0001), Q4 12.26 [11.25-13.37] (p < .001) and Q5 11.53 [10.57-12.57] (p < .0001). By contrast, there was no difference for iCCa. Deprivation was significantly associated with HCC in men (p = .0018) and women (p = .0009), but not with iCCA (p = .7407). CONCLUSION: The incidence of HCC is related to socio-economic environment, unlike iCCA. HCC and iCCA should be studied separately in epidemiological studies.

Impact of Food Insecurity on Outcomes Following Resection of Hepatopancreaticobiliary Cancer.

INTRODUCTION: Food insecurity (FI) may predispose individuals to suboptimal nutrition, leading to chronic disease and poor health outcomes. We sought to assess the impact of county-level FI on postoperative outcomes among patients undergoing resection of hepatopancreaticobiliary (HPB) cancer. METHODS: Patients who were diagnosed with HPB cancer between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Data on annual county-level FI were obtained from the Feeding America: Mapping the Meal Gap report and were categorized into tertiles. Textbook outcome was defined as no extended length of stay, perioperative complications, 90-day readmission, and 90-day mortality. Multiple logistic regression and Cox regression models were used to assess outcomes and survival relative to FI. RESULTS: Among 49,882 patients (hepatocellular: n = 11,937, 23.9%; intrahepatic cholangiocarcinoma: n = 2111, 4.2%; extrahepatic cholangiocarcinoma: n = 4047, 8.1%; gallbladder: n = 2853, 5.7%; pancreatic: n = 28,934, 58.0%), 6702 (13.4%) patients underwent a surgical resection. Median age was 75 years (interquartile range 69-82), and most patients were male (n = 25,767, 51.7%) and self-identified as White (n = 36,381, 72.9%). Overall, 5291 (10.6%) and 39,664 (79.5%) individuals resided in low or moderate FI counties, respectively, while 4927 (9.8%) patients resided in high FI counties. Achievement of textbook outcome (TO) was 56.3% (n = 6702). After adjusting for competing risk factors, patients residing in high FI counties had lower odds to achieve a TO versus individuals living in low FI counties (odds ratio 0.69, 95% confidence interval [CI] 0.54-0.88, p = 0.003). In addition, patients residing in moderate and high FI counties had a greater risk of mortality at 1- (referent, low, moderate: hazard ratio [HR] 1.09, 95% CI 1.05-1.14; high: HR 1.14, 95% CI 1.08-1.21), 3- (referent, low, moderate: HR 1.09, 95% CI 1.05-1.14; high: HR 1.14, 95% CI 1.08-1.21), and 5- (referent, low, moderate: HR 1.05, 95% CI 1.01-1.09; high: HR 1.07, 95% CI 1.02-1.13) years versus individuals from low FI counties. CONCLUSIONS: FI was associated with adverse perioperative outcomes and long-term survival following resection of an HPB malignancy. Interventions directed towards mitigating nutritional inequities are needed to improve outcomes among vulnerable HPB populations.

NRAS-mutated oncocytic benign liver lesion in an organ donor: Pitfalls and troubles in frozen section diagnosis and risk assessment.

BACKGROUND: In the transplant setting, the definition of the risk of neoplastic transmission from donor to recipient often requires intraoperative pathological evaluation on frozen sections. Although most lesions can be easily classified into acceptable or unacceptable risk according to the Italian National Guidelines, there are cases in which unusual histologic features cannot be further investigated because of the lack of ancillary techniques on frozen sections. CASE PRESENTATION: Here we present a case of a liver lesion in a 51-year-old male donor, subjected to histopathological on-call examination. The frozen sections showed a well-demarcated lesion consisting of epithelioid cells disposed in laminar structures and intermingled with a dense lymphocytic population: this led to organ discard with interruption of the donation process. The definitive histological analysis required an extensive immunohistochemical (IHC) investigation: the final diagnosis was "bile duct adenoma with oncocytic features", eventually confirmed by a strongly positive anti-mitochondrial IHC. Finally, an NGS panel analysis was performed, which revealed NRAS mutation. DISCUSSION: To the best of our knowledge, this is the first case of oncocytic bile duct adenoma confirmed by anti-mitochondrial IHC and with NRAS mutation. The most challenging aspect of this case was represented by the transplant setting. In fact, the oncocytic features and the dense lymphocytic infiltrate represented concomitant unusual histological features that led to the halt of the organ donation procedures.

Role of Intraoperative Assessment of Proximal Bile Duct Margin Status and Additional Resection of Perihilar Cholangiocarcinoma: Can Local Clearance Trump Tumor Biology? A Retrospective Cohort Study.

BACKGROUND: The aim of this study was to evaluate the clinical implications of the proximal bile duct margin status in resection of perihilar cholangiocarcinoma (PHCC). Intraoperative frozen section (IFS) analysis to assess the bile duct margin status is commonly used during PHCC resection. However, the impact of additional resection after obtaining a positive margin on the long-term outcome remains unclear. PATIENTS AND METHODS: Among the 257 patients who underwent PHCC resection, 190 patients with a negative distal margin were included and analyzed. IFS analysis of the proximal bile duct margin was performed in all patients. A positive margin was defined by the presence of either invasive cancer, or carcinoma, in situ. RESULTS: IFS analysis revealed an initial positive margin in 69 (36%) patients. Among 20 patients who underwent re-resection, only 11 patients achieved a negative margin (secondary R0). An initial positive margin was associated with poor long-term outcomes: recurrence-free survival (RFS) and overall survival (OS) were 16 and 25 months for patients with an initial positive margin, but 47 and 63 months for patients with an initial negative margin, respectively (p < 0.0001). In contrast, there was no difference in RFS or OS between patients with a secondary R0 margin, and those with a final R1 margin (14 vs. 16 months for RFS, p = 0.98, and 23 versus 25 months for OS, p = 0.63, respectively). CONCLUSION: An IFS-positive proximal hepatic duct margin dictates poor long-term outcomes for patients with resectable PHCC. Additional resection has minimal impact on survival, even when negative margin is achieved.

Methods of tissue preparation after EUS-guided tissue acquisition without rapid on-site assessment: Results of a randomized study.

In the absence of rapid on-site evaluation (ROSE), it is not clear which method of tissue preparation is best to process tissue obtained from EUS guidance. Cytological smearing (CS), cell block (CB), and direct histology (DH) are the available techniques. AIM: To compare the diagnostic yield of three techniques of tissue preparation for EUS-guided tissue acquisition without ROSE. METHODS: Patients who were referred for EUS-FNA of peri-gastrointestinal masses were recruited. Without ROSE, each lesion was biopsied with three needle passes, and the order in which tissue is prepared was randomized to either (i) CS + CB, (ii) CB only, or (iii) DH only. The prepared specimens were reviewed. RESULTS: A total of 243 specimens were taken from 81 patients. Tissue diagnosis was achieved in 78/81 (96.3%) of patients, including 63 neoplasms (PDAC [n = 45], pancreatic neuroendocrine tumors [PNET; n = 4], cholangiocarcinoma [n = 5], metastatic disease [n = 4], lymphoma [n = 1], linitis plastica [n = 2], leiomyoma [n = 2]) and 15 benign pathologies (chronic pancreatitis [n = 8], reactive nodes [n = 5], inflammatory biliary stricture [n = 1], and pancreatic rest [n = 1]). The three non-diagnostic cases were found to be PDAC (n = 2) and PNET (n = 1). Sensitivity and diagnostic accuracy was highest with DH (94 and 95%), which was significantly better than that by CS + CB (43 and 54%; P = 0.0001) and CB-only preparations (32 and 48.6%; P < 0.0001). There was no significant difference between the CS + CB and CB-only arms (P > 0.22). CONCLUSION: Without ROSE, our findings suggest that with just a single pass, DH should be the tissue preparation method of choice given its significantly higher diagnostic accuracy compared with CS and/or CB techniques.

The Evaluation of Clinical Status of Endoscopic Retrograde Cholangiography for the Placement of Metal and Plastic Stents in Cholangiocarcinoma Therapy.

Objective: Cholangiocarcinoma is a common malignant tumor that occurs in the bile duct system, which can be treated by using the endoscopic retrograde cholangiography (ERCP). This study was aimed at exploring the therapeutic effect of ERCP with metal stent and plastic stent for cholangiocarcinoma. Methods: The clinical data of 71 patients with cholangiocarcinoma treated by ERCP in our hospital from June 2020 to October 2021 were retrospectively analyzed. According to different stent types, the patients were divided into plastic stent group (n = 43) and metal stent group (n = 28). Patients in the plastic stent group and metal stent group were received with plastic stent and metal stent, respectively. The indexes of liver function (serum alkaline phosphatase (ALT), direct bilirubin (DBIL), glutamic oxaloacetic transaminase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL)), postoperative complications, success rate of stent implantation, and survival time of patients in the two groups were determined. Logistic multivariate regression analysis was used to analyze the prognostic factors of postoperative cholangiocarcinoma. Results: The liver function indexes of the two groups were significantly improved after treatment with the stent, in which the ameliorative effect in the metal stent group was better than that in the plastic stent group (P < 0.05). The incidence of postoperative complications in the plastic stent group and the metal stent group was 53.49% and 14.29%, respectively, and the success rate of stent placement was 60.47% and 96.43%, respectively. The incidence of complications in the metal stent group was lower than that in the plastic stent group, and the success rate of stent placement was higher than that in the plastic stent group (P < 0.05). The median survival time of patients in the plastic stent group and the metal stent group was 8.15 and 11.83 months, respectively. The survival time of patients in the metal stent group was longer than that of the plastic stent group. The median survival time of patients with types I, II, III, and IV was 12.73, 11.54, 10.57, and 9.36 months, respectively. The survival time of patients with stage I was significantly higher than that of patients with types II, III, and IV. There was an inverse relationship between the disease type and the survival time of patients. Logistic multivariate regression analysis showed that tumor diameter ≥ 5 cm, portal vein invasion, lymph node metastasis, and classification of hilar cholangiocarcinoma were the risk factors (P < 0.05) and metal stent type was the protective factor (P < 0.05). Conclusion: In the clinical treatment of patients with cholangiocarcinoma, the placement of metal stent and plastic stent under ERCP plays an important role. The placement of the metal stent under ERCP has a higher success rate and better prognosis and can prolong the survival time of patients to a greater extent, but the price of the metal stent is relatively expensive. For patients with an expected survival period of more than 4-6 months, the metal stent should be considered; otherwise, the plastic stent can be used to maintain cost-effectiveness. Therefore, it is necessary to comprehensively analyze the patient's economic affordability, expected survival time, stent drainage time, and personal needs and then select an appropriate treatment method.

The Cytomorphologic and Molecular Assessment of Bile Duct Brushing Specimens.

Biliary duct brushing cytology is the standard of care for the assessment of bile duct strictures but suffers from low sensitivity for the detection of a high-risk stricture. Pathologic diagnosis of strictures is optimized by integration of cytomorphology and molecular analysis with fluorescence in situ hybridization or next-generation sequencing. Bile duct cancers are genetically heterogeneous, requiring analysis of multiple gene panels to increase sensitivity. Using molecular analysis as an ancillary test for bile duct brushing samples aids in the identification of mutations that support the diagnosis of a high-risk stricture as well as the identification of actionable mutations for targeted therapies currently in clinical trials for the treatment of patients with bile duct cancer.

A National Assessment of T2 Staging for Intrahepatic Cholangiocarcinoma and the Poor Prognosis Associated with Multifocality.

BACKGROUND: T2 intrahepatic cholangiocarcinoma (ICC) is defined as a solitary tumors with vascular invasion or multifocal tumors including satellite lesions, multiple lesions, and intrahepatic metastases. This study aimed to evaluate the prognosis associated with multifocal tumors. METHODS: The National Cancer Database was queried from 2004 to 2017 for patients with non-metastatic ICC. The patients were grouped based on T2 staging, multifocality, and lymph node involvement. RESULTS: The study enrolled and classified 4887 patients into clinical (c) stage groups as follows: 15.2% with solitary T2N0 (sT2N0) tumors, 21.3% with multifocal T2N0 (mT2N0) tumors, and 63.5% with node-positive (TxN1) disease. Patients with (c)sT2N0 tumors had higher rates of surgical resection than those with (c)mT2N0 or (c)TxN1 disease (33.5% vs 19.7% vs 15.0%; p < 0.01). Median overall survival (OS) was better for the patients with (c)sT2N0 tumors than for those with multifocal and node-positive disease (15.4 vs 10.4 vs 10.4 months; p < 0.01). On multivariate analysis, (c)sT2N0 tumors were associated with better OS than (c)mT2N0 tumors [hazard ratio (HR), 1.31; 95% confidence interval (CI), 1.17-1.46; p < 0.01] or (c)TxN1 disease (HR,1.41; 95% CI 1.28-1.56; p < 0.01). In a subset analysis based on pathologic (p) staging of patients who underwent surgical resection with regional lymphadenectomy, multivariate analysis demonstrated that (p)sT2N0 tumors were associated with better OS than (p)mT2N0 tumors (HR,1.40; 95% CI 1.03-1.92; p = 0.03) or (p)TxN1 disease (HR, 2.05; 95% CI 1.62-2.58; p < 0.01). CONCLUSIONS: Multifocal T2N0 ICC is associated with poor OS and has a disparate prognosis compared with solitary T2N0 disease, even among patients who undergo resection. Future staging criteria should account for the poor outcomes associated with multifocal ICC.

Risk stratification of LI-RADS M and LI-RADS 4/5 combined hepatocellular cholangiocarcinoma: prognostic values of MR imaging features and clinicopathological factors.

OBJECTIVES: To investigate the role of clinicopathological factors and MR imaging factors in risk stratification of combined hepatocellular cholangiocarcinoma (cHCC-CCA) patients who were classified as LR-M and LR-4/5. METHODS: We retrospectively identified consecutive patients who were confirmed as cHCC-CCA after surgical surgery in our institution from June 2015 to November 2020. Two radiologists evaluated the preoperative MR imaging features independently, and each lesion was assigned with a LI-RADS category. Preoperative clinical data were also collected. Multivariate Cox proportional hazards model was applied to separately identify the independent factors correlated with the recurrence of cHCC-CCAs in LR-M and LR-4/5. Risk stratifications were conducted separately in LR-M and LR-4/5. Recurrence-free survival (RFS) rates and overall survival (OS) rates were analyzed by using the Kaplan-Meier survival curves and log-rank test. RESULTS: A total of 131 patients with single primary lesion which met the 2019 WHO classification criteria were finally included. Corona enhancement, delayed central enhancement, and microvascular invasion (MVI) were identified as predictors of RFS in LR-M. Mosaic architecture, CA19-9, and MVI were independently associated with RFS in LR-4/5. Based on the number of these independent predictors, patients were stratified into favorable-outcome groups (LR-ML subgroup and LR-4/5L subgroup) and dismal-outcome groups (LR-MH subgroup and LR-4/5H subgroup). The corresponding median RFS for LR-ML, LR-MH, LR-5L, and LR-5H were 25.6 months, 8.2 months, 51.7 months, and 18.1 months. CONCLUSION: Our study explored the prognostic values of imaging and clinicopathological factors for LR-M and LR-4/5 cHCC-CCA patients, and different survival outcomes were observed among four subgroups after conducting risk stratifications. KEY POINTS: • Corona enhancement, delayed central enhancement, and MVI were identified as predictors of RFS in cHCC-CCAs which were classified into LR-M. Mosaic architecture, CA19-9, and MVI were independently associated with RFS in cHCC-CCAs which were classified into LR-4/5. • Based on the identified risk factors, LR-M and LR-4/5 cHCC-CCA patients could be stratified into two subgroups respectively, with significantly different RFS and OS. • cHCC-CCA patients from LR-M did not always have worse RFS and OS than those from LR-4/5 in some cases.

Rapid assessment of Opisthorchis viverrini IgG antibody in serum: A potential diagnostic biomarker to predict risk of cholangiocarcinoma in regions endemic for opisthorchiasis.

BACKGROUND: Opisthorchiasis is caused by an infection with fish-borne liver flukes of the genus Opisthorchis. Opisthorchiasis frequently leads to chronic inflammation in the biliary tract and is classified as a group 1 biological carcinogen by the International Agency for Research on Cancer: a definitive risk for cholangiocarcinoma (CCA). METHODS: We used the rapid immunochromatographic test (ICT) to detect anti-Opisthorchis viverrini IgG and IgG4 subclass antibodies in sera of patients with CCA. The ICT kits were developed based on soluble antigens excreted and secreted by O. viverrini adult worms. RESULTS: ICT indicated sera was positive for IgG and IgG4 antibodies, respectively, in 22 (61.1%) and 15 (41.6%) participants of the 36 study participants diagnosed with CCA (P > 0.05). Our study also included groups with other cancers and with liver cirrhosis, where the IgG ICT and IgG4 ICT kits were 27.7% (13/47) and 25.5% (12/47) positive, respectively (P > 0.05). Neither total the IgG ICT nor the IgG4 ICT yielded positive results in a control group of 20 healthy participants. Moreover, the percentage positivity rate using the ICT for total IgG between the CCA group and the other cancers and liver cirrhosis group was significantly different (P < 0.05). By contrast, no significant difference between these groups was apparent in the ICT for IgG4 antibody. The CCA group was 6.53 times more likely to have positive anti-O. viverrini IgG antibody (odds ratio 6.53, P < 0.001) and 3.27 times more likely to have positive anti-O. viverrini IgG4 antibody (odds ratio 3.27, P = 0.010) than the non-CCA group. CONCLUSION: This information is of potential value for the development of a diagnostic biomarker to predict risk for O. viverrini infection-associated CCA.

Assessment of radiation sensitivity of unresectable intrahepatic cholangiocarcinoma in a series of patients submitted to radioembolization with yttrium-90 resin microspheres.

Radioembolization is a valuable therapeutic option in patients with unresectable intrahepatic cholangiocarcinoma. The essential implementation of the absorbed dose calculation methods should take into account also the specific tumor radiosensitivity, expressed by the α parameter. Purpose of this study was to retrospectively calculate it in a series of patients with unresectable intrahepatic cholangiocarcinoma submitted to radioembolization. Twenty-one therapeutic procedures in 15 patients were analysed. Tumor absorbed doses were calculated processing the post-therapeutic 90Y-PET/CT images and the pre-treatment contrast-enhanced CT scans. Tumor absorbed dose and pre- and post-treatment tumor volumes were used to calculate α and α3D parameters (dividing targeted liver in n voxels of the same volume with specific voxel absorbed dose). A tumor volume reduction was observed after treatment. The median of tumor average absorbed dose was 93 Gy (95% CI 81-119) and its correlation with the residual tumor mass was statistically significant. The median of α and α3D parameters was 0.005 Gy-1 (95% CI 0.004-0.008) and 0.007 Gy-1 (95% CI 0.005-0.015), respectively. Multivariate analysis showed tumor volume and tumor absorbed dose as significant predictors of the time to tumor progression. The knowledge of radiobiological parameters gives the possibility to decide the administered activity in order to improve the outcome of the treatment.

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

IMPORTANCE: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. OBJECTIVE: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. DESIGN, SETTING, AND PARTICIPANTS: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. INTERVENTIONS: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS) of 80% at 6 months. RESULTS: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). CONCLUSIONS AND RELEVANCE: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

Intraductal papillary neoplasm of the bile duct: Assessment of invasive carcinoma and long-term outcomes using MRI.

BACKGROUND & AIMS: Imaging characteristics for discriminating the malignant potential of intraductal papillary neoplasm of the bile duct (IPNB) still remain unclear. This study aimed to define the magnetic resonance (MR) imaging findings that help to differentiate IPNB with an associated invasive carcinoma from IPNB with intraepithelial neoplasia and to investigate their significance with respect to long-term outcomes in patients with surgically resected IPNB. METHODS: This retrospective study included 120 patients with surgically resected IPNB who underwent preoperative MR imaging with MR cholangiography before surgery from January 2008 and December 2017 in two tertiary referral centers. Clinical and MR imaging features of IPNB with intraepithelial neoplasia (n = 34) and IPNB with an associated invasive carcinoma (n = 86) were compared. Regarding significant features for discriminating IPNB with or without an associated invasive carcinoma, recurrence-free survival (RFS) rates were evaluated. RESULTS: Significant MR imaging findings for differentiating IPNB with an associated invasive carcinoma from IPNB with intraepithelial neoplasia were intraductal visible mass, tumor size ≥2.5 cm, multiplicity of the tumor, bile duct wall thickening, and adjacent organ invasion (all p ≤0.002). The 1-, 3-, and 5-year RFS rates for surgically resected IPNB were 93.8%, 79.1%, and 70.0%, respectively. RFS rates were significantly lower in patients with each significant MR imaging finding of IPNB with an associated invasive carcinoma than in those without significant MR imaging findings (all p ≤0.039). CONCLUSIONS: MR imaging with MR cholangiography may be helpful in differentiating IPNB with an associated invasive carcinoma from IPNB with intraepithelial neoplasia. Significant MR imaging findings of IPNB with an associated invasive carcinoma have a negative impact on RFS. LAY SUMMARY: Significant magnetic resonance imaging findings that differentiated between an intraductal papillary neoplasm of the bile duct (IPNB) with an associated invasive carcinoma and an IPNB with intraepithelial neoplasia were intraductal visible mass, tumor size ≥2.5 cm, multiplicity of the tumor, bile duct wall thickening, and adjacent organ invasion. Significant magnetic resonance imaging findings of invasive IPNB have a negative impact on recurrence-free survival.

Peripheral hepatojejunostomy: a last resort palliative solution in Greece during the economic crisis.

The geographical distribution of Greece and the growing proportion of uninsured patients make imperative the need for effective and efficient palliative solutions regarding obstructive jaundice due to hepatic malignancy, while repeated endoscopic interventions and all associated materials are either not accessible to the whole population or not even available on a daily basis due to the economic crisis and the difficulties on the hospital supply. On this basis, palliative hepatojejunostomy, introduced more than 50 years ago, could be revisited in the Greek reality in very selected cases and under these special circumstances. We report on two patients with locally advanced hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma, respectively, who were treated with a combination of double hepaticojejunostomy with peripheral hepatojejunostomy or peripheral hepatoejunostomy alone, respectively. Both patients experienced an adequate decompression of the biliary tract over more than a year. Palliative hepatojejunostomy could be an ultimate solution for selected patients and circumstances in Greece during the economic crisis.

Assessment of diffusion-weighted imaging for characterizing focal liver lesions.

In 150 patients, 153 hepatic lesions (39 metastases, 27 hemangiomas, 26 hepatocellular carcinomas, 25 cysts, 15 adenomas, 8 focal nodular hyperplasias, 5 abscesses, 4 hamartomas, and 4 cholangiocarcinomas) were evaluated during a 24-month period. Apparent diffusion coefficient (ADC) values of benign lesions (1.994×10(-3) mm(2) s(-1)) were significantly higher than ADC values of malignant lesions (1.070×10(-3) mm(2) s(-1)). Mean ADC value for solid benign lesions (1.143×10(-3) mm(2) s(-1)±0.214×10(-3) mm(2) s(-1)) was not significantly different from malignant lesions. ADC values did not allow differentiating malignant from benign solid lesions (area under the curve=0.61). ADC cutoff value threshold of 1.6×10(-3) mm(2) s(-1) yielded higher accuracy for differentiating benign from malignant lesions.

Cost utility analysis of endoscopic biliary stent in unresectable hilar cholangiocarcinoma: decision analytic modeling approach.

BACKGROUND/AIMS: Endoscopic biliary drainage using metal and plastic stent in unresectable hilar cholangiocarcinoma (HCA) is widely used but little is known about their cost-effectiveness. This study evaluated the cost-utility of endoscopic metal and plastic stent drainage in unresectable complex, Bismuth type II-IV, HCA patients. METHODOLOGY: Decision analytic model, Markov model, was used to evaluate cost and quality-adjusted life year (QALY) of endoscopic biliary drainage in unresectable HCA. Costs of treatment and utilities of each Markov state were retrieved from hospital charges and unresectable HCA patients from tertiary care hospital in Thailand, respectively. Transition probabilities were derived from international literature. Base case analyses and sensitivity analyses were performed. RESULTS: Under the base-case analysis, metal stent is more effective but more expensive than plastic stent. An incremental cost per additional QALY gained is 192,650 baht (US$ 6,318). From probabilistic sensitivity analysis, at the willingness to pay threshold of one and three times GDP per capita or 158,000 baht (US$ 5,182) and 474,000 baht (US$ 15,546), the probability of metal stent being cost-effective is 26.4% and 99.8%, respectively. CONCLUSIONS: Based on the WHO recommendation regarding the cost-effectiveness threshold criteria, endoscopic metal stent drainage is cost-effective compared to plastic stent in unresectable complex HCA.

New insight into reactive ductular cells of biliary atresia provided by pathological assessment of SOX9.

BACKGROUND: Biliary atresia (BA) patients may survive until adolescence after effective Kasai procedure (KP). If liver fibrosis progresses even after successful KP, liver transplantation (LTx) is inevitable. Elucidation of its cause and pathophysiology would open the possibility of treating these patients by non-invasive management. SOX9 is a transcription factor that regulates bile duct development and contributes to liver regeneration and fibrosis. To elucidate the role of SOX9 in BA liver, we investigated the SOX9 expression pattern. METHOD: Immunostaining with anti-SOX9 antibody was done on hepatic specimens obtained at the time of KP or LTx. We analyzed the association of SOX9 expression with clinical data. RESULTS: In BA livers, SOX9 was expressed in reactive ductular cells (RDCs), mostly with a nuclear-dominant pattern. SOX9 was also ectopically expressed in hepatocytes, which was more conspicuous at the timing of KP than LTx. SOX9 expression level was significantly correlated with age (days) at which KP was performed, AST and WBC count. CONCLUSIONS: SOX9 may contribute to RDC formation in BA patients, by affecting both RDCs and hepatocytes. SOX9 could be a key molecule to understand the mechanism of RDC formation, and this understanding would provide a therapeutic strategy for effective treatment of BA.