Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies.

Unprecedented advances have been achieved in hepatobiliary cancer treatment with immune checkpoint blockade (ICB). However, the efficacy of ICB in patients with hepatobiliary malignancies is still limited. Resistance to immunotherapies is often orchestrated by complicated tumor-host-microenvironment interactions but could also occur after initial efficacy, mostly when only partial responses are obtained. Clarification of cancer-resistance mechanisms will be beneficial to provide the rationale for the administration of personalized drugs. Here, we review the factors related to resistance to immune-targeted therapies in hepatobiliary malignancies and discuss the potential strategies for overcoming resistance and future directions of immunotherapy development.

Spine stereotactic radiosurgery for metastases from hepatobiliary malignancies: patient selection using PRISM scoring.

OBJECTIVE: Dose escalation via stereotactic radiation therapy techniques has been necessary for hepatobiliary malignancies in the primary and oligometastatic setting, but such dose escalation is challenging for spine metastases due to spinal cord proximity. Here, we investigate the role of spine stereotactic radiosurgery (SSRS) in the management of such metastases. METHODS: We retrospectively reviewed patients treated with SSRS to spinal metastases from hepatobiliary malignancies between 2004 and 2017 at our Institution. We used the Kaplan-Meier method to calculate overall survival (OS) and local control (LC) and Cox regression analysis to identify factors associated with disease-related outcomes. RESULTS: We identified 28 patients treated to 43 spinal metastases with SSRS for either HCC or cholangiocarcinoma. The 1-year LC and OS were 85% and 23%, respectively. The median time to death was 6.2 months, while median time to local failure was not reached. Tumor volume > 60 cc (SHR 6.65, p = 0.03) and Bilsky ≥ 1c (SHR 4.73, p = 0.05) predicted for poorer LC, while BED10 > 81 Gy trended towards better local control (SHR 4.35, p = 0.08). Child-Pugh Class (HR 3.02, p = 0.003), higher PRISM Group (HR 3.49, p = 0.001), and systemic disease progression (HR 3.65, p = 0.001) were associated with worse mortality based on univariate modeling in patients treated with SSRS; on multivariate analysis, PRISM Group (HR 2.28, p = 0.03) and systemic disease progression (HR 2.67, p = 0.03) remained significant. Four patients (10%) developed compression deformity and one patient (2%) developed radiation neuritis. CONCLUSION: SSRS provides durable local control in patients with metastatic hepatobiliary malignancies, with higher BED necessary to ensure excellent LC. PRISM scoring is a promising prognostic tool to aid SSRS patient selection.

Development and clinical usefulness of the liver hanging maneuver in various anatomical hepatectomy procedures.

PURPOSE: To assess the clinical application and usefulness of the liver hanging maneuver (LHM), proposed by Belghiti, for major hepatectomy, including its (1) historical development, (2) usefulness and application and (3) advantages and disadvantages, by reviewing the English literature published during the period 2001-2014. RESULTS: In major hepatic transection via the anterior approach, the deep area of transection around the vena cava is critical with regard to bleeding during right hemi-hepatectomy. Belghiti and other investigators identified avascular spaces that are devoid of short hepatic veins at the front of the vena cava and behind the liver. Forceps can be inserted into this space easily and then maneuvered to lift the liver using hanging tape. This procedure, termed LHM significantly reduces intraoperative blood loss and the transection time during right hemi-hepatectomy. LHM has been used in various anatomical hepatectomy procedures worldwide, including laparoscopic hepatectomy. The use of LHM markedly improves the amount of intraoperative blood loss, operative time and postoperative outcome. CONCLUSIONS: We conclude that the application of LHM is an important development in the field of liver surgery, although a further evaluation of its true impact on clinical outcomes is necessary.

Hepatobiliary malignancies in Wilson disease.

BACKGROUNDS & AIMS: Reports of hepatobiliary malignancies in Wilson disease are sparse. The aim of this study was to evaluate hepatobiliary malignancies in Wilson disease patients concerning the clinical course of tumour disease and pathological analysis of tumour tissue. METHODS: Multicenter cohort study of patients with confirmed diagnosis of Wilson disease treated at the Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, the university hospitals Heidelberg, Duesseldorf and Dresden, Germany, and the Department of Hepatology, University Leuven, Belgium. Occurrence, treatment and outcome of hepatobiliary tumours were analysed retrospectively. RESULTS: Of a total of 1186 patients, fourteen developed hepatobiliary malignancies. Eight were hepatocellular carcinomas (HCC) and six were intrahepatic cholangiocellular carcinomas (ICC). The prevalence of hepatobiliary malignancies in the cohort was 1.2% and the incidence was 0.28 per 1000 person years. Pathological analysis of tumour material showed no abnormal copper concentration. CONCLUSIONS: The rate of hepatobiliary malignancies in Wilson disease is very low, even in cirrhotic patients. As a result of the relevant number of ICC in addition to HCC histological analysis through surgical resection or biopsy should be mandatory when a suspect liver lesion is detected. The influence of copper depletion from Wilson disease-specific medical treatment on tumour activity remains to be elucidated.

Helicobacter pylori and Gastrointestinal Malignancies.

Helicobacter pylori infection is the principal trigger of gastric carcinogenesis and gastric cancer (GC) and remains the third leading cause of cancer-related death in both sexes worldwide. In a big Japanese study, the risk of developing GC in patients with peptic ulcer disease who received H. pylori eradication therapy and annual endoscopic surveillance for a mean of 9.9 years was significantly lower after successful eradication therapy compared to the group with persistent infection (0.21%/year and 0.45%/year, respectively, p = .049). According to a recent meta-analysis, H. pylori eradication is insufficient in GC risk reduction in subjects with advanced precancerous conditions (i.e., intestinal metaplasia and dysplasia). A microsimulation model suggested screening smokers over the age of 50 in the U.S. for serum pepsinogens. This would allow to detect advanced gastric atrophy with endoscopic follow-up of subjects testing positive as a cost-effective strategy to reduce GC mortality. In a Taiwanese study, the anti-H. pylori IgG-based test-and-treat program had lower incremental cost-effectiveness ratios than that with (13)C-urea breath test in both sexes to prevent GC whereas expected years of life lost for GC were higher and the incremental cost-effectiveness ratios of test-and-treat programs were more cost-effective in young adults (30-69 years old) than in elders (>70 years old). With respect to gastrointestinal malignancies other than GC, a meta-analysis confirmed the inverse association between H. pylori infection and esophageal adenocarcinoma. In a Finnish study, H. pylori seropositivity was associated with an increased risk of biliary tract cancers (multivariate adjusted OR 2.63; 95% CI: 1.08-6.37), another meta-analysis showed a slightly increased rate of pancreatic cancer in patients with CagA-negative strains (OR: 1.30; 95% CI: 1.02-1.65), whereas current data suggest that the association between H. pylori and colorectal neoplasms may be population dependent.

Incidence risk of hepatobiliary malignant neoplasms in the cohort of workers chronically exposed to ionizing radiation.

The increased risk of liver malignancies was found in workers of the first Russian nuclear production facility, Mayak Production Association, who had been chronically exposed to gamma rays externally and to alpha particles internally due to plutonium inhalation. In the present study, we updated the radiogenic risk estimates of the hepatobiliary malignancies using the extended follow-up period (1948-2018) of the Mayak worker cohort and the improved «Mayak worker dosimetry system-2013¼. The cohort comprised 22,377 workers hired at the Mayak PA between 1948 and 1982. The analysis considered 62 liver malignancies (32 hepatocellular carcinomas, 13 intrahepatic cholangiocarcinomas, 16 angiosarcomas, and 1 anaplastic cancer) and 33 gallbladder adenocarcinomas. The analysis proved the positive significant association of the liver malignancy risk (the total of histological types, hepatocellular carcinoma) with the liver absorbed alpha dose from internal exposure. The excess relative risk per Gy (95% confidence interval) of alpha dose (the linear model) was 7.56 (3.44; 17.63) for the total of histological types and 3.85 (0.95; 13.30) for hepatocellular carcinoma. Indications of non-linearity were observed in the dose-response for internal exposure to alpha radiation. No impact of external gamma-ray exposure on the liver malignancy incidence was found. In the study cohort, the number of angiosarcomas among various types of liver malignancies was very high (25.8%), and most of these tumors (73.3%) were registered in individuals internally exposed to alpha radiation at doses ranging between 6.0 and 21.0 Gy. No association with chronic occupational radiation exposure was observed for the incidence of gallbladder malignancies.

Recent Advances in Photodynamic Imaging and Therapy in Hepatobiliary Malignancies: Clinical and Experimental Aspects.

The therapeutic and diagnostic modalities of light are well known, and derivative photodynamic reactions with photosensitizers (PSs), specific wavelengths of light exposure and the existence of tissue oxygen have been developed since the 20th century. Photodynamic therapy (PDT) is an effective local treatment for cancer-specific laser ablation in malignancies of some organs, including the bile duct. Although curability for extrahepatic cholangiocarcinoma is expected with surgery alone, patients with unresectable or remnant biliary cancer need other effective palliative therapies, including PDT. The effectiveness of PDT for cholangiocarcinoma has been reported experimentally or clinically, but it is not the standard option now due to problems with accompanied photosensitivity, limited access routes of irradiation, tumor hypoxia, etc. Novel derivative treatments such as photoimmunotherapy have not been applied in the field hepatobiliary system. Photodynamic diagnosis (PDD) has been more widely applied in the clinical diagnoses of liver malignancies or liver vascularization. At present, 5-aminolevulinic acid (ALA) and indocyanine green (ICG) dyes are mainly used as PSs in PDD, and ICG has been applied for detecting liver malignancies or vascularization. However, no ideal tools for combining both PDD and PDT for solid tumors, including hepatobiliary malignancies, have been clinically developed. To proceed with experimental and clinical trials, it is necessary to clarify the effective photosensitive drugs that are feasible for photochemical diagnosis and local treatment.

Dysplasia in Gallbladder: What Should We Do?

INTRODUCTION: On occasional cholecystectomies, pathologists encounter incidental dysplasia in the gallbladder mucosa in the sections submitted per protocol for histologic examination. If dysplasia is identified, additional sections are taken and/or the gallbladder is entirely submitted to rule out underlying adenocarcinoma. The aim of our study was to assess the incidence of subsequent identification of invasive adenocarcinoma on additional sections, after an incidentally detected dysplasia was noted on a routine cholecystectomy section. We also aimed to study the significance of the incidental detection of dysplasia and adenocarcinoma, as well as showing the association of gallbladder dysplasia to synchronous or metachronous dysplasia/neoplasia in the biliary tract. MATERIAL AND METHODS: Our study was approved by the Institutional Review Board. We retrospectively identified 41 consecutive cases of routine cholecystectomies from 1991 to 2017, which had no clinical suspicion of neoplasia, and did not have any identifiable mass lesion, but on histopathologic analysis, had neoplasia (adenocarcinoma in 4 cases, and dysplasia in 37 cases). The pathologies of all cases were reviewed, and the diagnosis and grade of dysplasia were confirmed. The clinical information was obtained from the electronic medical records. RESULTS: Of the 37 cases with dysplasia, 10 (27%) had high-grade dysplasia (HGD) and the remaining showed low-grade dysplasia (LGD). All 4 cases of adenocarcinoma had some gross abnormalities (such as porcelain gallbladder, or ruptured, thickened, and roughened walls, or a granular mucosa). In contrast, none of the 37 cases with dysplasia had any gross abnormality. In 24 (of 37) cases of dysplasia, additional sections were submitted (median 8; ranging from 2 to 29), and in 11 cases, the gallbladder was entirely submitted. None of these cases showed any additional pathologic finding on the extra sections. Interestingly, 7 cases with dysplasia (18.9%; 6 LGD and 1 HGD) were associated with a concomitant pancreatobiliary malignancy. For the remaining 30 cases, follow-up information was available in 16 cases (53.3%) with a mean follow-up of 76.5 months (ranging from 12 to 204 months). None of these showed any subsequent development of pancreatobiliary neoplasms. CONCLUSION: Incidentally detected gallbladder dysplasia in a cholecystectomy specimen, without any gross abnormality, has almost no risk of a hidden invasive carcinoma. Although cholecystectomy is sufficient treatment for gallbladder dysplasia, in our study cohort, 18.9% of cases with incidental dysplasia in gallbladder had an associated pancreatobiliary carcinoma, which supports the hypothesis of multifocal neoplastic potential in the pancreatobiliary tree (also known as field effect). Although follow-up on 16 cases shows no subsequent development of any other pancreatobiliary neoplasm, this number is probably not enough to rule out a serial imaging follow-up of patients who have reported dysplasia in their gallbladder, to assess for subsequent development of neoplasia elsewhere in the pancreaticobiliary tree.

Selecting treatment sequence for patients with incidental gallbladder cancer: a neoadjuvant approach versus upfront surgery.

At MSKCC, over 50% of the patients presenting with gallbladder cancer have been diagnosed incidentally following elective cholecystectomy for presumed benign disease. While traditional management of incidental gallbladder cancer (IGBC) dictates re-resection with the ultimate goal of achieving cure, surgical decision-making must take into account that this malignancy is characterized by poor tumor biology with frequent distant recurrence. Since early and frequent distant recurrence is the most common cause of surgical failure, the surgical oncologist's goal should be to selectively re-resect only those patients most likely to benefit from an operation. The astute surgeon recognizes the high-risk patients who likely have micrometastatic disease at the time of diagnosis and alters the treatment sequence, delivering neoadjuvant chemotherapy. This strategy acts as a selection tool, as those progressing at distant sites during therapy are spared the morbidity and mortality of surgery and furthermore has the potential to treat micrometastatic disease. However, a chemotherapy first approach must be applied selectively since a poor response risks local progression to unresectability and a decrease in functional status that comes from the toxicities of dual agent chemotherapy that can impair surgical candidacy. To balance these risks and benefits, two other criteria for a neoadjuvant approach must be met: i) reliable identification of those patients who are at high risk of distant recurrence and who are, therefore, most likely to benefit from a systemic therapy first approach and ii) availability of effective chemotherapy options. In this review, we will outline the data and judgement we use to select a treatment sequence at our institution.

Intrahepatic cholangiocarcinoma in a patient with Wilson's disease: a case report.

The incidence of hepatobiliary malignancies, and especially intrahepatic cholangiocarcinoma (ICC), for patients with Wilson's disease (WD), is very low, even for cirrhotic patients. A 44-year-old male was admitted to our department for treatment of a liver tumor. He was diagnosed with WD at the age of 15. According to radiological findings, his liver tumor was a suspected hepatocellular carcinoma (HCC) or a combined hepatocellular and cholangiocellular carcinoma. A partial resection of liver segments 8 (S8) and 5 (S5) was subsequently performed due to the intraoperative suspicion of intrahepatic metastasis at the surface of S5. Postoperative histology revealed that the resected portion of S8 contained an ICC; the removed S5 portion comprised a regenerative nodule with hemosiderosis. To date, the patient has survived without tumor recurrence for more than 44 months following surgery. A survey of the literature, inclusive of case reports, would suggest that surgical resection is the primary course of action for a WD patient with ICC, if liver function can be preserved and curative resection performed.

Relationship Between Urinary 8-hydroxydeoxyguanine (8-OHdG) Levels and Clinicopathological Findings in Hepatobiliary Malignancies.

BACKGROUND/AIM: Oxidative stress is defined as an imbalance between the pro-oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases. MATERIALS AND METHODS: Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients. RESULTS: Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057). CONCLUSION: The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker.

Prognostic influence of the liver hanging maneuver for patients with hepatobiliary malignancies who underwent hepatic resections.

BACKGROUND: Prognostic influences of hepatic transection by an anterior approach using the liver hanging maneuver (LHM) has not been fully clarified. METHODS: We examined 233 patients who underwent major hepatectomy with the LHM (n = 75; hepatocellular carcinoma (HCC) in 35, colorectal liver metastasis (CLM) in 10, intrahepatic cholangiocarcinoma (ICC) in 14 and perihilar bile duct carcinoma (BDC) in 16) or without it (n = 158; HCC in 78, CLM in 21, ICC in 31 and BDC in 28). RESULTS: In HCC patients, cancer-positive margin rate, blood loss, transection time and prevalence of posthepatectomy ascites in the LHM group were significantly lower than those in the non-LHM group (p < 0.05). In CLM, transection time in the LHM group was significantly lower than that in the non-LHM group (p < 0.05). In BDC patients, amount of blood loss, transection time and prevalence of ascites in the LHM group were significantly lower than those in the non-LHM group (p < 0.05). In CLM patients, tumor recurrence rate in the non-LHM group was significantly higher than that in the LHM group and disease-free survival in the LHM group was significantly better than that in the non-LHM group in CLM patients and, however, this difference was not observed in a large CLM exceeding 5 cm. However, significant differences of posthepatectomy disease-free and overall survivals were not observed in HCC, ICC and BDC patients. CONCLUSIONS: Although advantages of LHM improving surgical records in major anatomical liver resections were clarified, oncological advantages in the long-term survival of LHM was still uncertain in the hepatobiliary malignancies.