Unresectable biliary tract cancer: Current and future systemic therapy.

For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options available for patients with unresectable BTC have drastically increased, with immunotherapy and targeted treatment gradually joining the ranks of guideline-recommended treatment regimens. The aim of the present review is to summarise the current knowledge on unresectable BTC focusing on epidemiology, anatomical distribution and current strategies for systemic treatment. We further outline ongoing clinical trials and provide an outlook on future therapeutic interventions. In the realm of gastrointestinal malignancies, the increasing number of systemic treatment options for BTC is finally delivering on the longstanding commitment to personalised oncology. This emphasises the need for considering a comprehensive genomic-based pathology assessment right from the initial diagnosis to fully leverage the expanding array of therapeutic options that have recently become accessible.

Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation. Summary: Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies. Key Messages: In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.

Novel endoscopic scoring system for immune mediated colitis: A Multicenter Retrospective Study of 674 Patients.

BACKGROUND & AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective international 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned one point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCES, and clinical symptoms graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4 . The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo Endoscopy Score (MES) of 3 was 74.6% while specificity of clinical symptom grading was much lower at 27.4% and 12.3% respectively. Early endoscopy was associated with timely SIT use (p<0.001, r=0.4084). CONCLUSIONS: This is the largest, multi-center study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells.

BACKGROUND: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. METHODS: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. RESULTS: Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. CONCLUSION: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment.

Imaging-Derived Biomarkers Integrated with Clinical and Laboratory Values Predict Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Purpose: To investigate the prognostic value of computed tomography (CT) derived imaging biomarkers in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and develop a predictive nomogram model. Patients and Methods: This retrospective study included 178 patients with histopathologically confirmed HCC who underwent liver transplantation between 2007 and 2021 at the two academic liver centers. We evaluated dedicated imaging features from baseline multiphase contrast-enhanced CT supplemented by several clinical findings and laboratory parameters. Time-to-recurrence was estimated by Kaplan-Meier analysis. Univariable Cox proportional hazard regression and multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to assess independent prognostic factors for recurrence. A nomogram model was then built based on the independent factors selected through LASSO regression, to predict the probabilities of HCC recurrence at one, three, and five years. Results: The rate of HCC recurrence after LT was 17.4% (31 of 178). The LASSO analysis revealed six independent predictors associated with an elevated risk of tumor recurrence. These predictors included the presence of peritumoral enhancement, the presence of over three tumor lesions, the largest tumor diameter greater than 3 cm, serum alpha-fetoprotein (AFP) levels exceeding 400 ng/mL, and the presence of a tumor capsule. Conversely, a history of bridging therapies was found to be correlated with a reduced risk of HCC recurrence. In addition, Kaplan-Meier curves showed patients with irregular margin, satellite nodules, or small lesions displayed shorter time-to-recurrence. Our nomogram demonstrated good performance, yielding a C-index of 0.835 and AUC values of 0.86, 0.88, and 0.85 for the predictions of 1-year, 3-year, and 5-year TTR, respectively. Conclusion: Imaging parameters derived from baseline contrast-enhanced CT showing malignant behavior and aggressive growth patterns, along with serum AFP and history of bridging therapies, show potential as biomarkers for predicting HCC recurrence after transplantation.

Etiology-independent activation of the LTß-LTßR-RELB axis drives aggressiveness and predicts poor prognosis in HCC.

BACKGROUND AND AIMS: HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of noncanonical NF-κB and its downstream effectors is not established. APPROACH AND RESULTS: Four human HCC cohorts (total n = 1462) and 4 mouse HCC models were assessed for expression and localization of NF-κB signaling components and activating ligands. In vitro , NF-κB signaling, proliferation, and cell death were measured, proving a pro-proliferative role of v-rel avian reticuloendotheliosis viral oncogene homolog B (RELB) activated by means of NF-κB-inducing kinase. In vivo , lymphotoxin beta was identified as the predominant inducer of RELB activation. Importantly, hepatocyte-specific RELB knockout in a murine HCC model led to a lower incidence compared to controls and lower maximal tumor diameters. In silico , RELB activity and RELB-directed transcriptomics were validated on the The Cancer Genome Atlas HCC cohort using inferred protein activity and Gene Set Enrichment Analysis. In RELB-active HCC, pathways mediating proliferation were significantly activated. In contrast to v-rel avian reticuloendotheliosis viral oncogene homolog A, nuclear enrichment of noncanonical RELB expression identified patients with a poor prognosis in an etiology-independent manner. Moreover, RELB activation was associated with malignant features metastasis and recurrence. CONCLUSIONS: This study demonstrates a prognostically relevant, etiology-independent, and cross-species consistent activation of a lymphotoxin beta/LTßR/RELB axis in hepatocarcinogenesis. These observations may harbor broad implications for HCC, including possible clinical exploitation.

Pneumatosis intestinalis in cancer patients who received immune checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy may give rise to immune-related adverse events (irAEs). Pneumatosis intestinalis (PI), or gas within the bowel wall, has very rarely been observed following ICI therapy, and its clinical significance is unclear. We described the clinical characteristics and outcomes of PI as a possible irAE in cancer patients. METHODS: We retrospectively identified 12 adult cancer patients with radiologic evidence of PI within 1 year after ICI exposure during January 2010-January 2023. Clinical characteristics, treatment, and outcomes were evaluated. RESULTS: The median age of our sample was 64 years. The most common cancer types were thoracic/head & neck and gastrointestinal. Eleven patients (92%) received anti-PD-1/L1 monotherapy, while 1 patient (8%) received a combination of anti-PD-1/L1 and anti-CTLA-4. PI occurred a median of 7 months after the first ICI dose. Half the patients (50%) were asymptomatic on diagnosis, and the most common presenting symptom was abdominal pain (42%). Six patients experienced complications, namely pneumoperitoneum (n = 6, 50%) and microperforation (n = 1, 8%), identified on imaging. Nine patients were treated with antibiotics and 3 patients were monitored conservatively. Nine patients (75%) resumed cancer treatment after PI. CONCLUSION: PI may develop as an irAE. While half of cases were incidental radiologic findings, management with antibiotics as well as hospitalization for observation may still be appropriate. The decision to restart cancer therapy and possibly resume ICI therapy remains to be elucidated. Further large-scale studies may be warranted to clarify the association between PI and ICI therapy.

Development and clinical validation of a novel algorithmic score (GAAD) for detecting HCC in prospective cohort studies.

BACKGROUND: Alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence-II (PIVKA-II [DCP]) are biomarkers for HCC with limited diagnostic value when used in isolation. The novel GAAD algorithm is an in vitro diagnostic combining PIVKA-II (DCP) and AFP measurements, age, and gender (biological sex) to generate a semi-quantitative result. We conducted prospective studies to develop, implement, and clinically validate the GAAD algorithm for differentiating HCC (early and all-stage) and benign chronic liver disease (CLD), across disease stages and etiologies. METHODS: Patients aged ≥18 years with HCC or CLD were prospectively enrolled internationally into algorithm development [n = 1084; 309 HCC cases (40.7% early-stage) and 736 controls] and clinical validation studies [n = 877; 366 HCC cases (47.6% early-stage) and 303 controls]. Serum samples were analyzed on a cobas® e 601 analyzer. Performance was assessed using receiver operating characteristic curve analyses to calculate AUC. RESULTS: For algorithm development, AUC for differentiation between early-stage HCC and CLD was 90.7%, 84.4%, and 77.2% for GAAD, AFP, and PIVKA-II, respectively. The sensitivity of GAAD for the detection of early-stage HCC was 71.8% with 90.0% specificity. Similar results were shown in the clinical validation study; AUC for differentiation between early-stage HCC and CLD was 91.4% with 70.1% sensitivity and 93.7% specificity. GAAD also showed strong specificity, with a lower rate of false positives regardless of disease stage, etiology, or region. CONCLUSIONS: The GAAD algorithm significantly improves early-stage HCC detection for patients with CLD undergoing HCC surveillance. Further phase III and IV studies are warranted to assess the utility of incorporating the algorithm into clinical practice.

Prognostic value of baseline MRI features in patients treated with thermal ablation for hepatocellular carcinoma.

PURPOSE: To investigate prognostic value of baseline MRI features for time-to-recurrence (TTR) and local recurrence in patients with early hepatocellular carcinoma (HCC). METHOD: Baseline and follow-up images of 88 patients treated with thermal ablation followed by adjuvant sorafenib or matching placebo due to HCC within the phase II prospective randomized trial (SORAMIC) were included. Baseline MRI images were evaluated in terms of atypical enhancement (lack of wash-in or wash-out), lesion diameter, tumor capsule, peritumoral enhancement on arterial phase, intratumoral fat, irregular margin, satellite lesions, and peritumoral hypointensity on hepatobiliary phase. Prognostic value of these features for TTR and local recurrence were assessed with univariable and multivariable Cox proportional hazard models. RESULTS: Recurrence at any location was diagnosed during follow-up in 30 patients, and the median TTR was 16.4 (95% CI, 15 - NA) months. The presence of more than one lesion (p = 0.028) and peritumoral hypointensity on hepatobiliary phase images (p = 0.012) at baseline were significantly associated with shorter TTR in univariable analysis. AFP > 15 mg/dL (p = 0.084), and history of cirrhosis (p = 0.099) were marginally non-significant. Peritumoral hypointensity on hepatobiliary phase images was the only significant risk factor for recurrence in multivariable analysis (p = 0.003). Local recurrence (adjacent to thermal scar) was diagnosed in eleven (8.3%) out of 132 lesions that underwent thermal ablation. The only significant risk factor for local recurrence was a lesion diameter larger than 3 cm (22.2% vs. 4.5%, p = 0.007). CONCLUSIONS: Peritumoral hypointensity on hepatobiliary phase can serve as imaging biomarker to identify increased recurrence risk in patients undergoing thermal ablation for early-stage HCC.

Colon Adenoma After Diagnosis of Immune Checkpoint Inhibitor-mediated Colitis.

Purpose: While the occurrence of colitis during immune checkpoint inhibitor (ICI) treatment is recognized as a sign of robust immune activation and correlates with better oncological outcomes, the long-term impact of ICI-mediated colitis on the colonic mucosa has not been studied. We thus aim to describe the colonoscopy and histology findings in patients at a follow-up time of ≥ 6 months post initial colitis event. Methods: This retrospective analysis included adult cancer patients diagnosed with ICI colitis at a tertiary cancer center between October 2013 and June 2020. The study group included patients diagnosed with immune mediated colitis who had also undergone a follow up colonoscopy or flex sigmoidoscopy. The control group was patients exposed to ICI without immune mediated colitis. We reported patients' colitis clinical course, treatment, outcomes, and endoscopic and histologic features at diagnosis and at follow-up time of ≥ 6 months. Results: Total 39 patients met the study criteria, with 82% being male, and 35.8% having melanoma. Most patients received a combination of CTLA-4 and PD-1/L1 inhibitors (82%). On initial endoscopic evaluation, inflammation without ulceration was reported in 76.9% of patients and active inflammation on histologic examination in 79.3% of patients. Most patients (79.4%) received corticosteroids, and 56.4% received add-on selective immunosuppressive therapy. Four patients received fecal microbiota transplantation. On follow-up, new incidence of colonic polyps was reported in 51.2% of patients, including adenomas in 33.3% among the colitis patients with median follow up duration of 12 months. The incidence of adenoma polyps 12 months after the colitis event was significantly higher compared to the control group without colitis based on the time-to-event analysis (p=0.041). Conclusion: At a median follow up of 12 months after their initial colitis diagnosis, 51.2% of the patients had new incidence of colonic polyps, including a third with adenoma, at a significantly higher incidence than the control group without colitis. Studies with larger sample sizes are needed to further define the long-term impact of colitis and its treatments on colon health and to refine recommendations for surveillance of colonic adenomas and colorectal cancer.

Concomitant Irradiation to Checkpoint Inhibitor Therapy of Hepatocellular Carcinoma Patients: A Systematic Retrospective, Single-Center Analysis.

INTRODUCTION: Immunotherapy has been established as the standard treatment option for patients with advanced hepatocellular carcinoma (aHCC). Despite the increased efficacy, disease progression occurs in a relevant proportion of patients even after an objective response. Combination concepts with locoregional therapy are currently under investigation for hepatic disease but are also in discussion for the control of distant metastasis. Radiotherapy is a highly effective treatment modality for local tumor control. It is also thought to increase the efficacy of checkpoint inhibition and sensitize distant lesions to the effects of immunotherapy, but may potentially increase adverse effects. In our center, few patients with aHCC treated with immune checkpoint inhibitors (ICIs) received concomitant radiotherapy for symptom or disease control. The aim of this study was to retrospectively analyze adverse effects and efficacy of concomitant radiotherapy in patients with aHCC treated with checkpoint inhibition. METHODS: To this aim, patients who received a combination of ICI and radiotherapy in our institution were retrospectively considered for analysis. The predefined inclusion criterion was radiotherapy after initiated checkpoint inhibition and continuation of ICI therapy for at least 8 weeks. Adverse effects and efficacy measurements were performed according to local standards. RESULTS: The database search of 2016-2021 revealed six consecutive patients fulfilling the predefined criteria for concomitant ICI and radiotherapy. Three patients received high-dose-rate brachytherapy (15 Gy) to treat progredient hepatic lesions. Two patients received stereotactic body radiotherapy (SBRT) (25-30 Gy) for symptom control, and 1 patient received brachytherapy and SBRT to treat metastases. No severe adverse events were reported in the period (<6 months) after concomitant radiotherapy. In 5 out of 6 cases, long-term tumor control could be achieved by this therapeutic combination. CONCLUSION: A good efficacy of concomitant radiotherapy and checkpoint inhibition has been achieved with no safety concerns. Further investigations should evaluate the safety, appropriate clinical context, and efficacy of this promising approach.

Changing treatment landscape associated with improved survival in advanced hepatocellular carcinoma: a nationwide, population-based study.

BACKGROUND AND AIMS: The treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort. METHODS: A nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed. RESULTS: We identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9-8.9) and in period A was 5.3 months (95% CI: 4.5-6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3-18.4) versus 4.8 months with sorafenib (95% CI: 4.0-7.1, p = 0.008). Costs for prescription drugs per patient increased from €6150 in 2015 to €9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from €1646 to €2149 (p = 0.0240). CONCLUSION: The approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs.

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

WHAT IS THIS SUMMARY ABOUT?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Patterns of pseudoprogression across different cancer entities treated with immune checkpoint inhibitors.

BACKGROUND: Pseudoprogression (PsPD) is a rare response pattern to immune checkpoint inhibitor (ICI) therapy in oncology. This study aims to reveal imaging features of PsPD, and their association to other relevant findings. METHODS: Patients with PsPD who had at least three consecutive cross-sectional imaging studies at our comprehensive cancer center were retrospectively analyzed. Treatment response was assessed according to immune Response Evaluation Criteria in Solid Tumors (iRECIST). PsPD was defined as the occurrence of immune unconfirmed progressive disease (iUPD) without follow-up confirmation. Target lesions (TL), non-target lesions (NTL), new lesions (NL) were analyzed over time. Tumor markers and immune-related adverse events (irAE) were correlated. RESULTS: Thirty-two patients were included (mean age: 66.7 ± 13.6 years, 21.9% female) with mean baseline STL of 69.7 mm ± 55.6 mm. PsPD was observed in twenty-six patients (81.3%) at FU1, and no cases occurred after FU4. Patients with iUPD exhibited the following: TL increase in twelve patients, (37.5%), NTL increase in seven patients (21.9%), NL appearance in six patients (18.8%), and combinations thereof in four patients (12.5%). The mean and maximum increase for first iUPD in sum of TL was 19.8 and 96.8 mm (+ 700.8%). The mean and maximum decrease in sum of TL between iUPD and consecutive follow-up was - 19.1 mm and - 114.8 mm (-60.9%) respectively. The mean and maximum sum of new TL at first iUPD timepoint were 7.6 and 82.0 mm respectively. In two patients (10.5%), tumor-specific serologic markers were elevated at first iUPD, while the rest were stable or decreased among the other PsPD cases (89.5%). In fourteen patients (43.8%), irAE were observed. CONCLUSIONS: PsPD occurred most frequently at FU1 after initiation of ICI treatment. The two most prevalent reasons for PsPD were TL und NTL progression, with an increase in TL diameter commonly below + 100%. In few cases, PsPD was observed even if tumor markers were rising compared to baseline. Our findings also suggest a correlation between PsPD and irAE. These findings may guide decision-making of ICI continuation in suspected PsPD.