Elderly Patients with Hepatocellular Carcinoma Benefit from Liver Transplantation as Much as Younger Ones.

Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience. Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (<65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A subgroup analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database. Results: Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% versus 63% and 46% (p = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% versus 58% and 44% (p = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% (p = 0.07) and 26%/14% (p < 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan. Conclusion: Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones.

Costs of a structured early detection program for advanced liver fibrosis and cirrhosis: insights on the "plus" of Check-up 35.

BACKGROUND: The implementation of an early detection program for liver cirrhosis in a general population has been discussed for some time. Recently, the effectiveness of a structured screening procedure, called SEAL (Structured Early detection of Asymptomatic Liver cirrhosis), using liver function tests (AST and ALT) and APRI to early detect advanced fibrosis and cirrhosis in participants of the German "Check-up 35" was investigated. METHODS: This study identifies the expected diagnostic costs of SEAL in routine care and their drivers and reports on prevailing CLD etiologies in this check-up population. The analysis is based on theoretical unit costs, as well as on the empirical billing and diagnostic data of SEAL participants. RESULTS: Screening costs are mainly driven by liver biopsies, which are performed in a final step in some patients. Depending on the assumed biopsy rates and the diagnostic procedure, the average diagnostic costs are between EUR 5.99 and 13.74 per Check-up 35 participant and between EUR 1,577.06 and 3,620.52 per patient diagnosed with fibrosis/cirrhosis (F3/F4). The prevailing underlying etiology in 60% of cases is non-alcoholic fatty liver disease. DISCUSSION: A liver screening following the SEAL algorithm could be performed at moderate costs. Screening costs in routine care depend on actual biopsy rates and procedures, attendance rates at liver specialists, and the prevalence of fibrosis in the Check-up 35 population. The test for viral hepatitis newly introduced to Check-up 35 as once-in-a-lifetime part of Check-up 35 is no alternative to SEAL.

Radiomics-Based Prediction of Future Portal Vein Tumor Infiltration in Patients with HCC-A Proof-of-Concept Study.

Portal vein infiltration (PVI) is a typical complication of HCC. Once diagnosed, it leads to classification as BCLC C with an enormous impact on patient management, as systemic therapies are henceforth recommended. Our aim was to investigate whether radiomics analysis using imaging at initial diagnosis can predict the occurrence of PVI in the course of disease. Between 2008 and 2018, we retrospectively identified 44 patients with HCC and an in-house, multiphase CT scan at initial diagnosis who presented without CT-detectable PVI but developed it in the course of disease. Accounting for size and number of lesions, growth type, arterial enhancement pattern, Child-Pugh stage, AFP levels, and subsequent therapy, we matched 44 patients with HCC who did not develop PVI to those developing PVI in the course of disease (follow-up ended December 2021). After segmentation of the tumor at initial diagnosis and texture analysis, we used LASSO regression to find radiomics features suitable for PVI detection in this matched set. Using an 80:20 split between training and holdout validation dataset, 17 radiomics features remained in the fitted model. Applying the model to the holdout validation dataset, sensitivity to detect occurrence of PVI was 0.78 and specificity was 0.78. Radiomics feature extraction had the ability to detect aggressive HCC morphology likely to result in future PVI. An additional radiomics evaluation at initial diagnosis might be a useful tool to identify patients with HCC at risk for PVI during follow-up benefiting from a closer surveillance.

A higher FIB-4 index is associated with an increased incidence of renal failure in the general population.

The Fibrosis-4 index (FIB-4) is a recommended noninvasive fibrosis test in patients at risk of liver fibrosis. Chronic liver diseases are often associated with kidney diseases. This study aimed to investigate the association between FIB-4 and the development of renal failure among the general population. For this study, we used the Disease Analyzer database, which includes diagnoses and basic medical and demographic data of patients followed in general practices in Germany. Using these data, we extensively matched patients with a FIB-4 index ≥ 1.3 (n = 66,084) to patients with a FIB-4 index < 1.3 (n = 66,084). The primary outcome was the incidence of renal failure or chronic renal failure during a 10-year period. Within 10 years of the index date, 9.2% of patients with a FIB-4 < 1.3 and 10.6% of patients with a FIB-4 ≥ 1.3 were diagnosed with renal failure (p = 0.007). The endpoint chronic renal failure was reached by 7.9% with a FIB-4 < 1.3 and 9.5% with a FIB-4 ≥ 1.3 (p < 0.001). A FIB-4 index ≥ 1.3 was associated with a slight increase in renal failure incidence (hazard ratio [HR]: 1.08, p = 0.009). There was an increasing association between an increase in FIB-4 index and the incidence of renal failure with the strongest association for a FIB-4 index ≥ 2.67 (HR: 1.34, p = 0.001). In sensitivity analyses, a significant association was found for the age group of 51-60 years (HR: 1.38, p < 0.001), patients with arterial hypertension (HR: 1.15, p < 0.001), obese patients (HR: 1.25, p = 0.005), and patients with lipid metabolism disorders (HR:1.22, p < 0.001). Conclusion: A higher FIB-4 index is associated with an increased incidence of renal failure. Therefore, the FIB-4 index may be useful in identifying patients who are at risk not only for liver-related events but also for renal disease.

The prognostic role of early tumor shrinkage in patients with hepatocellular carcinoma undergoing immunotherapy.

BACKGROUND: Early tumor shrinkage (ETS) has been identified as a promising imaging biomarker for patients undergoing immunotherapy for several cancer entities. This study aimed to validate the potential of ETS as an imaging biomarker for patients undergoing immunotherapy for hepatocellular carcinoma (HCC). METHODS: We screened all patients with HCC that received immunotherapy as the first or subsequent line of treatment at our tertiary care center between 2016 and 2021. ETS was defined as the reduction in the sum of the sizes of target lesions, between the initial imaging and the first follow-up. The ETS was compared to the radiologic response, according to the modified response evaluation criteria in solid tumors (mRECIST). Furthermore, we evaluated the influence of ETS on overall survival (OS), progression-free survival (PFS), and the alpha-fetoprotein (AFP) response. RESULTS: The final analysis included 39 patients with available cross-sectional imaging acquired at the initiation of immunotherapy (baseline) and after 8-14 weeks. The median ETS was 5.4%. ETS was significantly correlated with the response according to mRECIST and with the AFP response. Patients with an ETS ≥10% had significantly longer survival times after the first follow-up, compared to patients with < 10% ETS (15.1 months vs. 4.0 months, p = 0.008). Additionally, patients with both an ETS ≥10% and disease control, according to mRECIST, also had significantly prolonged PFS times after the initial follow-up (23.6 months vs. 2.4 months, p < 0.001). CONCLUSION: ETS was strongly associated with survival outcomes in patients with HCC undergoing immunotherapy. Thus, ETS is a readily assessable imaging biomarker that showed potential for facilitating a timely identification of patients with HCC that might benefit from immunotherapy.

13 C-Methacetin Breath Test Predicts Survival in Patients With Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

INTRODUCTION: The 13 C-methacetin breath test ( 13 C-MBT) is a dynamic method for assessing liver function. This proof-of-concept study aimed to investigate the association between 13 C-MBT values and outcomes in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). METHODS: A total of 30 patients with HCC were prospectively recruited. Of these, 25 were included in baseline and 20 in longitudinal analysis. 13 C-MBTs were performed before the first and second TACE session. Patients were followed for at least 1 year. RESULTS: At baseline, the median 13 C-MBT value was 261 µg/kg/hr (interquartile range 159-387). 13 C-MBT, albumin-bilirubin, Child-Pugh, and Model for End-Stage Liver Disease scores were associated with overall survival in extended univariable Cox regression ( 13 C-MBT: standardized hazard ratio [sHR] 0.297, 95% confidence interval [CI] 0.111-0.796; albumin-bilirubin score: sHR 4.051, 95% CI 1.813-9.052; Child-Pugh score: sHR 2.616, 95% CI 1.450-4.719; Model for End-Stage Liver Disease score: sHR 2.781, 95% CI 1.356-5.703). Using a cutoff of 140 µg/kg/hr at baseline, 13 C-MBT was associated with prognosis (median overall survival 28.5 months [95% CI 0.0-57.1] vs 3.5 months [95% CI 0.0-8.1], log-rank P < 0.001). Regarding prediction of 90-day mortality after second 13 C-MBT, the relative change in 13 C-MBT values yielded an area under the receiver-operating characteristic curve of 1.000 ( P = 0.007). DISCUSSION: Baseline and longitudinal 13 C-MBT values predict survival of patients with HCC undergoing TACE. The relative change in 13 C-MBT values predicts short-term mortality and may assist in identifying patients who will not benefit from further TACE treatment.

Baseline Splenic Volume Outweighs Immuno-Modulated Size Changes with Regard to Survival Outcome in Patients with Hepatocellular Carcinoma under Immunotherapy.

Background: An association between immunotherapy and an increase in splenic volume (SV) has been described for various types of cancer. SV is also highly predictive of overall survival (OS) in patients with hepatocellular carcinoma (HCC). We evaluated SV and its changes with regard to their prognostic influence in patients with HCC undergoing immunotherapy. Methods: All patients with HCC who received immunotherapy in first or subsequent lines at our tertiary care center between 2016 and 2021 were screened for eligibility. SV was assessed at baseline and follow-up using an AI-based tool for spleen segmentation. Patients were dichotomized into high and low SV based on the median value. Results: Fifty patients were included in the analysis. The median SV prior to treatment was 532 mL. The median OS of patients with high and low SV was 5.1 months and 18.1 months, respectively (p = 0.01). An increase in SV between treatment initiation and the first follow-up was observed in 28/37 (75.7%) patients with follow-up imaging available. This increase in itself was not prognostic for median OS (7.0 vs. 8.5 months, p = 0.73). However, patients with high absolute SV at the first follow-up continued to have impaired survival (4.0 months vs. 30.7 months, p = 0.004). Conclusion: High SV prior to and during treatment was a significant prognostic factor for impaired outcome. Although a large proportion of patients showed an SV increase after the initiation of immunotherapy, this additional immuno-modulated SV change was negligible compared to long-standing changes in the splanchnic circulation in patients with HCC.

Fully automated AI-based splenic segmentation for predicting survival and estimating the risk of hepatic decompensation in TACE patients with HCC.

OBJECTIVES: Splenic volume (SV) was proposed as a relevant prognostic factor for patients with hepatocellular carcinoma (HCC). We trained a deep-learning algorithm to fully automatically assess SV based on computed tomography (CT) scans. Then, we investigated SV as a prognostic factor for patients with HCC undergoing transarterial chemoembolization (TACE). METHODS: This retrospective study included 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020. A convolutional neural network was trained and validated on the first 100 consecutive cases for spleen segmentation. Then, we used the algorithm to evaluate SV in all 327 patients. Subsequently, we evaluated correlations between SV and survival as well as the risk of hepatic decompensation during TACE. RESULTS: The algorithm showed Sørensen Dice Scores of 0.96 during both training and validation. In the remaining 227 patients assessed with the algorithm, spleen segmentation was visually approved in 223 patients (98.2%) and failed in four patients (1.8%), which required manual re-assessments. Mean SV was 551 ml. Survival was significantly lower in patients with high SV (10.9 months), compared to low SV (22.0 months, p = 0.001). In contrast, overall survival was not significantly predicted by axial and craniocaudal spleen diameter. Furthermore, patients with a hepatic decompensation after TACE had significantly higher SV (p < 0.001). CONCLUSION: Automated SV assessments showed superior survival predictions in patients with HCC undergoing TACE compared to two-dimensional spleen size estimates and identified patients at risk of hepatic decompensation. Thus, SV could serve as an automatically available, currently underappreciated imaging biomarker. KEY POINTS: • Splenic volume is a relevant prognostic factor for prediction of survival in patients with HCC undergoing TACE, and should be preferred over two-dimensional surrogates for splenic size. • Besides overall survival, progression-free survival and hepatic decompensation were significantly associated with splenic volume, making splenic volume a currently underappreciated prognostic factor prior to TACE. • Splenic volume can be fully automatically assessed using deep-learning methods; thus, it is a promising imaging biomarker easily integrable into daily radiological routine.

Emerging immunotherapy for HCC: A guide for hepatologists.

HCC is one of the most common cancers worldwide, and the third leading cause of cancer-related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno-oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first-line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T-cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.

Outcomes in patients receiving palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND & AIMS: Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors. METHODS: From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards. RESULTS: Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels). CONCLUSIONS: Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy. LAY SUMMARY: Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.

Establishing an Ultrasound Screening Protocol for Chronic Liver Disease with a Handheld Device: A Pilot Project in Southern Ethiopia.

Chronic liver disease (CLD) poses significant challenges in the developing world. The prevalence of this problem and the health burden on local health services are not well understood. The diagnosis and monitoring of CLD are difficult in these settings because of limited access to expensive imaging with limited mobility and/or liver biopsy. The aim of this project was to develop and implement an efficient evidence-based robust ultrasound protocol for the assessment of chronic liver disease using a hand-held ultrasound device that could be effectively used in the developing world. A protocol was established using scoring systems that have established accuracy for the diagnosis of hepatic fibrosis/cirrhosis and hepatic steatosis. Included in the protocol was the identification of hepatic masses, portal venous enlargement, hepatic size and splenic size. Hepatic steatosis was common, identified in 46 of 94 participants (49%). Hepatic fibrosis was observed in only 13 of 94 participants (14%). A significant limitation of the methodology was the inability to validate the results with biopsy or other forms of cross-sectional imaging. The protocol was successfully implemented in a community in a rural setting in South Ethiopia with a mean examination time of around 6 min. It is feasible to use handheld ultrasound for the screening of CLD in remote settings. This project provides an evidence-based framework for further studies in this area.

Evaluation of IL-6 for Stepwise Diagnosis of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

Diagnosis of minimal hepatic encephalopathy (MHE) requires psychometric testing, which is time-consuming and often neglected in clinical practice. Elevated Interleukin-6 (IL-6) serum levels have been linked to MHE. The aim of this study was to investigate the usefulness of IL-6 as a biomarker in a stepwise diagnostic algorithm to detect MHE in patients with liver cirrhosis. A total of 197 prospectively recruited patients without clinical signs of hepatic encephalopathy (HE) served as the development cohort. Another independent cohort consisting of 52 patients served for validation purposes. Psychometric Hepatic Encephalopathy Score (PHES) was applied for the diagnosis of MHE. Fifty (25.4%) patients of the development cohort presented with MHE. Median IL-6 levels were more than twice as high in patients with MHE than in patients without HE (16 vs. 7 pg/mL; P < 0.001). On multivariable logistic regression analysis, higher IL-6 levels (odds ratio 1.036; 95% confidence interval [CI] 1.009-1.064; P = 0.008) remained independently associated with the presence of MHE. IL-6 levels ≥ 8pg/mL discriminated best between patients with and without MHE in receiver operating characteristic (ROC) analysis (area under the ROC 0.751). With a cutoff value of ≥7 pg/mL, further elaborate testing with PHES could be avoided in 38% of all patients with a sensitivity of 90% (95% CI 77%-96%) and a negative predictive value (NPV) of 93% (95% CI 84%-98%). This diagnostic accuracy was confirmed in the validation cohort (sensitivity 94%; NPV 93%). Conclusion: Using IL-6 serum levels as a biomarker in a stepwise diagnostic algorithm to detect MHE could substantially reduce the number of patients requiring testing with PHES and in turn the workload. IL-6 may have especially helped in patients who are unable to perform other screening tests.

NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options.

In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying aetiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation are characterised by several unique features: in contrast to virally driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and are more frequently diagnosed at an advanced stage. While locoregional treatments are probably equally effective regardless of HCC aetiology, the picture is less clear for systemic therapy. Tyrosine kinase inhibitors are probably equally effective, while there have been initial signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. Current international clinical practice guidelines for HCC do not consider aetiology, as there are insufficient data to draw specific conclusions or to recommend aetiology-specific modifications to the current management of patients with HCC. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC aetiology - and NAFLD/NASH in particular - influence the safety and efficacy of a given treatment.

Prevalence and clinical significance of clinically evident portal hypertension in patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND: Clinically evident portal hypertension (CEPH) was previously identified as a prognostic factor for patients with hepatocellular carcinoma (HCC). However, little is known about the prognostic influence of CEPH on the long-term outcome of patients with HCC undergoing transarterial chemoembolization (TACE), particularly in Western populations. OBJECTIVES: This study investigated the prevalence and prognostic influence of CEPH in a Western population of patients with HCC undergoing TACE. METHODS: This retrospective study included 349 treatment-naïve patients that received initial TACE treatment at our tertiary care center between January 2010 and November 2020. CEPH was defined as a combination of ascites, esophageal/gastric varices, splenomegaly and a low platelet count. We assessed the influence of CEPH and its defining factors on median overall survival (OS) in HCC patients. We compared the effects of CEPH to those of well-known prognostic factors. RESULTS: Of the 349 patients included, 304 (87.1%) patients had liver cirrhosis. CEPH was present in 241 (69.1%) patients. The median OS times were 10.6 months for patients with CEPH and 17.1 months for patients without CEPH (log rank p = 0.036). Median OS without a present surrogate was 17.1 months, while patients with one respectively more than two present CEPH surrogates had a median OS of 10.8 and 9.4 months (log rank p = 0.053). In multivariate analysis, CEPH was no significant risk factor for OS (p = 0.190). Of the CEPH-defining factors, only ascites reached significance in a univariate analysis. CONCLUSION: CEPH was present in more than two thirds of the patients with HCC undergoing TACE in our cohort of Western patients. Patients with CEPH had a significantly impaired survival in univariate analysis. However, no significance was reached in multivariate analysis. Thus, when TACE treatment is deemed oncologically reasonable, patients should not be excluded from TACE treatment due to the presence of surrogates of portal hypertension alone.

Immunonutritive Scoring for Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: Evaluation of the CALLY Index.

The novel CRP-albumin-lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the prognostic ability of the CALLY index for patients with HCC undergoing transarterial chemoembolization (TACE). We retrospectively identified 280 treatment-naïve patients with HCC that underwent an initial TACE at our institution, between 2010 and 2020. We compared the CALLY index to established risk factors in univariate and multivariate regression analyses for associations with median overall survival (OS). A low CALLY score was associated with low median OS (low vs. high CALLY: 9.0 vs. 24.0 months, p < 0.001). In the multivariate analysis, the CALLY index remained an independent prognostic predictor (p = 0.008). Furthermore, all factors of the CALLY index reached significance in univariate and in-depth multivariate analyses. However, the concordance index (C-index) of the CALLY index (0.60) was similar to the C-indices of established immunonutritive and inflammation scoring systems (range: 0.54 to 0.63). In conclusion, the CALLY index showed promise as a stratification tool for patients with HCC undergoing TACE. Notably, the CALLY index was not superior to other immunonutritive and inflammation scoring systems in predicting the median OS. Thus, future studies should re-evaluate the mathematical calculation of the index, particularly the contributions of individual parameters.

Refining Prognosis in Chemoembolization for Hepatocellular Carcinoma: Immunonutrition and Liver Function.

A combination of albumin-bilirubin (ALBI) grading and the Prognostic Nutritional Index (PNI) was identified recently as a highly predictive tool for patients with hepatocellular carcinoma (HCC) undergoing tumor ablation. The present study evaluated this combination in patients undergoing transarterial chemoembolization (TACE). Between 2010 and 2020, 280 treatment-naïve patients were retrospectively identified. The influence of ALBI grade, PNI and the novel ALBI-PNI on the median overall survival (OS) was assessed. In the next step, the prognostic ability of the combined approach was compared to established scoring systems. Both ALBI grade 2-3 and a low PNI were highly predictive for median OS (ALBI grade 1-3: 39.0 vs. 16.3 vs. 5.4 months, p < 0.001; high vs. low PNI: 21.4 vs. 7.5, p < 0.001). The combination of both resulted in a median OS of 39.0, 20.1, 10.3, and 5.4 months (p < 0.001). With a Concordance Index (C-Index) of 0.69, ALBI-PNI outperformed each individual score (ALBI 0.65, PNI 0.64) and was also better than BCLC, HAP, mHAP-II, and the Six-and-Twelve score (C-Indices 0.66, 0.60, 0.59, and 0.55). Thus, the easy-to-calculate ALBI-PNI may be a promising stratification tool for patients with HCC undergoing TACE, reflecting both immunonutritive status and liver function.

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma.

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months in the pCTX + TACE group versus 13.1 months in the pCTX group (p = 0.008). Controlling for albumin, bilirubin, ECOG (Eastern Cooperative Oncology Group) performance status, and UICC (Union for International Cancer Control) stage, the addition of TACE still conferred an OS benefit of 12.95 months (p = 0.014). A propensity score matching analysis yielded an OS benefit of 14 months from the time of unresectability for the pCTX + TACE group (p = 0.020). The addition of TACE to pCTX may provide an OS benefit for patients with unresectable iCCA. Thus, patients with liver-dominant iCCA undergoing standard-of-care pCTX should be considered for additional treatment with TACE.

The impact of portal vein tumor thrombosis on survival in patients with hepatocellular carcinoma treated with different therapies: A cohort study.

BACKGROUND: Portal vein tumor thrombosis (PVTT) is a frequent complication of hepatocellular carcinoma (HCC), which leads to classification as advanced stage disease (regardless of the degree of PVTT) according to the Barcelona Clinic Liver Cancer Classification. For such patients, systemic therapy is the standard of care. However, in clinical reality, many patients with PVTT undergo different treatments, such as resection, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), or best supportive care (BSC). Here we examined whether patients benefited from such alternative therapies, according to the extent of PVTT. METHODS: This analysis included therapy-naïve patients with HCC and PVTT treated between January 2005 and December 2016. PVTT was classified according to the Liver Cancer study group of Japan as follows: Vp1 = segmental PV invasion; Vp2 = right anterior or posterior PV; Vp3 = right or left PV; Vp4 = main trunk. Overall survival (OS) was analyzed for each treatment subgroup considering the extent of PVTT. We performed Cox regression analysis with adjustment for possible confounders. To further attenuate selection bias, we applied propensity score weighting using the inverse probability of treatment weights. RESULTS: A total of 278 treatment-naïve patients with HCC and PVTT were included for analysis. The median observed OS in months for each treatment modality (resection, TACE/SIRT, sorafenib, BSC, respectively) was 32.4, 8.1, N/A, and 1.7 for Vp1; 10.7, 6.9, 5.5, and 1.2 for Vp2; 6.6, 7.5, 2.9, and 0.6 for Vp3; and 8.0, 3.6, 5.3, and 0.7 for Vp4. Thus, the median OS in the resection group in case of segmental PVTT (Vp1) was significantly longer compared to any other treatment group (all p values <0.01). CONCLUSIONS: Treatment strategy for HCC with PVTT should not be limited to systemic therapy in general. The extent of PVTT should be considered when deciding on treatment alternatives. In patients with segmental PVTT (Vp1), resection should be evaluated.

The Current Landscape of Clinical Trials for Systemic Treatment of HCC.

The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different agents in various combinations and at different disease stages have been initiated. The first positive results reported for the combination of atezolizumab and bevacizumab, as the first line treatment of advanced HCC, will bring lasting change to the management of HCC and has increased the odds of success for alternative combination therapies. This review article seeks to provide clarity on the complex and evolving landscape of clinical trials on systemic treatments of HCC. It covers current trials which test various systemic treatments (i) in the first and second line in advanced HCC, (ii) in intermediate HCC, (iii) as adjuvant as well as (iv) neoadjuvant strategies, and (v) including immune interventions other than immune checkpoint inhibition.