Progressive Hepatocellular Carcinoma Research Articles

Assessment of Hepatocellular Carcinoma Patients Infected with Covid-19 Infection during the Pandemic

Hepatocellular carcinoma (HCC) patients are more susceptible to decompensation if they get Coronavirus disease 2019 (COVID-19) infection that leads to significant reduction in HCC related health services, reduction in surveillance activities and progression of HCC. On the other hand, symptoms of covid-19 infection are usually severe in HCC patients. Assessment of severity of covid-19 infection in HCC patients. And assessment of clinical course and outcome of HCC patients when they get infected by Covid-19. This is a retrospective case control study including 100 HCC patients (50 of them were infected by covid-19 while the other 50 were not infected). All patients were Egyptians presented to HCC clinic in national hepatology & tropical research institute (NHTMRI) from 1/2022 to 1/2023 assessed for covid-19 infection (by typical CT chest, covid swab and covid symptoms) and assessed for HCC staging (by Barcelona clinic liver cancer BCLC), clinical course over six months (by Child Pugh score) and mortality rates. Most of Covid-19 infected HCC patients had severe covid symptoms and progressive HCC course with mortality 72%, while low percentage of covid-19 HCC infected group were mild with stationary course. On the other hand, high percentage of non-infected HCC group have stationary HCC course with low mortality 24%. COVID-19 infection seems to have a significant effect on clinical course and outcome of HCC. Also, HCC patients are vulnerable to have more severe COVID-19 symptoms.

Safety and Efficacy of Selective Internal Radionuclide Therapy with 90Y Glass Microspheres in Patients with Progressive Hepatocellular Carcinoma after the Failure of Repeated Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is currently the standard of care in patients with unresectable hepatocellular carcinoma (HCC), and selective internal radionuclide therapy (SIRT) with 90Y microspheres is mainly used as an alternative modality in patients considered poor candidates for TACE. Treatment with sorafenib is the recommended option for patients with progressive disease after TACE. This study aims to evaluate the safety and efficacy of SIRT with glass microspheres in patients with progressive HCC after repeated TACE who are not eligible for treatment with sorafenib. Forty-seven patients with progressive HCC after a median of three TACE sessions (range 2-14) underwent SIRT (3.5 ± 1.5 GBq; liver target dose 110-120 Gy). Toxicity was recorded 4 and 12 weeks after treatment and reported according to the Common Terminology Criteria for Adverse Events Version 5.0. Treatment response was assessed three months after SIRT using multiphase computed tomography and modified criteria in solid tumors (mRECIST). Survival analyses were performed using Kaplan-Meier curves and a Cox proportional hazards model for uni- and multivariate analyses. Significant but reversible hepatotoxicity (≥grade 3) occurred in five patients (11%). No radioembolization-induced liver disease (REILD) was observed. The number of previous TACE sessions and cumulative administered activity did not predict the incidence of post-SIRT significant hepatotoxicity. Treatment responses consisted of partial responses in 26 (55%), stable disease in 12 (26%), and progressive disease in 9 (19%) patients. The median overall survival (OS) was 11 months (95% confidence interval (CI), 9-13), and objective responses to SIRT were associated with a longer OS (p = 0.008). Significant hepatotoxicity (≥grade 3) after SIRT was a contributor to impaired survival (median OS 6 months (95% CI, 4-8) vs. 12 months (95% CI, 10-14), p < 0.001). SIRT with glass microspheres is a safe and effective salvage treatment for patients with progressive HCC refractory to TACE who are considered poor candidates for sorafenib treatment.

A novel cholesterol metabolism-related ferroptosis pathway in hepatocellular carcinoma

BackgroundEmerging studies have reported the contribution of cholesterol to hepatocellular carcinoma (HCC) progression. However, the specific role and mechanism of cholesterol metabolism on spontaneous and progressive HCC development from the point of view of ferroptosis are still worth exploring. The present study aimed to reveal a novel mechanism of cholesterol metabolism-related ferroptosis in hepatocellular carcinoma cells.MethodsTwo microarray datasets (GSE25097, GSE22058) related to HCC were downloaded from Gene Expression Omnibus (GEO) datasets. Metabolomics analysis was performed by ultra performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). The cholesterol-related proteins were downloaded from HMBD. Ferroptosis-related genes were extracted from FerrDb database. Data sets were separated into two groups. GSE25097 was used to identify ferroptosis-related genes, and GSE22058 was used to verify results. During these processes, chemical–protein interaction (CPI), protein–protein interaction (PPI), the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Multivariate logistic regression analysis was used to test the associated pathway.ResultsWe identified 8 differentially expressed ferroptosis-related genes (HAMP, PTGS2, IL1B, ALOX15B, CDKN2A, RRM2, NQO1 and KIF20A) and 4 differentially expressed cholesterol-related genes (LCAT, CH25H, CEL and CYP7A1). Furthermore, based on the predicted results with STITCH, we identified indomethacin and IL1B as the essential node for cholesterol-mediated ferroptosis in hepatocellular carcinoma cell. Multivariate logistic regression analysis showed the activities of plasma IL1B in liver cancer patients enrolled have been significantly affected by the level of plasma cholesterol (P < 0.001) and the test result of IL1B is a predictor variable causing the changes of serum Fe levels (P < 0.001).ConclusionsOur findings shed new light on the association between cholesterol metabolism and ferroptosis in HCC, and suggest that IL1B is the necessary node for cholesterol to lead to ferroptosis process in HCC. Also, we identified the potential role of indomethacin in adjuvant therapy of HCC with complications of abnormal cholesterol metabolism.

Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis

Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12–72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.

O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), but its pathogenic mechanism remains to be explored. The RNA N6-methyladenosine (m6A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), plays a critical role in the HCC progression. However, the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive. Here, we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection. O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination. Mechanistically, YTHDF2 stabilized minichromosome maintenance protein 2 (MCM2) and MCM5 transcripts in an m6A-dependent manner, thus promoting cell cycle progression and HBV-related HCC tumorigenesis. Moreover, targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression. Taken together, our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m6A methylation and HCC progression. Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.

Potential Therapeutic Strategies to Combat HCC.

Hepatocellular carcinoma (HCC) is a complex, life-threatening and most common neoplasm in the world. HCC tumors are genetically and phenotypically heterogeneous, and involve various molecular mechanisms and stimulation of several signaling pathways, such as Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptors (EGFR), Insulin growth factor, Ras/extracellular signal-stimulated kinase, the mammalian goal of rapamycin (mTOR), c-mesenchymal- epithelial transition factor-1 (c-Met), Hedgehog, Wnt and apoptotic signaling. Lately, in patients, multi-kinase cascade blockers, such as sorafenib, selumetinib and regorafenib, have increased the survival rate of progressive HCC. This development presents a step forward towards the therapy of liver cancer infection and attests that molecular systemic rehabilitation can be useful in HCC treatment. The development of these systemic therapeutic agents has further expanded the research area for surplus molecular mediators to auxiliary increase the cure rate of patients. This article reviews the complete focus on cascades, current enduring clinical tests by means of HCC therapeutic mediators, and imminent prospects in the cure of HCC.

S3103 A Case of Rapidly Progressing Hepatocellular Carcinoma Hidden From Surveillance

Introduction: Hepatocellular carcinoma (HCC) accounts for over 90% of all liver cancers worldwide and carries a high mortality rate. Despite screening efforts, the incidence of HCC still remains high due to the prevalence of viral hepatitis, alcoholic cirrhosis, and non alcoholic fatty liver disease. At present, there are no screening guidelines focusing on non cirrhotic primary biliary cholangitis (PBC) patients. We herein present a case of an 84 year old female who was diagnosed with rapidly progressive HCC in the setting of PBC. Case Description/Methods: An 84 year old female previously diagnosed with anti-mitochondrial antibody negative PBC presented with one week history of diarrhea and 20lb unintentional weight loss over the past year. Physical exam was notable for non tender hepatomegaly. Significant laboratory values include ALP 337 U/L, AST 208 U/L, ALT 52 U/L, INR 1.1, bilirubin total 3.3 mg/dL, Hgb 9.1 g/dL, platelets 309 10^3/uL, and albumin 2.4 g/dL. Social history was negative for tobacco or alcohol use. A CT of the abdomen and pelvis was obtained and revealed a 16 cm mass encompassing the entirety of the right hepatic lobe. A subsequent AFP was >20,000 ng/mL, consistent with HCC and was discharged home with hepatology follow up. She presented 2 week later with shock and was found to have a ruptured HCC which eventually was the cause of death. 6 months prior to admission, she was noted to have normal liver enzymes and AFP <2 ng/mL, but no imaging was obtained as a fibroscan done 12 months prior to admission revealed a liver stiffness of 7.8 kPa (low to moderate probability of advanced fibrosis) and CAP of 229 dB/m (no liver steatosis) (Figure 1). Discussion: Patients with PBC have a slightly increased risk of HCC which is usually diagnosed in the setting of underlying cirrhosis. Current guidelines recommend surveillance in those patients with documented cirrhosis with imaging every 6 months. However, studies have shown that patients with PBC have a 2.4% risk of developing HCC at any histologic stage of PBC, with a male predominance. There are currently no screening guidelines for PBC, which may have led to an earlier diagnosis, and therefore treatment, in our patient who passed away only 2 weeks after presentation due to ruptured HCC. Given the outcome in this case, more aggressive screening might be beneficial even in the non-cirrhotic population who have underlying PBC.Figure 1.: CT and MRI visualizing HCC predominately in right hepatic lobe.

Impact of PNPLA3 p.I148M and Hepatic Steatosis on Long-Term Outcomes for Hepatocellular Carcinoma and HBsAg Seroclearance in Chronic Hepatitis B.

BackgroundCoexistence of hepatitis B and nonalcoholic fatty liver disease is common; however, little is known about the impact of hepatic steatosis and its major genetic determinants on the natural history of HBV infection. We aimed to study the effects of hepatic steatosis and PNPLA3 variant p.I148M on the risk of hepatocellular carcinoma (HCC) and the lifetime probability of HBsAg seroclearance, which is associated with functional remission and improved long-term outcome of HBV infection.MethodsWe conducted a cohort study of 2385 male, HBsAg-positive Taiwanese civil servants recruited in 1989–1992, and followed up until 2019. Cox regression with competing-risk models was used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs).ResultsOf 2385 participants, 628 experienced HBsAg seroclearance and 217 developed HCC. Hepatic steatosis, excess body-mass index, and the PNPLA3-148M variant were significantly associated with higher HBsAg seroclearance rate. However, multivariate analyses accounting for HBsAg seroclearance and various HCC risk factors showed that, while steatosis was associated with decreased HCC risk (sHR [95% CI]: 0.49 [0.36–0.66]), carriage of the PNPLA3-148M variant allele (vs II homozygotes: 1.64 [1.20–2.25] for MI heterozygotes; 1.83 [1.20–2.78] for MM homozygotes) and obesity (1.51 [1.07–2.13]) were associated with increased risk. The inverse hepatic steatosis-HCC association persisted after additional adjustment for other viral factors or using different follow-up time cut-offs to account for reverse causality. Moreover, the PNPLA3 MM genotype was positively associated with elevations of ALT and AST and liver cirrhosis, while hepatic steatosis was positively associated with ALT but inversely associated with AST and liver cirrhosis.ConclusionHepatic steatosis and PNPLA3-148M variant appeared to have distinct impacts on the development of HBV-related progressive liver disease and HCC. PNPLA3 p.I148M, but not a diagnosis of hepatic steatosis, can help to identify HBV carriers with high-risk fatty liver disease in the progression to HCC.

Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.

High expression of YKT6 associated with progression and poor prognosis of hepatocellular carcinoma

Background and objective The N-ethylmaleimide-sensitive fusion protein attachment protein receptor YKT6 is a key protein that controls the release of exosomes, was reported to play important roles in multiple cancers. However, the role of YKT6 in hepatocellular carcinoma (HCC) is still unknown. Methods Here we first used bioinformatics tools to analyze the YKT6 mRNA expression in HCC. In addition, we retrospectively collected 330 cancer tissue specimens from HCC patients and 180 para-cancerous tissue specimens, and detected YKT6 expression using immunohistochemical staining. Then the relationship between YKT6 expression and the clinical characteristics of HCC was analyzed, Kaplan–Meier analysis and Cox regression model were also performed to evaluate the impact of YKT6 expression on prognosis of HCC. Protein-protein interaction network of YKT6, and the gene enrichment analysis (GSEA) database were used to predict possible signal pathways regulated by YKT6 in HCC. Results The high expression rate of YKT6 in HCC (72.40%, 239/330) was higher than that in adjacent tissues (17.80%, 32/180, p < .001), and high expression of YKT6 was correlated with tumor size (p = 0.002), Edmondson Grade (p < .001), metastasis (p < .001), microvascular invasion (p = .005), AFP level (p = .002). Kaplan–Meier survival analysis showed that HCC patients with high YKT6 expression level had poorer prognosis. Meanwhile, multivariate Cox regression analysis showed that Edmondson grade (p = .009), metastasis (p = .049), YKT6 expression (p = .037) are independent risk factors for poor prognosis of HCC. Conclusions: Our results suggested that the upregulated expression of YKT6 is closely related to the progression HCC, which may be used as a potential biomarker for poor prognosis in HCC.

Clinical Characteristics of Long-Term Survivors After Sorafenib Treatment for Unresectable Hepatocellular Carcinoma: A Korean National Multicenter Retrospective Cohort Study.

Background/AimSorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment.MethodsThis multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles.ResultsThe patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (>1,000 ng/mL; HR = 0.361; P < 0.001).ConclusionThis large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.

Sulfasalazine synergistically enhances the inhibitory effects of imatinib against hepatocellular carcinoma (HCC) cells by targeting NFκB, BCR/ABL, and PI3K/AKT signaling pathway-related proteins.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related fatalities worldwide. Identification of second-line therapies for patients with progressive HCC is urgently required as the use of sorafenib and/or regorafenib remains unsatisfactory. Imatinib, a small-molecule kinase inhibitor, is used to treat certain types of cancer, and nuclear factor κB (NFκB) is a positive regulator of cancer cell expansion. The combined use of tyrosine kinase and NFκB inhibitors may have potential for treating HCC. The aim of this work was to assess the potential anticarcinogenic effects of imatinib and sulfasalazine alone or in combination on the human HCC cell lines HEPG2 and Huh-7. Both drugs were shown to affect the phosphoinositide 3-kinase/protein kinase B, phosphorylated signal transducer and activator of translation (p-STAT-3), breakpoint cluster region protein/Abelson proto-oncogene and NFκB pathways. At the transcriptional level, imatinib and sulfasalazine were found to synergistically down-regulate c-MET gene expression. When compared with the activities of either medication alone, combined use of imatinib and sulfasalazine enhanced inhibition of HCC cell proliferation and extended induction of apoptosis. In summary, the presented data suggest that sulfasalazine synergistically potentiates the antitumor effects of imatinib.

Roles of M6A Regulators in Hepatocellular Carcinoma: Promotion or Suppression.

Hepatocellular carcinoma (HCC) is the sixth globally diagnosed cancer with a poor prognosis. Although the pathological factors of hepatocellular carcinoma are well elucidated, the underlying molecular mechanisms remain unclear. N6-methyladenosine (M6A) is adenosine methylation occurring at the N6 site, which is the most prevalent modification of eukaryotic mRNA. Recent studies have shown that M6A can regulate gene expression, thus modulating the processes of cell self-renewal, differentiation, and apoptosis. The methyls in M6A are installed by methyltransferases ("writers"), removed by demethylases ("erasers") and recognized by M6A-binding proteins ("readers"). In this review, we discuss the roles of the above regulators in the progression and prognosis of HCC, and summarize the clinical association between M6A modification and hepatocellular carcinoma, so as to provide more valuable information for clinical treatment.

Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress

Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1−/− or Sod1KO mice) have increased oxidative stress, show accelerated aging and develop spontaneous hepatocellular carcinoma (HCC) with age. Similar to humans, HCC development in Sod1KO mice progresses from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) with fibrosis, which eventually progresses to HCC. Oxidative stress plays a role in NAFLD to NASH progression, and liver inflammation is the main mechanism that drives the disease progression from NASH to fibrosis. Because necroptosis is a major source of inflammation, we tested the hypothesis that increased necroptosis in the liver plays a role in increased inflammation and fibrosis in Sod1KO mice. Phosphorylation of MLKL (P-MLKL), a well-accepted marker of necroptosis, and expression of MLKL protein were significantly increased in the livers of Sod1KO mice compared to wild type (WT) mice indicating increased necroptosis. Similarly, phosphorylation of RIPK3 and RIPK3 protein levels were also significantly increased. Markers of pro-inflammatory M1 macrophages, NLRP3 inflammasome, and transcript levels of pro-inflammatory cytokines and chemokines, e.g., TNFα, IL-6, IL-1β, and Ccl2 that are associated with human NASH, were significantly increased. Expression of antioxidant enzymes and heat shock proteins, and markers of fibrosis and oncogenic transcription factor STAT3 were also upregulated and autophagy was downregulated in the livers of Sod1KO mice. Short term treatment of Sod1KO mice with necrostatin-1s (Nec-1s), a necroptosis inhibitor, reversed these conditions. Our data show for the first time that necroptosis-mediated inflammation contributes to fibrosis in a mouse model of increased oxidative stress and accelerated aging, that also exhibits progressive HCC development.

Baseline Sarcopenia is Associated with Lack of Response to Therapy, Liver Decompensation and High Mortality in Hepatocellular Carcinoma Patients.

Objective:hepatocellular carcinoma (HCC) is a dreadful complication of liver cirrhosis. Aim was to study the effect of sarcopenia on the survival in patients with HCC. Methods:we included 262 patients and were followed up for 12 months. Sarcopenia was calculated by skeletal muscle index (SMI). Sarcopenia was defined by SMI ≤39 cm2/m2 for women and ≤50 cm2/m2 for men. Results:patients with sarcopenia (n= 113, 43.1%) were older, mainly males, Child-Pugh class B and smokers. Patients with sarcopenia had lower survival than those without (10.09 vs. 11.72 months). Survival was also lower in Barcelona clinic liver cancer stage C than B and A (9.02 vs. 11.21 vs. 11.89 months). Age and sarcopenia were hazardous of mortality (p<0.05). There was statistically significant difference of serial SMI in patients without baseline sarcopenia unlike patients with baseline sarcopenia. On follow up patients with sarcopenia had higher incidence of ascites (45% vs. 20.4%), spontaneous bacterial peritonitis (21.7% vs. 11.6%), hepatic encephalopathy (28% vs. 11.5%) and bleeding (22.9% vs. 12.7%). Totally patients with sarcopenia had higher incidence of progressive HCC (39% vs. 25.5%). Conclusion:Sarcopenia is associated with lack of response to therapy, liver decompensation and higher mortality in hepatocellular carcinoma patients.

Exploratory Analysis of Lenvatinib Therapy in Patients with Unresectable Hepatocellular Carcinoma Who Have Failed Prior PD-1/PD-L1 Checkpoint Blockade.

Simple SummaryProgrammed cell death protein 1 (PD−1)/PD-ligand 1 (PD-L1) blockade is becoming a novel therapeutic option for a hepatocellular carcinoma. In this work, we evaluated efficacy and safety of lenvatinib following failure of PD-1/PD-L1 blockade. The median progression-free survival was 10 months (95% confidence interval (CI): 8.3–11.8) and the median overall survival was 15.8 months (95% CI: 8.5–23.2) since lenvatinib therapy initiation. The objective response rate was 55.6%, and the disease control rate was 86.1%. All of efficacy outcomes were better than those by lenvatinib treatment alone as the 1st line treatment therapy. No particular safety concerns were observed. It was speculated that lenvatinib right after failure of PD-1/PD-L1 blockade provided synergistic effect since anti-PD-1 antibodies can remain binding to CD8+T cells for more than several months. Lenvatinib demonstrated considerably high antitumor activity and good survival benefit with acceptable toxicity in patients with unresectable HCC when administered right after failure of PD-1/PD-L1 blockade.Although programmed cell death protein 1 (PD−1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD−1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4–8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5–100.0) mg and 12 (IQR, 64.4–100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3–11.8) and the median overall survival was 15.8 months (95% CI: 8.5–23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.

Early safety from a phase I, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected (inj) into liver tumors in combination with pembrolizumab (pem).

3015 Background: T-VEC is a genetically modified, oncolytic HSV-1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immunity. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with checkpoint inhibitors (Andtbacka JCO 2015, Chesney JCO 2017, Ribas Cell 2017). T-VEC has also demonstrated tolerable safety for intrahepatic inj (Hecht JCO 2018). This phase 1b, multicenter, open-label, dose escalation study (NCT02509507) evaluates the safety of intrahepatic inj of T-VEC in combination with intravenous (IV) pem in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated concentration (MTC) of T-VEC inj into liver tumors based on the incidence of dose-limiting toxicities (DLTs). DLT rate was evaluated with the mTPI up-and-down design. Eligible pts were ≥ 18 years, had progressive HCC or breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 5) or 108 PFU/mL (cohort 6) every 21 (±3) days (Q21D). Inj volume was based on lesion size. Pem (200 mg) was given IV Q21D. Results: Here we report on three cohorts: A5 (107 PFU/mL T-VEC + pem), A6 (108 PFU/mL T-VEC + pem), and B5 (107 PFU/mL T-VEC + pem). Twenty-nine pts were treated: 7 in A5, 17 in A6, 5 in B5. Median age was 61 years (range: 30, 76). Median number of inj was 4 and median treatment duration was 88 days. One DLT of cholestatic hepatitis was observed out of 6 DLT evaluable pts in cohort A5. No DLTs were observed in cohort A6 and B5. MTC was 108 PFU/mL in non-HCC patients; exploration of MTC in the HCC population is ongoing. Treatment-emergent adverse events (TEAEs) were consistent across cohorts. The most common treatment-emergent treatment-related adverse events (TETRAE) were pyrexia (79.3%), chills (37.9%), and nausea (37.9%). Eight pts (27.6%) had grade 3/4 TEAEs: 2pts (6.9%) related to the combination therapy and the rest not related to treatment. No fatal AEs were observed. Conclusions: T-VEC intrahepatic inj in combination with IV pem at standard doses has thus far been demonstrated as feasible and tolerable to continue further investigation. Clinical trial information: NCT02509507 .

Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma.

BackgroundNo trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC).ObjectivesConduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib.MethodsThe CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared.ResultsIn the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9–17.0] versus 10.6 [9.1–12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9–7.3] versus 3.1 [2.8–4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib (p ≤ 0.001).ConclusionsCabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01378-y) contains supplementary material, which is available to authorized users.

Percutaneous US-guided MWA of small liver HCC: predictors of outcome and risk factors for complications from a single center experience.

The aim of the present study was to identify predictors of outcome and complications in patients with small hepatocellular carcinoma (HCC) treated by percutaneous microwave ablation (MWA). Patients with non-previously treated small (≤ 3cm) HCCs who underwent ultrasound (US)-guided percutaneous MWA between July 2016 and January 2019 were included. For each patient, the following variables were registered: age, sex, albumin, platelet count, INR/PT, PTT ratio, total bilirubin, liver status, etiology of liver disease, Child-Pugh classification, tumor dimension, margin, and hepatic segment, tumor subcapsular, perihilar or perivascular location, HCC focality, ascites. During follow-up, complications and outcomes were registered. Variables were then analyzed in relation to both outcomes and complications. 74 patients were included. Mean CT follow-up was 6.2months (range 1-24months). At least one complication occurred in 48% of patients, the majority being asymptomatic imaging findings not requiring intervention. One major complication was registered (duodenal perforation: 1.3%). The occurrence of complications was associated with HCC multifocality and abnormal INR/PT, duodenal wall edema with tumor dimension, portal vein thrombosis with Child Pugh score, perihepatic free fluid with abnormal platelet count and comorbidities. Incomplete response rate at 1month was 18.9%. Local tumor progression and new HCC nodules rates were 13.5% and 27%, respectively. Incomplete response at 1month was associated with both alcoholic etiology of liver disease and II segment tumor location, new HCC nodules with PBC. Despite the small series analyzed, significant factors related with complications and outcomes may be kept in mind when planning the best treatment for each patient.

En Bloc lumpectomy of T12 vertebra for progressive hepatocellular carcinoma metastases following liver transplantation

Rationale:Liver transplantation (LT) is the preferred surgical option for the treatment of early hepatocellular carcinoma (HCC). In contrast, surgical treatment of progressive HCC metastasized to the spine following LT constitutes a considerable challenge. Here, we report the first case of progressive HCC metastasized to the T12 vertebra after local radiotherapy, treated successfully with en bloc lumpectomy following LT for HCC.Patient concerns:A 40-year-old man who had undergone LT for the treatment of HCC 2 months prior presented to our clinic with symptoms of progressive back pain. Magnetic resonance imagining (MRI) and positron emission tomography (PET) examinations showed a solitary metastasis at T12 without recurrence in the liver or metastasis to other organs.Diagnoses:The patient was diagnosed with HCC metastasized to the T12 vertebra after liver transplantation.Interventions:Local radiation therapy of the T12 vertebra was performed; however, the lesion continued to grow one month after irradiation. Accordingly, the patient was treated with en bloc lumpectomy of the T12 vertebra. After surgery, the patient reported significant pain relief. At 11 months post-surgery, a C4 metastasis with spinal cord compression was revealed by MRI. Multiple grafted liver metastases were also detected by ultrasound along with several lung metastases, which were discovered by X-ray. The patient was treated with a pedicle screw system and a mesh cage filled with frozen autografts for C4 metastasis.Outcomes:The patient died 15 months after liver transplantation due to recurrence in the liver and metastasis to the lung.Lessons:En bloc lumpectomy may be a viable therapeutic option for patients with progressive solitary spinal metastases after LT refractory to radiotherapy. Use of immunosuppressive therapy after LT may significantly inhibit immune function, making patients more susceptible to HCC recurrence and bone metastasis.