Localized Hepatocellular Carcinoma Research Articles

Identification and Validation of Ubiquitin-Specific Proteases as a Novel Prognostic Signature for Hepatocellular Carcinoma.

PurposeUbiquitin-specific proteases (USPs), as a sub-family of deubiquitinating enzymes (DUBs), are responsible for the elimination of ubiquitin-triggered modification. USPs are recently correlated with various malignancies. However, the expression features and clinical significance of USPs have not been systematically investigated in hepatocellular carcinoma (HCC).MethodsGenomic alterations and expression profiles of USPs were investigated in CbioPortal and The Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) dataset. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to establish a risk signature for HCC prognosis in TCGA LIHC cohort. Subsequently, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves and univariate/multivariate analyses were performed to evaluate the prognostic significance of the risk signature in TCGA LIHC and international cancer genome consortium (ICGC) cohorts. Furthermore, we explored the alterations of the signature genes during hepatocarcinogenesis and HCC progression in GSE89377. In addition, the expression feature of USP39 was further explored in HCC tissues by performing western blotting and immunohistochemistry.ResultsGenomic alterations and overexpression of USPs were observed in HCC tissues. The consensus analysis indicated that the USPs-overexpressed sub-Cluster was correlated with aggressive characteristics and poor prognosis. Cox regression with LASSO algorithm identified a risk signature formed by eight USPs for HCC prognosis. High-risk group stratified by the signature score was correlated with advanced tumor stage and poor survival HCC patients in TCGA LIHC cohort. In addition, the 8-USPs based signature could also robustly predict overall survival of HCC patients in ICGC(LIRI-JP) cohort. Furthermore, gene sets enrichment analysis (GSEA) showed that the high-risk score was associated with tumor-related pathways. According to the observation in GSE89377, USP39 expression was dynamically increased with hepatocarcinogenesis and HCC progression. The overexpression of USP39 was further determined in a local HCC cohort and correlated with poor prognosis. The co-concurrence analysis suggested that USP39 might promote HCC by regulating cell-cycle- and proliferation- related genes.ConclusionThe current study provided a USPs-based signature, highlighting its robust prognostic significance and targeted value for HCC treatment.

Immune Checkpoint Inhibitors in the Treatment of HCC.

Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.

Effectiveness of individual audio-visual coaching, respiratory modulated stereotactic body radiotherapy for localized hepatocellular carcinoma: Analysis of 29 cases from a single academic radiotherapy center.

Objectives:Recently, Stereotactic Body Radiotherapy (SBRT) has been suggested for managing hepatocellular carcinoma (HCC) curatively. Thus, we conducted this clinical study to evaluate retrospectively the effect of individualized audio-visual (AV) coaching, respiratory modulated SBRT.Materials and Methods:Between 2014 and 2018, 29 patients with inoperable Barcelona Clinic Liver Cancer (BCLC) stage 0-B HCC received AV coaching, respiratory-modulated SBRT. We constructed a task-oriented multidisciplinary team to establish a standard operation process of respiratory modulation procedures and developed our AV coaching devices. In the training period, a goodness-of-fit test was applied individually. SBRT was delivered with a total dose of 40–54 Gy in 5–6 fractions individually. Freedom from local progression (FFLP) and overall survival (OS) were estimated using SPSS (version 17, SPSS Inc., Chicago, IL, USA) life tables.Results:The patient characteristics were as follows: 32.7 ± 16 mm in maximum tumor diameter (range 11–94); BCLC stage 0: 3.4%, BCLC A: 48.3%, BCLC B: 48.3%; Child-Pugh classification A: 86.2%, Child-Pugh classification B: 13.8%, and a median of 2 prior liver-directed treatments (range 0–7). One-, 2-, and 3-year rates of FFLP of SBRT were 96.6%, 96.6%, and 96.6%, respectively. One-, 2-, and 3-year rates of OS were 81.5%, 72.4%, and 67.2%, respectively. No adverse event (AE) occurred in 41.4% of patients, 48.3% developed grade (G) 1–2 AE, 10.3% had G3 AE and none had G4-5 AE.Conclusion:Respiration-modulated SBRT is a promising noninvasive treatment option for patients with inoperable and localized HCC. Our data show that SBRT provides comparable tumor control to historical curative options like surgery and radiofrequency ablation of localized tumors. Thus, we are conducting a further prospective clinical trial with the intent to demarcate the clinical effectiveness of SBRT in a larger population of patients with HCC.

Microwave ablation for peribiliary hepatocellular carcinoma: propensity score analyses of long-term outcomes

Objective To compare the long-term outcomes of MWA as the first-line treatment for HCC in peribiliary versus non-peribiliary locations using propensity score matching analysis. Methods The study participants were recruited between April 2012 and October 2016. In total, 236 patients with HCC <5 cm who underwent ultrasonography-guided percutaneous MWA as the first-line treatment were enrolled. The patients were grouped into two according to tumor location: peribiliary (n = 74) and non-peribiliary (n = 162). The progression-free survival (PFS) and overall survival (OS) rates were compared before and after propensity score matching. Subgroup analyses were conducted for the peribiliary group according to the biliary grading. Results Propensity score matching yielded 63 matched pairs of patients. In the two matched groups, cumulative PFS rates were 29.0% and 14.0% in the peribiliary group, and 51.0% and 31.0% in the non-peribiliary group at 3 and 5 years, respectively. Corresponding OS rates were 51.0% and 49.0% in the peribiliary group, and 77.0% and 70.0% in the non-peribiliary group at 3 and 5 years, respectively. In addition, there were significant differences in major complication rates between the two groups (25.7% vs 8.0%; p < .001). In contrast to peribiliary HCCs adjacent to the second-degree branches of intrahepatic bile duct (67.1 ± 5.2 months), subgroup analysis indicated that the mean OS was significantly lower in peribiliary HCCs adjacent to the first-degree branches (51.2 ± 7.5 months) (p = .015). Conclusion The application of MWA for peribiliary HCC leads to a higher rate of complications and worse long-term tumor control than for non-peribiliary HCC. KEY POINTS The application of MWA for peribiliary HCC leads to a higher rate of complications than for non-peribiliary HCC. The application of MWA for peribiliary HCC leads to worse long-term tumor control than for non-peribiliary HCC. Abbreviations: Hepatocellular carcinoma (HCC); microwave ablation (MWA); α-fetoprotein (α-FP); local tumor progression (LTP); intrahepatic distal recurrence (IDR); progression-free survival (PFS); overall survival (OS).

Black race is associated with underutiliztion of transplantation for T1 hepatocellular carcinoma regardless of age or insurance status

Presenter: Kavin Sugumar MD | Case Western Reserve University School of Medicine Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Operative management of early, locoregional disease includes ablative techniques, liver resection, and liver transplantation. We compared the utilization of operative management of early clinical stage HCC in healthy patients by race. Methods: The National Cancer Database (2004-2016) was queried for non-Hispanic White (White) and non-Hispanic Black (Black) patients with localized clinical T1 HCC and Charlson-Deyo scores of 0-1. Patients who died before surgery, refused surgery, in whom surgery was contraindicated, or who had unclear management decisions were excluded. We compared rates of non-operative management and operative management (ablation, resection, or transplantation) by race, adjusting for demographic and clinical variables by multivariable logistic regression, and overall survival using Cox proportional hazards regression models. We performed marginal standardization with logistic regression to ascertain adjusted probabilities of resection or transplantation in the subset of patients under 70 years of age and with insurance (private, Medicare, or Medicaid). Results: A total of 25029 patients were included in the analysis (White = 20410; Black = 4619). Black patients were more likely to be younger (61vs 64 years), treated at academic facilities (68.4% vs 60.7%) and live closer to the treating facility (7.1 vs 19.9 miles). Black patients were less likely to have private health insurance or Medicare (69.1 vs 84.4%) and more likely to have Medicaid (20.2% vs 9.2%). Median tumor size was similar between groups (3.3 vs 3.3cm). Black patients were more likely to receive non-operative management than White patients (58.1% vs 55.0%). After adjusting for demographic and clinical variables, Black race was independently associated with a lower likelihood of undergoing any operative intervention (OR 0.89, 95% CI 0.82-0.97). When stratified by type of operative intervention, there was no association between Black race and ablation (OR 0.93, 95% CI 0.83-1.04). Black patients were more likely to undergo resection of clinical T1 HCC (OR 1.23, 95% CI 1.09-1.38) and less likely to undergo transplantation (OR 0.60, 95% CI 0.49-0.72). Transplantation was associated with the longest median overall survival (127.7 months), compared to resection (58.2 months), ablation (38.0 months), and non-operative management (18.2 months; p50 years, with private insurance, or Medicare (Figure A and B). Conversely, Black race was associated with a lower probability of transplantation in all age groups or insurance payor groups (Figure C and D). Conclusion: In a national cohort of patients with clinical T1 HCC, Black race is associated with lower rates of hepatic transplantation and higher rates of hepatic resection regardless of age or insurance payor status. The etiology of these disparities is likely multifactorial, and correcting the root causes represents a critical area for improvement in care.

Over-expression of long non-coding RNA insulin-like growth factor 2-antisense suppressed hepatocellular carcinoma cell proliferation and metastasis by regulating the microRNA-520h/cyclin-dependent kinase inhibitor 1A signaling pathway

ABSTRACT Primary liver cancer is the sixth most common cancer and the third leading cause of malignancy-related death worldwide in 2020, with 75–85% of hepatocellular carcinoma (HCC). Evidences have verified that long noncoding RNAs (lncRNAs) play key roles in HCC onset and development. However, the function and mechanism of lncRNA insulin-like growth factor 2-antisense (IGF2-AS) in HCC remain unclear. Herein, IGF2-AS expression profile in HCC patients was first investigated based on The Cancer Genome Atlas (TCGA) database and local HCC patients, followed by prognostic value evaluation using Kaplan–Meier method; then, the bioinformatics analysis, dual-luciferase reporter assay, Spearman correlation assay, function gain, and loss with rescue experiments were applied to investigate the biological function and the involved molecular mechanisms of IGF2-AS in HCC oncogenesis and development. Our results showed that IGF2-AS expression was significantly down-regulated in HCC cells and tissues; lower IGF2-AS expression was significantly associated with poor prognosis of HCC patients; IGF2-AS over-expression inhibited the viability, colony formation, invasion, and migration, while promoted apoptosis in vitro, and inhibited HCC xenograft growth in vivo; IGF2-AS sponged microRNA-520h (miR-520h) to up-regulate IGF2-AS expression, and miR-520h over-expression or cyclin-dependent kinase inhibitor 1A (CDKN1A) silencing reversed IGF2-AS reduced aggressive behaviors of HCC cells. In conclusion, IGF2-AS is a tumor-suppressor in HCC, and lower IGF2-AS expression is associated with poor prognosis of HCC patients; IGF2-AS inhibits HCC oncogenesis and development by IGF2-AS/miR-520h/CDKN1A pathway. Therefore, IGF2-AS may serve as a new biomarker for HCC management.

Surgical management of hepatocellular carcinoma patients with portal vein thrombosis: The United States Safety Net and Academic Center Collaborative Analysis.

Although consensus guidelines generally discourage any surgical management (ASM; i.e., resection and/or transplantation) in patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT), recent series from Asia have challenged this paradigm. Patients from the US Safety Net Collaborative database (2012-2014) with localized HCC and radiographically confirmed PVT were propensity-score matched based on demographic and clinicopathologic factors associated with receipt of ASM and overall survival (OS). OS was compared between patients undergoing ASM and those not selected for surgery. Of 1910 HCC patients, 207 (14.5%) had localized disease and PVT. The majority received either liver-directed therapies (LDTs; 34%) and/or targeted systemic therapies (36%). Twenty-one patients (10.1%) underwent ASM (resection [n = 11], transplantation [n = 10]); a third experienced any complication with no 30-day mortalities. Independent predictors of undergoing ASM were younger age, recent hepatology consultation, and lower model of end-stage liver disease (MELD) score. After matching for age, comorbidities, MELD, tumor size, receipt of LDT, or systemic therapy, OS was significantly longer for patients selected for ASM versus non-ASM patients (median not reached vs. 5.8 months, p < .001). In a large North American multi-institutional cohort, a minority of HCC patients with PVT were selected for ASM. Resection or transplantation was associated with improved survival and may have a role in the multimodality management in selected patients.

Multi-Institutional Prospective Registry of Hypofractionated Proton Beam Radiotherapy in Patients with Unresectable Liver Tumors

Recent advances in radiotherapy techniques have allowed ablative doses to be safely delivered to inoperable liver tumors. In this setting, proton therapy has the potential to further spare the uninvolved liver. This study evaluated the safety and efficacy of hypofractionated proton beam therapy for liver tumors, predominantly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We queried the prospective registry of the Proton Collaborative Group for patients undergoing definitive proton radiotherapy for liver tumors. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. To date, 63 patients have been treated at 9 institutions between 2013 and 2019. Thirty (47.6%) had HCC and 25 (39.7%) had ICC. Prior treatment had been given to 38 (60.3%) patients. Thirteen patients (20.6%) were treated with 5-fraction regimens, 46 (73.0%) were treated with 15-fraction regimens, and 4 (6.3%) were treated with 25-fraction regimens. The median dose and biological equivalent dose (BED) delivered was 58.1 GyE (range, 32.5 to 75) and 80.5 GyE (range, 53.6 to 100), respectively. The median mean liver BED was 13.9 GyE. Three (4.8%) patients experienced at least one grade ≥3 toxicity. There was no grade 5 toxicity. With median follow-up of 5.1 months (range, 0.1 to 40.8), the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC (Table 1, with previous comparable phase I/II studies). The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or less (84.6%, p = 0.031). There was no difference in LC between patients undergoing 5- versus 15-fraction regimens (p = 0.35). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. Hypofractionated, ablative proton beam therapy results in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose escalation. Higher dose correlates with improved LC, highlighting the importance of proton therapy in this patient population.Abstract 3391; TableMGH/MDACC (n = 92)PMH (n = 102)Current study (n = 63)ModalityProtonPhotonProtonNumber of fractions1565, 15, and 25Median BED (GyE)80.457.680.5Median longest dimension (cm)5.77.24.4Grade ≥3 toxicity (%)4.8304.8Local control2-year HCC: 94.8% 2-year ICC: 94.1%1-year HCC: 87%1-year HCC: 91.2% 1-year ICC: 90.9%Table abbreviations: BED, biological equivalent dose; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; MGH, Massachusetts General Hospital; MDACC, MD Anderson Cancer Center; PMH, Princess Margaret Hospital. Open table in a new tab

Treatment Strategy of Transarterial Chemoembolization for Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) is a first-line treatment for patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer stage B (BCLC-B). There are two major techniques of TACE: conventional TACE (cTACE) using iodized oil and gelatin sponge particles, and TACE using drug-eluting beads (DEB-TACE). The latest randomized controlled trial proved the superiority of cTACE regarding local effects over DEB-TACE; however, cTACE also damages the liver more severely. Therefore, cTACE should be performed for localized HCCs as selectively as possible. On the other hand, DEB-TACE has less liver toxicity and is favorable for patients with an advanced age, large and/or bilobar tumors, or a poor liver function. However, some BCLC-B HCCs are TACE-resistant and the concept of TACE unsuitability (mainly up-to-7 criteria out) has been proposed by Asia-Pacific Primary Liver Cancer Expert Meeting. Systemic therapy is recommended for patients with TACE-unsuitable HCC; however, the condition of TACE-unsuitable HCC does not always rule out TACE monotherapy and some up-to-7 criteria out tumors may also be good candidates for superselective cTACE when localized in limited liver segments. The sequential therapy of an antiangiogenic and TACE is also a novel option for patients with TACE-unsuitable HCC, antiangiogenic-refractory HCC, or even down-staged HCC.

Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.

Surgical Management of Localized Hepatocellular Carcinoma in Times of Crisis: A Strategic Approach to Resource Utilization.

The management of localized hepatocellular carcinoma (HCC) is complex and requires multidisciplinary consideration. In times of crisis when resources are limited and the health of patients might be compromised, as is the case with COVID-19, a strategic approach that takes into account tumor characteristics, patient factors, and available treatment options can optimize patient outcomes while balancing resource utilization. Herein, we detail our group’s management strategy for patients with localized HCC during the global pandemic that carefully considers individual patient needs and those of the institutional workforce, the local healthcare system, and the greater patient community we serve.

Abstract 3750: STEAP2 is upregulated and necessary for hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity

Abstract To understand potential molecular mechanisms that drive hepatocellular carcinoma (HCC) progression, we performed RNA sequencing from paired adjacent non-tumor liver and HCC tumor tissues of nine local HCC patients which revealed significant involvement of a gene coding for Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) protein. STEAP2 is a metalloreductase involved in the reduction and indirectly, uptake, of iron and copper ions. We found significantly higher levels of total copper in HCC tissues than those in paired adjacent non-tumor tissues. The upregulation of STEAP2 expression in HCC was confirmed at its protein level and in TCGA and other published HCC gene expression datasets. Hepatic copper overload is associated with Wilson's disease and a known risk factor for HCC, therefore, we hypothesize that STEAP2 upregulation and copper accumulation contribute to HCC progression. Paired HCC and adjacent non-tumor tissues were collected for RNA sequencing, metal ion measurement, and measurements of STEAP2 levels with RT-qPCR and Western blot. Public HCC datasets were queried for STEAP2 expression in HCC and non-tumor tissues. HCC cell lines with knockdown (KD) and overexpression (OE) of STEAP2 were created to perform mechanistic studies including measurements of copper levels and MAP kinase activities, cell proliferation, migration, and anchorage independent growth in vitro and tumor growth in vivo. STEAP2 is significantly upregulated in various HCC gene expression datasets; its expression is positively associated with tumor grade. STEAP2 KD in HCC cell lines decreased cell growth, migration, invasion, and xenograft tumor growth, while STEAP2 OE showed opposite effects. STEAP2 KD in HCC cells also reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEATP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited cell migration. Thus, STEAP2 appears to play a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment. Citation Format: Carla R. Zeballos, Acarizia Easley, Hakim Bouamar, Guixi Zheng, Xiang Gu, Yang Junhua, Yidong Chen, Francisco Cigarroa, LuZhe Sun. STEAP2 is upregulated and necessary for hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3750.

Long-Term Survival Analysis of Transarterial Chemoembolization Plus Radiotherapy vs. Radiotherapy for Hepatocellular Carcinoma With Macroscopic Vascular Invasion.

Background: Macroscopic vascular invasion (MVI) is a terminal manifestation of hepatocellular carcinoma (HCC) and carries an extremely poor prognosis. In Chinese and Korean HCC guidelines, transarterial chemoembolization (TACE), or/and radiotherapy (RT) is adopted for treatment of MVI. In the current study, we aimed to compare the long-term outcome of TACE + RT to that of RT alone in patients with local advanced HCC with MVI.Methods: In this retrospective study, 148 treatment-naive patients of HCC with MVI were enrolled. Of the patients enrolled, 49 received TACE + RT treatment, whereas 99 patients received RT alone as a monotherapy. Overall survival (OS), progression-free survival (PFS), and intrahepatic control were evaluated using univariable and propensity score–matched analyses.Results: During follow-up, 126 patients (85.1%) died. The median follow-up time was 55.0 months in the RT group and 57.0 months in the TACE + RT group. The TACE + RT group showed better OS and PFS than the RT group, but intrahepatic control was comparable in these two groups. Of 41 cases well-pairs after propensity score matching, the associations between TACE + RT and better OS and PFS remained (15.0 vs. 8.0 months, and 8.0 vs. 4.0 months, all P < 0.05). The 1-, 2-, 3-, and 5-years OS rates in the TACE + RT group were 56.1, 28.6, 20.8, and 15.7 vs. 31.5%, 13.1%, 9.8%, and 6.7% in the RT group, respectively (P = 0.017). The 6-, 12-, and 24-months rates in the TACE + RT group were 51.2, 39.0, and 23.1% vs. 36.6%, 13.9%, and 11.1% in the RT group, respectively (P = 0.04). Two patients (4.1%) experienced radiation-induced liver disease (RILD), and one (2.0%) experienced RT-related gastrointestinal (GI) bleed in the TACE + RT groups. Nine patients (9.1%) experienced RILD, and two (2.0%) experienced RT-related GI bleed in the RT groups.Conclusion: Transarterial chemoembolization + RT had well-complementarity with no more complications than RT alone, providing a better PFS and OS compared with RT-alone treatment for HCC with MVI.

Whole exome sequencing identifies clinically relevant mutational signatures in resected hepatocellular carcinoma

AbstractBackground &amp; AimsMost patients develop recurrent disease despite curative surgery for hepatocellular carcinoma (HCC). No standard adjuvant therapy is available and molecular predictors of outcome are poorly understood.MethodsWe conducted a multicentre pilot study on patients with localized HCC following surgical resection. Patients received up to 6 months of oral gefitinib as adjuvant therapy. Clinical end points included recurrence‐free survival (RFS) and overall survival (OS), and exploratory analyses were conducted from whole exome sequencing data.ResultsA total of 65 patients were screened for the study, of which 40 were eligible. The median age was 63 years (range, 44‐80). Most patients (80%) were positive for hepatitis B or C. With a median follow‐up of 4.5 years, the median RFS was 24 months. Median OS was not reached. High Child‐Pugh score and advanced T‐stage (3‐4) were independent predictors for both OS and RFS. Mutational signatures for exposure to aristolochic acid (AA), as characterized by a majority of T:A &gt; A:T mutations, were observed in 18 cases (55%). HCC without AA mutagenesis was associated with early recurrences or death within 2 years of surgery (P = .037). HCC with high T &gt; A mutations was associated with better OS (HR 0.29, 95% CI 0.09‐0.90, P = .033). Conversely, HCC with high C &gt; T mutations was associated with worse OS (HR 4.55, 95% CI 1.20‐17.31, P = .026).ConclusionsMutational signatures may carry prognostic significance in HCC following curative resection. Patient outcomes with gefitinib as adjuvant therapy after resection for HCC were modest, highlighting the need for urgent research in this area of unmet clinical need. ClinicalTrials.gov number, NCT00282100.

PD-1 targeted immunotherapy for advanced hepatocellular cancer: Current utilization and outcomes in the United States.

e16647 Background: Novel oncological treatment strategies for hepatocellular carcinoma (HCC) include immunotherapies targeting programmed death protein 1 (PD-1). To date there is scarce data on the current real-world clinical utilization of immunotherapy for HCC in the US. Methods: The Flatiron Health EHR-derived de-identified database was queried in October 2019 for adult patients with advanced HCC. PD-1 targeted immunotherapy (PD-1 IMT) included Nivolumab and Pembrolizumab. Overall survival (OS) was evaluated using Cox proportional hazards models. Multivariable analyses adjusted for patient demographics (age, gender, race), documented liver disease risk factors (obesity, diabetes, alcohol abuse, hepatitis), documented liver disease complication (ascites, encephalopathy), local HCC treatment (resection, radiofrequency ablation, transarterial chemoembolization [TACE], transarterial radioembolization [TARE]) and systemic Sorafenib. Subgroup analyses were performed in patients with documented clinical performance status (Eastern Cooperative Oncology Group; ECOG) and albumin/bilirubin results (all measured nearest to HCC diagnosis). Results: A total of 2,912 patients with advanced HCC were included, of which n = 345 (11.8%) received PD-1 IMT. Utilization of PD-1 IMT continuously increased from 2004, accounting for 20.9% of all cases in 2018/19. Patients treated with and without PD-1 IMT were comparable regarding demographics, comorbidities and liver disease. PD-1 IMT was more commonly administered at academic centers (20.3% vs. 13% in non-academic centers, p &lt; 0.001), and in patients receiving Sorafenib, TACE, TARE or HCC resection (vs. none of these treatments, each p &lt; 0.05). Median follow-up time was 36.1 months. In univariate analyses, administration of PD-1 IMT was associated with longer OS (vs. no PD-1 IMT; HR = 0.67, 95% CI: 0.58-0.78, p &lt; 0.001; OS rates in the table). In multivariable analyses, PD-1 IMT receipt was an independent prognosticator (vs. no PD-1 IMT; HR = 0.54, 95% CI: 0.46-0.63, p &lt; 0.001). In a subset of n = 1560 patients, this effect persisted after adjustment for ECOG, albumin and bilirubin results (HR = 0.58; 95% CI: 0.48-0.69, p &lt; 0.001). Conclusions: PD-1 targeted immunotherapy is increasingly used for advanced HCC, accounting for up to 20.9% of cases in 2018/19. After adjustment for potential confounders, immunotherapy was associated with an overall survival benefit. [Table: see text]

Feasibility of Solo Single-Incision Laparoscopic Surgery in Non-anatomical Minor Liver Resection: a Propensity Score-Matched Analysis

BackgroundWe introduced solo surgery using a laparoscopic scope holder to wide an operator’s activity range and reduce instrument crowding and clashing in single incisional surgery. This study aimed to compare the surgical outcomes of solo single-incision laparoscopic surgery (SILS) and conventional multiport laparoscopic surgery (MULS) for hepatocellular carcinoma (HCC). MethodsAmong 477 consecutive patients between January 2004 and December 2017, 214 patients were included. To overcome selection bias, we performed 1:1 match using propensity score matching between SILS and MULS. Baseline characteristics, operative outcomes, and postoperative complications were compared. ResultsNo significant differences in baseline characteristics and pathologic features were found between the two groups. Operation time, estimated blood loss, and postoperative major complication were not significantly different (119.0 min vs 141.6 min, p = 0.275; 200.0 mL min vs 373.3 min, p = 0.222; 0 vs 0, p = 1.000). However, postoperative hospital stay was significantly shorter in SILS (2.73 days vs 7.67 days, p = 0.005). ConclusionsSolo SILS had comparable postoperative complications and feasibility in the aspect of operation time and hospital stay compared with conventional MULS for a favorable located single HCC.

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. For patients who are resistant to monotherapy, multimodal therapy is a basic oncologic principle that incorporates surgery, radiotherapy (RT), and chemotherapy providing survival benefits for patients with most types of cancer. Although liver has low tolerance for radiation, high-precision RT for local HCC minimizes the likelihood of radiation-induced liver disease (RILD) in noncancerous liver tissue. RT have several therapeutic benefits, including the down-staging of tumors to make them resectable and repression of metastasis. The DNA damage response (DDR) is a cellular response to irradiation (IR), including DNA repair of injured cells and induction of programmed cell death, thereby resulting in maintenance of cell homeostasis. Molecules that block the activity of proteins in DDR pathways have been found to enhance radiotherapeutic effects. These molecules include antibodies, kinase inhibitors, siRNAs and miRNAs. MicroRNAs (miRNAs) are short non-coding regulatory RNAs binding to the 3′-untranslated regions (3′-UTR) of the messenger RNAs (mRNAs) of target genes, regulating their translation and expression of proteins. Thus, miRNAs and their target genes constitute complicated interactive networks, which interact with other molecules during carcinogenesis. Due to their promising roles in carcinogenesis, miRNAs were shown to be the potential factors that mediated radiosensitivity and optimized outcomes of the combination of systemic therapy and radiotherapy.

Genistein Enhances Radiosensitivity of Human Hepatocellular Carcinoma Cells by Inducing G2/M Arrest and Apoptosis.

New radiosensitizers are urgently needed for radiation therapy patients with localized hepatocellular carcinoma (HCC) that is refractory to radical surgery. We previously found that genistein, a major soy isoflavone, exerts radioprotective effects on L-02 normal liver cells at low concentrations. Here, we report that 5 µM genistein shows less harm to L-02 cells than HCC cells and that it significantly enhances the radiosensitivity of HCC cells by enhancing DNA damage, chromosomal aberrations and cell cycle arrest at G2/M phase and by exacerbating apoptosis. Mechanistically, genistein aggravates X-ray-induced decreases in the levels of phospho-Bad (Ser136) but enhances the levels of phospho-Chk2 (Thr68), phospho-ATM (Ser1981) and γ-H2AX. Micro-array analysis indicated that downregulation of POU6F and CCNE2 expression and upregulation of FBXO32 and cyclin B1 expression might play vital roles in genistein-induced radiosensitivity. These findings suggest genistein as an interesting candidate for adjuvant radiotherapy for HCC and indicate that genistein causes less harm to normal cells than HCC cells by inducing G2/M arrest and apoptosis.

Posttransplant Management of Recipients Undergoing Liver Transplantation for Hepatocellular Carcinoma. Working Group Report From the ILTS Transplant Oncology Consensus Conference.

Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.

Laparoscopic versus open mesohepatectomy for centrally located hepatocellular carcinoma

Centrally located liver tumors that involve Couinaud’s segment I, IV, V and VIII are surrounded by the inferior vena cava (IVC), the hepatic vein [the middle hepatic vein (MHV) or the right hepatic vein], and the first branch of the Glisson’s pedicle, which need difficult surgical techniques. Extended hemihepatectomy (EH) is a standard procedure to achieve curative resection for centrally located liver tumors when the preoperative hepatic reserve is sufficient.