Novel preoperative strategies to improve hepatocellular carcinoma resectability.
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ABSTRACT:
SUBMITTER: Tustumi F
PROVIDER: S-EPMC9944542 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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Novel preoperative strategies to improve hepatocellular carcinoma resectability.
Tustumi Francisco F Coelho Fabrício Ferreira FF Herman Paulo P
Hepatobiliary surgery and nutrition 20230116 1
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Project description:Hepatocellular carcinoma (HCC), one of the most fatal malignancies in the world, is usually diagnosed in advanced stages due to late symptom manifestation with very limited therapeutic options, which leads to ineffective intervention and dismal prognosis. For a decade, tyrosine kinase inhibitors (TKIs) have offered an overall survival (OS) benefit when used in a first-line (sorafenib and lenvatinib) and second-line setting (regorafenib and cabozantinib) in advanced HCC, while long-term response remains unsatisfactory due to the onset of primary or acquired resistance. Recently, immunotherapy has emerged as a promising therapy in the treatment of several solid tumors, such as melanoma and non-small cell lung cancer. Moreover, as the occurrence of HCC is associated with immune tolerance and immunosurveillance escape, there is a potent rationale for employing immunotherapy in HCC. However, immunotherapy monotherapy, mainly including immune checkpoint inhibitors (ICIs) that target checkpoints programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and the cytotoxic T lymphocyte antigen-4 (CTLA-4), has a relatively low response rate. Thus, the multi-ICIs or the combination of immunotherapy with other therapies, like antiangiogenic drugs and locoregional therapies, has become a novel strategy to treat HCC. Combining different ICIs may have a synergistical effect attributed to the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of antiangiogenic drugs in ICIs can enhance antitumor immune responses via synergistically regulating the vasculature and the immune microenvironment of tumor. In addition, locoregional treatments can improve antitumor immunity by releasing the neoplasm antigens from killed tumor cells; in turn, this antitumor immune response can be intensified by immunotherapy. Therefore, the combination of locoregional treatments and immunotherapy may achieve greater efficacy through further synergistic effects for advanced HCC. This review aims to summarize the currently reported results and ongoing trials of the ICIs-based combination therapies for HCC to explore the rational combination strategies and further improve the survival of patients with HCC.
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Project description:Hepatocellular carcinoma (HCC) is the third most frequent source of deaths associated with cancer after lung cancer in the world despite recent innovative treatment techniques. Liver transplantation, hepatic resection, and percutaneous ablation techniques hold great promise as potentially curative treatments for patients at early stages. Nevertheless, most of the patients are not suitable for these curative treatments due to their advanced disease stages at the time of diagnosis. Food and Drug Administration (FDA) approved tyrosine kinase inhibitor, sorafenib is a standard therapy for advanced-stage HCC patients which extends overall survival for several months. However, its therapeutic efficacy is restricted by adverse events and drug resistance which limits the number of patients benefiting from this systemic chemotherapeutic drug. During the last decade, novel approaches including but not limited to immunotherapies, ablation methods, and chemotherapeutic drugs were proposed to enhance sensitivity to sorafenib, improve therapeutic efficacy, and prohibit adverse events through novel delivery routes, utilization of nanoparticle carriers, and combination with other therapeutic agents. However, studies are still being conducted to optimize the efficiency of sorafenib and reduce its adverse events. In this review paper, we examine research studies evaluating novel delivery methods to reduce drug-related cytotoxicity to improve patient tolerance to sorafenib and its therapeutic efficacy in patients with HCC. Moreover, therapeutic approaches with the synergistic potential to combine with sorafenib are briefly summarized.
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Project description:Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.
| S-EPMC4334449 | biostudies-literature
Project description:BackgroundEmerging evidence suggests that long non-coding RNA (lncRNA) plays a crucial part in the development and progress of hepatocellular carcinoma (HCC). The objective was to develop novel molecular-clinicopathological prediction methods for overall survival (OS) and recurrence of HCC.ResultsAn 8-lncRNA-based classifier for OS and a 14-lncRNA-based classifier for recurrence were developed by LASSO COX regression analysis, both of which had high accuracy. The tdROC of OS-nomogram and recurrence-nomogram indicates the satisfactory accuracy and predictive power. The classifiers and nomograms for predicting OS and recurrence of HCC were validated in the Test and GEO cohorts.ConclusionsThese two lncRNA-based classifiers could be independent prognostic factors for OS and recurrence. The molecule-clinicopathological nomograms based on the classifiers could increase the prognostic value.MethodsHCC lncRNA expression profiles from the cancer genome atlas (TCGA) were randomly divided into 1:1 training and test cohorts. Based on least absolute shrinkage and selection operator method (LASSO) COX regression model, lncRNA-based classifiers were established to predict OS and recurrence, respectively. OS-nomogram and recurrence-nomogram were developed by combining lncRNA-based classifiers and clinicopathological characterization to predict OS and recurrence, respectively. The prognostic value was accessed by the time-dependent receiver operating characteristic (tdROC) and the concordance index (C-index).
| S-EPMC7377850 | biostudies-literature
Project description:The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, largely due to hepatitis B virus (HBV), hepatitis C virus and liver cirrhosis. Chronic HBV infection is estimated to cause 55%-60% of the cases of HCC worldwide and over 70% in Asian countries. Liver resection is currently the mainstay of treatment due to the low surgical mortality, a wider treatment indication, and simplicity of post-treatment follow-up. There is an ever-increasing demand on surgeons to perform curative liver resection in HCC, with the hope of avoiding tumor recurrences. Hepatitis B-related-HCC has distinct clinicopathological features, which should be considered when treating the disease. The author presents a review of the recently evolving strategies and emerging therapies to improve HCC postresectional outcomes and focus on perioperative measures to improve patient outcome, with particular reference to the current status of adjuvant therapies in HCC patients after liver resection.
| S-EPMC4168080 | biostudies-literature
Project description:IntroductionNecroptosis is a novel pattern of immunogenic cell death and has triggered an emerging wave in antitumor therapy. More evidence has suggested the potential associations between necroptosis and intra-tumoral heterogeneity. Currently, the underlying role of necroptosis remains elusive in hepatocellular carcinoma (HCC) at antitumor immunity and inter-tumoral heterogeneity.MethodsThis study enrolled a total of 728 HCC patients and 139 immunotherapy patients from eight public datasets. The consensus clustering approach was employed to depict tumor heterogeneity of cancer necroptosis. Subsequently, our study further decoded the heterogeneous clinical outcomes, genomic landscape, biological behaviors, and immune characteristics in necroptosis subtypes. For each patient, providing curative clinical recommendations and developing potential therapeutic drugs were used to promote precise medicine.ResultsWith the use of the weighted gene coexpression network analysis (WGCNA) algorithm, necroptosis-associated long non-coding RNAs (lncRNAs) (NALRs) were identified in HCC. Based on the NALR expression, two heterogeneous subtypes were decoded with distinct clinical outcomes. Compared to patients in C1, patients in C2 harbored superior pathological stage and presented more unfavorable overall survival and recurrence-free survival. Then, the robustness and reproducibility of necroptosis subtypes were further validated via the nearest template prediction (NTP) approach and classical immune phenotypes. Through comprehensive explorations, C1 was characterized by enriched immune-inflammatory and abundant immune infiltration, while C2 possessed elevated proliferative and metabolic activities and highly genomic instability. Moreover, our results indicated that C1 was more prone to obtain desirable benefits from immunotherapy. For patients in C2, numerous underlying therapeutic agents were developed, which might produce significant efficacy.ConclusionThis study identified two necroptosis subtypes with distinct characteristics, decoding the tumor heterogeneity. For an individualized patient, our work tailored corresponding treatment strategies to improve clinical management.
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Project description:Hepatocellular carcinoma (HCC) represents a significant contributor to cancer-related morbidity and mortality with increasing incidence in both developing and developed countries. Embolotherapy as a locoregional therapeutic strategy consists of trans-arterial or "bland" embolization (TAE), trans-arterial chemoembolization (TACE), and selective internal radiotherapy (SIRT). Trans-catheter arterial therapies can be applied along all stages of HCC, either as an alternative or neoadjuvant to surgical resection/transplantation in very early and early stage HCC or as a palliative option for local disease control in unresectable and advanced stage HCC. In advanced stage HCC, SIRT did not demonstrate superiority in comparison to systemic treatment options in several recent large prospective trials, though for carefully selected patients, may confer improved tolerability with similar disease control rates. The latest embolotherapeutic techniques and literature as they pertain to the management of HCC, as well as future directions, are reviewed in this article.
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Project description:ObjectivesThis study aims to better characterize potential responders of Y-90-radioembolization at baseline through analysis of clinical variables and contrast enhanced (CE) MRI tumor volumetry in order to adjust therapeutic regimens early on and to improve treatment outcomes.MethodsFifty-eight HCC patients who underwent Y-90-radioembolization at our center between 10/2008 and 02/2017 were retrospectively included. Pre- and post-treatment target lesion volumes were measured as total tumor volume (TTV) and enhancing tumor volume (ETV). Survival analysis was performed with Cox regression models to evaluate 65% ETV reduction as surrogate endpoint for treatment efficacy. Univariable and multivariable logistic regression analyses were used to evaluate the combination of baseline clinical variables and tumor volumetry as predictors of ≥ 65% ETV reduction.ResultsMean patients' age was 66 (SD 8.7) years, and 12 were female (21%). Sixty-seven percent of patients suffered from liver cirrhosis. Median survival was 11 months. A threshold of ≥ 65% in ETV reduction allowed for a significant (p = 0.04) separation of the survival curves with a median survival of 11 months in non-responders and 17 months in responders. Administered activity per tumor volume did predict neither survival nor ETV reduction. A baseline ETV/TTV ratio greater than 50% was the most important predictor of arterial devascularization (odds ratio 6.3) in a statistically significant (p = 0.001) multivariable logistic regression model. The effect size was strong with a Cohen's f of 0.89.ConclusionWe present a novel approach to identify promising candidates for Y-90 radioembolization at pre-treatment baseline MRI using tumor volumetry and clinical baseline variables.Key points• A decrease of 65% enhancing tumor volume (ETV) on follow-up imaging 2-3 months after Y-90 radioembolization of HCC enables the early prediction of significantly improved median overall survival (11 months vs. 17 months, p = 0.04). • Said decrease in vascularization is predictable at baseline: an ETV greater than 50% is the most important variable in a multivariable logistic regression model that predicts responders at a high level of significance (p = 0.001) with an area under the curve of 87%.
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Project description: Not available
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Project description:Hepatocellular carcinoma (HCC) is a malignancy that requires multidisciplinary evaluation to develop individualized and tailored treatment concepts. While liver resection and transplantation represent the mainstay of curative treatment in patients with early-stage HCC, disease recurrence remains an important burden. Immune checkpoint inhibitors (ICI) have become standard of care in the palliative setting, achieving promising response rates with overall good tolerability. Accordingly, ICIs are being evaluated in (neo)adjuvant concepts in order to improve survival. Nevertheless, neoadjuvant therapies are not recommended by current guidelines as they have not been proven to improve the outcome in large Phase III trials yet. Especially in the context of liver transplantation (LT), perioperative ICI usage is in need of a particularly critical risk-benefit assessment, as the immunotherapy may significantly increase the risk of rejection. In this review, we summarize available data on ICI-based perioperative treatment strategies in HCC. We discuss current drawbacks and challenges of this treatment concept and specifically highlight the risk of allograft rejection when ICI are given in patients (subsequently) considered for liver transplantation.
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