Clinical Practice Guidelines

EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma☆

Activation of the Hedgehog signaling pathway is linked to the initiation and development of human hepatocellular carcinoma (HCC). However, its impact on clinical outcomes and the HCC microenvironment remains unclear.

We performed comprehensive analyses of Hedgehog pathway genes in a large cohort of HCC patients. Specifically, we utilized univariate Cox regression analysis to identify Hedgehog genes linked to overall survival, and the LASSO algorithm was used to construct a Hedgehog-related gene pattern. We subsequently examined the correlation between the Hedgehog pattern and the HCC microenvironment employing the CIBERSORT and ssGSEA algorithms. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the anti-PD-L1 treatment dataset (IMvigor210) are used to evaluate the clinical response of the Hedgehog pattern in predicting immune checkpoint inhibitors.

We found that the Hedgehog activation score (HHAS), a prognostic score based on 11 Hedgehog genes, was significantly associated with HCC patient survival. Patients exhibiting high HHAS experienced markedly reduced survival rates compared to those with low HHAS, and HHAS emerged as an independent prognostic factor for HCC. Functional enrichment analysis unveiled the association of the HHAS phenotype with functions related to the immune system, and further investigation demonstrated that HCC patients exhibiting low HHAS displayed elevated levels of anti-tumor immune activation in CD8⁺ T cells, while high HHAS were linked to immune escape phenotypes and increased infiltration of immune suppressive cells. In addition, in the Immune Checkpoint Inhibitor (ICI) cohort of IMvigor210, patients with higher HHAS had worse ICI treatment outcomes and shortened survival time, indicating that the HHAS is a useful indicator for predicting patient response to immunotherapy.

In summary, our study offers valuable insights for advancing research on Hedgehog and its impact on tumor immunity, which provides an opportunity to optimize prognosis and immune therapy for HCC.

Gastrointestinal (GI) cancers, including colorectal, gastric, esophageal, pancreatic, and liver, are associated with high mortality and morbidity rates worldwide. One of the underlying reasons for the poor survival outcomes in patients with these malignancies is late disease detection, typically when the tumor has already advanced and potentially spread to distant organs. Increasing evidence indicates that earlier detection of these cancers is associated with improved survival outcomes and, in some cases, allows curative treatments. Consequently, there is a growing interest in the development of molecular biomarkers that offer promise for screening, diagnosis, treatment selection, response assessment, and predicting the prognosis of these cancers. Extracellular vesicles (EVs) are membranous vesicles released from cells containing a repertoire of biological molecules, including nucleic acids, proteins, lipids, and carbohydrates. MicroRNAs (miRNAs) are the most extensively studied non-coding RNAs, and the deregulation of miRNA levels is a feature of cancer cells. EVs miRNAs can serve as messengers for facilitating interactions between tumor cells and the cellular milieu, including immune cells, endothelial cells, and other tumor cells. Furthermore, recent years have witnessed considerable technological advances that have permitted in-depth sequence profiling of these small non-coding RNAs within EVs for their development as promising cancer biomarkers -particularly non-invasive, liquid biopsy markers in various cancers, including GI cancers. Herein, we summarize and discuss the roles of EV-associated miRNAs as they play a seminal role in GI cancer progression, as well as their promising translational and clinical potential as cancer biomarkers as we usher into the area of precision oncology.

The diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis relies on non-invasive criteria based on international guidelines. The advent of systemic therapies warrants reconsideration of the role of biopsy specimens in the diagnosis of HCC. Accordingly, we investigated the diagnostic performance of the LI-RADS 2018 and the AASLD 2011 criteria.

Consecutive patients with cirrhosis who underwent a biopsy for suspected HCC between 2015 and 2020 were included. The available imaging studies (computed tomography and/or magnetic resonance imaging) were blindly reviewed by two independent radiologists. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for LI-RADS, AASLD, and biopsies.

In total, 167 patients underwent both available biopsy and imaging. Of the 137 relevant biopsies, 114 patients had HCC (83.2%), 12 (9%) had non-HCC malignant lesions, and 11 (8%) had benign nodules. The PPV and NPV of the biopsies were 100% and 62%, respectively; 30 biopsies were non-contributive. The PPV and NPV of the LI-RADS categories were 89% and 32.8% for LR-5 and 85.5% and 54.5% for LR-4 + 5 + TIV, respectively. The PPV and NPV of the 2011 AASLD criteria were 93.2% and 35.6%, respectively. The interobserver kappa (k = 0.380) for the LR-5 categories was reasonable. Of 100 LR-5 nodules, 11 were misclassified, in particular one case was a colorectal metastasis, and two cases were cholangiocarcinomas, of which nine were identified through biopsy, whereas six were correctly classified according to LI-RADS (LR-M or LR-TIV). Fifty percent of macrotrabecular HCC and 48.4% of poorly differentiated HCC (Edmonson 3 and 4) were not classified as LR-5.

LI-RADS 2018 did not outperform the AASLD 2011 score as a non-invasive diagnosis of HCC. Tumor biopsy allowed restoration of an accurate diagnosis in 11% of LR-5 cases. A combined radiological and histological diagnosis should be considered mandatory for good treatment assessment.

Although biopsy is not required for hepatocellular carcinoma diagnosis when the LI-RADS criteria are met according to current guidelines, our study underscores the limits of radiology and the need for biopsy when hepatocellular carcinoma is suspected. Histological findings could change therapeutics of liver tumors even if only for a small proportion of patients. Histological proof of the type of cancer is a standard in oncology.

Hepatocellular carcinoma (HCC), the sixth most common cancer globally, is associated with high mortality rates and more than 830,000 annual deaths. Despite advances in the available management options including surgical resection and local ablative therapies, recurrence rates after the initial treatment exceed 50%, even among patients who have undergone curative-intent therapy. Moreover, postsurgical HCC recurrence occurs in about 70% of cases five years postoperatively. The management of recurrent HCC remains undefined. This review discusses different predictors for HCC recurrence after each treatment modality and different approaches available to stratify these patients. More specific guidelines for managing HCC recurrence and strict surveillance protocols for such recurrence after initial HCC management are needed.

Hepatocellular carcinoma (HCC) is now a common cause of cancer death, with no obvious change in patient survival over the past few years. Although the traditional therapeutic modalities for HCC patients mainly involved in surgery, chemotherapy, and radiotherapy, which have achieved admirable achievements, challenges are still existed, such as drug resistance and toxicity. The emerging gene therapy of clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9-based (CRISPR/Cas9), as an alternative to traditional treatment methods, has attracted considerable attention for eradicating resistant malignant tumors and regulating multiple crucial events of target gene-editing. Recently, advances in CRISPR/Cas9-based anti-drugs are presented at the intersection of science, such as chemistry, materials science, tumor biology, and genetics. In this review, the principle as well as statues of CRISPR/Cas9 technique were introduced first to show its feasibility. Additionally, the emphasis was placed on the applications of CRISPR/Cas9 technology in therapeutic HCC. Further, a broad overview of non-viral delivery systems for the CRISPR/Cas9-based anti-drugs in HCC treatment was summarized to delineate their design, action mechanisms, and anticancer applications. Finally, the limitations and prospects of current studies were also discussed, and we hope to provide comprehensively theoretical basis for the designing of anti-drugs.