Hepatocellular Carcinoma: Novel Molecular Targets in Carcinogenesis for Future Therapies

Background. Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Materials and Methods. A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: “hepatocellular carcinoma,” “molecular hepatocarcinogenesis,” “targeted therapy,” and “immunotherapy.” Discussion and Conclusion. Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.</jats:p

The Immune System in Hepatocellular Carcinoma and Potential New Immunotherapeutic Strategies

Background. Hepatocellular carcinoma is a major health problem worldwide and the third most common cause of cancer-related death. HCC treatment decisions are complex and dependent upon tumor staging. Several molecular targeted agents have been evaluated in clinical trials in advanced HCC. Despite of only modest objective response rates according to the Response Evaluation Criteria in Solid Tumors, several studies showed encouraging results in terms of prolongation of the time to progression, disease stabilization, and survival. Cellular immunotherapy would improve the immune state and has potential in enhancing the therapeutic outcome for HCC patients.Materials and Methods. A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: “hepatocellular carcinoma,” “molecular hepatocarcinogenesis,” “targeted therapy,” “molecular immunological targets,” “tumour-associated antigens,” “Tregs,” “MDSCs,” “immunotherapy.”Discussion and Conclusion. Treatment strategies combining blockade of immunoregulatory cell types such as Tregs and MDSCs and of inhibitory receptors, with vaccine-induced activation of TAA-specific T cells, may be necessary to achieve the most effective therapeutic antitumour activity in HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.</jats:p

Biopsy in chronic liver disease: proposal for a shared path between clinicians and pathologists

Introduction. Liver biopsy is fundamental for characterizing chronic liver disease. Effective communication between specialists during the diagnostic process is crucial. This project aims to outline a diagnostic path shared by clinicians and pathologists, and to propose practical solutions at different stages of the diagnostic work-up, from clinical suspicion to the histology report in patients with chronic liver diseases. Methods. A panel of experts, within the methodological framework of lean management, joined two rounds of discussion sharing their professional experiences. They reached an agreement on the essential phases and actions of the diagnostic process, and built a shared diagnostic workflow. Results. The panel agreed on the importance of a standardized form to be filled with all relevant clinical and laboratory data to ensure the flow of information between the clinician and the pathologist. Further decisions were reached on the following practical issues: the advantage of performing liver biopsies in dedicated centers, the need for homogeneous procedures, and the minimum quality standards in all phases, including reporting. Finally, the panel agreed on the usefulness of digital pathology to exchange observations and opinions and to create a territorial network to discuss challenging cases. Conclusion. Sharing a diagnostic path between the pathologist and the clinician can be a powerful tool to improve both the timing and accuracy of the histology report

Cirrhosis and liver transplantation in patients co-infected with HIV and hepatitis B or C:an observational cohort study

This study assessed the likelihood of referral for liver transplantation assessment in a prospective cohort of patients co-infected with HIV and hepatitis B or C with complications of cirrhosis. There were 141 co-infected patients from 11 UK centres with at least one complication of cirrhosis recorded (either decompensation or hepatocellular carcinoma) out of 772 identified with cirrhosis and/or HCC. Only 23 of these 141 (16.3%) were referred for liver transplantation assessment, even though referral is recommended for co-infected patients after the first decompensation episode

The current treatment situation and definitions of a cure for chronic HBV infection

HBV vaccination, while effective in reducing incident chronic disease in endemic regions, will not have the desired impact on the rates of end-stage liver disease in chronically infected persons. Over three decades, IFN-α and nucleoside analogs have reduced the morbidity from the disease. A large reservoir of chronic infection remains. The natural history of HBV infection is still being defined. Understanding the interactions between HBV and the host will be fundamental to achieving higher rates of cure. Curing hepatitis B will require several steps for either eradication, or a functional cure in the host. It is unclear whether covently closed circular DNA chromatin would need to be cleared to cure hepatitis B, or whether low threshold levels would slow the disease. </jats:p

Comparison between bicarbonate-based and Stewart methods to assess metabolic acid-base disorders in internistic patients. A pilot study

Aim: To assess the acid-base status in a cohort of internistic patients, using traditional and “modern” methods, to compare their different sensitivity to detect metabolic disorders and to evaluate a possible relationship between classical and alternative parameters.Patients and Methods: 143 assessment of acid-base and electrolytes balance on 121 internistic patients (76 males and 45 females, mean age 73.9 ± 10,8 years) were examined according to bicarbonate-based and Stewart methods.Results: The traditional method detected 81 cases (56.6 %) of metabolic alkalosis and 15 cases (10.4 %) of metabolic acidosis. The Stewart method detected 92 cases (64.3 %) of metabolic alkalosis and 22 cases (15.3%) of metabolic acidosis.Traditional method failed to detect 11 cases of metabolic alkalosis (chi square = 1.443; p = 0.226), and 7 cases of metabolic acidosis (chi square = 1.118; p = 0.290) when compared to Stewart's method. A significant relationship was observed between Strong Ion Gap (SIG) and Anion Gap corrected for albumin concentration (AGcorr) (r= 0.53; p &lt;0.001).Conclusions: Our result showed that traditional method is useful to assess acid-base status in internistic clinical setting as well as Stewart's method because no significant difference was found between the two approaches. Nevertheless, the light disagreement observed between the two methods suggests that in a small percentage of cases the traditional method can fail to detect metabolic acid-base abnormalities.</jats:p