Autoimmune Atrophic Gastritis: The Role of miRNA in Relation to Helicobacter Pylori Infection

IntroductionMicroRNAs (miRNAs) have been proposed as diagnostic markers, biomarkers of neoplastic progression, and possible therapeutic targets in several immune-mediated diseases. We aimed to analyze the expression profile of selected miRNAs (miR21, miR142, miR223, miR155) in patients with autoimmune atrophic gastritis (AAG), patients with non-autoimmune multifocal atrophic gastritis (MAG), and healthy control subjects (HC).Materials and methodsA total of 103 patients with AAG were consecutively recruited for this study among those attending our gastroenterology outpatient clinic. Participating patients were divided into two groups: primary, not Helicobacter pylori (HP)-associated related AAG (n=57, P-AAG) and HP-associated AAG (n=46, HP-AAG); this subgroup included HP-positive patients, patients with previously reported HP infection, and patients harboring antral atrophy, considered as a stigma of HP infection. We also included 20 sex-age-matched MAG patients and 10 HC. Upper endoscopy with gastric biopsies were performed on each AAG and MAG patient. Circulating levels of miR21-5p, miR142-3p, miR223-3p, and miR155-5p were measured by RT-PCR in all groups.ResultsMiR-21 was over-expressed in P-AAG (p=0.02), HP-AAG (p = 0.04), and MAG (p=0.03) compared with HC. By contrast, miR-142 was more expressed in HC than in HP-AAG (p=0.04) and MAG (p=0.03). MiR-155 showed no significant differences among the four subgroups, while, unexpectedly, miR-223 was overexpressed in HC compared to P-AAG (p=0.01), HP-AAG (p=0.003), and MAG (p<0.001), and was higher in P-AAG than in MAG (p=0.05).ConclusionsMiR-21 was over-expressed in patients with gastric precancerous conditions irrespective of etiology, while in the same subgroups miR-142 and miR-223 were under-expressed compared to healthy controls. Controlling miRNAs up- or downregulation could lead to a breakthrough in treating chronic autoimmune diseases and potentially interfere with the progression to cancer

Crosstalk between MicroRNAs and Oxidative Stress in Coeliac Disease

MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in regulating gene expression. Many studies, mostly conducted on pediatric patients, suggested that oxidative stress and several miRNAs may play an important role in coeliac disease (CeD) pathogenesis. However, the interplay between oxidative stress and miRNA regulatory functions in CeD remains to be clarified. In this review, we aimed to perform a literature review on the role of miRNAs and oxidative stress in adult CeD patients and to analyze their potential interactions. In this direction, we also reported the preliminary results of a pilot study we recently performed

Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment

BACKGROUND: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. METHODS: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. RESULTS: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). CONCLUSIONS: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis

Characteristics and outcome of anti-hepatitis D virus positive patients with hepatocellular carcinoma

Background &amp; aims: Chronic hepatitis D virus (HDV) often leads to end-stage liver disease and hepatocellular carcinoma (HCC). Comprehensive data pertaining to large populations with HDV and HCC are missing, therefore we sought to assess the characteristics, management, and outcome of these patients, comparing them to patients with hepatitis B virus (HBV) infection. Methods: We analysed the Italian Liver Cancer database focusing on patients with positivity for HBV surface antigen and anti-HDV antibodies (HBV/HDV, n = 107) and patients with HBV infection alone (n = 588). Clinical and oncological characteristics, treatment, and survival were compared in the two groups. Results: Patients with HBV/HDV had worse liver function [Model for End-stage Liver Disease score: 11 vs. 9, p &lt; .0001; Child-Turcotte-Pugh score: 7 vs. 5, p &lt; .0001] than patients with HBV. HCC was more frequently diagnosed during surveillance (72.9% vs. 52.4%, p = .0002), and the oncological stage was more frequently Milan-in (67.3% vs. 52.7%, p = .005) in patients with HBV/HDV. Liver transplantation was more frequently performed in HBV/HDV than in HBV patients (36.4% vs. 9.5%), while the opposite was observed for resection (8.4% vs. 20.1%, p &lt; .0001), and in a competing risk analysis, HBV/HDV patients had a higher probability of receiving transplantation, independently of liver function and oncological stage. A trend towards longer survival was observed in patients with HBV/HDV (50.4 vs. 44.4 months, p = .106). Conclusions: In patients with HBV/HDV, HCC is diagnosed more frequently during surveillance, resulting in a less advanced cancer stage in patients with more deranged liver function than HBV alone. Patients with HBV/HDV have a heightened benefit from liver transplantation, positively influencing survival

BIOMARCATORI CIRCOLANTI E FATTORI CLINICI ASSOCIATI CON LA PROGNOSI NEI PAZIENTI CON CARCINOMA EPATOCELLULARE

Il carcinoma epatocellulare (HCC) è uno dei tumori più comuni al mondo e, nonostante i recenti progressi nella sua gestione, è ancora gravato da un'elevata mortalità. La previsione della prognosi nei pazienti con HCC è molto complessa e devono essere considerate diverse variabili (tra cui il carico tumorale, la funzionalità epatica residua e le condizioni cliniche). Allo scopo di stratificare accuratamente la prognosi del paziente, è inoltre necessario identificare biomarcatori circolanti affidabili. Infatti, l'alfa-fetoproteina (AFP), nonostante sia comunemente usata nell'HCC, non è completamente soddisfacente come marcatore prognostico. L'obiettivo primario di questa tesi è stato quello di valutare alcune molecole coinvolte nello sviluppo e nella progressione dell'HCC, come potenziali biomarcatori prognostici circolanti. In particolare, sono state studiate serpine (squamous cell carcinoma antigen [SCCA]-IgM), molecole di angiogenesi (hypoxia-inducible factor [HIF]-1 and vascular endothelial growth factor [VEGF]), microRNA (miR-21 e miR-122), prostaglandine (prostaglandina E2) e score infiammatori (platelets-to-lymphocytes ratio [PLR] and neutrophils-to-lymphocytes ratio [NLR]). Nella seconda parte della tesi sono stati indagati la sorveglianza, lo stadio tumorale e il trattamento, aspetti clinici essenziali da considerare per il miglioramento della sopravvivenza del paziente. I risultati ottenuti dimostrano che le molecole valutate sono potenzialmente utili nella stratificazione della prognosi del paziente e meritano una validazione in ampi studi prospettici. Inoltre, i risultati di questa tesi confermano l'importanza centrale della sorveglianza, forniscono il razionale per un'appropriata stadiazione e trattamento di grandi tumori monofocali, mostrano i cambiamenti nel tempo dell’uso e dell’efficacia della chemioembolizzazione transarteriosa, e dimostrano l’efficacia e la sicurezza della capecitabina nel trattamento dell'HCC. In quest’era della medicina personalizzata e di precisione, lo sviluppo di biomarcatori prognostici e predittivi, potenzialmente utili anche nel guidare il trattamento, e un'attenta gestione clinica sono fondamentali per migliorare la sopravvivenza del paziente.Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and, despite recent advances in its management, it is still burdened with high mortality. Prognostic prediction in HCC is very complex and several variables (among which tumor burden, residual liver function and clinical conditions) must be considered. With the aim of accurately stratify patient prognosis, reliable circulating biomarkers are urgently needed. Indeed, alpha-fetoprotein (AFP), despite being commonly used in HCC, is not completely satisfactory in prognostic prediction. The primary aim of this thesis was to evaluate as potential circulating prognostic biomarkers some molecules involved in HCC development and progression. In particular, serpins (squamous cell carcinoma antigen [SCCA]-IgM), angiogenesis molecules (hypoxia-inducible factor [HIF]-1 and vascular endothelial growth factor [VEGF]), microRNAs (miR-21 and miR-122), prostaglandins (prostaglandin E2) and inflammatory-based scores (platelets-to-lymphocytes ratio [PLR] and neutrophils-to-lymphocytes ratio [NLR]) were investigated. In the second part of the thesis, surveillance, cancer stage and treatment, which are essential clinical aspects to be considered for improving patient survival, were investigated. The results obtained demonstrate that the biomarkers evaluated are potentially useful in stratifying patient prognosis and deserve a validation in large prospective studies. Moreover, the results of this thesis confirm the central importance of surveillance, provide the rationale for appropriate staging and treatment of large monofocal tumors, show the changes over time of transarterial chemoembolization application and effectiveness, and demonstrate the efficacy and safety of capecitabine in the treatment of HCC. In this personalized and precision medicine era, the development of prognostic and predictive biomarkers, possibly useful also in guiding treatment, and a careful clinical management are fundamental to improve patient survival

Management of Hepatocellular Carcinoma Recurrence after Liver Transplantation

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10–15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies

Systemic therapies for hepatocellular carcinoma: an evolving landscape

In the last few years, there has been a significant widening of the landscape of systemic therapy for unresectable hepatocellular carcinoma (HCC) patients. After the landmark drug sorafenib, several other molecules have been approved for treatment in first-line (lenvatinib) and second-line (regorafenib, cabozantinib, and ramucirumab) regimens. Very recently, another important step forward has been made with the demonstration that the combination of an anti-programmed death ligand 1 and an anti-vascular endothelial growth factor (atezolizumab + bevacizumab) provides better survival results compared to sorafenib, thus becoming the new paradigm in first-line treatment of HCC. In consideration of this rapidly evolving situation, with the availability of many potential active drugs, the American Society of Clinical Oncology recently published a guideline in order to advise on the selection of systemic treatment options. However, also considering the uncertainties and the unmet needs in the current treatment of patients with advanced liver cancer is mandatory

Angiogenesis and Hepatocellular Carcinoma: From Molecular Mechanisms to Systemic Therapies

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the “primum movens” of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments