Risultati per: Terapia sistemica del carcinoma epatocellulare

Introduction
Sebaceous gland carcinoma (SGC) of the eyelid is an aggressive tumour with the ability to metastasise and an increased morbidity. Controversies regarding the epidemiology of this malignant eyelid tumour is widespread in the scientific literature. Western reports repeatedly describes eyelid SGC as a rare occurring tumour in general, accounting for 1%–3% of all eyelid tumours, however studies from Asia have uncovered a higher frequency of eyelid SGC including 54% of all eyelid tumours in Japan, and 43%–56% in India. We wish to retrieve observational data of eyelid SGC prevalence in proportion to total eyelid tumours, from pathological studies published worldwide to resolve this controversy.

Methods and analysis
We will search Ovid Medline, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Google Scholar to identify published reports on eyelid SGC prevalence proportions, aiming to clarify the incidence of the tumour. We will include observational clinicopathological studies reporting prevalence with confirmed histopathology. No limitations on publication date or language will be applied. Data from the individual studies and study quality will be extracted by two individual reviewers. Study quality will be assessed using the JBI Critical Appraisal Instrument for Studies Reporting Prevalence Data. Raw proportions will be transformed and pooled using a random effects model for meta-analysis. And subgroup analysis according to geography will be performed. If data are deemed unsuitable for a meta-analysis, a narrative synthesis will be presented. We will judge the certainty of evidence and present whether this has an overall effect on the results. The results may shed light on a long-standing academic disparity of the scientific literature.

Ethics and dissemination
This systematic review does not require ethical approval. The results of this proposed review will be the subject to a publication in an international peer-reviewed journal within the ophthalmic or pathological specialty.

PROSPERO registration number
CRD42023487141.

Objectives
The study aimed to assess the feasibility, acceptability and safety of delivering a home-based telehealth exercise intervention to older patients with hepatocellular carcinoma (HCC).

Design
Non-randomised feasibility study.

Setting
Patients were recruited from UK outpatient liver cancer clinics.

Participants
Patients were aged ≥60 years with HCC, with post-treatment imaging reporting a complete response, partial response or stable disease.

Intervention and data collection
Patients were invited to attend synchronous online exercise sessions, twice weekly for 10 weeks. Physical function and patient-reported outcomes were assessed pre-intervention and post-intervention. Qualitative data were collected via semistructured interviews after intervention completion.

Primary outcome measures
Recruitment, retention, exercise adherence and safety.

Results
40 patients were invited to participate and 19 (mean age 74 years) provided consent (recruitment rate 48%). Patients completed 76% of planned exercise sessions and 79% returned to the clinic for follow-up. Hand grip strength (95% CI 1.0 to 5.6), Liver Frailty Index (95% CI –0.46 to –0.23) and time taken to perform five sit-to-stands (95% CI –3.2 to –1.2) improved from pre-intervention to post-intervention. Patients reported that concerns they had relating to their cancer had improved following the intervention (95% CI 0.30 to 5.85). No adverse events occurred during exercise sessions.
Qualitative data highlighted the importance of an instructor in real time to ensure that the sessions were achievable, tailored and well balanced, which helped to foster motivation and commitment within the group. Patients reported enjoying the exercise intervention, including the benefits of peer support and highlighted perceived benefits to both their physical and mental health. Patients felt that the online sessions overcame some of the barriers to exercise participation and preferred attending virtual sessions over face-to-face classes.

Conclusions
It is feasible, acceptable and safe to deliver supervised group exercise via videoconferencing to patients with HCC in their own homes. These findings will inform the design of a future, adequately powered randomised controlled trial to evaluate the efficacy of the intervention.

Trial registration number
ISRCTN14411809.

Objective
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.

Design
Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice.

Results
These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials.

Conclusion
HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient’s life.

Primary liver cancer is the third-leading cause of cancer-related mortality globally, accounting for over 700 000 deaths each year.1 In the last decade, the contribution of diet has been unravelled as a significant driver of hepatic oncogenesis.2 Specifically, diets high in fat have been associated with increased risk for the development of metabolic dysfunction-associated steatohepatitis (MASLD) and hepatocellular carcinoma (HCC) in many epidemiological studies,3 4 and these findings have been recapitulated in various in vitro and in vivo models. Although the link between diet and tumourigenesis has been convincingly established, the underlying mechanisms remain poorly understood. In Gut, Bu et al hypothesised that exogenous metabolites from the diet might play a direct regulatory role in protein signalling and specifically in the activation of protein kinase B (AKT).5 The PI3K-AKT pathway is a well-characterised transducer of extracellular signals and promotes tumourigenesis…

Objectives
The relationship between Ki-67 expression and the prognosis of patients with oesophageal squamous cell carcinoma (ESCC) has been extensively studied. However, their findings were inconsistent. Consequently, the present meta-analysis was performed to identify the precise value of Ki-67 in predicting the prognosis of ESCC.

Design
The current meta-analysis was carried out in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Data sources
Electronic databases of PubMed, Embase, Web of Science and Cochrane Library were systematically searched until 26 September 2023.

Statistical methods
Pooled HRs and corresponding 95% CIs were calculated to estimate the role of Ki-67 in predicting overall survival (OS) and disease-free survival (DFS) in ESCC. Between-study heterogeneity was evaluated using Cochrane’s Q test and I2 statistics. Specifically, significant heterogeneities were identified based on p50% so the random-effects model should be used; otherwise, the fixed-effects model should be used. The relationship between Ki-67 and clinicopathological characteristics of ESCC was evaluated by combining ORs with their corresponding 95% CIs.

Results
11 articles with 1124 patients were included in the present meta-analysis. Based on our analysis, increased Ki-67 expression was markedly associated with poor OS (HR 1.62, 95% CI 1.15 to 2.28, p=0.006) and DFS (HR 1.72, 95% CI 1.22 to 2.43, p=0.002) in ESCC. Moreover, subgroup analysis revealed that Ki-67 upregulation significantly predicted OS and DFS when a Ki-67 threshold of >30% was used. Nonetheless, Ki-67 was not significantly associated with sex, T stage, N stage, TNM stage, tumour differentiation or tumour location.

Conclusions
In the present meta-analysis, high Ki-67 expression significantly predicted OS and DFS in patients with ESCC, especially when Ki-67 >30% was used as the threshold. These results suggest that Ki-67 could serve as an effective and reliable prognostic indicator for ESCC.

This nonrandomized clinical trial evaluates the efficacy and safety of a tailored approach with nivolumab plus ipilimumab as an immunotherapeutic boost in patients with metastatic urothelial carcinoma.

Objective
The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.

Design
RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9.

Results
MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of β-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC.

Conclusions
CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC.

The advent of immune checkpoint inhibitors, particularly monoclonal antibodies (mAbs) that target the programmed cell death protein 1 (PD-1) or its ligand (PD-L1), has revolutionised cancer treatment across various malignancies. Despite this groundbreaking progress, a considerable cohort of patients fails to derive benefit from anti-PD(L)1 mAb therapy due to primary and secondary resistance mechanisms. The percentage of patients who respond to these treatments varies among different tumour types, ranging from 40% in more sensitive tumours, like metastatic melanoma, to virtually zero in less sensitive tumours such as glioblastoma.1 Hepatocellular carcinoma (HCC), one of the deadliest solid tumours, emerges as a moderately sensitive tumour, where monotherapy with anti-PD(L)1 agents demonstrates a response in only about 15% of cases.2 These encouraging yet constrained clinical outcomes have elevated immunotherapy to a pivotal status in clinical practice, instigating evaluations of combinatory approaches with other agents alongside anti-PD(L)1 mAbs to…