Risultati per: Linee guida per la gestione del carcinoma basocellulare

Several studies have highlighted the significance of targeting fat mass and obesity-associated protein (FTO) in gastrointestinal cancers including hepatocellular carcinoma (HCC) .1 The recent study from the group of Irene Oi-Lin Ng presented in Gut by Chen et al2 introduces new insights into the molecular dynamics of HCC, focusing on the pivotal role of FTO in the disease’s pathophysiology. Functioning as an eraser of N6-methyladenosine (m6A), FTO modulates RNA stability and translation. In the context of HCC, FTO’s activity leads to the stabilisation of oncogenic transcripts, thereby promoting cancer cell proliferation and survival.3 The study identifies glycoprotein non-metastatic melanoma protein B (GPNMB) as a downstream effector of FTO (figure 1). By diminishing the m6A modification on GPNMB, FTO enhances its stability, thereby protecting it from YTHDF2-mediated degradation. This stabilisation facilitates the incorporation of GPNMB into small extracellular vesicles (sEVs), which are…

Objective
Fat mass and obesity-associated protein (FTO), an eraser of N 6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown.

Design
The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment.

Results
FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8+ T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8+ T cells, resulting in the inhibition of CD8+ T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment.

Conclusion
Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC). Recent studies have highlighted the bidirectional impacts between host genetics/epigenetics and the gut microbial community. Host genetics influence the composition of gut microbiome, while the gut microbiota and their derived metabolites can induce host epigenetic modifications to affect the development of MASLD. The exploration of the intricate relationship between the gut microbiome and the genetic/epigenetic makeup of the host is anticipated to yield promising avenues for therapeutic interventions targeting MASLD and its associated conditions. In this review, we summarise the effects of gut microbiome, host genetics and epigenetic alterations in MASLD and MASLD-HCC. We further discuss research findings demonstrating the bidirectional impacts between gut microbiome and host genetics/epigenetics, emphasising the significance of this interconnection in MASLD prevention and treatment.

Introduction
The exact role of hepatic arterial infusion chemotherapy (HAIC) in advanced hepatocellular carcinoma (aHCC) is still unknown. The combination of HAIC and sorafenib has been proven to be more effective than sorafenib alone in the first-line treatment of aHCC. The aim of the study is to evaluate the efficacy and safety of HAIC plus regorafenib in the second-line treatment of aHCC.

Methods and analysis
This is a multicenter, open-label, randomised controlled phase III trial. A total of 294 patients with aHCC, who are unable to tolerate the first-line systemic therapy or progress after the first-line systemic therapy, will be enrolled in the study. The patients will be randomly (2:1) assigned into the combination treatment group (HAIC plus regorafenib, n=196) and the control group (regorafenib alone, n=98). HAIC and regorafenib (160 mg/day) will be given in a 4-week cycle. The primary endpoint is overall survival in the intention-to-treat population. The second endpoints include progression-free survival, overall response rate, time to progression, etc. The radiological assessments will be based on the criteria of Response Evaluation Criteria in Solid Tumors 1.1.

Ethics and dissemination
This study is approved by the ethics committee of Cancer Hospital, Chinese Academy of Medical Sciences. All participants are required to provide written informed consent. The results of this study will be disseminated through peer-reviewed publications and esteemed academic conferences.

Trial registration number
Chinese Clinical Trial Registry (ChiCTR2300073075).

Introduction
Treatment combination of pembrolizumab plus platinum and 5-fluorouracil (PF) has increased the survival of recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The combination of platinum and gemcitabine (PG) has been shown to be superior to PF in the treatment of R/M nasopharyngeal carcinoma patients. Therefore, we hypothesise that the combination of pembrolizumab with PG would be comparable to pembrolizumab with PF as a first-line treatment in R/M HNSCC.

Methods and analysis
This is an open-label, multicentre, single-arm, phase 2 study of pembrolizumab plus PG for first-line treatment in subjects with R/M HNSCC in Malaysia. The study is conducted using the Optional Simon optimal 2-stage design. At the initial stage, 26 subjects will be enrolled and if seven or more patients achieve an objective response rate (ORR), then 63 patients will be enrolled. Subjects will be given pembrolizumab 200 mg3 every 3 weeks up to 35 cycles in combination with chemotherapy for up to six cycles of platinum (either cisplatin at 35 mg/m2 intravenous on day 1 and day 8 or carboplatin at area under the curve 5 intravenous on day 1 of each 3-week cycle) and gemcitabine at 1250 mg/m2 intravenous on days 1 and 8 of a 3-week cycle. The primary end point is the ORR as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points include the overall survival, progression free survival, response duration and safety. The exploratory objectives include relationships of microbiome profiles, prognostic and predictive biomarkers with the clinical responses.

Ethics and dissemination
The study was approved by the ethics committee of the University Malaya Medical Centre (202213–10884). Findings will be disseminated through conference presentations and peer review publications.

Trial registration number
ClinicalTrials.gov (www.clinicaltrial.gov); NCT05286619.

This phase 2 nonrandomized clinical trial assesses the efficacy and safety of dual immune checkpoint inhibition in patients with aggressive thyroid carcinoma.

This nonrandomized clinical trial examines whether matched-targeted therapy based on tumor mutation status with a PD-L1 inhibitor is associated with improved overall survival among patients with anaplastic thyroid carcinoma.

Currently, patients with hepatocellular carcinoma (HCC) in the United States are assigned a uniform score relative to the median MELD at transplant (MMaT-3) after a minimum 6-month waiting period. Here, we develop a risk stratification model for patients with HCC, using the available and objective variables at time of listing.

New England Journal of Medicine, Volume 391, Issue 21, Page 2061-2063, November 28, 2024.