Search Results for: Terapia sistemica del carcinoma epatocellulare

Background
The potency of T cell-mediated responses is a determinant of immunotherapy effectiveness in treating malignancies; however, the clinical efficacy of T-cell therapies has been limited in hepatocellular carcinoma (HCC) owing to the extensive immunosuppressive microenvironment.

Objective
Here, we aimed to investigate the key genes contributing to immune escape in HCC and raise a new therapeutic strategy for remoulding the HCC microenvironment.

Design
The genome-wide in vivo clustered regularly interspaced short palindromic repeats (CRISPR) screen library was conducted to identify the key genes associated with immune tolerance. Single-cell RNA-seq (scRNA-seq), flow cytometry, HCC mouse models, chromatin immunoprecipitation and coimmunoprecipitation were used to explore the function and mechanism of adenylate cyclase 7 (ADCY7) in HCC immune surveillance.

Results
Here, a genome-wide in vivo CRISPR screen identified a novel immune modulator-ADCY7. The transmembrane protein ADCY7 undergoes subcellular translocation via caveolae-mediated endocytosis and then translocates to the nucleus with the help of leucine-rich repeat-containing protein 59 (LRRC59) and karyopherin subunit beta 1 (KPNB1). In the nucleus, it functions as a transcription cofactor of CCAAT/enhancer binding protein alpha (CEBPA) to induce CCL5 transcription, thereby increasing CD8+ T cell infiltration to restrain HCC progression. Furthermore, ADCY7 can be secreted as exosomes and enter neighbouring tumour cells to promote CCL5 induction. Exosomes with high ADCY7 levels promote intratumoural infiltration of CD8+ T cells and suppress HCC tumour growth.

Conclusion
We delineate the unconventional function and subcellular location of ADCY7, highlighting its pivotal role in T cell-mediated immunity in HCC and its potential as a promising treatment target.

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.

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…

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.

Ma dovrà rimanere in terapia intensiva per 48 ore

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).

Stabilizza vista e può ridurre necessità iniezioni intravitreali

Da biopsia liquida a studio cellule epatiche, per malattie rare

Efficace nel 30% dei pazienti che non risponde alle altre cure

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.

Immunotherapy has represented a novel and cutting-edge approach to treating patients with many types of metastatic cancers in recent years, transforming outcomes for patients who previously had limited options. Immunotherapy enhances the body’s natural defenses to target and eliminate cancer cells. The agents used are immune checkpoint inhibitors that target specific sites within the immune system, particularly focusing on T cells and their interactions with cancer cells or antigen-presenting cells. The primary sites at T cells of action include the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). The US Food and Drug Administration (FDA) has approved several immunotherapy agents, and each could have different modes of action targeting these sites in various cancers. In 2020, pembrolizumab, a PD-1 inhibitor, was approved for the treatment of patients with anaplastic thyroid carcinoma. In 2 nonrandomized phase 2 clinical trials in this issue of JAMA Oncology, Sehgal et al and Cabanillas et al explored the applications of immunotherapy in treating patients with aggressive thyroid cancer.

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.

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

Over the last several years, the prognosis for patients with nasopharyngeal cancer has improved due to therapeutic advances. As a result, the staging system has lagged behind, creating a discrepancy between expected and actual treatment outcomes. Given this incongruence, an updated staging system is warranted to accurately capture the successful change in patient survival. In JAMA Oncology, Pan et al present the American Joint Committee on Cancer (AJCC) version 9 TNM Staging System for nasopharyngeal carcinoma (NPC). They retrospectively analyzed tumor biological features and overall survival of 4914 patients from an international cohort diagnosed with NPC. Based on their results, they propose reclassification of stage I to III for localized disease, stage IV distant metastatic disease, while also adding radiological extranodal extension (ENE) as a criterion for N3.