Risultati per: Carcinoma della prostata

Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a United States cohort.

Objective
Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, 42PD-1, in HCC progression and resistance to nivolumab ICB.

Design
We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of 42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of 42PD-1 monoclonal antibody was determined in HCC humanised mouse models.

Results
We found distinct T cell subsets, which did not express PD-1 but expressed its isoform 42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. 42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of 42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated 42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models.

Conclusion
Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-42PD-1 antibody for HCC immunotherapy.

This Special Communication describes the development of expert multidisciplinary consensus guidelines on the management of common presentations of thymic carcinoma.

In Reply We thank Gao and colleagues for their interest and comments on our meta-analysis. JUPITER-06 was only published on March 3, 2022. As such, it was not included in the analysis because the systematic search was concluded on October 1, 2021. Notwithstanding, the discordance of our findings and those reported by Wu and colleagues is of interest. The notable findings from the 2-stage meta-analysis conducted by Wu et al appear to be driven by treatment effects from JUPITER-06.

This cohort study compares outcomes in very high-, high-, and low-risk National Comprehensive Cancer Network groups of cutaneous squamous cell carcinoma and compares outcomes stratified by Mohs micrographic surgery and wide local excision.

To the Editor We read with great interest the meta-analysis by Yap et al. This meta-analysis investigated the effectiveness of both first-line and second-line immune checkpoint inhibitor (ICI)–based regimens for patients with advanced esophageal squamous cell carcinoma (ESCC) when programmed death ligand 1 (PD-L1) expression is low. Currently, the inconsistent regulatory approvals of the use of ICIs among authoritative organizations (eg, European Medicines Agency, US Food and Drug Administration) based on PD-L1 expression have led to confusion among physicians in clinical practice. It is of great importance to collect the published data and unify the conclusion to provide clear guidance for initiating ICI-based therapy in certain subgroups.

New England Journal of Medicine, Volume 388, Issue 24, Page 2262-2273, June 2023.

Objective
To evaluate the efficacy and safety of combination immunochemotherapy regimens for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Design
Meta-analysis and systematic review.

Data sources
PubMed, Embase, Web of Science and Cochrane library and the Clinicaltrials.gov clinical trials registry were searched up to 14 March 2022.

Eligibility criteria for selecting studies
We included randomised controlled trials that compared combination immunochemotherapy with conventional chemotherapy for R/M HNSCC. Primary outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse effects (AEs).

Data extraction and synthesis
Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data.

Results
A total of 1214 relevant papers were obtained after the initial search, and five papers that met the inclusion criteria were included; these studies included a total of 1856 patients with R/M HNSCC. Meta-analysis showed that the OS and PFS of patients with R/M HNSCC in the combination immunochemotherapy group were significantly longer than those in the conventional chemotherapy group (HR=0.84; 95% CI 0.76, 0.94; p=0.002; HR=0.67; 95% CI 0.61, 0.75; p

In Sardegna nel 2021 sono stati ricoverati 262 pazienti

Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown.

Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression.

New England Journal of Medicine, Volume 388, Issue 19, Page 1767-1778, May 2023.

Objective
Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.

Design
We performed 5’and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts.

Results
Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells’ cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients.

Conclusion
True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.

Bollipo et al1 presented recommendations for SARS-CoV-2 infections in patients with chronic liver diseases (CLDs). Since their publication, at least three SARS-CoV-2 vaccinations are recommended for all persons regardless of comorbidities.2 Cancer and CLD are associated with impaired immune responses to SARS-CoV-2 vaccines.3–6 However, patients with GI cancer, especially with hepatobilary carcinoma (HBC), are under-represented in published studies. In this prospective, longitudinal study, 120 patients with GI cancer, including 32.5% HBC, participated (table 1). Patients under anticancer therapy were analysed compared with patients with GI cancer in follow-up care (≥1 year off anticancer therapy). We present profound data on humoral response rates (SARS-CoV-2 antispike and surrogate neutralisation antibodies (sNAB) using SARS-CoV-2 IgG II Quant chemiluminescent microparticle immunoassay (Abbott Laboratories) and cPass SARS-CoV-2 Neutralization Antibody Detection Kit (GenScript), respectively). Of note, the ELISA analysing levels of sNAB…