Risultati per: Carcinoma cutaneo a cellule squamose

This nonrandomized controlled trial ancillary study evaluates the survival outcomes associated with corticosteroid use during nivolumab treatment for patients with metastatic renal cell carcinoma.

Da ricercatori italiani e americani. Utile anche contro i tumori

Objectives
The prognosis of invasive micropapillary carcinoma (IMPC) of the breast is determined by many clinicopathological factors. This study aims to identify prognostic factors and develop reliable nomogram to predict the overall survival (OS) in patients with IMPC.

Design
Log-rank test and Cox proportional hazards analysis were used to identify variables and construct a nomogram based on the training cohort. C-index and calibration curves were performed to evaluate the performance of the model in the training cohort and validation cohorts.

Setting
We collected the patient data from the Surveillance, Epidemiology and End Results (SEER) database. This database holds data related to the cancer incidence from 18 population-based cancer registries in the USA.

Participants
The SEER database was used to screen 754 eligible patients as the study cohort. The whole cohort was randomly divided into a training cohort (n=377) and a validation cohort (n=377).

Results
Age at diagnosis, hormone receptors, number of positive regional lymph nodes and clinical stage were independent prognostic factors for patients with IMPC. The calibration curves presented excellent consistency between the actual and nomogram-predict survival probabilities in the training and validation cohorts. The C-index values of the nomogram were 0.794 and 0.774 for OS in the training and validation cohorts, respectively.

Conclusions
The novel nomogram provides new insights of the risk of each prognostic factor and can assist doctors in predicting the 1-year, 3-year and 5-year OS in patients with IMPC.

Objective
Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting.

Design
Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481).

Results
Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8+ T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPAR) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8+ T cell dysfunction. A selective PPAR antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPAR induction. Moreover, higher baseline PPAR expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types.

Conclusion
We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPAR/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.

New England Journal of Medicine, Volume 389, Issue 5, Page 476-478, August 2023.

This prognostic study assesses the prognostic and predictive value of the modified Glasgow prognostic score during treatment in patients with metastatic renal cell carcinoma.

Over the past decade, significant strides have been made in treating metastatic renal cell carcinoma (mRCC). The introduction of immune-checkpoint inhibitor (ICI)-based treatment regimens for treating mRCC has significantly improved survival outcomes compared with sunitinib, a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). These regimens include the combination of ICI with either another ICI or a VEGF-TKI, such as nivolumab plus ipilimumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus axitinib. The median overall survival (OS) of patients with mRCC currently stands at approximately 55 months, a dramatic improvement from approximately 18 months just a decade ago. As a next step in clinical development, triplet therapy is now being explored in advanced disease. The recently reported phase 3 COSMIC-313 clinical trial showed improved efficacy of triplet therapy regimen comprising nivolumab, ipilimumab, and cabozantinib over the combination of nivolumab plus ipilimumab. However, to date, there has not been evidence to support treatment escalation or deescalation based on either imaging or biomarker-based response after initiating therapy. In this context, the PDIGREE study (NCT03793166) investigated an imaging response-based treatment strategy after beginning treatment with nivolumab plus ipilimumab. Patients with mRCC who experienced complete response or progressive disease at 3-month imaging assessment were assigned to receive nivolumab maintenance and cabozantinib, respectively. Patients who experience neither complete response nor progressive disease (ie, those with stable disease and partial response) were randomized to either continuation of nivolumab monotherapy or the addition of cabozantinib to nivolumab. However, patients with stable disease results on imaging scans may not represent a homogeneous group of patients and have variable survival outcomes. Thus, developing a reliable on-treatment prognostic or predictive biomarker may refine these imaging-based response-adapted treatment escalation or deescalation strategies.

Introduction
Cabozantinib monotherapy is an option for treatment of advanced renal cell carcinoma (RCC). However, cabozantinib dose modification and discontinuation due to symptomatic adverse events (AEs) remains a challenge. The use of patient-reported outcomes (PROs) may help manage symptomatic AEs, which is reported to lead to improved quality of life (QOL), avoidance of drug discontinuation and better survival. This study aims to investigate the clinical benefits of PROs in patients with RCC receiving cabozantinib and the most appropriate medium for PRO monitoring (electronic [e]-PRO or paper-PRO).

Methods and analysis
This study is being conducted at about 35 sites in Japan. Patients aged ≥18 years with unresectable or metastatic RCC initiating treatment with cabozantinib monotherapy are eligible and will be randomised to: (1) e-PRO monitoring, (2) paper-PRO monitoring or (3) usual care without PRO monitoring. Recruitment began in December 2021 (target sample size, 105). Patients start treatment with cabozantinib 60 mg once daily, and in the PRO groups, will record daily medication intake, weight, temperature, blood pressure and AEs. Endpoints include the proportion of patients with a ≥5-point deterioration on the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-19; primary endpoint), progression-free survival, QOL, dose adjustments, relative dose intensity, treatment-emergent AEs and frequency of interventions for AEs outside of the scheduled visits. Patient and physician opinions of the PRO monitoring systems and patient compliance with e-PRO/paper-PRO input are also being measured.

Ethics and dissemination
The study is being conducted in compliance with the Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical Practice and the Clinical Trials Act. Written informed consent is being obtained from all patients, and the protocol has been approved by the Hokkaido University Hospital Certified Review Board (approval number, CRB021-005). The results will be presented at conferences and submitted to a peer-reviewed journal.

Trial registration number
jRCTs011210055.

New England Journal of Medicine, Volume 389, Issue 2, Page 188-190, July 2023.

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.

Un brevetto Università Ca’ Foscari di Venezia e Cro di Aviano

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.