Risultati per: Carcinoma della prostata

Introduction
Current clinical guidelines recommend systematic antitumour therapy as the primary treatment option for patients with stage IIIb hepatocellular carcinoma (HCC) based on the China liver cancer (CNLC) staging criteria. Several different targeted therapeutics have been applied in combination with immunotherapeutic regimens to date in patients with advanced HCC. The present study was developed to evaluate the relative safety and efficacy of hepatectomy of HCC in combination with targeted apatinib treatment and immunotherapeutic camrelizumab treatment CNLC-IIIb stage HCC patients with the goal of providing evidence regarding the potential value of this therapeutic regimen in individuals diagnosed with advanced HCC.

Methods and analysis
This is a multicentre phase II trial with single-arm in which patients undergo hepatectomy in combination with targeted treatment (apatinib) and immunotherapy (camrelizumab). Patients will undergo follow-up every 2–3 months following treatment initiation to record any evidence of disease progression and adverse event incidence for a minimum of 24 months following the discontinuation of treatment until reaching study endpoint events or trial termination. The primary endpoint for this study is patient mortality.

Ethics and dissemination
This study protocol was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital (KS2022[124]). The results of this study will be submitted for publication in a peer-reviewed journal.

Trial registration number
NCT05062837.

Objective
The objective of this study was to evaluate the comparative cost-effectiveness of lenvatinib (LEN) plus transarterial chemoembolisation (TACE) (LEN-TACE) and LEN alone to treat advanced hepatocellular carcinoma (HCC) from the perspective of the Chinese healthcare system.

Design
A three-state partitioned survival model using clinical survival data from a phase III LAUNCH trial, a 5-year time horizon for costs and quality-adjusted life years (QALYs) was constructed to analyse the cost-effectiveness of LEN-TACE. Clinical inputs were extracted from the LAUNCH trial, with outcomes extrapolated using standard and flexible parametric survival models. Costs and utilities derived from published literature were discounted at an annual rate of 5%. Sensitivity analyses and scenario analyses were conducted to test the robustness of the model.

Setting
The Chinese healthcare system perspective.

Participants
A hypothetical Chinese cohort of patients with advanced HCC.

Interventions
TACE plus LEN versus LEN.

Primary outcome measure
Costs, QALYs, incremental cost-effectiveness ratio (ICER).

Results
Base-case analysis revealed that LEN-TACE would be cost-effective in China at the willingness-to-pay (WTP) threshold of $37 663 per QALYs, with improved effectiveness of 0.382 QALYs and additional cost of $12 151 (ICER: $31 808 per QALY). The probabilistic sensitivity analysis suggested that LEN-TACE had a 93.5% probability of cost-effectiveness at WTP threshold of three times gross domestic product per capital ($37 663). One-way deterministic sensitivity analysis indicated that the duration of LEN treatment in both two arms, utility of progression-free survival and the cost of TACE had a greater impact on the stability of ICER values. Scenario analyses results were in line with base-case analysis.

Conclusions
LEN-TACE might be a cost-effective strategy compared with LEN for the first-line treatment of patients with advanced HCC in China.

Introduction
Prompt detection of hepatocellular carcinoma (HCC) in patients with chronic liver diseases is critical for enhancing prognosis. Existing imaging techniques and serum markers fall short of clinical needs. This study aims to establish a non-invasive diagnostic model for early HCC detection in the Chinese population.

Methods and analysis
This prospective, multicentre, observational study will enrol 2000 participants, including HCC patients, those with chronic liver diseases (hepatitis, cirrhosis and benign liver space-occupying lesions), and healthy individuals. The study will collect demographic data and blood samples, which will be used to test α-fetoprotein (AFP), des–carboxy-prothrombin (DCP) and circulating tumour DNA (ctDNA) methylation. The GAMAD (Gender+Age+Methylation+AFP+DCP) model involving gender, age, ctDNA methylation signature, AFP and DCP will be developed and blindly validated in training and validation sets (1400 and 600 cases, respectively). Primary endpoints include sensitivity, specificity and accuracy (receiver operating characteristic curves; area under the curve value) of GAMAD for HCC and/or high-risk HCC groups. Secondary endpoints involve comparing GAMAD with the established GALAD (Gender+Age+AFP-L3+AFP+DCP) model and each blood index (AFP, DCP and methylation signature) to evaluate: (1) GAMAD’s clinical utility for HCC patients in all stages according to different staging systems; (2) GAMAD’s discrimination ability for patients in various subgroups, including liver cirrhosis (LC) related HCC and LC, hepatitis B virus (HBV) related HCC and HBV, hepatitis C virus (HCV) related HCC and HCV, and non-alcoholic fatty liver disease (NAFLD) related HCC and NAFLD.

Ethics and dissemination
This trial has been approved by the Medical Ethics Committees of the First Hospital of Jilin University (#22K073-001), the Eastern Hepatobiliary Surgery Hospital, Naval Medical University (#EHBHKY2023-H0003-P001) and Tianjin Third Central Hospital (#IRB2023-007-01). All participants in the trial will provide written informed consent. Results of this study will be disseminated in peer-reviewed scientific journals and at conferences nationally and internationally.

Trial registration number
NCT05626985.

Objective
We aimed to construct and validate a prognostic nomogram to predict cancer-specific survival (CSS) after surgery in patients with advanced endometrial carcinoma (EC).

Design
Retrospective cohort study.

Setting and participants
The Surveillance, Epidemiology, and End Results (SEER) Database contains cancer incidence and survival data from population-based cancer registries in the USA. A total of 5445 patients from the SEER Database diagnosed with advanced EC between 2004 and 2015 were included and randomised 7:3 into a training cohort (n=3812) and a validation cohort (n=1633).

Outcome measure
CSS.

Results
The nomograms for CSS included 10 variables (positive regional nodes, age, tumour size, International Federation of Gynecology and Obstetrics (FIGO) stage, grade, ethnicity, income, radiation, chemotherapy and historical stage) based on the forward stepwise regression results. They revealed discrimination and calibration using the concordance index (C-index) and area under the time-dependent receiver operating characteristic curve, with a C-index value of 0.7324 (95% CI=0.7181 to 0.7468) and 0.7511 (95% CI=0.7301 to 0.7722) for the training and validation cohorts, respectively. Using calibration plots, a high degree of conformance was shown between the predicted and observed results. Additionally, a comparison of the nomogram and FIGO staging based on changes in the C-index, net reclassification index and integrated discrimination improvement demonstrated that the nomogram had better accuracy and efficacy.

Conclusions
We successfully constructed an accurate and effective nomogram to predict CSS in patients with advanced EC, which may help clinicians determine optimal individualised treatment strategies for patients with advanced EC. The predictive performance of the nomogram was evaluated thoroughly, but only internally. Therefore, further validation using different data sources is warranted in future related studies.

Objectives
The primary objective of our study was to evaluate the effectiveness of renal cell carcinoma (RCC) screening in renal transplant (RT) recipients.

Design
Single-centre retrospective study.

Setting and participants
1998 RT recipients who underwent RT at Memorial Hermann Hospital (MHH) Texas Medical Center (TMC) between 1 January 1999 and 31 December 2019 were included and we identified 16 patients (0.8%) with RCC. An additional four patients with RCC who underwent RT elsewhere but received follow-up at MHH TMC were also included. Subject races included white (20%), black (50%), Hispanic (20%) and Asian (10%).

Outcome measures
The RCC stage at diagnosis and outcomes were compared between patients who were screening versus those who were not.

Results
We identified a total of 20 patients with post-RT RCC, 75% of whom were men. The median age at diagnosis was 56 years. RCC histologies included clear cell (75%), papillary (20%) and chromophobe (5%). Patients with post-RT RCC who had screening (n=12) underwent ultrasound or CT annually or every 2 years, whereas eight patients had no screening. All 12 patients who had screening had early-stage disease at diagnosis (stage I (n=11) or stage II (n=1)) and were cured by nephrectomy (n=10) or cryotherapy (n=2). In patients who had no screening, three (37.5%) had stage IV RCC at diagnosis and all of whom died of metastatic disease. There was a statistically significant difference in RCC-specific survival in patients who were screened (p=0.01) compared with those who were not screened.

Conclusion
All RT recipients who had RCC diagnosed based on screening had early-stage disease and there were no RCC-related deaths. Screening is an effective intervention in RT recipients to reduce RCC-related mortality.

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

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.