Risultati per: Carcinoma ovarico e POCUS. Un caso clinico

Introduction
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and mortality rates have continued to rise despite advancements in treatment. Six-monthly ultrasound surveillance is recommended by professional bodies for early detection of HCC in high-risk cohorts. However, surveillance rates remain poor; only 20% of patients attend for regular surveillance. Population health outreach strategies may be able to enhance surveillance rates by addressing patient-related barriers to engagement with healthcare. Using a co-design approach, we have developed outreach material in tandem with patients, with the aim of boosting HCC surveillance. VIGILANT aims to compare the effectiveness of bespoke mailed surveillance invitations with or without patient navigators (PNs) in improving attendance rates at surveillance appointments.

Methods and analysis
This is a two-arm randomised controlled trial that will recruit 652 participants. Participants will be patients with chronic liver disease or cirrhosis, who are eligible for HCC surveillance as defined by criteria from the National Institute for Health and Care Excellence and European Association for the Study of the Liver. Participants will be randomised (in a 1:1 ratio) to receive either (a) a mailed surveillance invitation or (b) a mailed invitation plus telephone call reminder from a PN 1 week prior to the appointment. The primary objective is to evaluate the impact of PNs and mailed invitations on attendance rates. Secondary objectives include rates of diagnosis of early-stage HCC among patients undergoing surveillance and cost-effectiveness of each arm.

Ethics and dissemination
Approval has been sought to conduct the research from Aberdeen Research Ethics Committee (REC Reference: 335338). The study is sponsored by Imperial College London and funded by RM Partners (West London Cancer Alliance). Study findings will be presented at medical conferences and published in peer-reviewed journals.

Trial registration number
NCT06635694.

In Reply The Letter from Dr Lin and colleagues raises important points regarding the recent publication of the COMET trial for low-risk DCIS that merit further consideration.

To the Editor The COMET trial compared active monitoring with guideline-concordant care in patients with low-risk ductal carcinoma in situ (DCIS).

Usl, il paziente è un giovane in ‘buone condizioni generali’. Da febbraio ad aprile 61 quelli registrati

Background
Despite the success of immune checkpoint blockade, a lack of understanding of the hepatocellular carcinoma (HCC) immune microenvironment impedes its development.

Objective
We aim to elucidate the essential function of E-twenty-six-specific sequence variant 5 (ETV5) in regulating the immune microenvironment in HCC.

Design
Humanised mouse models, murine orthotopic models and diethylnitrosamine/carbon tetrachloride (DEN/CCl4)-induced HCC models were used to examine the function of ETV5. The downstream targets of ETV5 were screened using chromatin immunoprecipitation sequencing, CUT&Tag and RNA sequencing. Immune cells were examined using flow cytometry and immunofluorescence. S100 calcium-binding protein A9 (S100A9) was targeted by neutralising antibodies.

Results
Overexpression of ETV5 in HCC cells facilitated HCC metastasis and immune escape by recruiting and enhancing the immunosuppressive capabilities of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, ETV5 transactivated programmed death ligand 1 (PD-L1) and S100A9 expression. Inhibition of S100A9 or myeloid-specific knockout of toll-like receptor 4 (TLR4)/receptor for advanced glycation endproducts (RAGE), the receptors of S100A9, impeded ETV5-induced PMN-MDSC recruitment. Meanwhile, S100A9 within the tumour microenvironment elevated ETV5 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor-kappa B pathway. Additionally, ETV5 transcriptionally upregulated PD-L1 in MDSCs as well, thereby augmenting their immunosuppressive functions. Myeloid-specific Etv5 knockout attenuated HCC progression. We developed monoclonal neutralising-S100A9 antibodies that effectively inhibited ETV5-mediated PMN-MDSC infiltration. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy significantly suppressed ETV5-mediated HCC progression.

Conclusion
ETV5 facilitates HCC progression and metastasis by promoting the recruitment, infiltration and activation of PMN-MDSCs. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy holds great promise as an effective combinational treatment strategy for ETV5-positive HCC.

Background
Tumour-infiltrating T cells can mediate both antitumour immunity and promote tumour progression by creating an immunosuppressive environment. This dual role is especially relevant in hepatocellular carcinoma (HCC), characterised by a unique microenvironment and limited success with current immunotherapy.

Objective
We evaluated T cell responses in patients with advanced HCC by analysing tumours, liver flushes and liver-draining lymph nodes, to understand whether reactive T cell populations could be identified despite the immunosuppressive environment.

Design
T cells isolated from clinical samples were tested for reactivity against predicted neoantigens. Single-cell RNA sequencing was employed to evaluate the transcriptomic and proteomic profiles of antigen-experienced T cells. Neoantigen-reactive T cells expressing 4-1BB were isolated and characterised through T-cell receptor (TCR)-sequencing.

Results
Bioinformatic analysis identified 542 candidate neoantigens from seven patients. Of these, 78 neoantigens, along with 11 hotspot targets from HCC driver oncogenes, were selected for ex vivo T cell stimulation. Reactivity was confirmed in co-culture assays for 14 targets, with most reactive T cells derived from liver flushes and lymph nodes. Liver flush-derived T cells exhibited central memory and effector memory CD4+ with cytotoxic effector profiles. In contrast, tissue-resident memory CD4+ and CD8+ T cells with an exhausted profile were primarily identified in the draining lymph nodes.

Conclusion
These findings offer valuable insights into the functional profiles of neoantigen-reactive T cells within and surrounding the HCC microenvironment. T cells isolated from liver flushes and tumour-draining lymph nodes may serve as a promising source of reactive T cells and TCRs for further use in immunotherapy for HCC.

Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.
In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.

Introduction
Uterine serous carcinoma (USC) accounts for 40% of endometrial cancer-related deaths. The standard of care for stages III and IV USC yields a 20%–30% survival at 2 years and a 10%–20% survival at 3–5 years. Recent advances in the second-line treatment of advanced or recurrent USC are rapidly evolving. Targeted therapeutic approaches with the use of lenvatinib plus pembrolizumab, as well as the use of trastuzumab deruxtecan, offer new hope for successful second-line therapies for patients. However, further investigation into novel targeted therapeutic approaches is warranted, given the high burden of disease associated with this aggressive histological subtype. USC shares clinical and genomic similarities with epithelial ovarian cancer, suggesting a correlation with ‘BRCAness’. Niraparib, a potent PARP1 and PARP2 inhibitor, was shown to have a positive impact on platinum-sensitive recurrent ovarian cancer, regardless of the presence or absence of BRCA status. Our hypothesis is that patients with stage III, stage IV and platinum-sensitive recurrent USC receiving niraparib maintenance in addition to standard therapy for USC may have an improved progression-free survival.

Methods and analysis
Participating sites include the primary site, Northwell Health Zucker Cancer Centre, and secondary site, Rutgers Cancer Institute of NJ. Females over the age of 18 with stage III, stage IV or platinum-sensitive recurrent USC will be recruited and enrolled based on inclusion/exclusion criteria. 24 subjects will be enrolled during phase 1 and 21 subjects will be enrolled during phase 2, over a total of 3 years. Patients will receive an individualised dose of niraparib daily every 28 days per cycle for 1 year or until progression of disease. Follow-up of disease status will continue for 5 years poststudy treatment. This phase II clinical trial will employ a Simon two-stage minimax design to test the null hypothesis that the 1 year response rate is

Introduction
Oesophageal squamous cell carcinoma (ESCC) is a globally challenging digestive tract malignancy with poor prognosis and limited treatment options. Early-stage ESCC is often asymptomatic, leading to a late-stage diagnosis in many cases. Neoadjuvant therapy combined with surgery is the standard treatment approach for locally advanced ESCC. In recent years, immunotherapy has shown significant efficacy in ESCC. However, various neoadjuvant treatment regimens, including chemotherapy, radiotherapy and immunotherapy, have produced inconsistent outcomes. This study aims to evaluate the efficacy and safety of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) combined with immunotherapy compared with nCRT alone.

Methods and analysis
This is a prospective, multicentre, randomised, controlled phase III trial enrolling 420 patients with locally advanced thoracic ESCC. Patients will be randomly assigned (1:1:1) into three groups: (A) nCT plus sintilimab, (B) nCRT plus sintilimab or (C) nCRT alone. The primary endpoints are pathological complete response and event-free survival. Secondary endpoints include the objective remission rate, disease control rate, R0 resection rate, major pathological remission rate, disease-free survival, overall survival, patient quality of life and patient-reported outcomes. Data will be analysed using both the intention-to-treat and per-protocol approaches, with multiple imputation methods for handling missing data.

Ethics and dissemination
The study has been approved by the Ethics Committee for Medical Research and New Medical Technology of Sichuan Cancer Hospital (approval number: SCCHEC-02-2022-108). Written informed consent will be obtained from all participants. The findings will be disseminated through peer-reviewed journals and conference presentations.

Trial registration number
NCT05244798

To the Editor We commend Dawson and colleagues on the completion of the pivotal NRG Oncology/RTOG 1112 phase 3 trial. We emphasize a few considerations critical for the interpretation of this landmark trial.

To the Editor We read with interest the recent article by Dawson and colleagues. This multicenter, phase 3 study (RTOG 1112) offers robust evidence on stereotactic body radiotherapy (SBRT) followed by sorafenib in the treatment of locally advanced hepatocellular carcinoma (HCC). Although the primary outcome, overall survival (OS), did not demonstrate a statistically significant difference between the SBRT with sorafenib and sorafenib alone groups, a multivariable analysis adjusted for stratification factors revealed a 28% lower mortality risk for the SBRT plus sorafenib group. The study holds positive implications because its enrollment criteria matched radiologists’ clinical practices for treating patients with HCC. Several issues should be considered in designing and conducting future clinical studies in similar contexts.

In Reply Sherry et al and Song et al provide insightful remarks on the NRG/RTOG 1112 clinical trial that strengthen the conclusion regarding stereotactic body radiotherapy (SBRT) being associated with clinically important improvements in overall survival (OS) in patients with hepatocellular carcinoma (HCC). Using an adjusted model specific to phase 3 randomized clinical trials, Sherry et al estimate that the probability that SBRT and sorafenib improves OS was 97%, despite the univariate OS primary analysis with a hazard ratio (HR) of 0.77 (90% CI, 0.59 to 1.01) and 1-sided P value of .06, not meeting the statistically significant threshold. They point out that information provided by a P value of .06 vs .05 is nearly identical because P value is a continuous statistic, not binary. In fact, for the present study, the P value for the univariate OS end point was .055, but was reported as .06, consistent with the journal’s reporting guidelines. In addition to reporting effect sizes and clinical importance of the effect sizes, a consortium of statisticians recommended to “report P values to a single significant figure unless the P value is close to .05, in which case, report to 2 significant figures.” The Lancet requires that all P values should be reported to 2 significant figures, unless P 

This cohort study examines how risk factor number is associated with the risk of recurrence, metastasis, and disease-related death in cutaneous squamous cell carcinoma.

New England Journal of Medicine, Ahead of Print.

Objectives
This post hoc study aimed to evaluate the cost-effectiveness of hepatic artery infusion chemotherapy (HAIC) with fluorouracil, leucovorin and oxaliplatin (HAIC-FO) compared with sorafenib in patients with advanced hepatocellular carcinoma (HCC). The analysis was conducted from the perspective of Chinese payers.

Design
A cost-effectiveness analysis was performed using a Markov model derived from data obtained in the FOHAIC-1 trial (phase 3 randomised controlled trial; conducted 2017–2020).

Setting
The study was conducted in tertiary care centres in China.

Participants
The study included advanced HCC patients enrolled in the FOHAIC-1 trial. Inclusion criteria followed the trial protocols, with patients stratified by disease severity (including the presence of Vp4 portal vein tumour thrombus (PVTT) and high tumour burden).

Interventions
HAIC-FO (fluorouracil, leucovorin and oxaliplatin) was compared with sorafenib for cost and health outcomes.

Primary outcome measure
The primary outcome was the incremental cost-effectiveness ratio (ICER), calculated as the additional cost per quality-adjusted life year (QALY) gained.

Results
Sorafenib yielded 0.66 QALYs at a cost of $15 011.73, whereas HAIC-FO yielded 1.00 QALY at a cost of $18 470.98. The ICER of HAIC-FO compared with sorafenib was $10 235.56 per QALY, which was below the willingness-to-pay (WTP) threshold of $30 492.00 per QALY. Sensitivity analyses confirmed that HAIC-FO remained cost-effective across variable assumptions, with probabilistic sensitivity analysis showing a 99.9% probability of cost-effectiveness at the WTP threshold. Subgroup analyses demonstrated more favourable ICERs for patients with Vp4 PVTT ($7003.33 per QALY) and those with high tumour burden ($7382.86 per QALY).

Conclusions
HAIC-FO is a more cost-effective treatment for advanced HCC than sorafenib from the Chinese payer’s perspective, particularly in patients with Vp4 PVTT and/or high tumour burden. Further research is needed to explore long-term economic implications and real-world effectiveness data.

Trial registration number
NCT03164382.