Royal Free London NHS Foundation Trust

Multiparametric MRI (mpMRI) has transformed the diagnostic pathway for suspected prostate cancer by improving the detection of clinically significant prostate cancer (csPCa) and reducing unnecessary biopsies. However, its negative predictive value declines in higher-risk populations, and up to 30

People with a cancer signal detected via multi-cancer early detection (MCED) screening need timely access to confirmatory diagnostic testing. We estimated the likely change in demand for diagnostic testing in England if MCED screening were introduced. Diagnostic demand was modelled based on (1) estimates of the volume of people aged 50–79 years who would be referred for diagnostic investigation following a ‘cancer signal detected’ result after MCED screening and (2) MCED test performance metrics. Predicted usage was compared with current annual usage using routine NHS datasets. In an established MCED screening programme, assuming 70% of the total eligible population is screened annually (~13 million), the relative change in diagnostic demand was greatest for colonoscopy (+2.09%; +13,730 each year); the greatest absolute change was for computed tomography (CT; +0.76%; +62,320). This equates to +1040 colonoscopies and +4720 CT scans for every million screened. The predicted relative increase in diagnostic testing generated by MCED screening is small, though a large eligible population and maximum uptake could translate into a large number of procedures. Cancer diagnoses brought forward in time through screening should reduce diagnostic use for symptomatic presentations in the future.

Background Chronic hepatitis B virus (HBV) infection disproportionately affects people living with HIV, who are often excluded from functional cure studies.Objective This study investigates CD8+ T cell profiles in HBV mono-infection versus HBV/HIV co-infection, examining the impact of long-term therapy on virus-specific responses to inform therapeutic strategies for immune restoration.Design We analysed CD8+ T cell responses in 61 participants (HBV n=20, HBV/HIV n=20, HIV n=21), on suppressive antiviral therapy, assessing transcriptomic and proteomic profiles, focusing on exhaustion markers alongside virus-specific functional capabilities.Results Transcriptomic analysis revealed distinct signatures in co-infection, with upregulation of TCR signalling genes, inhibitory pathways and progenitor-exhausted markers (XCL2, TCF7, PDCD1, IL7R). This profile scored highly for a precursor exhausted (Tpex) CD8+ T cell signature, reflecting stemness that maintains plasticity despite chronic antigen exposure. Proteomic analysis confirmed higher frequencies of Tpex (TCF-1+CD127+PD-1+) CD8+ T cells in co-infection, while HBV mono-infection showed predominance of terminally exhausted ToxhighTCF-1-CD127- cells. Tpex enrichment extended to HBV-specific populations corresponding with more robust, polyfunctional HBV-specific responses in co-infection against surface and core antigens. HBV-specific CD8 T cells maintained enhanced proliferative capacity and checkpoint responsiveness to anti-PDL1 blockade compared with HBV mono-infection. While co-infection was characterised by lower HBsAg levels and longer treatment duration, these factors alone did not account for the distinct immunological profiles.Conclusions People with well-controlled HBV/HIV co-infection maintain robust CD8+ T cell responses with preserved stem-like properties supporting antiviral function. These results challenge assumptions about additive immune dysfunction in dual chronic infections and highlight the need for tailored immune-modulatory therapies.

BACKGROUND:HIV-specific broadly neutralising antibodies (bNAbs) can maintain viral control after interrupting antiretroviral therapy (ART). We investigated the duration and efficacy of Fc-engineered long-acting bNAbs (LS-bNAbs) in maintaining ART-free HIV control compared with placebo. METHODS:RIO is a double-blind, randomised, placebo-controlled trial. Eligibile participants were adults age 18-60 years, initiated on ART in early-stage HIV infection, virally suppressed on ART, and had no evidence of viral insensitivity to 10-1074. Participants were randomly assigned (1:1) to receive two LS-bNAbs (3BNC117-LS and 10-1074-LS) in arm A or saline placebo in arm B; participants and study staff were masked to assignment. Eligible participants interrupted ART after receiving blinded intravenous infusions of either bNAbs or placebo. A second optional infusion was offered after 20 weeks for participants who remained virally suppressed without ART. The primary outcome was time to viral rebound 20 weeks after ART interruption, defined as either the first of six consecutive plasma HIV RNA measurements greater than 1000 copies per mL, or two measurements greater than 100 000 copies per mL. All randomly assigned participants were included in the analyses. This study is registered with ClinicalTrials.gov, NCT04319367. FINDINGS:68 participants were randomly assigned, 34 to each arm. By week 20, viral rebound had occurred in eight participants in arm A and 30 in arm B; 75% (95% CI 61-92) of participants in arm A did not have viral rebound, compared with 11% (4-29) of participants in arm B. Participants in arm A were 91% less likely to rebound than were those in arm B (hazard ratio 0·09; 95% CI 0·04-0·21, p<0·0001). There were 326 adverse events in arm A and 260 in arm B, including 19 treatment-related or procedure-related adverse events in arm A and 41 in arm B. Of nine serious adverse events, none were treatment-related. The most commonly reported treatment-related or procedure-related adverse events were fatigue, lethargy, or somnolence: 11 in arm A and nine in arm B. There were two severe adverse events (anal abscesses) possibly related to the study protocol, both in the placebo arm. INTERPRETATION:Long-acting bNAbs can sustain extended ART-free viral control in people treated during early-stage HIV and represent a promising step towards achieving ART-free HIV remission. FUNDING:Gates Foundation.

Introduction:The phase 3 REFLECT trial demonstrated the efficacy and safety of lenvatinib versus sorafenib in the first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC). We report results from STELLAR, a non-interventional post-marketing study. The primary objectives were to characterize hepatotoxicity and overall safety of lenvatinib in patients from Western regions with uHCC. Methods:STELLAR was a prospective, open-label, observational, phase 4 study of patients treated with lenvatinib (n = 193). A cohort of sorafenib-treated patients (n = 123) was included as an internal reference group. The treating physician made the decision to treat patients with lenvatinib or sorafenib before enrollment. Study drugs were administered according to the Summary of Product Characteristics guidelines. Safety and efficacy evaluations were performed according to standard clinical practice at each site. The primary endpoint was safety. Secondary endpoints included treatment exposure and overall survival. Results:The median duration of treatment with lenvatinib or sorafenib was 6.5 months (range, 0.2-33.1 months) and 4.4 months (range, 0.5-30.7 months), respectively. Hepatotoxicity treatment-emergent adverse events (TEAEs) were observed in 26.9% of lenvatinib-treated patients and 33.3% of sorafenib-treated patients. The most frequently reported hepatotoxicity TEAEs were hepatic encephalopathy (7.8%; lenvatinib cohort) and ascites (11.4%; sorafenib cohort), respectively. Overall, 85.0% of lenvatinib-treated patients and 84.6% of sorafenib-treated patients experienced ≥1 TEAE. Median overall survival (95% CI) was 16.9 months (14.1-not estimable) in lenvatinib-treated patients. Conclusion:Our findings support the established safety and efficacy of lenvatinib in first-line patients with uHCC.