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PubMed2026

Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial.

BACKGROUND: Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. We assessed whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality-of-life harms without compromising oncological outcomes. METHODS: STAR-TREC is an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial in five European countries. Eligible patients were aged 16 years or older in the UK or aged 18 years or older elsewhere, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and rectal adenocarcinoma (≤40 mm staged as mrT1-T3bN0). In phase 2, participants were randomly assigned (1:1:1) to LCCRT-based organ preservation (LCCRT-OP; 50 Gy in 25 fractions plus oral capecitabine 825 mg/m2 twice daily), SCRT-based organ preservation (SCRT-OP; 25 Gy in five fractions), or primary TME. Phase 2 assessed feasibility, with recruitment at months 12 and 24 as the primary endpoint and feasibility thresholds of four or more and six or more randomisations per month, respectively. Phase 3 adopted a partially randomised patient-preference design, allowing participants to choose either organ preservation or TME. Participants that chose organ preservation were randomly assigned (1:1) to receive LCCRT-OP or SCRT-OP using centralised, computer-generated assignment, with stratification by country and MRI T category (≤T3a vs T3b) using minimisation. The phase 3 primary endpoint was organ-preservation 30 months after treatment initiation, defined as absence of TME, stoma, or local recurrence, which was assessed in the modified intention-to-treat population, which included participants in phase 2 and phase 3. After a planned interim analysis of unmasked phase 2 data, the trial steering committee and independent data monitoring committee recommended reporting a 12-month, modified intention-to-treat analysis of implementation outcomes for participants recruited before Aug 8, 2023. This study is registered with ISRCTN (14240288) and is closed. FINDINGS: Between June 14, 2017, and April 8, 2024, 503 participants were enrolled at 37 sites. Phase 2 enrolled 120 participants, with recruitment rates of three and six participants per month at months 12 and 24, respectively. Overall, 12-month TME-free survival was 60% (47 of 78 participants). After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month median TME-free survival not reached [95% CI not reached-not reached] vs 7·6 months [95% CI 6·4-not reached]; hazard ratio [HR] 3·7 [95% CI 1·7-8·0]; posterior probability of superiority >99·5%). The trial steering committee and independent data monitoring committee therefore recommended expanded analysis of 426 participants recruited before Aug 8, 2023: 120 from phase 2 and 306 from phase 3. 17 participants withdrew before treatment, leaving 409 in the modified intention-to-treat population: 163 allocated to LCCRT, 168 to SCRT, and 78 to primary TME. 116 (28%) participants were female and 293 (72%) were male. Among participants who opted for organ preservation, 12-month TME-free survival was 78·5% (95% CI 72·4-85·1) with LCCRT and 60·6% (53·6-68·4) with SCRT (HR 1·90 [95% CI 1·29-2·81]). The most common grade 3-4 serious adverse events were gastrointestinal disorders (four [2%] with LCCRT vs six [4%] with SCRT vs six [8%] with TME) and procedural complications (three [2%] with LCCRT vs five [3%] with SCRT vs five [6%] with TME). One participant allocated to primary TME died after an anastomotic leak. INTERPRETATION: These early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months. Organ-preservation might also reduce treatment-related toxicity compared with primary TME. Longer follow-up is needed for the prespecified 30-month endpoint and definitive functional and oncological outcomes. FUNDING: Cancer Research UK, Stand Up to Cancer, Dutch Cancer Society, Danish Cancer Society, Kom Op Tegen Kanker, Cancerfonden, ALF Region Stockholm, RCC Region Stockholm.

Humans↗
PubMed2026

Pegcetacoplan Delivers Real-World Therapeutic Benefits and Reduces Disease Burden for Patients With Paroxysmal Nocturnal Haemoglobinuria: A Systematic Literature Review of Pegcetacoplan Real-World Clinical and Patient-Reported Outcomes.

AIMS: Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired, non-malignant haematological disorder that, if left untreated, can lead to significant morbidity. This systematic literature review (SLR) summarized real-world evidence (RWE) for pegcetacoplan, a complement 3/3b inhibitor (C3i) available since 2021. METHODS: The SLR (PROSPERO-CRD420251043506) followed 2020 PRISMA guidelines and included RW studies of pegcetacoplan (n > 1 pts.; English; to April 2025) in adults (age ≥ 18 years) with PNH. RESULTS: Of 409 identified records, 39 qualified, representing 12 distinct studies. Six studies (n = 4-39) reported median haemoglobin (Hb) with baseline 8.1-9.6 g/dL. Ending median Hb and maximum pegcetacoplan durations were: 12.0 g/dL at 12 months, 11.1-12.1 g/dL at 6 months (3 studies), and 11.1 g/dL at 3 months (1 study). In 4 other studies (n = 48-70), ending mean Hb (maximum pegcetacoplan duration) was: 11.3 g/dL (7.2 months), 11.5 g/dL (6.6 months), 11.5 g/dL (5.9 months), and 11.58 g/dL (3 months). Six studies reported reduced absolute reticulocyte count (ARC; n = 4-39) from baseline median 155-301 × 109/L to median 56-106 × 109/L from 14 days of pegcetacoplan, maintained to maximum pegcetacoplan of 1-12 months. Three studies reported lactate dehydrogenase (LDH; n = 4-62); all showed reductions from baseline median 543.0 to 161.7 U/L after 3 months, and baseline median 299.5-316.0 U/L to 193.5-187.0 U/L after 6 months of pegcetacoplan. In complement 5 inhibitor-naïve, LDH reduced from 977.8 to 358.9 U/L after 8.4 months, and 503.6 to 292.5 U/L in C5i-experienced after 7.2 months. Three studies (n = 4-63) reported reduced LDH from above the upper limit of normal levels. Six studies (n = 23-70) reported reduced red blood cell transfusions (RBCt) after maximum pegcetacoplan durations of up to 12 months, and median durations of 3.0 and 10.2 months. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale scores in 1 study increased from baseline (mean 28.4) to 38.6 at 3 months, 36.3 at 6 months, and 34.9 at 9 months of pegcetacoplan treatment. Two studies reported FACIT-Fatigue scores of 34.6-40.1 with pegcetacoplan for ≥ 1 month. EQ-5D mean utility scores (0.85-0.94) in 2 studies were comparable to population normative values. On the Short-Form 36 Health Survey, mental and physical component scores were slightly lower than US normative values. CONCLUSIONS: RWE indicates pegcetacoplan is associated with improved haematological outcomes, reduced RBCt dependence and fatigue, and enhanced HRQoL. These findings from real-world studies with diverse cohorts support generalizability and are broadly comparable with clinical trial evidence.

Humans↗
PubMed2026

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22&#xb7;3 months (95% CI 21&#xb7;5-23&#xb7;0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6&#xb7;8 months (95% CI 5&#xb7;7-7&#xb7;1) in the ivonescimab plus chemotherapy group versus 4&#xb7;4 months (4&#xb7;1-5&#xb7;5) in the placebo plus chemotherapy group (hazard ratio [HR] 0&#xb7;52; 95% CI 0&#xb7;41-0&#xb7;66; p<0&#xb7;0001). At a median follow-up of 29&#xb7;7 months (95% CI 27&#xb7;7-31&#xb7;0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16&#xb7;8 months (14&#xb7;3-19&#xb7;0) in the ivonescimab plus chemotherapy group versus 14&#xb7;0 months (12&#xb7;8-15&#xb7;7) in the placebo plus chemotherapy group (HR 0&#xb7;79; 0&#xb7;62-1&#xb7;01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING: Summit Therapeutics.

Humans↗
PubMed2026

Beyond Glycaemia: Fear of Hypoglycaemia, Cognition and Functional Mobility After Advanced Hybrid Closed-Loop Therapy in Older Adults With Type 1 Diabetes: A Prespecified Secondary Analysis of a Randomised, Single-Centre Study.

BACKGROUND: Evidence on psychological, cognitive and functional outcomes of advanced diabetes technologies in older adults with long-standing type 1 diabetes (T1D) remains limited. We evaluated whether initiation of advanced hybrid closed-loop (AHCL) therapy was associated with changes in fear of hypoglycaemia, diabetes distress, psychological well-being, cognition, frailty-related measures and mobility-related function in adults aged &#x2265;&#x2009;65&#x2009;years with T1D. METHODS: This prespecified, exploratory secondary analysis was conducted within a single-centre, open-label, randomised, controlled, parallel-group trial including adults aged &#x2265;&#x2009;65&#x2009;years with long-standing T1D. Participants were randomly assigned (1:1) to initiate AHCL therapy using the MiniMed 780G system or to continue standard diabetes treatment. The secondary outcomes included WHO-5, the 17-item Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey-II (HFS-II), Montreal Cognitive Assessment, Digit Symbol Substitution Test, Fried frailty phenotype and performance-based functional measures. No formal sample-size calculation was performed for these secondary outcomes. RESULTS: Thirty-one participants were randomised and 29 completed 12&#x2009;months of follow-up and were included in the treatment-effect analyses. In the baseline-adjusted primary analysis, AHCL therapy was associated with a lower HFS-II score than standard treatment (adjusted mean difference -18.9; 95% CI: -32.4 to -5.4; nominal p&#x2009;=&#x2009;0.008), although this finding did not remain statistically significant after Holm correction (adjusted p&#x2009;=&#x2009;0.104) or in an exploratory model additionally adjusted for sex (difference -13.6; 95% CI: -32.2 to 5.0; p&#x2009;=&#x2009;0.145). Diabetes distress, psychological well-being, global cognition and processing speed did not differ between groups. In sex-adjusted sensitivity analyses, the between-group differences remained statistically significant for 6-min walk distance (92.6&#x2009;m; 95% CI: 36.8 to 148.3; p&#x2009;=&#x2009;0.002) and Timed Up and Go performance (-2.27&#x2009;s; 95% CI: -4.28 to -0.27; p&#x2009;=&#x2009;0.028), but not for gait speed (0.27&#x2009;m/s; 95% CI: -0.05 to 0.59; p&#x2009;=&#x2009;0.099). At 12&#x2009;months, 12 of 14 AHCL participants were robust and 2 were pre-frail; in the control group, 11 of 15 were robust and 4 were pre-frail. No participant was classified as frail at follow-up. CONCLUSIONS: In this small, selected cohort, AHCL therapy was associated with a nominally lower fear-of-hypoglycaemia score and better performance on selected mobility-related tests over 12&#x2009;months. The fear-of-hypoglycaemia finding did not remain statistically significant after correction for multiple comparisons or additional adjustment for sex. Six-minute walk distance and Timed Up and Go remained statistically significant in the exploratory sex-adjusted sensitivity analyses, whereas the gait-speed difference did not. No measurable between-group deterioration in global cognition or processing speed was observed. These exploratory findings require confirmation in larger studies with balanced representation by sex and direct measurement of physical activity. These findings also support a person-centred clinical message: older age alone should not be regarded as a barrier to AHCL when treatment is introduced with individualised education and appropriate ongoing support.

Humans↗
PubMed2026

Outcomes of Response-Based Watch-and-Wait and Surgical Management After Total Neoadjuvant Therapy for Rectal Cancer: A Systematic Review and Meta-analysis.

BackgroundTotal neoadjuvant therapy (TNT) increases clinical complete response rates in locally advanced rectal cancer (RC), allowing response-based management strategies such as watch-and-wait (WW) as an alternative to total mesorectal excision (TME). Outcomes associated with WW after TNT remain incompletely defined. This study aimed to compare oncologic and organ-preservation outcomes between WW and surgical management following TNT.MethodsA systematic search was conducted in PubMed, Scopus, and Cochrane Central up to April 2025. Observational studies comparing WW and TME following TNT were included. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed with I2 statistics. Secondary outcomes included tumor regrowth, salvage surgery, and permanent stoma. Risk of bias was evaluated using ROBINS-I.ResultsSix studies comprising 793 patients were analyzed. WW showed no significant difference compared with TME regarding local recurrence (OR 1.36, 95% CI 0.07-26.17; I2 = 80%), distant metastases (OR 0.62, 95% CI 0.29-1.33; I2 = 49%), 5-year disease-free survival (HR 0.97, 95% CI 0.71-1.31; I2 = 51.7%), or overall survival (HR 1.03, 95% CI 0.81-1.30; I2 = 27.9%). Permanent stoma rates were lower with WW (OR 0.12, 95% CI 0.01-1.23; I2 = 71%), becoming significant after sensitivity analysis (OR 0.04, 95% CI 0.01-0.19).ConclusionWW after TNT offers oncologic outcomes comparable to TME, with high organ preservation and reduced surgical morbidity in highly selected patients.

Humans↗
PubMed2026

Comfort and Usability of Digital Versus Conventional Custom-Fit Mouthguards: A Randomized Clinical Trial.

BACKGROUND/OBJECTIVES: The use of mouthguards protects teeth and the supporting tissues against impacts. Digital impressions and 3D-printed models can reduce manufacturing steps and minimize discomfort. This study evaluated the fit, comfort, and usability of custom-made mouthguards, obtained by conventional and digital workflow, in amateur athletes. MATERIALS AND METHODS: Amateur athletes were recruited for this randomized, double-blind, crossover clinical study. Each participant received two 4-mm-thick custom-fit mouthguards made of ethylene vinyl acetate (EVA) sheets using two protocols: conventional impression using alginate to produce dental stone cast (CMP) and intraoral digital scanning to produce 3D-printed resin models (DMP). Each mouthguard was worn during all training and matches over 3&#x2009;months. The order of mouthguard use was randomly assigned. Patient satisfaction with the impression protocol and mouthguard use, model accuracy, and mouthguard fit were assessed. RESULTS: Overall, 46 participants completed the study. The DMP protocol required less execution time (p&#x2009;=&#x2009;0.023), caused less discomfort (p&#x2009;=&#x2009;0.018), anxiety (p&#x2009;=&#x2009;0.008), nausea (p&#x2009;=&#x2009;0.027), difficulty breathing (p&#x2009;<&#x2009;0.001), and unpleasant taste (p&#x2009;=&#x2009;0.006) compared to the CMP protocol. The pain (p&#x2009;=&#x2009;0.971) perceived by the participants was similar in both impression protocols. The CMP-mouthguards were considered to be better fitting by the majority of participants (p&#x2009;=&#x2009;0.027). Between-group comparisons revealed that DMP-mouthguard caused less discomfort immediately postadaptation (p&#x2009;=&#x2009;0.034), with no significant differences observed at 30 or 90&#x2009;days. CONCLUSIONS: The digital workflow demonstrated to be efficient in the fabrication of mouthguards. Digital impression was more comfortable, requiring less execution time, with more accurate printed models and produced mouthguards with reported comfort and fit levels similar to those manufactured conventionally.

Humans↗
PubMed2026

Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults.

Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling. However, the ability to augment Nrf2 activation and its effects on age- and disuse-related vascular dysfunction in humans remains limited. In a double-blind, randomized, placebo-controlled study design 20 younger adults (8M/12F, age 27&#x202f;&#xb1;&#x202f;7&#x202f;y) and 24 older adults (12M/12F, age 67&#x202f;&#xb1;&#x202f;8&#x202f;y) were randomized to receive either placebo or PB125 (200&#x202f;mg/day, Nrf2 activator) across three visits: baseline, 2 weeks of supplementation, and following either 5 days of bed rest (old) or 2 weeks of limb immobilization (young). Brachial and popliteal artery flow-mediated dilation (FMD), passive leg movement-induced (PLM) leg blood flow (LBF) and vascular conductance (LVC) and serum antioxidant status (superoxide dismutase, SOD) were assessed at each timepoint. Compared to placebo, 2 weeks of PB125 increased brachial (PB125: 2.8&#x202f;&#xb1;&#x202f;1.5 to 3.8&#x202f;&#xb1;&#x202f;1.3%, p&#x202f;<&#x202f;0.0001) and popliteal FMD (PB125: 1.5&#x202f;&#xb1;&#x202f;1.5 to 2.3&#x202f;&#xb1;&#x202f;1.4%, p&#x202f;=&#x202f;0.033) in older, but not younger adults (both, p&#x202f;>&#x202f;0.27). During bed rest, PB125 preserved brachial (3.8&#x202f;&#xb1;&#x202f;1.3 to 3.6&#x202f;&#xb1;&#x202f;1.4%, p&#x202f;=&#x202f;0.543) and popliteal FMD (2.3&#x202f;&#xb1;&#x202f;1.4 to 2.7&#x202f;&#xb1;&#x202f;1.4%, p&#x202f;=&#x202f;0.269), LVC (1.1&#x202f;&#xb1;&#x202f;0.8 to 1.1&#x202f;&#xb1;&#x202f;1.5 AUC, p&#x202f;=&#x202f;0.530) and circulating SOD concentrations (28.3&#x202f;&#xb1;&#x202f;7.2 to 28.6&#x202f;&#xb1;&#x202f;8.6 U/mL, p&#x202f;=&#x202f;0.888) in older adults compared to placebo (all, p&#x202f;<&#x202f;0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4&#x202f;&#xb1;&#x202f;2.8 to 3.4&#x202f;&#xb1;&#x202f;1.8%, p&#x202f;=&#x202f;0.302) in younger adults compared to placebo (p&#x202f;<&#x202f;0.05). These findings demonstrate targeted Nrf2 activation with PB125 improves age-related vascular endothelial dysfunction while preserving vascular function and antioxidant capacity following periods of disuse.

Humans↗
PubMed2026

A homogeneous immunoassay based on AlphaLICA technology for detecting florfenicol residues in animal-derived foods.

Florfenicol (FF), a broad-spectrum amide antibiotic widely used in livestock, poultry, and aquaculture, poses potential threats to food safety and public health due to its residual accumulation. In this study, a novel homogeneous immunoassay based on Amplified Luminescent Proximity Homogeneous Assay (AlphaLICA) technology was developed for the first time for rapid screening of FF residues in milk and egg matrices. By covalently immobilizing the FF-BSA conjugate and goat anti-mouse IgG onto luminescent and photosensitive microspheres, respectively, the method achieved wash-free, homogeneous quantitative detection through a competitive immunoreaction. Under optimized conditions, the assay exhibited a linear range of 0.2-16.2 ng mL-1, with a limit of detection of 9.7 pg mL-1 and a limit of quantification of 183 pg mL-1. The intra- and inter-batch coefficients of variation ranged from 3.08% to 5.70% and 2.44% to 7.09%, respectively. Spike recovery rates in milk and egg matrices ranged from 93.18% to 107.17% (RSD &#x2264; 5.57%). Cross-reactivity with 11 other common antibiotics, including chloramphenicol and thiamphenicol, was below 0.1%, demonstrating excellent specificity. Comparative analysis with a commercial ELISA kit showed high consistency (r2 = 0.9332, p < 0.001). With high sensitivity, strong specificity, simple operation, and a detection time of only 10 min, this method provides a reliable technical platform for high-throughput, rapid monitoring of FF residues in milk and egg matrices.

Journal Article↗
PubMed2026

Reduced Length of ADT and ARTA With XRT in High-Risk Prostate Cancer (RELAX): A Randomised Controlled Trial.

AIM: To assess the efficacy of a short, intensified regimen of androgen deprivation therapy (ADT) and androgen receptor-targeted agent (ARTA) with curative-intent external beam radiotherapy (XRT) for high-risk prostate cancer (HRPCa) staged with prostate specific membrane antigen (PSMA) imaging. MATERIALS AND METHODS: The RELAX (Reduced Length of ADT and ARTA with XRT in high-risk prostate cancer) trial is a multicentre, phase II randomised non-inferiority trial comparing 9 months of ADT and 6 months of ARTA against the standard 24-month ADT, with definitive dose-escalated hypofractionated pelvic radiotherapy for PSMA-staged non-metastatic HRPCa. The primary endpoint is 5-year disease-free survival (DFS), defined from randomisation to first biochemical or clinico-radiological recurrence or any-cause death. Secondary endpoints include biochemical failure-free survival, metastasis-free survival, overall survival, testosterone recovery, treatment-related adverse effects, and patient-reported outcomes. Participants are monitored with serial serum PSA and testosterone levels, CTCAE and PRO-CTCAE assessments, and PSMA-PETCT at recurrence. The non-inferiority margin is set at 10% absolute difference from an expected 5-year DFS of 85% in the standard arm, with intention-to-treat analysis. The trial is ethics board approved and funded by institutional intramural grant, and registered on clinicaltrials.gov (NCT06818682). RESULTS: The planned accrual of 206 participants commenced in February 2025, with nearly a third of enrolment completed till date. CONCLUSION: The RELAX trial incorporates contemporary standards of PSMA-based staging, dose-escalated hypofractionated radiotherapy, and ARTA for HRPCa. The results are expected to inform the efficacy of a shorter, intensified androgen suppression strategy against the prevailing standard of long-term ADT for these patients.

Humans↗
PubMed2026

Effect of flavored on!&#xae; nicotine pouch products on smoking behaviors: A sequential, multiple assignment, randomized controlled trial.

PURPOSE: To evaluate whether flavored versus unflavored nicotine pouch (NP) access affects cigarette reduction and smoke exposure among adults who smoke daily, and whether delayed flavor introduction affects these outcomes. METHODS: Adults who smoked &#x2265;&#x2009;5 cigarettes/day (CPD) with interest in replacing cigarettes with NPs were enrolled in a remote, six-week, sequential multiple assignment randomized trial (n&#x2009;=&#x2009;402 randomized; n&#x2009;=&#x2009;400 analyzed). Participants were randomized to immediate access to seven NP flavors (Flavor), unflavored-only access for six weeks (Original), or unflavored-only for three weeks followed by flavor access (Delayed Flavor). Primary outcomes were &#x2265;&#x2009;50% reduction in weekly mean expired-air carbon monoxide (CO) from baseline and mean CO at Week 6. Secondary outcomes included &#x2265;&#x2009;50% CPD reduction, mean CPD, CO-verified 7-day abstinence, and incident smoke-free days. RESULTS: At Week 6, Flavor and Original did not differ in &#x2265;&#x2009;50% CO reduction (14.3% vs 14.2%; IRR=1.0, 95% CI=0.6-1.8) or mean CO (18.3 vs 16.5&#x2009;ppm; &#x3b2;=1.9, 95% CI=-1.3-5.0). CPD decreased across groups by Week 6, with no differences between Flavor and Original in &#x2265;&#x2009;50% CPD reduction (50.3% vs 51.6%; IRR=1.0, 95% CI=0.8-1.2) or CO-verified abstinence (9.3% vs 8.9%; IRR=1.0, 95% CI=0.5-2.2). Flavor increased smoke-free days early, with attenuation over time. Among Week 3 non-responders, delayed flavor access increased &#x2265;&#x2009;50% CPD reduction at Week 6 (33.3% vs 18.6%; IRR=1.8, 95% CI=1.0-3.2). CONCLUSIONS: NP access supported cigarette reduction regardless of flavor availability, but flavors may accelerate smoke-free days and improve response among individuals who do not reduce cigarette consumption with unflavored products alone.

Humans↗
PubMed2026

Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin: A Randomized Controlled Trial.

BACKGROUND: Fear of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of community-acquired pneumonia (CAP) frequently leads to empiric vancomycin coverage. Data evaluating the use of MRSA polymerase chain reaction (PCR) nasal swab testing to guide vancomycin de-escalation is limited for patients in the intensive care unit (ICU). METHODS: Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin (STOP-Vanc) is a pragmatic, prospective, single-center, non-blinded randomized trial in which adult ICU patients with suspicion of CAP were randomized 1:1 to receive usual care either with (intervention) or without (control) the addition of MRSA nares PCR testing following ICU admission. The primary outcome was vancomycin-free hours alive, defined as the expected number of hours alive and free of vancomycin use within the first 7 days of trial enrollment as estimated using a longitudinal proportional odds state transition model adjusted for baseline covariates. RESULTS: A total of 277 adult ICU patients were randomized. Methicillin-resistant Staphylococcus aureus PCR nasal swab testing had a negative predictive value (NPV) of 98.9% in the intervention arm. The primary endpoint, vancomycin-free hours alive, was 105.7 in the control arm and 109.7 in the intervention arm (adjusted difference, 4 hours; 95% CI, -9.5-18.2; P = .458). CONCLUSIONS: Despite MRSA PCR nasal swab testing demonstrating a high NPV in this critically ill population, MRSA PCR nasal swab testing did not decrease the duration of vancomycin use or 30-day mortality among ICU patients with suspected CAP. Additional clinician education and antimicrobial stewardship interventions might be needed to reduce vancomycin use in this patient population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT06272994 (STOP-Vanc).

Humans↗
PubMed2026

Durvalumab and tremelimumab, with or without lenvatinib, combined with transarterial chemoembolisation in participants with embolisation-eligible hepatocellular carcinoma (EMERALD-3): a global, randomised, open-label, sponsor-blinded, phase 3 study.

BACKGROUND: Transarterial chemoembolisation (TACE), a standard treatment for embolisation-eligible hepatocellular carcinoma (HCC), induces tumour immune responses. Single tremelimumab regular interval durvalumab (STRIDE) is a standard treatment in advanced HCC. In this phase 3 trial, we assessed the efficacy and safety of STRIDE, with or without lenvatinib, plus TACE, in participants with embolisation-eligible HCC. METHODS: EMERALD-3 is a phase 3, randomised, open-label, sponsor-blinded study, conducted at 177 medical sites in 21 countries. Eligible participants were 18 years or older (aged &#x2265;21 years in Egypt or Singapore) at screening and had confirmed HCC (by imaging or histopathologically from biopsy specimen, surgery, or both) not amenable to curative surgery, curative ablation, or transplantation but amenable to TACE. Participants had Child-Pugh class A liver function, an Eastern Cooperative Oncology Group performance status of 0-1, and at least one measurable target intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumours. Participants were randomly allocated in a 1:1:1 ratio to receive STRIDE plus lenvatinib plus TACE, STRIDE plus TACE, or TACE until each group reached its preplanned enrolment target of 175 participants. After the STRIDE plus TACE group reached its enrolment target, randomisation was adjusted to continue in a 1:1 ratio between the STRIDE plus lenvatinib plus TACE group and TACE group until approximately 275 participants were enrolled in each of these two groups. Randomisation used a centrally assigned interactive response technology system, stratified by region, baseline tumour burden, and previous palliative embolisation. In the STRIDE plus lenvatinib plus TACE group, on the first day, participants were given 300 mg tremelimumab intravenously, followed by 1500 mg durvalumab plus oral lenvatinib (8 mg for <60 kg bodyweight or 12 mg for &#x2265;60 kg bodyweight); participants then received 1500 mg durvalumab every 4 weeks plus once-daily lenvatinib for up to 36 cycles. In the STRIDE plus TACE group, participants were given 300 mg tremelimumab and 1500 mg durvalumab intravenously on the first day, followed by 1500 mg durvalumab every 4 weeks. The technique and number of TACE procedures were at the investigators' discretion, with the first procedure administered at least 7 days after the first dose of durvalumab in the two investigation treatment groups and within 7 days of random allocation in the TACE group. The primary endpoint was progression-free survival for STRIDE plus lenvatinib plus TACE versus TACE. Key secondary endpoints were overall survival for STRIDE plus lenvatinib plus TACE versus TACE and progression-free survival and overall survival for STRIDE plus TACE versus TACE. This study was registered with ClinicalTrials.gov (NCT05301842), with enrolment completed. FINDINGS: From March 28, 2022, to Nov 20, 2024, 1124 participants were screened. The full analysis set comprised 760 participants, who were randomly allocated to STRIDE plus lenvatinib plus TACE (n=293), STRIDE plus TACE (n=175), or TACE (n=292). 633 (83%) participants were male and 127 (17%) were female; 548 (72%) were Asian. At the first data cutoff (Sept 2, 2025); the overall median follow-up for progression-free survival was 10&#xb7;0 months (IQR 4&#xb7;6-17&#xb7;2); median follow-up for progression-free survival was 11&#xb7;0 months (IQR 4&#xb7;8-18&#xb7;4) for STRIDE plus lenvatinib plus TACE and 8&#xb7;3 months (4&#xb7;1-15&#xb7;5) for TACE. Median progression-free survival was 13&#xb7;0 months (95% CI 12&#xb7;2-16&#xb7;7) for STRIDE plus lenvatinib plus TACE versus 9&#xb7;8 months (8&#xb7;0-11&#xb7;4) for TACE (HR 0&#xb7;70 [95% CI 0&#xb7;57-0&#xb7;86]; p=0&#xb7;0007). At the second data cutoff (Feb 23, 2026) and a median follow-up for overall survival of 24&#xb7;6 months (IQR 16&#xb7;5-31&#xb7;5) for STRIDE plus lenvatinib plus TACE and 22&#xb7;9 months (14&#xb7;9-30&#xb7;2) for TACE, median overall survival was 39&#xb7;5 months (95% CI 34&#xb7;1-not reached) for STRIDE plus lenvatinib plus TACE and 34&#xb7;7 months (28&#xb7;8-not reached) for TACE (HR 0&#xb7;84 [95% CI 0&#xb7;65-1&#xb7;09]; p=0&#xb7;18). At this data cutoff, median progression-free survival was 12&#xb7;9 months (95% CI 10&#xb7;2-15&#xb7;9) for STRIDE plus TACE and 8&#xb7;1 months (6&#xb7;5-10&#xb7;2) for the first 175 participants randomised to TACE (HR 0&#xb7;71 [95% CI 0&#xb7;56-0&#xb7;91]), with median follow-up of 10&#xb7;3 months (IQR 4&#xb7;6-23&#xb7;7) for STRIDE plus TACE and 7&#xb7;7 months (3&#xb7;0-18&#xb7;5) for the first 175 participants randomly allocated to TACE. The most common adverse events of maximum grade 3 or 4 were hypertension (34 [12%] of 287) for STRIDE plus lenvatinib plus TACE, post-embolisation syndrome and anaemia (ten [6%] of 175 each) for STRIDE plus TACE, and post-embolisation (17 [6%] of 290) for TACE. 184 (64%) participants receiving STRIDE plus lenvatinib plus TACE, 89 (51%) receiving STRIDE plus TACE, and 68 (23%) receiving TACE had serious adverse events. Treatment-related adverse events with an outcome of death during the treatment-emergent period occurred in seven (2%) of 287 participants who received STRIDE plus lenvatinib plus TACE (two for myocarditis; and one each for hepatic failure, haemophagocytic lymphohistiocytosis, septic shock, cardiac failure, and unknown cause), none of 175 participants who received STRIDE plus TACE, and two (1%) of 290 participants who received TACE (one each for acute myocardial infarction and unknown cause). INTERPRETATION: STRIDE plus lenvatinib plus TACE showed a statistically significant progression-free survival improvement versus TACE. These findings support a STRIDE-based regimen as a potential new treatment option for people with embolisation-eligible HCC; additional follow-up is being conducted for final analysis of overall survival across treatment groups. FUNDING: AstraZeneca.

Adult↗
PubMed2026

Candidate biomarkers for early Giardia duodenalis infection revealed by time-resolved secretome proteomics.

Giardia duodenalis is a zoonotic protozoan parasite that causes giardiasis in humans and other mammals. Early diagnosis remains challenging because current diagnostic methods, including microscopy and enzyme-linked immunosorbent assays (ELISAs), primarily detect established infections. Consequently, a critical diagnostic gap exists during the early stage of infection within the first 2-48&#xa0;h following exposure. To address this limitation, we characterized the proteins released by in vitro-cultured G. duodenalis trophozoites under serum-free conditions and evaluated their potential as early diagnostic biomarkers. Proteomic analysis of culture supernatants collected during early trophozoite incubation identified 31,773 peptides corresponding to 2504 quantifiable proteins. Temporal profiling showed distinct secretion patterns, including proteins that peaked during the early stage, progressively accumulated over time, or remained persistently abundant throughout the incubation period. Based on their secretion characteristics and predicted immunogenic properties, five candidate biomarkers were selected for further evaluation. Polyclonal antibodies raised against selected candidates successfully detected the corresponding proteins in serum-free culture supernatants, providing preliminary evidence for their potential utility as early-stage diagnostic targets. These findings identify stage-associated candidate proteins that may serve as a resource for future early giardiasis diagnostic development, provide a valuable resource for investigating host-parasite interactions, and establish a foundation for future diagnostic assay development. However, further validation in clinical and biological samples is required to confirm their diagnostic applicability. SIGNIFICANCE: Giardiasis, caused by Giardia duodenalis, is a major diarrheal disease worldwide. Although enzyme-linked immunosorbent assays (ELISAs) provide rapid detection, their diagnostic utility is limited by the lack of biomarkers capable of identifying infection during its earliest stages, creating a critical gap in the detection of active infection within 2-48&#xa0;h following exposure. Using data-independent acquisition proteomics, this study provides a time-resolved characterization of proteins released by G. duodenalis trophozoites into serum-free culture supernatants. Our findings reveal temporal secretion dynamics of protein secretion and identify candidate biomarkers with potential utility for the development of early-stage diagnostic assays pending rigorous biological and clinical validation. In addition, this proteomic resource provides a foundation for investigating host-parasite interactions and may facilitate the development of future point-of-care diagnostic strategies.

Giardiasis↗
PubMed2026

Older adults with resectable gastric cancer undergoing perioperative chemotherapy or preoperative chemoradiotherapy plus perioperative chemotherapy: A secondary analysis of the AGITG TOPGEAR phase III trial.

PURPOSE: To evaluate treatment adherence, adverse events, and survival in older (&#x2265;70 years) adults undergoing perioperative treatment for gastric cancer. METHODS: Patients with resectable gastric/gastro-esophageal junction adenocarcinoma (ECOG 0-1) enrolled in the phase III TOPGEAR trial were randomized to perioperative chemotherapy (ECF/ECX or FLOT) alone or perioperative chemotherapy plus preoperative chemoradiotherapy (45&#x202f;Gy in 25 fractions with concurrent fluoropyrimidine). In this exploratory analysis, treatment completion, grade &#x2265;&#x202f;3 adverse events (CTCAE v3.0), surgical outcomes, overall survival (OS) and progression-free survival (PFS) were compared between older and younger adults. RESULTS: Of the 574 patients enrolled, 135 (24%) were &#x2265;&#x202f;70 years. Older adults more frequently required preoperative chemotherapy dose reductions, omissions, or delays (chemoradiotherapy: 55% vs 35%, p&#x202f;=&#x202f;0.004; chemotherapy: 60% vs 48%, p&#x202f;=&#x202f;0.087). Rates of grade &#x2265;&#x202f;3 adverse events were comparable between older and younger patients (chemoradiotherapy: 66% vs 67%, p&#x202f;=&#x202f;0.874; chemotherapy: 68% vs 59%, p&#x202f;=&#x202f;0.220), but older adults more often had hematologic toxicity and grade &#x2265;&#x202f;3 diarrhea in the chemotherapy group (56% vs 37%, p&#x202f;=&#x202f;0.006; 21% vs 6%, p&#x202f;<&#x202f;0.001). Resection rates, grade 3/4 surgical complications, number of removed lymph nodes, and 30-/90-day mortality were similar by age. OS and PFS were comparable across age groups, with numerically favorable outcomes for older adults (OS: HR 0.86, 95% CI 0.58-1.26 [chemoradiotherapy]; HR 0.75, 95% CI 0.51-1.11 [chemotherapy]; PFS: HR 0.78, 95% CI 0.53-1.15 [chemoradiotherapy]; HR 0.70, 95% CI 0.47-1.03 [chemotherapy]). CONCLUSIONS: Older adults with gastric cancer achieved comparable oncologic outcomes to younger patients, despite more frequent treatment modifications and higher hematologic toxicity.

Humans↗
PubMed2026

Meta-Analysis of the Efficacy of Ultrasound-Guided Mammotome Minimally Invasive Surgery and Traditional Open Surgery in the Therapy of Benign Breast Tumors.

ObjectiveTo systematically analyze the efficacy of ultrasound-guided mammotome minimally invasive surgery and traditional open surgery in the therapy of benign breast tumors.MethodsA computerized search retrieved original literature on the therapeutic effects of ultrasound-guided mammotome minimally invasive surgery and traditional open surgery for benign breast tumors from authoritative databases, including CNKI, Wanfang, VIP, Web of Science, PubMed, ScienceDirect, Cochrane Library, and Embase. The search covered from database inception to January 2024, using a strategy of subject terms combined with free terms. The retrieved literature was screened, data were extracted, and quality was evaluated. Meta-analysis was performed using RevMan 5.4 software.ResultsA total of 8 literatures were included in the study, and a total of 1909 patients with benign breast tumors were found from 2018 to 2023. The results of meta-analysis showed that the operation time [MD = -12.79, 95%CI (-14.04, -11.55), P < 0.00001], intraoperative blood loss [MD = -11.55, 95%CI (-14.74, -8.36), P < 0.00001], healing time [MD = -2.73, 95%CI (-4.03, -1.43), P < 0.00001] and complication rate [MD = 0.17, 95%CI (0.12, 0.26), P < 0.00001] was apparently different from traditional open surgery (P < 0.05).ConclusionUltrasound-guided mammotome minimally invasive surgery can effectively shorten the operation time of patients with benign breast tumors, reduce intraoperative blood loss, promote healing, and reduce the risk of complications. The effect is better than that of traditional open surgery.

Humans↗
PubMed2026

Comparative efficacy and safety of pharmacokinetically guided and body surface area-based 5-fluorouracil dosing in colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Body surface area (BSA)-based 5-fluorouracil (5-FU) dosing remains the standard in colorectal cancer despite substantial interpatient pharmacokinetic variability, which may lead to underexposure, treatment failure, or severe toxicity. This systematic review and meta-analysis evaluated whether pharmacokinetically guided 5-FU dosing improves efficacy and safety compared with conventional BSA-based dosing. METHODS: PubMed/MEDLINE, Embase, and Scopus databases were searched from inception to the final search date. The search identified 1,802 records: PubMed/MEDLINE, 47; Embase, 118; and Scopus, 1,637 records. Comparative randomized and non-randomized studies evaluating pharmacokinetically guided, area under the curve-guided, or therapeutic drug monitoring-based 5-FU dosing versus BSA-based dosing in colorectal cancer were included. Random-effects models were employed. The risk of bias was assessed using RoB 2 and ROBINS-I, and the certainty of evidence was evaluated using GRADE. RESULTS: Five studies comprising 809 unique patients were included. Across the primary severe-toxicity analysis, the pooled denominator was 1,338 reported observations, including 625 in the PK-guided 5-FU dosing arm and 713 in the BSA-based 5-FU dosing arm, because one study reported severe toxicity by treatment cycle rather than by patient. PK-guided dosing was associated with lower severe or grade&#x2009;&#x2265;&#x2009;3 toxicity (RR 0.50, 95% CI 0.33-0.76; P&#x2009;=&#x2009;0.001; I&#xb2;=79%). PK-guided dosing was also associated with a higher objective response rate (RR 1.50, 95% CI 1.24-1.80; P&#x2009;<&#x2009;0.0001) and disease control rate (RR 1.18, 95% CI 1.07-1.30; P&#x2009;=&#x2009;0.001). Severe diarrhea was reduced (RR 0.33, 95% CI 0.18-0.62; P&#x2009;=&#x2009;0.0006), whereas mucositis, neutropenia/leukopenia, and hand-foot syndrome were not significantly different between dosing strategies. CONCLUSION: PK-guided 5-FU dosing was associated with lower severe toxicity and diarrhea and higher objective response and disease-control rates than conventional BSA-based dosing. However, the evidence was derived from a small and clinically heterogeneous group of studies, and progression-free or overall-survival benefits could not be established. The findings apply predominantly to metastatic colorectal cancer treated with infusional 5-FU within FOLFOX- or FOLFIRI-based regimens. CLINICAL TRIAL REGISTRATION: Not applicable. This study was a systematic review and metaanalysis, and not a clinical trial.

Humans↗
PubMed2026

Proteomic analysis of cisplatin-induced spermatogenesis defects in mice.

BACKGROUND: Cisplatin is a crucial chemotherapeutic agent used for treating various cancers; however, its excessive use can cause irreversible damage to the reproductive system, and the protein expression profile of cisplatin-induced testicular injury remains unclear. METHODS: Male C57BL/6 mice were treated with cisplatin at various doses, and testes were collected for histological, immunofluorescence, and proteomic analyses. Germ cell loss and apoptosis were assessed using H&E staining, TUNEL assays, and immunofluorescence for LIN28A, SYCP3, MVH, and CDK1. Label-free quantitative proteomics identified differentially expressed proteins, which were analyzed for functional enrichment and protein-protein interactions. RESULTS: We observed that cisplatin treatment led to smaller testes, reduced sperm count, and a significant decrease in the number of spermatocytes and spermatids in mice. Label-free quantitative proteomic analysis revealed that cisplatin significantly reduced the expression of cyclin-dependent kinase 1 (CDK1), a key spermatogenesis regulator, in the testes. Reduction in CDK1 expression is correlated with spermatogenic arrest, particularly in spermatocytes. CONCLUSION: These findings highlight the critical role of CDK1 in cisplatin-induced spermatogenic dysfunction and provide new insights into fertility preservation strategies for patients with cancer undergoing chemotherapy.

Animals↗
PubMed2026

From premature adrenarche to adult metabolic risk and hyperandrogenism: a systematic review and meta-analysis.

CONTEXT: Idiopathic premature adrenarche (IPA) has been associated with a higher risk of metabolic and reproductive dysfunction, but long-term/adult outcomes remain incompletely known. OBJECTIVE: To assess the relationship between IPA and metabolic syndrome, as well as polycystic ovarian syndrome, in premenarcheal adolescent and adult women. METHODS: We conducted a systematic review and meta-analysis of observational studies reporting outcomes in females with IPA after menarche. Databases were searched through February 2025. Primary outcomes included body mass index (BMI), insulin resistance markers, and clinical and biochemical markers of hyperandrogenism. Data were pooled using random-effects models. The GRADE approach was applied to assess the certainty of evidence. RESULTS: A total of 21 studies comprising 635 females with IPA and 307 age-matched controls were included. Compared to controls, IPA individuals showed significantly higher BMI (mean difference: 1.4; CI: 1.0-1.9), fasting insulin, and homeostasis model assessment of insulin resistance, indicating persistent insulin resistance. Markers of hyperandrogenism, including Ferriman-Gallwey score, dehydroepiandrosterone sulfate, and Free androgenic index, were also elevated. Secondary analyses revealed higher triglycerides, lower high-density lipoprotein, increased leptin, and greater carotid intima-media thickness, supporting an early pattern of cardiometabolic risk. GRADE assessment rated most outcomes as low certainty. CONCLUSION: Women with a history of IPA are at increased risk of long-term insulin resistance and hyperandrogenism, with early signs of adverse cardiometabolic profiles. These findings support the need for long-term monitoring in this population.

Humans↗