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PubMed2026

Hot vs cold knife for endoscopic ablation of posterior urethral valves: a systematic review by the EAU-YAU paediatric urology working group.

INTRODUCTION: Posterior urethral valves (PUV) are the most frequent cause of congenital lower urinary tract obstruction in males. Despite early surgical ablation, up to 22% of patients develop chronic kidney disease and 11% progress to end-stage renal disease. Multiple endoscopic modalities have been described for valve ablation but the optimal technique remains uncertain. This systematic review aims to determine whether cold or hot knife ablation provides superior effectiveness for primary endoscopic treatment of PUV in a single surgical session. MATERIAL AND METHODS: A systematic search of PubMed and Embase databases was conducted to identify studies comparing cold and hot knife techniques for endoscopic ablation of PUV in children, covering all publications up to December 2025. The review was performed in accordance with PRISMA 2020 guidelines and was prospectively registered in PROSPERO (ID CRD420251180556). Original studies including patients <18 years who underwent primary valve ablation with postoperative cystoscopy or VCUG and ≥6 months of follow-up were included. Quality assessment was done using RoB 2.0 for randomized trials and MINORS for observational studies. RESULTS: A total of 1581 studies were identified, of which 26 met the inclusion criteria, comprising one randomized controlled trial, five prospective, and 20 retrospective studies constituting a sum of 1725 paediatric patients. The overall methodological quality of included studies was moderate, with marked heterogeneity in design, follow-up duration, and outcome reporting, limiting direct comparisons across series. Thus statistical analysis was not possible. Of these, 829 (48.1%) underwent cold valve ablation and 896 (51.9%) underwent hot ablation techniques. Within the cold group, most patients were treated with a cold knife (80.2%), followed by balloon dilatation (7%), the Mohan valvotome (6.5%), cold hook (5%), and, rarely, a modified venous valvulotome (1.3%). Among hot techniques, 32.8% of procedures were performed by electro-fulguration with a resectoscope, 29.4% using a Bugbee electrode, 23.8% with a hook electrode and 14% with laser-based systems. Follow-up ranged from 6 months to 22 years across studies. Single-session success rates for valve ablation ranged from 22% to 100% in the cold resection group and from 71.4% to 100% in the hot resection group. Reintervention for residual valves was reported in 0%-78% of cold cases and in 0%-28.6% of hot resections. Urethral stricture rates ranged from 0% to 11.1% after cold incision and from 0% to 23.8% after hot techniques. Reporting of postoperative outcomes such as urinary tract infection, incontinence, bladder dysfunction, vesicoureteral reflux (VUR) resolution, hydronephrosis improvement, and renal function varied widely among studies and was assessed using different methodologies. CONCLUSIONS: Both cold and hot ablation techniques for PUV achieved high single-session success rates and low complication rates. Cold resection appeared slightly safer, although this finding should be interpreted cautiously given the heterogeneity and observational nature of the available data.

Humans↗

PubMed2026

Relationship between participant-reported outcomes, residual beta cell function and metabolic parameters in youth with newly diagnosed type 1 diabetes.

AIMS/HYPOTHESIS: Clinical trials of interventions to preserve beta cell function in new-onset type 1 diabetes frequently employ participant-reported outcome measures (PROMs). However, the expected changes in PROMs scores immediately following diagnosis and their association with residual beta cell function, metabolic markers and continuous glucose monitoring (CGM) are unclear. METHODS: Repeated PROMs including Paediatric Quality of Life Inventory diabetes module (PedsQL) and hypoglycaemia fear survey (HFS) were recorded from participants aged 10-18 years with newly diagnosed type 1 diabetes and their parents in two clinical trials: CLOuD (N=97, hybrid closed loop [HCL] vs multiple daily injections [MDI]) and USTEKID (N=72, ustekinumab immunotherapy vs placebo). Scores were compared with serial mixed meal-stimulated C-peptide levels (AUC C-peptide), HbA1c and CGM data. RESULTS: PedsQL and HFS scores for children/adolescents and their parents showed wide variation between individuals but did not change substantially within individuals over the first 48 months from diagnosis. Baseline scores were highly predictive of scores at 12-48 months (p<0.001). PedsQL scores were higher (better) in those reported by children/adolescents than by their parents (p<0.01). In contrast, HFS scores were higher in parents than children (p<0.001), indicating more fear. Strong correlations were observed between child and parent scores (p<0.001). No significant improvement in these scores was detected following intervention (ustekinumab or HCL). Meta-analysis revealed modest but statistically significant associations between HbA1c and PedsQL (β(std)=-0.11; 95% CI -0.20, -0.03) and HFS (β(std)=0.11; 95% CI 0.00, 0.21), and between CGM time in range and PedsQL (β(std)=0.14; 95% CI 0.03, 0.26) but not HFS (β(std)=-0.05; 95% CI -0.16, 0.06). Beta cell function (AUC C-peptide) was strongly associated with HbA1c (β(std)=-0.29; 95% CI -0.39, -0.20) and CGM time in range (β(std)=0.41; 95% CI 0.30, 0.52). Higher beta cell function showed a trend towards better PedsQL (β(std)=0.11; 95% CI -0.03, 0.25) and lower HFS (β(std)=-0.05; 95% CI -0.17, 0.07) but this did not reach statistical significance. CONCLUSIONS/INTERPRETATION: PedsQL and HFS scores changed little during the first 48 months after diagnosis of type 1 diabetes. These scores showed modest but statistically significant associations with measures of glucose management (HbA1c and CGM time in range), whereas the relationships with residual beta cell function (C-peptide) were weaker and did not reach significance. The modest size of these effects suggests current PROMs capture only limited aspects of the clinical benefit associated with beta cell preservation. Future research should incorporate psychometric instruments that are specifically adapted for young people using modern diabetes technologies and undergoing disease-modifying therapy, to ensure outcomes are meaningfully represented in early-stage type 1 diabetes trials.

Adolescent↗

PubMed2026

Efficacy, acceptability, and related outcomes of pharmacological interventions for acute bipolar mania: a systematic review and dose-related network meta-analysis across different age groups.

BACKGROUND: Acute bipolar mania carries negative social and economic consequences. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar mania, considering dose effects across different age groups. METHODS: We conducted a network meta-analysis (NMA) to search for randomized controlled trials (RCTs) comparing pharmacological interventions with one another or placebo in acute bipolar mania patients, indexed in PubMed/MEDLINE, Embase, Web of Science, and Scopus (from inception through 2025.12.24). Co-primary outcomes were change in manic symptoms/response/and acceptability. Tolerability/remission and rate of adverse events were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. RESULTS: 113 RCTs, encompassing 49 distinct treatment combinations, included 20,666 participants. Sensitivity analysis retaining only low-risk-of-bias studies and excluding outliers for possible effect modifiers indicated that risperidone 3 mg/day(SMD = -7.57;95%C.I. = -8.25;-5.85); tamoxifen 160 mg/day(SMD = -1.73;95%C.I. = -2.32;-1.13); rivastigmine 3 mg/day(SMD = -1.13;95%C.I. = -1.06;-0.58); haloperidol 30 mg/day(SMD = -0.96;95%C.I. = -1.25;-0.75); valproate 750 mg/day(SMD = -0.76;95%C.I. = -1.48;-0.58); tamoxifen 40 mg/day(SMD = -0.75;95%C.I. = -1.41;-0.59); celecoxib 400 mg/day(SMD = -0.74;95%C.I. = -1.20;-0.38); paliperidone extended-release 12 mg/day(SMD = -0.62; 95%C.I. = -0.91;-0.32); olanzapine 15 mg/day(SMD = -0.59;95%C.I. = -0.60;-0.38); olanzapine 20 mg/day(SMD = -0.52;95%C.I. = -0.66;-0.38); risperidone 4 mg/day(SMD = -0.53;95%C.I. = -0.76;-0.29); allopurinol 600 mg/day(SMD = -0.54;95%C.I. = -0.67;-0.22); cariprazine 12 mg/day(SMD = -0.49;95%C.I. = -0.66;-0.33); risperidone 4.2 mg/day(SMD = -0.46;95%C.I. = -0.75;-0.17); lithium 1500 mg/day(SMD = -0.42;95%C.I. = -0.57;-0.28); ziprasidone 160 mg/day(SMD = -0.49;95%C.I. = -0.68;-0.31); asenapine 20 mg/day(SMD = -0.38;95%C.I. = -0.53;-0.22); haloperidol 8 mg/day(SMD = -0.34;95%C.I. = -0.63;-0.05); aripiprazole 15 mg/day(SMD = -0.33;95%C.I. = -0.61;-0.06) outperformed placebo. Ziprasidone 160 mg/day, celecoxib 200 mg/day, asenapine 20 mg/day, and asenapine 10 mg/day proved more efficacious than placebo in children. No statistically significant differences were reported between treatments and placebo for response/remission/acceptability/tolerability, and manic/hypomanic switch. A meta-regression of efficacy effect sizes against the adapted AMSTAR-Plus content scores showed that larger SMDs were associated with lower AMSTAR scores, indicating lower study quality, warranting further caution for such large efficacy estimates. CONCLUSIONS: Our findings are consistent with previous NMAs and current guidelines, expanding the current knowledge base while concurrently appraising different drugs, doses, and age groups.

Humans↗

PubMed2026

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans↗

PubMed2026

Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS: ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS: 36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION: The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING: National Cancer Institute of the National Institutes of Health.

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 ≥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 ≥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 10·0 months (IQR 4·6-17·2); median follow-up for progression-free survival was 11·0 months (IQR 4·8-18·4) for STRIDE plus lenvatinib plus TACE and 8·3 months (4·1-15·5) for TACE. Median progression-free survival was 13·0 months (95% CI 12·2-16·7) for STRIDE plus lenvatinib plus TACE versus 9·8 months (8·0-11·4) for TACE (HR 0·70 [95% CI 0·57-0·86]; p=0·0007). At the second data cutoff (Feb 23, 2026) and a median follow-up for overall survival of 24·6 months (IQR 16·5-31·5) for STRIDE plus lenvatinib plus TACE and 22·9 months (14·9-30·2) for TACE, median overall survival was 39·5 months (95% CI 34·1-not reached) for STRIDE plus lenvatinib plus TACE and 34·7 months (28·8-not reached) for TACE (HR 0·84 [95% CI 0·65-1·09]; p=0·18). At this data cutoff, median progression-free survival was 12·9 months (95% CI 10·2-15·9) for STRIDE plus TACE and 8·1 months (6·5-10·2) for the first 175 participants randomised to TACE (HR 0·71 [95% CI 0·56-0·91]), with median follow-up of 10·3 months (IQR 4·6-23·7) for STRIDE plus TACE and 7·7 months (3·0-18·5) 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↗