Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are primarily driven by activating mutations in KIT or PDGFRA. Although tyrosine kinase inhibitors (TKIs), particularly imatinib, have substantially improved outcomes, most patients with advanced disease eventually develop resistance, resulting in disease progression. Methods: We performed a narrative review with scoping approach of interventional clinical trials registered on ClinicalTrials.gov between January 2020 and July 2025 to characterize the contemporary investigational therapeutic landscape in GIST. Eligible studies included clinical trials evaluating novel agents, combinations, or alternative strategies beyond current regulatory approvals. Trial characteristics, therapeutic classes, endpoints, enrollment, and funding sources were analyzed. Results: A total of 27 ongoing trials were identified. Most studies were phase I/II and focused on metastatic or unresectable disease, predominantly in the second-line or later settings. TKIs remained the dominant therapeutic class, included in over 70% of trials, either as monotherapy or in combination. Emerging strategies comprised antibody-drug conjugates, immune checkpoint inhibitors, HIF inhibitors, FGFR inhibitors, and epigenetic modulators. Only four phase III trials were identified, reflecting the difficulty of conducting large, randomized studies in GIST. No trial used overall survival or quality of life as a primary endpoint. Conclusions: The current investigational landscape in GIST is largely focused on overcoming TKI resistance in advanced disease. Molecular stratification and personalized approaches dominate ongoing research, but evidence generation remains limited by small sample sizes and slow recruitment. Future trials integrating innovative therapeutic platforms and patient-centered outcomes are essential to improve long-term disease control and quality of life.
Lumbar spinal endoscopy has long been mischaracterized by payers as investigational. Such claims conflict with decades of refinement, randomized trials, and policy precedent. We reviewed the historical evolution, prospective trials, meta-analyses, and policy milestones of transforaminal endoscopic lumbar discectomy (TELD), with emphasis on coding, reimbursement, and comparative effectiveness. Evidence demonstrates that TELD, performed with direct visualization, provides durable outcomes with complication, reoperation, and conversion rates equal or superior to open decompression. Meta-analyses confirm comparable effect sizes to microsurgery, while selective integration with motion-preserving adjuncts extends durability in complex cases. TELD has matured into a safe and durable technology. It is not limited to lateral recess disease but is capable of effectively addressing central stenosis, including select cases with low-grade spondylolisthesis. TELD's trajectory mirrors that of other coverage-adopted technologies, and its future impact depends on structured training to ensure reproducibility and broad patient access. This work establishes that transforaminal endoscopy, performed with direct visualization, is not limited to lateral recess disease. TELD can safely and effectively address central stenosis, including selected cases with low-grade spondylolisthesis. Contemporary evidence demonstrates durable outcomes comparable to open decompression. The next step is structured training to ensure reproducibility across the broader surgical community, thereby securing patient access to this established and codified technique within recognized coverage frameworks.
Premedications used to prevent paclitaxel-associated infusion hypersensitivity reactions (iHSRs) can cause undesirable toxicities, such as sleep disturbance and weight gain. Although phase II data suggest that discontinuing premedications after paclitaxel-associated iHSRs may be safe and feasible in select patients without prior iHSRs, no prospective randomized trials have evaluated this approach. This randomized clinical trial enrolled patients with breast cancer receiving paclitaxel chemotherapy. Those who experienced no iHSRs with the first 2 doses of paclitaxel were randomized to either continue standard premedications (control arm) or to discontinue all premedications (investigational arm). Both arms were followed longitudinally for any subsequent iHSRs requiring parenteral rescue medications. Additionally, changes in weight, drug-related side effects, and quality of life were assessed. A total of 98 patients were randomized; 89 were evaluable (46 in the control arm and 43 in the investigational arm). Only 1 (2.3%) patient in the investigational arm experienced an iHSR, which resolved with rescue medications. No iHSRs occurred in the control arm. The estimated proportion of subjects who experienced a hypersensitivity reaction (exact binomial 95% CI) was 2.3% (95% CI, 0.1%-12.3%) in the investigational arm and 0.0% (95% CI, 0.0%-7.7%) in the control arm. Patients in the investigational arm reported significantly less sleep disruption (0.5 vs 1.7; P=.002) and unwanted appetite increases (1.0 vs 2.5; P=.0018). Discontinuation of premedications after 2 uneventful paclitaxel doses was not associated with a high rate of subsequent iHSRs and resulted in fewer steroid-related side effects. This strategy may reduce unnecessary medication exposure, improve patient experience, and streamline clinical workflows. For patients who do not experience iHSRs during the first 2 paclitaxel treatments, discontinuing premedications appears safe and may improve tolerability.
Gastroenteropancreatic (GEP) malignancies are a major cause of cancer-related mortality, with many patients presenting at advanced stages where curative options are limited. Outcomes remain suboptimal, particularly beyond first-line therapy, highlighting the need for novel approaches. Fibroblast activation protein (FAP)-targeted radioligand therapy (RLT) has emerged as a biologically rational strategy that exploits the stromal compartment of desmoplastic tumors. FAPI PET/CT enables noninvasive assessment of target expression and supports a theranostic framework for patient selection. This review summarizes current clinical evidence on Lutetium-177 ( 177 Lu)-FAP RLT in GEP cancers, including pancreatic, biliary, gastric, and colorectal malignancies. Available data, largely from small and heterogeneous early-phase studies, demonstrate feasibility and acceptable short-term safety, with hematologic toxicity as the main concern. Objective responses are uncommon; however, disease stabilization and symptomatic benefit have been observed in selected patients. Key limitations include variable tumor retention, heterogeneous selection criteria, and the lack of standardized dosimetry and response assessment. Overall, 177 Lu-FAP RLT remains investigational but represents a biologically compelling but still clinically unproven biomarker-driven strategy, whose current role is best confined to investigational settings and highly selected patients. Future progress requires optimized ligand design, standardized imaging and dosimetry, and prospective clinical trials to define its clinical role.
Pediatric patients with heart failure increasingly rely on ventricular assist devices as a bridge to transplantation. The Berlin Heart EXCOR Pediatric is the only durable ventricular assist device specifically approved for infants and small children, but its IKUS driver limits mobility and quality of life. The EXCOR Active Driver was developed to address these limitations by improving mobility, battery life, and physiological adaptability. This prospective, multicenter clinical trial evaluated the performance, safety, and clinical outcomes of a novel driving system in pediatric patients. Forty subjects were enrolled under a U.S. Food and Drug Administration-approved investigational device exemption, followed by 118 additional patients under a continued access protocol. Primary endpoints included the incidence of major device malfunction, adverse events, and successful outcomes-defined as survival to transplantation, recovery, or continued support at 90 days postimplantation. Adjudication of adverse events was conducted by an independent Clinical Events Committee, with oversight provided by a Data Safety Monitoring Board. Outcomes were assessed using descriptive statistics and competing risk models. Among 40 investigational device exemption patients (mean age: 38.2 months; 55% with congenital heart disease), there were no episodes of major device malfunction. At 90 days, 65% remained on support, 17.5% had undergone transplantation, 15.0% were converted to another support modality, and 1 patient was explanted for recovery. Stroke incidence was 12.5%, and 90-day mortality rate was 0%. Among 118 continued access protocol patients, there were no major device malfunctions. At the time of data abstraction, 37% (n = 44) had undergone transplantation, 31% (n = 37) were alive on device, 6% (n = 7) had the device explanted for recovery, 23% (n = 27) had been converted to another support modality, and 3 patients had withdrawal of support. Survival at 90 days was 98.1%. This novel active driving system demonstrated excellent safety and reliability in a real-world, high-risk pediatric population, with no major device malfunctions. This trial also validates the feasibility of leveraging a clinical registry infrastructure for class III device evaluation, offering a scalable and cost-efficient model for device approvals.
Periodontitis is among the most prevalent chronic inflammatory diseases worldwide and may affect vascular health beyond the oral cavity. Framed within the concept of an oral-vascular axis, this review synthesizes clinical and mechanistic evidence linking periodontal disease with atherosclerotic cardiovascular disease (ASCVD). Epidemiological studies and meta analyses consistently associate periodontitis with higher risks of coronary heart disease (CHD), stroke, and cardiovascular mortality, with modest but reproducible effect sizes that persist after adjustment for traditional risk factors. However, heterogeneous study designs and residual confounding preclude definitive causal inference. Interventional evidence is currently dominated by surrogate endpoints, and event-level cardiovascular benefit from periodontal therapy remains unproven. Mechanistically, chronic periodontal inflammation may influence endothelial function and atherogenesis through interlocking pathways that can be viewed as a spatiotemporal, dual-regulatory network of immunity and metabolism: local dysbiosis and barrier disruption increase systemic access to microbial ligands and vesicular cargo, while systemic immune activation interacts with metabolic remodeling to shape inflammatory set-points and vascular susceptibility. Microbe-derived and host-microbe co-metabolites may further modulate redox balance, inflammatory tone, and vascular homeostasis within this network. We highlight limitations of existing interventional trials, methodological challenges in microbiome- and genetics-based causal inference, and priorities for translational research. Clinically, the oral-vascular axis motivates interdisciplinary exchange and research-facing collaboration that integrates oral health assessment with immune and vascular phenotyping, while recognizing that cardiovascular benefit from periodontal interventions remains investigational and requires event-driven validation.
To quantify bladder wall relaxation times in men without and with lower urinary tract symptoms (LUTS) using three-dimensional (3D) magnetic resonance fingerprinting (MRF). Following informed consent, 51 men (mean age 68.2 years, range 46-80) on active surveillance for prostate cancer underwent multiparametric MRI that included an investigational 3D MRF sequence. Anterior bladder wall T1 and T2 relaxation times were measured from the quantitative maps. Anterior bladder wall thickness (BWT) was measured and prostate and transition zone (TZ) volumes were estimated, from the conventional T2w images. Body mass index (BMI), LUTS scores (AUA-SI), risk factors for metabolic syndrome, history of diabetes (DM), and medications prescribed for LUTS were documented from the electronic medical record. The Kruskal-Wallis rank sum test, Wilcoxon rank sum exact test, and Fisher's exact test were used to assess the associations between clinical variables, categorical imaging data, and mean T1 and T2 relaxation times. Native bladder wall T1 relaxation times were longer in men with higher AUA-SI scores [AUA-SI 0-7: 1,496 ms vs. AUA-SI 8-20: 1,787 ms vs. AUA-SI 21-35: 2,063 ms, p = 0.03] while native bladder wall T2 relaxation times were similar [AUA-SI 0-7: 67 ms vs. AUA-SI 8-20: 78 ms vs. AUA-SI 21-35: 122 ms, p = 0.3]. Native bladder wall T1 relaxation times were shorter in diabetic men compared to non-diabetic men (1239 ms vs. 1633 ms, p < 0.001), while T2 relaxation times were similar (86 ms vs. 62 ms, p = 0.4). Prostate and TZ volume, and BWT were similar in men without and with LUTS and DM. 3D MRF of the bladder is feasible, provides in-vivo tissue characterization of the bladder wall in men with LUTS.
Parkinsonian disorders, including Parkinson's disease, Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy, are progressive neurodegenerative conditions with no treatment options to slow disease progression. This systematic review provides an overview of evidence of disease-modifying therapies that have been evaluated in clinical studies across these disorders, based on a comprehensive literature search up to May 2025. Eligible studies included clinical trials investigating pharmacological interventions aimed at slowing disease progression. Most clinical development has focused on Parkinson's disease, with limited progress in other Parkinsonian disorders. Therapies targeting alpha-synuclein, such as monoclonal antibodies and small molecules, have shown target engagement but limited clinical efficacy. Glucocerebrosidase-enhancing agents, particularly ambroxol, demonstrated promising biomarker and clinical signals in early-phase trials. Glucagon-like peptide-1 receptor agonists and kinase inhibitors have yielded mixed results, with some agents progressing to phase 3 trials. Neurotrophic factors, cell survival and neuroprotective therapies, stem cell therapies, and anti-inflammatory agents remain largely investigational, with limited evidence of efficacy. Repurposed drugs, including memantine and riluzole, have shown preliminary signals of benefit, though confirmatory trials are lacking. Despite substantial research efforts, no disease-modifying therapy has been approved for any Parkinsonian disorder. The heterogeneity of disease mechanisms and the limitations of current clinical endpoints, such as the Unified Parkinson's Disease Rating Scale, underscore the need for biomarker-driven approaches and stratified trial designs. Future success will likely depend on improved patient selection, mechanistic targeting, and the integration of fluid and imaging biomarkers to demonstrate disease modification.
Child maltreatment has been associated with biological hallmarks of aging, including telomere shortening and epigenetic instability; however, its influence on physiological age and homeostatic dysregulation in early life remains unclear. The current study examined pediatric versions of physiological age and homeostatic dysregulation in children aged 8-13 with and without exposure to maltreatment. Maltreatment exposure was determined based on investigational records within 12 months prior to enrollment. Physiological measures were trained and validated utilizing external datasets - the National Health and Nutrition Examination Survey III and IV, respectively. Physiological age was computed using the Klemera-Doubal Method to indicate physiological developmental status. Homeostatic dysregulation level was computed as the Mahalanobis distance from an external reference group. 216 females and 245 males with a mean age of 11.4 years (SD 1.5) were included (76.6% White, 13.2% Black, and 13.0% Hispanic, 76.6% with maltreatment). Exposure to maltreatment was not associated with changes in physiological age but was associated with greater homeostatic dysregulation. Further analyses by maltreatment type and sex revealed that physical abuse was associated with greater homeostatic dysregulation, while sexual abuse was associated with delayed physiological development, specifically in males. Exposure to multiple types of maltreatment was associated with greater homeostatic dysregulation among males, but not among females. This study revealed that recent exposure to certain types of maltreatment may impair physiological development or regulation in children, with sex-specific patterns suggesting greater effects in males. Findings further indicate that physiological development composites in youth are sensitive to the impact of child maltreatment and can be incorporated in future work to evaluate the long-term sequelae of adverse exposures in pediatric populations. As the impact of maltreatment was only nominally significant after correction for multiple testing, validation work in other samples is needed.
Deupirfenidone is a strategically deuterated form of pirfenidone that retains pharmacodynamic activity but has a differentiated pharmacokinetic profile that may enable improved efficacy and favorable tolerability in patients with idiopathic pulmonary fibrosis (IPF). To evaluate the efficacy and safety of deupirfenidone compared with placebo and pirfenidone in patients with IPF. Patients were randomized 1:1:1:1 to deupirfenidone 550 mg TID, deupirfenidone 825 mg TID, pirfenidone 801 mg TID or placebo. The primary endpoint was the rate of change in forced vital capacity (FVC) for the combined arms of deupirfenidone versus placebo at 26 weeks. The primary and secondary analyses used Bayesian and frequentist approaches, respectively. 257 patients with IPF were randomized and the proportion on treatment at end of study was 80.0%, 68.3%, 64.6%, and 78.1% for the placebo, pirfenidone, deupirfenidone 550 mg, and deupirfenidone 825 mg arms, respectively. Posterior mean change in FVC for placebo was -110.71 mL (95% credible interval (CI), -148.75, -70.98) and for the combined deupirfenidone arms was -48.42 mL (95% CI, -87.66, -9.04) with a posterior mean difference of 62.29 mL (95% CI l, -6.13, 115.73; posterior probability, 0.985). Using a frequentist approach, the adjusted mean change in FVC for the placebo arm was -112.5 mL (95% CI, -167.2, -57.8) and for the deupirfenidone 825 mg arm was -21.5 mL (95% CI, -78.2, 35.1); the adjusted mean difference was 91.0 mL (95% CI, 12.2, 169.7; P = .02). The most common adverse events for each active treatment arm were gastrointestinal. In patients with IPF, treatment with deupirfenidone slowed lung disease progression over 26 weeks. Clinicaltrials.gov number NCT05321420. ELEVATE IPF was a phase 2 b trial that studied the safety, tolerability, and effectiveness of the investigational drug deupirfenidone 550 mg TID (three times daily) and deupirfenidone 825 mg TID, compared to an approved antifibrotic drug, pirfenidone 801 mg TID, and placebo in patients living with idiopathic pulmonary fibrosis. The rate of decline in lung function measured by forced vital capacity at 26 weeks was significantly less for deupirfenidone 825 mg TID compared to placebo and was similar to the natural decline in lung function seen in healthy older adults. Deupirfenidone was also generally safe and well tolerated. These results support the continued development of deupirfenidone in IPF.
Safety margins are used in nonclinical risk assessment of investigational drugs and are calculated as the ratio of drug exposure in nonclinical test systems to that in humans. This manuscript explores theoretical and practical considerations of using unbound versus total drug exposures when evaluating safety margins across nonclinical safety studies for small molecules, highlighting current gaps in regulatory guidance and the inconsistent application of total versus unbound exposure in safety margin calculations within the industry. An IQ Working Group evaluated industry practices and regulatory interactions to highlight points to consider regarding the use of total versus unbound exposures for nonclinical risk assessment. Companies were surveyed to understand current practices and identify key determinants influencing the decision-making process regarding safety margin reporting. Results indicate significant variations in the use of total versus unbound concentrations influenced by the type of toxicity study, magnitude of species differences in plasma protein binding, and stages of drug development. Despite these variations, there is a general trend of using total exposure for in vivo and unbound concentrations for in vitro studies. The findings underscore the need for additional regulatory guidance and strategies to standardize safety margin reporting, thereby enhancing consistency and improving nonclinical safety risk assessments.
The impact of intravenous (IV) thrombolysis on the outcomes of aspiration thrombectomy as the primary endovascular approach to stroke in patients with large vessel occlusion is unknown. The Imperative Trial was a prospective, investigational device exemption, multicenter trial of first-line aspiration thrombectomy that assessed the safety and efficacy of the Zoom System, including a novel 0.088 inch aspiration catheter in patients with stroke within 8 hours of onset. We compared procedural, technical, and clinical outcomes of aspiration thrombectomy based on whether patients had received IV thrombolytics prior to the intervention. Among the 260 patients treated with front-line aspiration thrombectomy using the Zoom System, 125 (48%) received IV thrombolysis prior to aspiration. Rates of modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b achieved with the Zoom System were higher in the aspiration-only group than in the combined group (92% vs 81%, P=0.016). Rates of mTICI ≥2c and first pass effect were similar. The use of rescue devices to achieve mTICI ≥2b was less frequent in the aspiration-only group than in the combined group (2% vs 10%, P=0.008). The rates of functional independence (modified Rankin Scale (mRS) score 0-2) in the aspiration-only group and the combined group were 50% and 59%, respectively (P=0.16). Univariate (P=0.30) and multivariate (P=0.47) ordinal regression analyses showed no significant correlation of mRS 0-2 with IV thrombolysis. Both groups had similar safety outcomes including rates of symptomatic intracranial hemorrhage and 90-day mortality. Aspiration thrombectomy alone may result in higher rates of successful reperfusion and reduce the need for rescue devices compared with the combined approach with IV thrombolysis.
Emerging therapies for multiple myeloma (MM) have significantly improved patient outcomes extending survival and advancing treatment toward more targeted, effective, and less toxic approaches. However, the disease remains incurable. Analyze the therapeutic landscape of MM by evaluating drug candidates in clinical trials from 2014 to 2024. Data were extracted from ClinicalTrials.gov (CTG) and Cortellis Drug Discovery Intelligence (CDDI), including active and completed studies with results on newly diagnosed and refractory MM. Joinpoint regression models estimated Annual Percent Changes (APCs) and Average Annual Percent Changes (AAPC). Data were examined by clinical trial characteristics, targeting strategies, and potential impact on treatment advancements. A total of 1091 trials from CDDI and 1947 from CTG were screened, yielding 365 studies eligible for detailed analysis. Phase I trials were the most common (n = 182; 49.9%), and biologic agents represented the majority of the investigational therapies (n = 251; 68.8%). Among intervention types, cell therapies were predominant (n = 171; 46.8%), with CAR-T products targeting BCMA (n = 107), CD19 (n = 16), and GPRC5D (n = 12) emerging as the most studied in recent years. Before the joinpoint, the number of active trials grew by 1.86% per year (95% CI: 1.67-2.06), corresponding to an average increase of 11.9 studies annually. After the joinpoint, growth accelerated to 3.69% per year (95% CI: 3.19-4.19), equivalent to 26.5 additional trials each year. Across the entire study period, the weighted average annual percentage change (AAPC) was 2.63%. The rise in MM clinical trials highlights a shift toward biologic therapies, particularly immunotherapies and gene therapies like CAR-T.
Surgical treatment remains the cornerstone of recurrent respiratory papillomatosis (RRP) management; however, aggressive disease often requires frequent procedures with cumulative morbidity. Contemporary systemic options now include systemic bevacizumab and human papillomavirus (HPV)-specific immunotherapies, with immune checkpoint inhibition under investigation. We systematically reviewed the efficacy and safety of systemic therapies for juvenile- and adult-onset RRP, emphasizing current clinician-relevant treatment options. We comprehensively searched PubMed, Scopus, Web of Science, and the Cochrane Library from inception until January 2026. The included studies evaluated any available systemic treatment for managing adult or juvenile-onset RRP. The main outcomes were complete remission, partial response, and adverse events. All the data analyses were performed using STATA 18 BE. We included 35 studies comprising 925 patients. In juvenile-onset RRP, pooled complete remission with systemic bevacizumab was 60% (95% CI 34-87%), and pooled partial response was 46% (95% CI 21-71%). In adult-onset RRP, pooled complete remission with systemic bevacizumab was 44% (95% CI 26-62%), and pooled partial response was 61% (95% CI 43-79%). The most frequently reported bevacizumab adverse events were hypertension (40%), proteinuria (26%), and epistaxis (22%). HPV-specific immunotherapies (including FDA-approved zopapogene imadenovec-drba [Papzimeos; PRGN-2012] for adults and investigational INO-3107) and PD-1/PD-L1-directed therapies demonstrated encouraging early-phase activity but were too heterogeneous for quantitative pooling. Systemic bevacizumab remains the most mature systemic option with consistent real-world evidence and published dosing guidance. HPV-specific immunotherapy has recently transformed adult RRP management with an FDA-approved, short-course treatment option; ongoing studies will clarify optimal sequencing with bevacizumab and the role of checkpoint inhibition.
Viral reactivation is a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT), particularly in the setting of intensified graft-versus-host disease (GVHD) prophylaxis using in vivo or ex vivo T-cell depletion. Reactivation of BK virus, JC virus, adenovirus, and other opportunistic pathogens is especially problematic, as effective FDA-approved antiviral therapies are limited or unavailable, with pediatric recipients being at particular risk. Virus-specific T cells (VSTs) represent a compelling immunotherapeutic strategy to restore antiviral immunity and control refractory viral infections after HCT. However, VSTs are not currently FDA approved in the United States and are accessible only at a small number of academic centers under investigational new drug oversight, limiting their broader clinical impact. In this review, we convened a panel of experts to summarize the current landscape of VST therapy, including clinical indications, efficacy, and safety outcomes across multiple viral targets. We also identify key challenges in the field, including regulatory barriers, manufacturing scalability, product standardization, and distribution. Finally, we discuss potential strategies to facilitate more reliable and equitable access to VSTs, including collaborative manufacturing models and alternative regulatory pathways, with the goal of integrating these therapies more broadly into post-transplant care.
Background/Objectives: Early-phase clinical trials (EPCTs) focus on safety and preliminary efficacy, often assessed by RECIST (Response Evaluation Criteria in Solid Tumours) tumour response. Health-related quality of life (HRQoL) is rarely evaluated in EPCTs and may not align with radiological outcomes. Methods: The PEARLER (Patient Experience in Early-Phase Cancer Clinical Trials) study evaluated the demographics, tumour response, HRQoL, and therapy type in two early-phase trial units in Australia between August 2023 and 2024. Patients completed the EORTC QLQ-C30 at baseline and follow-ups. The Global Health Status (GHS) score was selected as the primary HRQoL measure. Tumour response was assessed using RECIST 1.1. Spearman correlation and Kruskal-Wallis testing assessed the associations between RECIST, cross-sectional GHS change (ΔGHS; follow-up minus baseline), and therapy types. Multilevel models were used to evaluate longitudinal GHS values per RECIST category. Results: Of 122 patients recruited to the PEARLER study, 74 patients had paired RECIST and HRQoL data (complete response (CR) n = 0; partial response (PR) n = 15; stable disease (SD) n = 39; progressive disease (PD) n = 20). The median change in GHS was zero across RECIST groups, with broad individual variability. Notably, 18 of 54 patients (33.3%) with stable or responding disease experienced HRQoL decline. Meanwhile, 10 of 20 (50%) patients with PD experienced stable or improving HRQoL. The best RECIST response and ΔGHS showed a weak but statistically significant negative relationship (Spearman ρ = -0.28, p = 0.017), with the Kruskal-Wallis test demonstrating χ2 = 6.20 (p = 0.045), indicating modest group differences driven by the deterioration in PD patients. The multilevel model demonstrated a lower GHS in patients with PD, with no statistically significant interaction of GHS change over time with the RECIST response (p = 0.226). Conclusions: HRQoL change is largely independent of radiologic tumour response and therapy type in EPCT participants. Patients experienced a HRQoL decline despite tumour response. Incorporating patient-reported outcomes alongside RECIST and safety outcomes is important to fully capture the impact of investigational therapies and guide patient-centred trial designs.
To systematically review and critically appraise human evidence on potential health effects of aluminium adjuvanted vaccines. Systematic review following PRISMA (preferred reporting items for systematic review and meta-analysis) 2020 guidelines. Six databases and trial registries were searched from inception to 3 March 2023 then updated to 27 November 2025. Reference lists of eligible studies were also screened. Human studies assessing health outcomes after aluminium adjuvanted vaccination, including randomised controlled trials, cohort studies, case series, and ecological studies. Investigational vaccines, case reports, and review articles were excluded. Two reviewers screened studies (with AI assistance for the 2023-25 update), extracted data, and assessed risk of bias (using RoB 2.0, ROBINS-I, or an adapted tool for case series). Certainty of evidence was rated using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). The review included 59 studies (37 case series, 11 randomised controlled trials, nine cohort studies, two ecological studies). High quality evidence from randomised controlled trials and large cohorts consistently showed no association between aluminium adjuvanted vaccines and serious or long term health outcomes, such as asthma, autism spectrum disorders, or other chronic conditions. Studies on macrophagic myofasciitis were generally small and methodologically limited, and did not provide credible evidence of a causal association (very low certainty). Localised persistent nodules or granulomas were observed infrequently after diphtheria-tetanus-pertussis vaccines, consistent with delayed type hypersensitivity (<1%, self-limited; moderate to low certainty). For common adverse events (eg, headache, myalgia), high certainty randomised controlled trials found no consistent increase in risk with aluminium adjuvanted formulations. When differences were observed, they were small and predominantly mild to moderate in severity. Evidence was dominated by methodologically limited studies, with most case series and ecological studies at serious or critical risk of bias. Conclusions are primarily supported by higher quality randomised controlled trials and cohort evidence. Current evidence does not support causal associations between aluminium adjuvanted vaccines and serious or long term health outcomes. The most consistently documented reactions were persistent nodules or granulomas that are uncommon, local, and self-limited hypersensitivity reactions. These findings are broadly consistent with post-licensure surveillance findings. The predominance of methodologically limited studies for some outcomes highlights the need for higher quality research. PROSPERO CRD42023462831.
Background/Objectives: Platelet-rich plasma (PRP) is an autologous blood-derived biologic enriched in platelets and bioactive mediators. In urology and sexual medicine, PRP has been promoted for erectile dysfunction (ED) and a growing range of urogenital disorders on the premise that it may support angiogenesis, neuroregeneration, immune modulation, and tissue remodeling. However, clinical uptake has outpaced high-quality evidence, while heterogeneity in PRP preparation, characterization, and delivery limits interpretability and reproducibility. This structured narrative review aims to critically integrate mechanistic, preclinical, and clinical evidence regarding PRP use in ED, Peyronie's disease (PD), stress urinary incontinence (SUI), interstitial cystitis/bladder pain syndrome (IC/BPS), and selected emerging indications. We further aim to identify sources of heterogeneity and propose an actionable minimum reporting framework (PRP-Uro Checklist) to guide future research. Methods: A structured search of PubMed/MEDLINE was conducted for studies published between 2021 and 2025. The relevant literature on PRP use in ED, PD, SUI, IC/BPS, and related indications was included for critical narrative synthesis. Emphasis was placed on PRP classification and preparation variables, outcome measure validity, and sources of heterogeneity across studies. Results: Mechanistic and preclinical evidence supports PRP's potential to modulate nerve repair, angiogenesis, extracellular matrix remodeling, and immune polarization through a complex secretome of growth factors, cytokines, and extracellular vesicles (EVs). Clinical evidence suggests that intracavernosal PRP may improve erectile function in selected populations, but effect size, durability, and superiority over placebo remain uncertain due to small trials, substantial placebo effects, short follow-up, and incomplete biologic characterization. Evidence for PRP in PD, SUI, and IC/BPS remains preliminary and is derived largely from small cohorts, proof-of-concept studies, or uncontrolled designs, although early findings suggest potential symptom benefit and acceptable short-term tolerability. Across indications, inconsistent PRP reporting, particularly the absence of absolute platelet dose, leukocyte quantification, activation method, and standardized treatment protocols, represents a major barrier to reproducibility and evidence synthesis. Conclusions: PRP is biologically plausible and appears broadly safe, but its role in urology and sexual medicine remains investigational and is not yet supported by guideline-level evidence. To enhance reproducibility and interpretation, we propose a Minimum PRP Reporting Checklist for Urology and Sexual Medicine Trials (PRP-Uro Checklist). Future progress requires rigorous standardized reporting, indication-specific biologic characterization, rigorously designed sham-controlled trials, clinically meaningful endpoints, and longer-term follow-up.
5-Aminolevulinic acid (5-ALA) induces tumor-selective accumulation of protoporphyrin IX (PpIX), enabling fluorescence-guided visualization of malignant tissue. In urologic oncology, the most established application is photodynamic diagnosis (PDD) during transurethral resection of non-muscle-invasive bladder cancer, in which fluorescence can identify occult carcinoma in situ and additional papillary lesions; however, specificity may decline in the presence of inflammation, recent instrumentation, or intravesical therapy. Renal applications are emerging: oral 5-ALA before partial nephrectomy can highlight some renal tumors, but fluorescence is often heterogeneous, can overlap with normal parenchyma, and is affected by histologic subtype, necrosis, blood attenuation, and device-dependent optics. Evidence in upper tract urothelial carcinoma and prostate cancer remains preliminary, with small cohorts and practical challenges in endoscopic or robotic workflows, alongside systemic adverse events such as hypotension and photosensitivity. This review synthesizes clinical and preclinical studies of 5-ALA-based fluorescence guidance across bladder, kidney, upper tract, and prostate malignancies, focusing on where the technology is ready for practice versus where it remains investigational. We discuss common pitfalls in interpretation and implementation and outline future directions, including quantitative fluorescence and spectroscopy, standardized dosing and imaging protocols, and prospective multicenter trials linking fluorescence guidance to residual disease, recurrence, margin status, and patient-centered outcomes.
Racial and ethnic inequities persist in medication treatment initiation and adherence for pregnant and postpartum people with opioid use disorder (OUD). Our objective was to understand the experiences of "positive outliers," specifically pregnant and postpartum people of color with OUD who utilized medication treatment and engaged in a randomized clinical trial for buprenorphine despite historical, cultural, and structural barriers. We conducted two sets of semi-structured qualitative interviews. First, trained peers with lived expertise as mothers in recovery interviewed individuals who identified with a non-white race and/or ethnicity and enrolled in the Medication Treatment for OUD in Expectant Mothers (MOMs) trial (NCT03918850). Second, we interviewed principal investigators, clinicians, and research coordinators from the 13 MOMs trial sites. We used an inductive thematic approach informed by the Social Ecological Model of Racism and Anti-Racism. Transcripts were double-coded and reviewed until consensus was reached. Preliminary findings from participant and staff interviews were merged and triangulated with peers to inform theme development. We completed 17 interviews with MOMs trial participants from 7 sites. Participants identified as Hispanic (29%), Black non-Hispanic (24%), multi-racial Hispanic (18%), multi-racial non-Hispanic (18%), and American Indian, Native Hawaiian, or Pacific Islander (12%). Thirty-two interviews with trial staff were also completed. Three themes emerged: (1) Although some participants expected racist treatment and research exploitation, all participants interviewed reported non-discriminatory, non-judgmental care within the MOMs trial; (2) Compassionate care, frequent, personalized, and integrated encounters, and emotional support helped counteract prior stigmatizing and discriminatory health care interactions, enabling participants of color to feel particularly supported, trusted, and empowered during the MOMs trial; and (3) Despite pervasive cultural stigma around addiction and concerns about taking an investigational drug while pregnant, participants expressed that pregnancy status, care team trust, and transparent communication with MOMs trial staff encouraged medication utilization and adherence. Facilitators of successful engagement in the MOMs trial and retention in medication treatment among pregnant and postpartum people of color with OUD included non-judgmental care, sustained trust, and frequent contact. Key perinatal OUD clinical interventions and trial improvements include personalized communication and scheduling flexibility to promote engagement of marginalized populations.