Citations

Purpose To explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma. Methods Single-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria. Results Initial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity ( p = 0.034), hypertension ( p = 0.017), and diabetes mellitus ( p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus ( p = 0.01) and obesity ( p = 0.04) remained significantly associated with earlier T category on initial presentation. Conclusion Among patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Abstract High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Background Light chain (AL) amyloidosis is a rare disease caused by the misfolding of immunoglobulin light chains produced by a plasma cell dyscrasia. Patients can present with involvement of many organs, including the heart, kidneys, liver, nerves, and other sites, resulting in a high symptom burden. Timely and accurate diagnosis is important to prevent organ failure and improve patient survival. Objective These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients and clinicians in the timely and effective diagnosis of AL amyloidosis. Methods ASH formed a multidisciplinary guideline panel that included 22 individuals representing various medical specialties (academic and community hematology, nephrology, neurology, cardiology, internal medicine, and pathology) as well as 1 patient representative. The group was balanced to minimize potential bias from conflicts of interest. The University of Kansas Medical Center supported the guideline development process, including updating or performing systematic evidence reviews (up to 6 March 2023). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results The panel agreed on 12 recommendations. Conclusions The use of serum immunofixation, urine immunofixation, and serum free light chains enhances the clinical suspicion of AL amyloidosis. The diagnosis of AL amyloidosis can be made effectively through surrogate biopsies, which require both a bone marrow biopsy and fat-pad sampling; however, target organ biopsies may be favored in certain clinical situations.

Importance Acute invasive fungal rhinosinusitis (AIFRS) is a rapidly progressive and potentially life-threatening infection that predominantly affects immunocompromised patients. Recent advances in diagnostic imaging, antifungal therapy, and surgical techniques may have altered its incidence, morbidity, and mortality. Objective To evaluate temporal trends in the pooled proportion, morbidity, and mortality of AIFRS in immunocompromised patients and assess the association of diagnostic and therapeutic advances. Data Sources Systematic searches of Ovid MEDLINE, Ovid Embase, PubMed, Scopus, Web of Science, Cochrane, and Google Scholar from 1977 through October 20, 2025, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Study Selection Prospective, retrospective, and cross-sectional studies and case series reporting pooled proportion, morbidity, or mortality of AIFRS in immunocompromised patients were included. Non-English articles, reviews, editorials, and studies with fewer than 10 patients were excluded. Data Extraction and Synthesis Two independent reviewers extracted data using standardized templates; disagreements were resolved by consensus. Risk of bias was assessed using the Newcastle-Ottawa Scale and Murad tool for case series. Random-effects meta-analysis generated pooled proportion, morbidity, and mortality rates with 95% CIs. Heterogeneity was quantified using I 2 statistics. Meta-regression and sensitivity analyses evaluated temporal trends and study-level effects. Main Outcomes and Measures Pooled proportion, morbidity, and mortality rates of AIFRS stratified by publication period (1983-2012 vs 2013-2025). Results A total of 205 studies comprising 48 437 immunocompromised patients (median [range] age, 49.4 [5.2-68.8] years), including 10 311 (21.3%) with AIFRS, were analyzed. The pooled proportion was 11.8% (95% CI, 7.9%-17.2%), rising to 16.6% (95% CI, 8.7%-29.2%) in studies from 2013 to 2025. Overall mortality was 31.2% (95% CI, 28.3%-34.3%), declining from 41.9% (95% CI, 35.0%-49.1%) before 2013 to 28.2% (95% CI, 25.1%-31.4%) after 2013. Morbidity was 37.0% (95% CI, 32.9%-41.4%), with similar rates across periods (39.3% before 2013 vs 36.4% after 2013). The most common complications were vision loss, exophthalmos/proptosis, and orbital exenteration. Conclusions and Relevance This systematic review and meta-analysis suggests that the pooled proportion of AIFRS among immunocompromised patients has increased while mortality has declined, reflecting advances in diagnostic and therapeutic approaches. Early detection and aggressive management remain critical to improving outcomes.

Abstract Measurable residual disease (MRD) assessment has become central to risk-adapted treatment strategies in multiple myeloma, yet the prognostic value of MRD negativity following autologous stem cell transplantation (ASCT) across individual high-risk cytogenetic abnormalities (HRCAs) remains unclear. We analyzed 351 newly diagnosed patients who achieved MRD negativity (sensitivity 2.4×10 − 6 ) at Day 100 following ASCT and had baseline cytogenetic data available. Median follow-up was 50.4 months. Standard-risk cytogenetics were present in 46% (n = 162), while 34% (n = 118) had one HRCA and 20% (n = 71) had ≥ 2 HRCAs. Despite uniform MRD negativity, several HRCAs continued to confer inferior progression-free survival (PFS). Compared with the standard-risk group (4-year PFS 84%), patients with del(17p), 1q21+, t(4;14), or MAF translocations [t(14;16)/t(14;20)] had significantly lower 4-year PFS rates: 56% (HR 2.89; p = 0.0001), 60% (HR 2.46; p = 0.0001), 43% (HR 3.50; p = 0.0001), and 58% (HR 2.51; p = 0.01), respectively. Isolated del(17p) and 1q21 + also conferred inferior PFS. The 4-year PFS was 65% for patients with one HRCA (HR 2.31; p = 0.0004) and 55% for those with ≥ 2 HRCAs (HR 2.75; p = 0.0001). In this large MRD-negative post-ASCT cohort, several HRCAs, including isolated HRCAs, remained clinically meaningful drivers of inferior PFS, highlighting that early MRD negativity does not uniformly mitigate the impact of high-risk biology.

Background A substantial proportion of patients with chronic rhinosinusitis (CRS) remain partly controlled or uncontrolled despite endoscopic sinus surgery (ESS) and maximal medical therapy. For these difficult-to-treat cases, topical antibiotic irrigations have been proposed as an adjunctive therapy, particularly when delivered via large-volume, low-pressure systems that enhance sinus penetration post-ESS. Evidence on their efficacy and prescribing patterns in this population remains limited. Objective This study aims to evaluate the use and outcomes of topical antibiotic irrigations in patients with difficult-to-treat CRS. Methods A retrospective, multi-site cohort study was conducted across tertiary academic medical centers. Adult patients with persistent CRS symptoms despite bilateral full-house ESS and conventional postoperative medical management were included. Patients with cystic fibrosis or granulomatosis with polyangiitis were excluded. Demographic, clinical, and treatment data were collected. Primary outcomes were infection resolution at 8 weeks and changes in Sino-Nasal Outcome Test-22 (SNOT-22) scores. Results Sixty-seven patients met inclusion criteria. Mupirocin (41.8%), tobramycin (23.9%), and gentamicin (17.9%) were the most commonly prescribed agents. After 8 weeks, 62.7% of patients achieved infection clearance. Among 44 patients with SNOT-22 data, scores improved significantly from 34.8 ± 20.2 to 21.8 ± 14.7 ( P < .001). Improvement in SNOT-22 scores was more pronounced in patients who cleared the infection compared to those who did not. Conclusion Large-volume topical antibiotic irrigations were associated with high infection resolution rates and clinically meaningful SNOT-22 improvements in patients with difficult-to-treat CRS. These findings support their potential utility as an adjunctive therapy in select postsurgical patients and warrant further prospective investigation.

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

392 Background: PAC+RAM is the standard second-line therapy for advanced GEA. However, PAC-related neuropathy is a major challenge, particularly since many pts have pre-existing neuropathy from prior platinum exposure. An effective “neuropathy-free” regimen remains an unmet need. We evaluated FTD-TPI+RAM as an alternative to PAC+RAM. Methods: This multi-center, randomized, phase II study enrolled GEA pts who progressed on or were intolerant to fluoropyrimidine+ platinum therapy. Pts were randomized to FTD-TPI+RAM (Arm A) or PAC+RAM (arm B) at a 1:1 ratio. The primary endpoint was progression-free survival (PFS), defined as time interval between randomization date and the date of disease progression or death; Secondary endpoints included overall survival (OS) and adverse events (AEs). The design hypothesized non-inferiority (NI) of Arm A to Arm B with a NI margin of hazard ratio 1.19. 90 PFS events from 116 pts provide 80% power with a one-sided alpha of 0.15. The interim futility analysis, conducted in December 2024 with 20 events, did not cross the futility boundary (Z statistic ≥ 1.172 ) and continued enrolling pts. The trial closed enrollment in March 2025 due to slow accrual. At the time of interim analysis, 20 events had occurred and the Z statistic was 0.4532. Final analysis included the 29 pts that were eligible, consented, randomized, and received any protocol treatment. Results: Among 29 pts (15 Arm A; 14 Arm B), baseline characteristics were balanced (in Arms A vs B, median age 64 vs 63; 80% vs 85.7% male; 86.7%% vs 78.6% White; 80% vs 78.6% ECOG 1). At data freeze of 8/4/2025, 26 PFS events were reported. Median PFS was 3.2 vs. 3.9 months in Arm A vs. Arm B (HR 1.37, 95% CI 0.61-3.02). NI was not demonstrated (Z =0.34, threshold for NI<-1.036). Median OS was 8.4 vs. 10.7 months, in Arms A and B, respectively. Grade ≥3 AEs occurred in 93% (Arm A) vs 71% (Arm B) with hematologic AEs occurring more frequently in Arm A than Arm B (53% vs 29%). Peripheral sensory neuropathy (any grade) occurred more frequently in Arm B (86%) vs. Arm A (47%). Conclusions: Although NI was not achieved due to early closure and small sample size, FTD-TPI+RAM was relatively safe and associated with less neuropathy compared with PAC+RAM. This regimen warrants further evaluation for pts in whom neuropathy limits taxane use. Clinical trial information: NCT04660760 .

Abstract Background Isolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF). Method We included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests. Result Compared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance ( T = 2.0, p < 0.05, Figure 2). Conclusion Our study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.