Citations

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

ABSTRACT Background In chronic liver disease, fat and fibroinflammatory changes often coexist. However, their biomarkers, proton density fat fraction (PDFF) and T 1 , are typically assessed separately. Their reproducibility under mutual confounding remains unclear. Purpose To assess multicenter, multi‐vendor reproducibility of confounder‐corrected chemical shift‐encoded (CSE)‐MRI‐based PDFF mapping and MOLLI‐based T 1 mapping using a combined PDFF‐T 1 phantom. Study Type Prospective phantom study. Phantom Commercial PDFF‐T 1 Phantom (Model 725) with varying PDFF (0%–30%) and T 1 (200–1400 ms) values. Field Strength/Sequence 1.5 T and 3 T multi‐echo, three‐dimensional spoiled‐gradient‐echo (SGRE) sequence for PDFF mapping, and MOLLI sequence (5(3)3 acquisition scheme) using two‐dimensional SGRE readouts for T 1 mapping across four centers and vendors. Assessment PDFF and T 1 maps were acquired using standardized protocols. PDFF maps were reconstructed locally, while T 1 maps were generated using a centralized algorithm. All maps were quantitatively analyzed by a single radiologist using standardized region‐of‐interest placement. Phantom temporal stability was assessed at one center across five sessions over 9 months (baseline, retest, 1 week, 6 and 9 months). Statistical Tests Intraclass correlation coefficients (ICC), reproducibility coefficients (RDC), and linear regression analysis were used. A p value < 0.05 was considered statistically significant. Results PDFF showed overall excellent reproducibility (ICC = 0.987, RDC = 3.7%), with increased variability at higher T 1 values (RDC up to 7.9% at T 1 = 1400 ms). T 1 mapping showed good reproducibility in the absence of fat (RDC 16–161 ms at PDFF = 0%), but moderate to poor reproducibility in the presence of fat, with RDC increasing up to 1553 ms at PDFF 30%. Temporal stability was excellent ICC ≥ 0.998 for both PDFF and T 1 , and RDC of 1.1%–1.3% for PDFF and 52–57 ms for T 1 . Data Conclusion This phantom study demonstrated high reproducibility of PDFF, whereas T 1 reproducibility deteriorated at higher fat and T 1 levels, underscoring the need for fat‐corrected T 1 mapping for reliable assessment of fibroinflammatory changes. Evidence Level N/A. Technical Efficacy Stage 1.

ABSTRACT Macrophages play a central role in determining the outcomes of healing, coordinating regeneration in some injuries and scar formation in others. In both cases, this coordination involves the cross-talk between macrophages and surrounding cells. But what drives the different cross-communication pathways to determine healing outcomes is not well known. In this study, we make use of the mouse digit tip amputation model, in which an amputation through the third phalangeal element (P3) is able to completely regenerate whereas an amputation through the second phalangeal element (P2) forms a scar. We identify a population of macrophages that is specific to the P3 regenerating digit. By integrating single-cell RNAseq, spatial transcriptomics, and metabolomic analyses, we show that this population localizes specifically to the growing bone front, express BMP ligands that drive downstream BMP activation in neighboring osteoblasts and is governed by a two-part metabolic switch involving increased fatty acid oxidation coupled with reduced glycolytic activity. This spatially restricted, BMP-expressing macrophage population is entirely absent in the scar-forming P2 injury, and our data indicate that environmental conditions unique to the regenerating digit are responsible for its emergence. Together these findings identify a regeneration-specific macrophage signaling center for patterned bone formation and suggest that targeting the metabolic conditions that drive this population could improve the efficacy of regenerative therapies.

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

Abstract Cerebral blood flow is stabilized through dynamic adjustments across both macro‐ and microvascular compartments. While dynamic cerebral autoregulation (dCA) quantifies upstream pressure–flow coupling, downstream microvascular responses are less well characterized and may represent a distinct but functionally linked process. This study tested whether a two‐component cascade model, treating dCA and an empirically derived index of microvascular function (MF) as sequential stages can represent the integrated regulation of cortical oxygenation. Data from 41 healthy adults (20–45 years) were analysed. Beat‐to‐beat mean arterial pressure (MAP), middle cerebral artery flow velocity (CBFV) and cortical oxyhaemoglobin (O 2 Hb) were recorded during supine spontaneous oscillations and forced oscillations at 0.05 Hz using repeated sit–stand manoeuvres. Transfer function analysis quantified frequency‐domain gain, phase and coherence for MAP→CBFV (dCA), CBFV→O 2 Hb (MF) and MAP→O 2 Hb (total pathway). The cascade model was computed as the product of dCA and MF transfer functions. The cascade model derived indices showed strong correlations with total pathway gain, phase and coherence measures during both spontaneous and forced oscillations, with improved linear coupling under forced oscillations. These results support the applicability of a two‐component cascade model for integrated cerebrovascular regulation and suggest that serial interactions between macrovascular and microvascular regulatory mechanisms jointly shape the frequency‐dependent propagation of arterial pressure to brain‐tissue oxygenation dynamics. image Key points Cerebral blood flow is stabilized by coordinated regulation across large arteries and microvessels, but their dynamic interaction has not been experimentally modelled. We examined whether a two‐component cascade model linking upstream dynamic cerebral autoregulation and downstream microvascular function can explain how blood pressure oscillations influence cortical oxygenation. In 41 healthy adults, we recorded beat‐to‐beat blood pressure, middle cerebral artery blood flow velocity and near‐infrared spectroscopy‐derived oxygenation during rest and sit–stand manoeuvres, and analysed them using transfer function analysis. Gains, phases and coherences derived from the cascade model closely matched those from the direct blood pressure–O 2 Hb relationship, particularly under forced oscillations during sit–stand, demonstrating the model's physiological relevance. The cascade model provides a mechanistic framework to separate and quantify large‐ and small‐vessel contributions to cerebral blood flow regulation, with potential application in future studies of ageing and cerebrovascular disease.

Abstract Background The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine–specific recommendations in the United States for the gender-diverse population. Content This document outlines pathology- and laboratory medicine–specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following 5 topics: (a) reference intervals and interpretation of laboratory tests impacted by use of GAHT (testosterone for transgender men; estradiol with or without antiandrogens for transgender women), focusing on those stably on GAHT for 6 months or longer; (b) transfusion medicine considerations for the gender-diverse patient population, (c) consideration of gender diversity in autopsy and death investigation, (d) interpretation of histology from tissues that are impacted by GAHT and surgical procedures; and (e) pathology and laboratory medicine informatics challenges and opportunities. Summary A relatively small group of laboratory tests is significantly impacted by GAHT. The histology of some tissues shows changes attributable to GAHT or to nonhormonal medical procedures. Autopsy and transfusion medicine practices for the gender-diverse population currently lack standardization, although this is evolving. The landscape of pathology informatics related to gender diversity is complicated by varying electronic health record and laboratory informatics systems functionality.

Background: The most critical exam components in patients seeking rhinoplasty have not been established. Objective: To identify concordance among experienced rhinoplasty surgeons regarding the most important exam features for various deformities. Methods: An online questionnaire was distributed to board-certified facial plastic and plastic surgeons experienced in rhinoplasty, with seven nasal deformity categories: dorsal hump, crooked nose, boxy tip, pinched tip, droopy tip, saddle nose, and nonallergic nasal obstruction. For each, respondents were asked to rank the three most important anatomic regions to examine from the following: nasal bones, midvault cartilage, skin, radix, facial profile, lip, tip, septum, internal nasal valve, nostrils, inferior and middle turbinates. For each ranked region, up to three important features were chosen. Normalized Attention Scores (NAS) were calculated to determine agreement amongst surgeons. Results: A total of 13 facial plastic and 8 plastic surgeons were invited to participate and completed the questionnaire. All cases had high agreement demonstrated by NAS, with the dorsal hump case exhibiting the greatest variability in responses. Conclusions: In this survey of 21 rhinoplasty surgeons, there was general agreement regarding the most relevant anatomical structures and features, which may provide a conceptual foundation for identifying key exam features for seven common complaints in patients seeking rhinoplasty.

Abstract Background: Pyrimidine synthesis is a therapeutic vulnerability in cancer but inhibition results in toxicity to normal cells. Differential targeting of CTP synthase 1 (CTPS1), sparing the CTPS2 isoenzyme, is a therapeutic strategy in lymphoid cancers, supported by human genetic studies, that can potentially avoid toxicity; however, CTPS2 activity may compensate in epithelial tumours. Loss of CTPS2 protein expression characterises 25% of solid tumours and is predicted to expose a synthetic lethal vulnerability to CTPS1 inhibition. Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing &gt;1,300-fold selectivity over CTPS2. In preclinical studies, CTPS2 expression was confirmed as a key modulator of response to CTPS1 inhibition, and dencatistat induced tumour regression in an in vivo model of CTPS2 negative ovarian cancer. Study design: The study comprises a standard 3+3 phase 1a dose escalation design, in which intra-patient dose escalation is encouraged, followed by a phase 1b safety expansion. The dose escalation study is recruiting participants with high grade advanced tumours who have exhausted standard of care therapy (excluding haematological cancers, salivary gland tumours and low grade tumours of any tissue). In addition, participants with high grade serous ovarian cancer whose tumours lack expression of CTPS2 (per central laboratory testing by immunohistochemistry) are eligible for backfill into cleared cohorts during dose escalation. The recommended phase 2 dose (RP2D) will be nominated based on safety, tolerability, target engagement and early signs of clinical efficacy. The phase 1b safety expansion study will recruit participants with CTPS2 negative ovarian, lung or endometrial cancer who will receive treatment at the RP2D. Standard inclusion criteria apply; patients with ECOG performance score &gt;2 (&gt;1 for phase 1a in France) or active/symptomatic CNS metastases are not eligible. The primary objectives of the study are to evaluate the safety and tolerability of single agent dencatistat and to determine the RP2D for further development. Secondary objectives comprise evaluation of pharmacokinetic properties and preliminary clinical activity. Exploratory endpoints include evaluation of target engagement, molecular features associated with response, and determination of drug metabolites. The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain. Citation Format: Donna M. Graham, David Sommerhalder, Douglas Orr, Rowan Miller, Neeharika Makani, David O'Malley, Ira Winer, Philip A. Beer, Karen Smith, Maureen Higgins, John R. Hawse, Xiyin Wang, Saravut J. Weroha, Christophe Massard, Patricia Roxburgh. Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT075.

Abstract Alzheimer's disease (AD) continues to pose a major public health challenge. Since its launch in 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has played a pivotal role in advancing the field by providing a comprehensive, open‐access, longitudinal dataset that integrates neuroimaging, biomarker, genetic, and clinical data related to AD. We used standard literature search methods to identify ∼1830 publications from 2023 to mid‐2025 that used ADNI data or samples. This review highlights key ADNI studies with direct clinical applications. We describe how these have impacted the development and validation of plasma biomarkers, improved clinical trials, assessed AD therapies, and developed methods for diagnosis and prediction using clinical, fluid, and imaging biomarkers. These contributions are underlain by an improved understanding of biological mechanisms of disease progression in AD and highlight ADNI's central role in advancing translational research and accelerating progress toward more effective, individualized care for patients with AD.

ABSTRACT Background Visceral myopathy (VSCM) is an ultra‐rare life‐threatening condition characterized by severe impairment of gastrointestinal (GI), genitourinary, and uterine smooth muscle. This disorder represents a significant clinical challenge due to variable presentation and the lack of standardized diagnostic and therapeutic protocols. Methods To discuss advances in the field, scientists and clinicians with a special interest in VSCM met in Arenzano, Genova, Italy in October 2024 for the second International Forum on Visceral Myopathy 2024 (IFVM2024) ( https://ifvm2024.ge.ibf.cnr.it/ ). Key Results As in the previous edition of the event ( https://poic‐e‐dintorni.org/efvm‐2022/ ), attendees included clinicians and researchers from around the world who study this disease, representatives from support organizations, patients affected by VSCM and their families, and companies that co‐funded the event. The present manuscript aims to summarize knowledge shared during the IFVM2024 conference, thus providing an updated state‐of‐the‐art summary of VSCM biology and disease management. Conclusions Here, we pay particular attention to the epidemiology of the disease, histopathology, genetics, novel treatments, advances in molecular and cell biology, experimental models, and the lived experiences and impact of this disorder on families.