Citations

Abstract INTRODUCTION New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS Harmonized amyloid PET data from 4216 participants were used in genome‐wide survival, tissue‐specific gene expression, and genetic covariance analyses of EAOA. RESULTS Variants in apolipoprotein E ( APOE ), ABCA7 , and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7 , associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7 , which was associated with increased amyloid pathology at autopsy. Multiple immune‐related diseases shared genetic covariance with EAOA. DISCUSSION APOE , ABCA7 , and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue‐specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E ( APOE ) , ABCA7 , and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue‐specific expression analyses.

Importance Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood. Objective To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated. Design, Settings, and Participants This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor−positive ERBB2 -negative (formerly HER2 -negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025. Intervention Random assignment to CET or ET. Main Outcomes and Measures Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes. Results Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was −3.02 (95% CI, −5.33 to −0.72; P = .01) for premenopausal and −2.37 (95% CI, −3.92 to −0.82; P = .003) for postmenopausal participants. Conclusions and Relevance This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT01272037

Abstract Immune checkpoint inhibitor–associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

ABSTRACT Background Previous studies on the relationship between prediabetes, HbA1c and cognitive trajectories show mixed results. Therefore, we investigated the association of prediabetes, diabetes and HbA1c with change in global and domain‐specific cognitive scores in cognitively unimpaired (CU) adults, as well as the potential effect modification by sex or age. Methods This longitudinal study included 4236 CU persons aged ≥ 50 years from the population‐based Mayo Clinic Study of Aging. We ran linear mixed‐effect models with baseline prediabetes, diabetes and HbA1c predicting longitudinal global and domain‐specific (i.e., memory, language, attention/executive function, and visuospatial skills) cognitive z‐scores and raw scores. Models were adjusted for age, sex, education, medical comorbidity, repeated cognitive testing, and ApoEɛ4. We additionally ran models with sex and age interactions. Results Compared to normoglycemic individuals, individuals with prediabetes and diabetes showed poorer performance on cognitive tests, i.e., TMT‐B, category fluency, and block design subtest over time. Additionally, the presence of prediabetes, diabetes, longer diabetes duration and higher HbA1c were associated with faster global and domain‐specific cognitive decline over a median follow‐up of 6.4 years (range 1–19). Three‐way interactions showed that the effect of diabetes on decline in global cognition, attention and visuospatial domains was more pronounced in women than in men. Age did not modify the effect of diabetes or higher HbA1c on cognition. Conclusions The results suggest that prediabetes and diabetes significantly shorten the timeframe before a potentially clinically noticeable change in global and domain‐specific cognition is reached. Thus, lifestyle modification to reverse prediabetes and prevent diabetes could potentially reduce the rate of cognitive decline in aging populations. The findings differed by sex (i.e., the effect of diabetes on decline in global cognition, attention and visuospatial domains was more pronounced in women than men).

Abstract Background Subglottic stenosis (SS) is a type of laryngotracheal stenosis defined by a location of less than 1.5 cm below the glottis or the vocal cords. Approximately 20% of cases are idiopathic. Objective We performed a systematic literature review of idiopathic subglottic stenosis (ISS) complicating pregnancy. Search Strategy PubMed, Scopus, and clinicaltrials.gov databases were queried from inception through August 10, 2023 with the following terms: idiopathic subglottic tracheal stenosis, subglottic stenosis, subglottic stenoses, tracheal stenosis, tracheal stenoses, and pregnancy. This systematic review was conducted according to the methods described in the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) guidelines for reporting systematic reviews. Selection Criteria Studies detailing cases of ISS affecting pregnancy were included and studies reporting SS in pregnancy from a known etiology were excluded. Data Collection and Analysis Our search identified 31 peer‐reviewed published cases of ISS complicating pregnancy that met the inclusion criteria. We also included two additional cases from our institution. Publication bias was checked by the Joanna Briggs Institute critical appraisal tools. Descriptive statistical analyses were performed using Excel. Main Results A majority of patients (26/33, 79%) were diagnosed with ISS during the reported pregnancy. Prior to pregnancy, 20/33 (61%) patients had a working diagnosis or reported symptoms of airway obstruction. Of these patients, 9/20 (45%) carried a diagnosis of asthma, and 6/20 (30%) carried a diagnosis of ISS. Specific symptoms prior to pregnancy were reported in 10/33 (30%) patients. The most common symptoms in these patients were dyspnea (10/10, 100%) and stridor (4/10, 40%). During pregnancy, all patients experienced worsening respiratory symptoms, with dyspnea (31/33, 94%), stridor (18/33, 55%), cough (13/33, 39%), hoarseness (7/33, 21%), and wheeze (5/33, 15%) being the most common symptoms. A total of 22/33 (67%) patients required medical and/or surgical management with dilation and/or excision during pregnancy. Postpartum outcomes were reported in 27/33 (82%) patients, and 1/27 (3.7%) required a tracheostomy immediately postpartum. The majority (18/27, 67%) of these patients required intervention postpartum, while 9/27 (33.3%) were asymptomatic. Conclusion ISS should be considered in pregnant patients with worsening respiratory symptoms despite medical management of asthma. If high clinical suspicion for upper airway obstruction exists, an otolaryngology referral for evaluation with bronchoscopy is recommended.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract E1910 evaluated the addition of blinatumomab to chemotherapy in adults with B-acute lymphoblastic leukemia (ALL). The addition of blinatumomab in patients (pts) with measurable residual disease (MRD) negative (neg) B-ALL significantly improved both relapse-free and overall survival (NEJM 2024; 391: 320-33)1. Given the increasing use of blinatumomab and the E1910 backbone chemotherapy regimen, we evaluated > Grade 3 toxicities on this trial in further detail. We assessed toxicity among the MRD-neg pts by age, gender, body mass index (BMI), combined cytogenetic-molecular risk, and number of cycles of blinatumomab received. We also evaluated toxicities during induction since this trial used a modified chemotherapy backbone. Methods: The eligibility, combined cytogenetic-molecular risk, and treatment have been previously described.1 All toxicities were > Grade 3 by CTCAE version 4 with at least a possible relationship to treatment. Descriptive statistics were used to summarize the occurrence and rates of toxicities and Fisher's exact test was used to compare differences in proportions between groups. Analysis of induction included all pts who started treatment. Analysis of Step 3 toxicities included MRD-neg pts who started treatment on the blinatumomab (n=111) or chemotherapy only arm (n=112). Results: Pt characteristics: For induction (n=488), median age was 51 years (yrs) (range 30-70); 48.6% female. Combined cytogenetic-molecular risk: favorable (13.5%); intermediate (12.9%); no risk assigned (16.2%); unfavorable (57.4%). For induction, we compared toxicities for E1910 (n=488) to pts treated on a prior young adult study (n=289) (C10403) (Blood Adv 2021; 5(2): 504-12). The incidence of hyperglycemia (8% vs. 31.1%, p< 0.001), aspartate aminotransferase (AST) increase (6.1% vs. 12.8%, p=0.002), alanine aminotransferase increase (ALT) (11.7% vs. 28.7%, p< 0.001), and hyperbilirubinemia (11% vs. 19%, p=0.002) were significantly lower in E1910 pts. The incidence of pancreatitis (1.8%), thromboembolic events (4.5%), and febrile neutropenia (25.4%) in E1910 was similar to C10403. Toxicities in the MRD-neg pts in the blinatumomab arm (n=111): Despite a high incidence of neutropenia (74.8%) and thrombocytopenia (55.9%) in Step 3, there was a relatively low incidence of sepsis (7.2%), bacteremia (1.8%), cytokine release syndrome (CRS) (3.6%) and neurologic adverse events (0-6.3%). There was a higher incidence of neurological or psychiatric events in the blinatumomab arm (23%) versus chemotherapy arm (5%) (p < 0.001) when all events were combined. There was a numerically higher incidence of ataxia (4.4% vs. %, p=0.16) and dysphasia (11.1% vs. 3%, p=0.12) in pts > 55 yrs and a higher incidence of neutropenia (80.3% vs. 66.7%, p=0.12) and thrombocytopenia (62.1% vs. 46.7%, p=0.12) in the younger pts (age < 55 yrs). In pts with a BMI < 30 kg/m2 (vs. > 30 kg/m2), there was a significantly higher incidence of leukopenia (51.7% vs. 26.4%, p=0.007) and thrombocytopenia (65.5% vs. 45.3%, p=0.037). However, this did not translate into an increased incidence of bleeding or infectious complications. By gender, females had a higher numerical incidence of AST increase (8.8% vs. 0%, p=0.057) and CRS (7% vs. 0% p=0.12); whereas males had a higher incidence of catheter- related infections (7.4% vs. 0%, p=0.05) and hyperglycemia (11.1% vs. 3.5%, p=0.16). A little more than half (56.8%) of pts received 4 cycles of blinatumomab with the remainder of pts receiving 1 (10.8%), 2 (28.8%), or 3 cycles (3.6%). Pts receiving 3-4 cycles of blinatumomab vs. 1-2 cycles of blinatumomab had a statistically higher incidence of anemia (38.8% vs. 6.8%, p< 0.001), neutropenia (98.5% vs. 38.6%, p< 0.001), and thrombocytopenia (83.6% vs. 13.6%, p< 0.001), likely related to being on treatment for a longer period of time. Conclusions: Blinatumomab was well tolerated with no significant toxicity differences noted by age, gender, or number of cycles of blinatumomab received. Pts with a lower BMI did have an increased incidence of leukopenia and thrombocytopenia, possibly related to flat dosing of the drug. However, this did not translate into increased complications. Toxicites during induction were notably few, which suggests that this backbone with age adjustments may serve as a good backbone for future trials. Blinatumomab is being evaluated with low dose chemotherapy and other targeted agents in ongoing trials.

Abstract Background: Chronic myelomonocytic leukemia (CMML) is a universally fatal adult myeloid neoplasm with a median survival of 32 months and no approved therapies that alter its natural history. Although most patients initially present asymptomatically, disease progression (DP) is inevitable and its biological triggers remain poorly understood. Anecdotes and small case series suggest that acute inflammatory events (AIE) may precipitate hyperleukocytosis and DP in some patients, but fragmented care in the U.S. has hindered large-scale retrospective analyses. To address this gap, we launched a prospective, multi-institutional observational study to systematically evaluate the relationship between AIEs and DP. Our aim is to identify modifiable, cell-extrinsic stressors that contribute to disease destabilization and inform strategies for prolonging the indolent phase of CMML. Methods: We enrolled patients with WHO-defined CMML in a clinically asymptomatic state, defined by: (1) MPN-SAF TSS <20, (2) no CMML-directed therapy, (3) no symptomatic splenomegaly, and (4) transfusion independence. Key exclusions included active malignancy, uncontrolled infection, or inability to attend monthly visits. Over 24 months, participants underwent monthly interviews to document AIEs, including flares of chronic illness e.g. gout, infections, surgery procedures, cardiovascular events, and trauma. AIE severity was graded by hospitalization status. Blood samples were collected at each visit, with bone marrow collected when clinically indicated. Cytokine profiling was performed using Olink Reveal assays, and genomic data were integrated to assess mutation-specific inflammatory patterns. DP was defined by worsening symptoms (MPN-SAF TSS ≥20 with ≥50% increase), new transfusion needs, therapy initiation, symptomatic splenomegaly, or transformation to CMML-2/AML. Descriptive statistics summarized baseline and AIE data. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Results: A total of 102 patients were enrolled over 2 years, with a median follow-up of 1 year (range, 0.5–1.5). The median age was 72 years; 71 were male and 31 female. By FAB criteria, 38 had myeloproliferative-type CMML, and 8 met WHO 2022 criteria for CMML-2. CPSS-Mol risk distribution was: 49.0% low, 26.5% intermediate-1, 37.3% intermediate-2, and 3.99% high. A total of 260 AIE were recorded in 77 patients. The most common AIEs were surgical procedures (n=115 events in 53 patients), flares of chronic disease (n=99 in 38), and infections (n=87 in 47). DP occurred in 28 patients: 18 met symptom-defined criteria, 13 met disease-defined criteria, and 3 met both. Longitudinal labs showed significant post-AIE increases in WBC (6.29 → 7.73 ×10⁹/L, p = 0.02) and platelets (112 → 131 ×10⁹/L, p = 0.03), with no change in hemoglobin (p = 0.27). Progressors had significantly lower hemoglobin than non-progressors (11.6 vs. 12.7 g/dL, p = 0.037), with no differences in WBC or platelet counts (p > 0.5). Among those with DP, 25 of 28 had at least one AIE. AIE presence was significantly associated with DP (OR 3.76, p = 0.04). Flares of chronic disease conferred a threefold increased risk of DP (OR 3.37, p = 0.008) and remained an independent risk factor after adjusting for CPSS-Mol risk (OR 3.6, p = 0.009). Severe AIEs requiring hospitalization trended toward higher risk but were not statistically significant (OR 2.3, p = 0.09). Among the 44 patients with genomic data, all AIE-positive patients (29/29) harbored at least one epigenetic regulator mutations (TET2, DNMT3A, ASXL1, IDH1/2), compared to 12/15 AIE-negative patients (p = 0.034). Signaling mutations (JAK2, CBL, NRAS, KRAS) were also enriched in AIE-positive cases (11/29 vs. 1/15, p = 0.035). No significant differences were found in spliceosome or tumor suppressor mutations. No genomic features distinguished progressors from non-progressors, regardless of whether there was an AIE. Conclusion: In this interim analysis of a prospective multi-institutional CMML cohort, AIE were significantly associated with DP. Ongoing work is aimed at sequentially annotating genomic alterations and profiling secreted factors before and after AIEs. While this study continues to accrue and mature, these findings support inflammation as a modifiable driver to CMML biology and progression and lay the groundwork for future studies investigating inflammatory or supportive interventions to delay disease evolution.

Abstract Background: Recent approvals and clinical trials have established covalent BTK inhibitors (BTKis), including ibrutinib, acalabrutinib, and zanubrutinib, as effective agents for the treatment of mantle cell lymphoma. Multiple BTKi-based regimens are recommended by experts and clinical guidelines in both the first-line and later-line settings. Additional approvals of the noncovalent BTKi pirtobrutinib and multiple CAR T-cell therapies have also advanced the management of patients who have progressed on covalent BTKi therapy. In light of these developments in treatment strategies for mantle cell lymphoma (MCL), this study compares trends in treatment choice among experts and healthcare professionals (HCPs) in an online treatment decision support tool. Methods: An online decision support tool, developed with 5 US-based experts in MCL, was launched in April 2023 and updated in April 2025. The tool provided treatment recommendations for various clinical scenarios involving newly diagnosed (ND) or relapsed/refractory (R/R) MCL, incorporating factors such as age, fitness, previous therapies, and response duration. HCPs entered specific patient characteristics along with their intended treatment choice. The tool then displayed expert recommendations for that scenario, and HCPs were asked whether these recommendations influenced their treatment decision. HCP-entered data and expert recommendations were analyzed to identify common trends and divergence in current BTKi therapy use. Results: The 2023 online tool was used by 119 HCPs who entered 148 patient scenarios, and the 2025 online tool was used by 69 HCPs who entered 96 patient scenarios. In 2023, for patients with ND MCL who had later-stage disease or were not eligible for radiation therapy (n = 75), 64% of expert-recommended treatments included BTKis, with the ECHO and TRIANGLE regimens representing 12% and 17% of recommendations, respectively. In 2025, 81% of expert recommendations were BTKi-based regimens, with ≥3 experts recommending a BTKi regimen in 66 of 67 unique ND case scenarios. The ECHO and TRIANGLE regimen each represented 28% to 29% of expert recommendations. In addition, 51% of recommendations for patients with 17p deletions or TP53 mutations consisted of the BOVen regimen. The percentage of HCPs who indicated that they were considering a BTKi-based regimen in the setting of ND MCL was 17% (13 of 75 ND cases) in 2023 and 66% (44 of 67 ND cases) in 2025. The use of both the ECHO and TRIANGLE regimens by HCPs increased from 5% and 4%, respectively, in 2023 to 19% for each in 2025. In 2025, 6% of HCPs considered the BOVen regimen for patients with TP53 mutation (n = 17). In 2023 and 2025, approximately 50% of the HCP-entered patient cases for previously treated MCL had not received a BTKi (n = 48 and n = 18, respectively). For these scenarios, 94% and 98% of expert recommendations consisted of covalent BTKis in 2023 and 2025, respectively. HCPs selected covalent BTKis for 68% of cases in 2023 and 89% of cases in 2025. For patients with R/R MCL previously treated with a BTKi, CAR T-cell therapy represented 36% of expert recommendations in 2023 (23 scenarios) and 60% in 2025 (18 scenarios). By contrast, 4% and 11% of HCPs considered CAR T-cell therapy for these patients in 2023 and 2025, respectively. For HCPs reporting on the tool's clinical impact (n = 96), 35% indicated expert recommendations changed their intended therapy, 41% stated their treatment plan matched the recommendations, 10% cited barriers to implementing recommendations, and 14% remained undecided on optimal treatment. Conclusions:This analysis highlights the ongoing adoption of expert-recommended treatments into real-world clinical practice. Our data suggest that expert and HCP use of BTKi therapy in the ND MCL setting has increased in recent years. In R/R MCL, CAR T-cell therapy appears to be considered infrequently by HCPs. Barriers to implementation of expert recommendations warrant further investigation. Enhanced decision support tools and targeted educational initiatives could help increase the use of expert treatment recommendations and potentially improve patient outcomes.