Citations

Abstract Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as “lineage drift” were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of <40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

Objectives: Early identification of patients living with cancer at higher risk of death from an infection is critical in infection mortality prevention. We characterize patients living with cancer at the highest risk of dying from an infection. Methods: 7,529,481 US cancer survivors (1992 to 2015) were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Standardized mortality ratios (SMRs) and 95% CIs were calculated. Fine-gray survival analysis was performed to calculate hazard ratios by adjusting for the effects of competing risks (eg, deaths due to causes other than infection). Results: Among 7,529,481 patients living with cancer (1992 to 2015), 101,167 (1.3%) died of infection. The rate of infection-specific mortality was 27.19/10,000 person-years, with an SMR of 3.29 (95% CI: 3.26-3.32, P <0.001). Patients who were older, male, black, and unmarried were at a greater risk of fatal infection. Overall, the risk of infection-specific mortality for patients living with cancer is greatest 1 year after diagnosis compared with the general population (SMR: 8.68, 95% CI: 8.53-8.84; P< 0.0001), and this risk decreases with follow-up time (SMR at >10 y after diagnosis: 2.93, 95% CI: 2.87-3.00; P< 0.0001). Among patients with Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and Kaposi Sarcoma, 9.2%, 11.5%, and 82.2% of all deaths within the first year after cancer diagnosis occurred due to acute infectious disease. In contrast, for patients with liver cancer, the relative percentage of infection-specific mortality increases with follow-up time from 3.5% at <1 year after cancer diagnosis and 10.4% at 10+ years of follow-up. Conclusion: The results of this study characterize infection mortality in patients living with cancer, which can guide more targeted research and interventions in this population.

Abstract Background: Resilience, quantified by the brief resilience scale (BRS), has been recognized for its role in pain and symptomatology in musculoskeletal conditions. The role of psychological factors in the clinical presentation and outcomes of FAI surgery continues to be poorly understood. Methods: This is a prospective multicenter study of FAI patients undergoing primary hip arthroscopy. PROMs were administered at baseline, 3-, and 6-months post-op and included the Patient Reported Outcomes Measurement Information System (PROMIS) domains of anxiety and depression, as well as Hip Disability and Osteoarthritis and Outcome Score (HOOS), modified Harris Hip Score (mHHS), and International Hip Outcome Tool (iHOT-12). Resilience was characterized by BRS score and divided into low (“L”, score&lt;3), normal (“N”, score 3-4.3), and high resilience (“H”, score&gt;4.3). Results: 675 patients were included with a mean age of 24.9±7.8 years and female predominance (56%). Mean BRS scores were 3.7±0.7 (1.5-5.0). 13.8% (n=93) had low resilience, 65.9% (n=445) had normal resilience, and 20.3% (n=137) had high resilience. Lower resilience had more severe symptoms in HOOS pain (p&lt;0.001), HOOS sports (p=0.003), HOOS ADL (p&lt;0.001), HOOS QoL (p&lt;0.001), iHOT-12 (p=0.002), and mHHS (p&lt;0.001). Anxiety (L: 50.5%/N: 14.4%/H: 2.2%) and depression (L: 38.7%/N: 8.8%/H: 2.9%) were higher in lower resilience groups (all p&lt;0.001) and this trend stayed consistent in female and male sub-analyses with females having greater anxiety and depression symptoms. The follow-up cohort with 3- and 6-months follow-up was 487 patients and had similar baseline characteristics as the baseline cohort. Lower resilience had lower postoperative PROs (with similar change) (p&lt;0.05). After treatment, rates of anxiety or depression decreased from 22.1% to 15.6% with the low resilience group having the highest change from 62.9% to 45.9%. Conclusion: Low resilience correlates with more severe symptoms and predicts anxiety/depression in FAI. 13.8% had low resilience while 20.3% had high resilience. Lower resilience had worse postoperative PROs. Particularly in patients with low resilience at presentation, rates of anxiety or depression symptoms decreased postoperatively. Further studies are needed to understand the role of resilience in longer-term outcomes of FAI and whether concurrent psychological treatment will help improve patient outcomes after hip arthroscopy for FAI.

Abstract Introduction: Low-dose computed tomography (CT) has been increasingly utilized in FAI due to its improved ability to characterize the complex and variable hip morphologies of FAI patients, compared to plain radiographs. This study defined FAI morphology between females and males as well as across adolescents, young adults, and older adults. Methods: A multi-center, prospective cohort of FAI patients undergoing primary arthroscopy was performed. Patients 14-45 years of age with idiopathic FAI were included. Low-dose CT was used for preoperative planning. Analysis focused on acetabular and femoral morphology and the differences between females/males and adolescents (A,14-18.9)/young adults (Y,19-24.9)/older adults (O,25+). Adolescents were the reference group during analysis. Results: There were 604 patients with CT data. Mean age was 24.9 years with 55.9% female. Males had more anterosuperior coverage (i.e. 64.2% vs 62.5% at 1:00), lower version (14.1° vs 18.0°), smaller femoral neck-shaft angles (130.9° vs 133.4°), and larger alpha angles (i.e. 72.1° vs 58.6° at 1:00) compared to females. Multivariable analysis demonstrated that females had associations with more femoral anteversion (OR: 1.05,CI: 1.03-1.07) and larger femoral neck-shaft angles (OR: 1.11,CI: 1.06-1.16). Males has associations with larger alpha angles at 1:00 (OR: 1.05,CI: 1.02-1.07) and 1:30 (OR: 1.03,CI: 1.00-1.06) as well as radial coverage at 1:00 (OR: 1.18,CI: 1.11-1.26). For females, adolescents had slightly less radial coverage at 2:00 (49.9%) compared to young (51.2%) and older adults (51.4%). Femoral neck-shaft angle decreased across age groups (A: 134.4°,Y: 133.0°,O: 132.7°). Alpha angles increased at 2:00 with age (A:54.6°,Y:55.3°,O:58.7°). Multivariable analysis had femoral neck-shaft angle decreasing for young (OR: 0.932,CI: 0.87) and older adults (OR:0.92,CI: 0.86-0.98) and it also had alpha angle at 1:15 increasing for young adults (OR: 1.03,CI: 1.00-1.06) and older adults (OR: 1.03,CI: 1.01-1.06). Males did not have any appreciable differences alpha angles, femoral version, or acetabular coverage across age groups. Conclusion: Differences in morphology identified on CT exist between females and males as well as across age groups for females. These differences may offer insight into disease pathomechanics between these patient populations. Further studies should confirm these findings and look at how they affect patient outcomes after treatment.

Abstract Introduction: Femoroacetabular impingement commonly causes labral and cartilage damage. Understanding what clinical and CT-morphological factors are associated with increased labral and acetabular cartilage damage may give insight into the FAI pathophysiology. The present study aims to identify factors associated with labral and cartilage damage. Method: This is a prospective, multicenter cohort of patients undergoing primary arthroscopy for treatment of symptomatic FAI. Enrollment was between 2020 and 2022. The current study investigated predictive factors of advanced labral damage (detachment or full-thickness tear length &gt;4cm) and advanced acetabular cartilage damage (delamination or full-thickness defect ≥200mm2). Finally, we performed external validation for the previously reported RAPID score that predicts high-grade cartilage injury. Results: There were 647 patients in the cohort. For labral injuries, there were 384/647 (59.4%) detachments and 154/647 (23.8%) full-thickness defects, with labral tears ≥4cm was present in 100/558 (17.9%) hips. Older age (OR:1.04, p=0.002), males (OR:1.83,p=0.005), and larger alpha angles at 2:00 (OR:1.02,p=0.04) were associated with full-thickness labral injuries. Older age (OR:1.06,p&lt;0.001) and larger alpha angles at 2:00 (OR:1.03,p=0.01) were associated with tears ≥4cm. 258/679 (38.0%) patients had delamination or full-thickness cartilage defects. Older age (OR:1.09,p&lt;0.001), males (OR:1.91 p=0.003), decreased IRF (OR:0.95,p&lt;0.001), higher femoral version (OR:1.02,p=0.04), and larger alpha angles at 1:30 (OR:1.06,p&lt;0.001) were associated with delamination or defect cartilage injuries. Advanced acetabular cartilage damage ≥200mm2 was present in 109/679 (16.8%) hips and was associated with larger alpha angles at 2:00 (OR:1.07,p&lt;0.001), decreased IRF (OR:0.95,p&lt;0.001), and males (OR:2.52,p=0.002), and age (OR:1.05,p=0.002). For RAPID score external validation, we used our data for their model (sex, Tonnis OA Grade, radiographic alpha angle) and found an AUC of 0.685. With an adjusted model using CT alpha angles, AUC improved to 0.703. Our final model improved the AUC to 0.809 and included age, sex, IRF, femoral version, and CT alpha angles. Conclusion: FAI commonly has associated labral and cartilage injuries. The current study found multiple predictive factors for advanced labral and cartilage injuries as well as for larger lesions. A model including age, sex, IRF, femoral version, and CT alpha angles appears to best predict acetabular cartilage damage. Further research should investigate how these affect outcomes.

Abstract Key unanswered questions in biology center on the causes, consequences, and maintenance of sexual reproduction (“sex”). Genome-driven processes are central to the evolutionary and genetic mechanisms inherent to sex, making genomic resources a fundamental part of answering these questions. We present the first genome assembly for a species that is uniquely well-suited for the study of (a)sex in nature, Potamopyrgus antipodarum . This New Zealand snail is unusual in featuring multiple separate transitions from obligately sexual to obligately asexual reproduction, leading to the coexistence of phenotypically similar sexual and asexual forms, a feature that is required to directly study the maintenance of sex. These separately derived asexual lineages constitute separate evolutionary experiments, providing a powerful means of characterizing how the absence of sex affects genome evolution. Our genome assembly provides critical steps towards understanding causes and consequences of sex in this system and important resources for the rapidly growing P. antipodarum and molluscan genomics research community. In characterizing this genome, we uncovered unexpected evidence for a recent whole-genome duplication (WGD) in P. antipodarum . This discovery sets the stage for using P . antipodarum to evaluate processes of rediploidization following WGD and assess whether WGD might drive transitions to asexuality.

Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred ninety‐nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini‐Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid‐positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236–248