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.

Key Points Pediatric preemptive kidney transplantation rates in the United States vary by socioeconomic status (SES). The HOUsing-based index of SES, an individual-level SES measure derived from residential addresses, effectively predicts pediatric preemptive kidney transplant rates. Background Preemptive kidney transplantation in children is associated with better patient and graft survival compared with transplants after dialysis. However, preemptive kidney transplantation rates in children remain low. This study aimed to evaluate the effect of socioeconomic status (SES) on preemptive transplantation in children. Methods Our study included 173 Minnesota-resident pediatric kidney transplant recipients (younger than 18 years) transplanted at the University of Minnesota from 2010 to 2020. Using the HOUsing-based index of SES (HOUSES) index, a validated, individual SES measure based on housing units categorized into quartiles (Q1: lower SES; Q2–Q4: higher SES), we applied mixed-effects multivariable logistic models to examine the effects of HOUSES on preemptive kidney transplants and pretransplant dialysis duration. Results Of 173 pediatric kidney transplant recipients, 46 (26.6%) received a preemptive transplant, and of 109 recipients with dialysis duration data, 39 (35.8%) received dialysis for >1 year. After adjusting for age at kidney failure, sex, donor type, insurance type, and underlying cause of kidney failure, we observed significantly lower odds of preemptive transplantation among Q1 recipients compared with Q2–4 recipients (adjusted odds ratio, 0.31; 95% confidence interval, 0.11 to 0.90; P = 0.03). Conclusions Using the HOUSES index, we found significant socioeconomic disparities in preemptive kidney transplantation rates among children.

Abstract Although a direct link between cardiac lymphatics and congenital heart disease (CHD) has not been established, research indicates that abnormalities in the cardiac lymphatic system are involved in several congenital disorders that present with cardiac defects. However, this contribution remains poorly understood and is still an emerging area of study. One theory proposes that abnormal lymphatic development, which can present as cystic hygroma or increased nuchal translucency, may give rise to heart defects such as coarctation of the aorta, hypoplastic left heart syndrome, or bicuspid aortic valves. The genetic pathways for the development of the cardiac lymphatic system and the heart’s major vessels may overlap; therefore, mutations in these genes could result in simultaneous defects in both systems. The close anatomical proximity between cardiac lymphatics and the great vessels of the heart suggests a “cause and effect” relationship, where an abnormality in one could affect the other and lead to congenital defects. Given that congenital heart disease is the most common birth defect in the United States, this systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, seeks to explore the potential link between cardiac lymphatics and CHD. Understanding this connection could have significant clinical implications by paving the way for new diagnostic approaches and therapeutic strategies for CHDs.

AbstractWith increasing opportunities for minors to undergo genomic testing, factors influencing young people's decision stability and instability regarding genomic testing are unclear. This interpretive description study examines decision stability when adolescents (13–17) and young adults (18–21) decide whether to learn genetic testing results. Adolescents and young adults enrolled in a clinical trial chose whether they wanted to learn genetic testing results and could modify their decisions during a study visit or 2 weeks later. A purposive sample of clinical trial participants was invited to participate in an interview exploring their decision preferences, confidence level, and factors impacting decision stability. Twenty‐two participants chose to learn all (n = 7), some (n = 7), or no genetic test results (n = 8). Perceptions of the impact of personal genetic information on one's quality of life and sense of reproductive goals and responsibilities were driving factors for people who chose to learn no or some genetic results, while curiosity influenced those who chose to learn all. Prior health and healthcare experiences and others' influence also factored into decision‐making about receiving results. Decision stability varied among individuals but increased over time and was positively influenced by parents, baseline decision confidence, and fear of missing out on the opportunity to learn genetic information. Participants felt favorably about the opportunity to change their decision 2 weeks after the study visit. Among study participants, decision stability was high, as was satisfaction with decisions regarding how much personal genetic information to learn. The results suggest that adolescent and young adult genetic research participants may experience high decision stability and confidence in making choices regarding personal genetic testing, especially when a window of opportunity for change is available. Researchers and clinicians should consider the benefits and challenges of offering multiple checkpoints to bolster decision stability.

Abstract Oligodendrogliomas are initially slow-growing brain tumors that are prone to malignant transformation despite surgery and cytotoxic therapy. Understanding of oligodendroglioma evolution and new treatments for patients have been encumbered by a paucity of patient-matched newly diagnosed and recurrent tumor samples for multiplatform analyses, and by a lack of preclinical models for interrogation of therapeutic vulnerabilities that drive oligodendroglioma growth. Here we integrate spatial and functional analyses of tumor samples and patient-derived organoid co-cultures to show that synaptic connectivity is a hallmark of oligodendroglioma evolution and recurrence. We find that patient-matched recurrent oligodendrogliomas are enriched in synaptic gene expression programs irrespective of previous therapy or histologic grade. Analyses of spatial, single-cell, and clinical data reveal epigenetic misactivation of synaptic genes that are concentrated in regions of cortical infiltration and can be used to predict eventual oligodendroglioma recurrence. To translate these findings to patients, we show that local field potentials from tumor-infiltrated cortex at the time of resection and neuronal hyperexcitability and synchrony in patient-derived organoid co-cultures are associated with oligodendroglioma proliferation and recurrence. In preclinical models, we find that neurophysiologic drugs block oligodendroglioma growth and pathologic electrophysiology. These results elucidate mechanisms underlying oligodendroglioma evolution from an indolent tumor to a fatal disease and shed light on new biomarkers and new treatments for patients.

BACKGROUND: Bioprosthetic valve dysfunction and reoperations/reinterventions are common after aortic valve replacement (AVR) with bioprosthetic valves, leading to cycles of left ventricular (LV) pressure overload and unloading. The purpose of this study was to compare postoperative changes in LV structure and function and their relationship to clinical outcomes in young patients who underwent AVR with bioprosthetic valves (Bio_AVR group) versus mechanical prosthetic valves (Mech_AVR group). METHODS: Retrospective study of adults with congenital heart disease who underwent AVR at Mayo Clinic (2003–2023). The Bio_AVR group was matched 1:2 to the Mech_AVR group. LV indices (LV mass index, relative wall thickness, LV global longitudinal strain, averaged e′, and averaged E/e′) and clinical indices (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and New York Heart Association class) were assessed preoperatively, and at 1, 5, and 10 years post-AVR. RESULTS: We studied 151 and 302 patients in the Bio_AVR and Mech_AVR groups, respectively (age 38±16 years, 58% males). Both groups had similar LV and clinical indices at baseline and 1 year post-AVR. However, the Bio_AVR group had higher LV mass index, relative wall thickness, and averaged E/e′, and lower averaged e′ and LV global longitudinal strain at 5 and 10 years post-AVR. Of 51 patients from the Bio_AVR group who underwent a second AVR, there was less robust improvement in LV indices and clinical indices after the second AVR compared with the first AVR. CONCLUSIONS: AVR with a bioprosthetic valve was associated with progressive LV hypertrophy and dysfunction, and worsening clinical status compared with mechanical prosthetic valves. This provides further evidence against the use of bioprosthetic AVR in young patients.

Abstract Introduction: Labral injury at the time of open and arthroscopic hip preservation surgery for symptomatic femoroacetabular impingement (FAI) is managed with debridement versus refixation by the treating surgeon based on tear pattern, tissue quality, and hip morphology. While refixation has been favored based on mid-term outcomes in some series, differences in the long-term patient reported outcomes (PROMS) have not been defined in well-designed and matched prospective series. Methods: This study consisted of a prospective, multi-center cohort that underwent primary surgical treatment for symptomatic FAI. Patients were included if they underwent corrective osteoplasty and a labral refixation or a labral debridement procedure. Using a ratio of 1:1, hips with labral refixation and labral debridement were matched by age, sex, and surgical approach. Postoperative assessments were conducted at a minimum 8 years after surgery using PROMS and assessment of reoperations. Results: A total of 237 hips (n=188 labral refixation, n=49 labral debridement) met the inclusion criteria for the current study. 48 hips from the labral refixation and 48 hips from debridement groups with mean follow-up of 10.3±1.7 years and 10.6±2.1 years respectively were included. No significant differences were observed in the femoral head, acetabular cartilage grade, or labral grade between the groups. The mHHS improved 19.8±19.6 and 23.4±16.8 from baseline to the final follow-up in the labral refixation and debridement groups, respectively (p=0.43). There were no significant differences in PROMS between the labral refixation and debridement groups. Overall, 66% and 76% of the labral refixation and debridement groups achieved the MCID for the mHHS respectively (p=0.30). There were more revision surgeries with labral refixation than with debridement (10.4% vs. 2.1%, p=0.09), but more conversions to total hip replacement in the labral debridement group (8.3% vs. 4.2%, p=0.38), but neither of these differences were statistically significant. Discussion: Both labral refixation and debridement are effective with durable improvement in PROMS at a mean of 10 years in a prospective cohort of patients treated surgically for symptomatic FAI. No significant differences in baseline or final PROMS were observed, and similar rates of revision and conversion to hip replacement were observed in the debridement and refixation groups.

Abstract Background: Long-term outcomes of FAI surgery are critical to understand it’s hip preserving ability, yet few studies have reported mid to long-term survivorship following FAI surgery. The purpose of this study was to report rates of treatment failure after first-generation FAI surgery at an average 10- year follow-up. Methods: A prospective, multicenter cohort study assessed patients treated for FAI with hip arthroscopy or surgical dislocation by seven surgeons at four institutions from 2008 to 2012. Inclusion criteria included primary surgery and diagnosis of isolated cam or combined cam/pincer type FAI. At an average 10-year follow-up, 362/452 eligible hips (80.1%) achieved follow-up. Cox proportional hazards model was used to identify predictors of conversion to total hip arthroplasty (THA). Results: Three hundred and sixty two hips were evaluated at a mean of 10.0 ± 2.3 years follow-up. At time of final follow-up, 34 hips (9.2%) had undergone conversion to THA at a mean of 5.2 ± 3.1 years post-operatively. An additional 18 patients (4.9%) underwent non-arthroplasty revision preservation surgery at a mean of 2.0 ± 1.5 years post-operatively. The Kaplan Meier survivorship rates after 5 and 10 years of surgery were 94.9% and 95.2% for conversion to THA and 91 % and 95.2% for revision hip preservation. Older age (HR:1.06, CI: 1.01-1.10; p=0.009), BMI≥30 (HR:4.14, CI:1.52-11.24, p=0.005), male sex (HR:3.23, CI: 1.18-9.09, p=0.02), and lower baseline mHHS (HR:1.03, CI: 1.01-1.04, p=0.01) were significant predictors of conversion to THA. Conclusion: This study demonstrates that FAI surgery yields durable outcomes with the majority of patients (85.9%) not requiring revision surgery or conversion to total hip arthroplasty at an average 10 years. Age 30 years, male sex, and obesity were significantly associated with the risk of THA conversion.