Citations

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell–specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia.

Long-term outcomes of surgical treatment for pediatric developmental dysplasia of the hip (DDH) are not well defined. The purpose of this study was to report long-term radiographic and clinical outcomes, survivorship free of total hip arthroplasty (THA), and predictors of subsequent THA following childhood treatment of DDH. This study was a single-institution retrospective review of hips treated for DDH with closed or open reduction at a minimum 10-year follow-up. 107 patients (119 hips) were included with a mean patient age of 3.3 years at childhood treatment. At mean 30.5 years follow-up, 24 hips had undergone THA (20%). Mean patient age at time of THA was 33.5 years. None of the hips treated with closed reduction alone required THA, whereas 8 hips treated with open reduction (25%) underwent THA. Hips with patient age > 4 years at the time of treatment had lower survivorship at 35 years follow-up (50% vs. 85%; p < 0.001). Additionally, femoral osteotomy (OR 2.0, p < 0.001), and previous treatment elsewhere (27% vs. 16%; p < 0.01) were associated with subsequent THA. Early referral and appropriate intervention may prove important, as age and prior treatment were predictive of subsequent THA.

Background Previous literature has postulated a relationship between greater hamstring stiffness and a higher risk of sustaining injury. Shear wave elastography (SWE) presents a relatively new means for non-invasive evaluation of soft tissue elasticity pre- and post- injury or intervention. Purpose 1. (1) To establish baseline hamstring stiffness measures for young competitive athletes and (2) determine effect of targeted neuromuscular training (TNMT) on shear wave stiffness of the hamstring. Study Design Un-blinded, prospective, non-randomized, cohort study. Methods Six-hundred forty-two lower extremities from 321 high school and collegiate basketball athletes (177 F: 139 M) were examined for hamstring stiffness prior to the start of their competitive basketball season. Teams were cluster assigned to either the control or intervention (TNMT) group. Subjects in the control group underwent regular season activities as directed, with no influence from the research team. For the TNMT group, the research team introduced a hamstring targeted dynamic warm-up program as an intervention focused on activating the hamstring musculature. Results Collegiate status was significant to hamstring stiffness for both sexes (p ≤ 0.02), but hamstring stiffness did not correlate to age or sex (r 2 ≤ 0.08). Intervention was a significant factor to hamstring stiffness when the hip was positioned in extension (p ≤ 0.01), but not in deeper flexion (p = 0.12). This effect was sex-specific as TNMT influenced hamstring stiffness in females (p = 0.03), but not in males (p ≥ 0.13). Control athletes suffered three HAM injuries; TNMT athletes suffered 0 hamstring injuries. Conclusion Higher SWE measurements correlated with increased risk of injury, male sex, and collegiate athletics. TNMT intervention can lessen muscle stiffness which may reduce relate to injury incidence. Intervention effectiveness may be sex specific. Level of Evidence II

Abstract Background: Young women with DCIS are at increased risk of recurrence and second BC compared to older women and may derive the greatest benefit from risk reduction strategies. Little is known about treatment decision-making, engagement in preventive behaviors, or fear of recurrence among young DCIS survivors. Thus, we sought to investigate treatment and prevention issues in this population. Methods: Using a multicenter prospective cohort that enrolled 1302 women with stage 0-IV BC at age ≤40, we identified participants with DCIS only who completed surveys in the year following diagnosis (dx). Surveys assessed treatment decisions, lifestyle factors (alcohol, smoking, physical activity [PA]), and fear of recurrence (Lasry Scale). Data was summarized with descriptive statistics and groups were compared with Fisher’s exact test. Results: Among 87 patients (median age 38, range 26-40), 75 had available treatment decision data, 19 (25%) of whom had breast-conserving surgery (BCS), 11 (15%) unilateral mastectomy (UM), and 45 (60%) bilateral mastectomy (BM). Most (77%) indicated their doctor said BCS was an option or recommended, including 34 (59%) who had BM. Of 40 patients who reported a patient-driven surgical decision, 73% had BM, 13% UM, and 15% BCS. Among 15 patients who reported the decision as doctor-driven, none had BM, 27% UM, and 73% BCS. Those who had BM were more likely to be extremely confident about the decision (80% vs. 73% UM vs. 53% BCS, p=0.022). Adjuvant tamoxifen was used by 10/27 (37%) patients with ER+ DCIS who had BCS/UM. Most who took tamoxifen reported this decision was shared with their doctor (90%); 1 reported the decision was made on her own. Of the 17 patients who did not take tamoxifen, 88% indicated their doctor said endocrine therapy was an option or recommended. Among all 87 patients, 31 (36%) were former and 3 (4%) were current smokers at baseline assessment (median 5 months post-dx); 51 (59%) never smoked. Overall, 4 quit within 1 year of dx. Most patients (83%) were current drinkers at baseline, though 79% consumed &lt;5 alcoholic beverages/week; 8% reported lower consumption at 1 year. Regarding PA at 1 year, 73% (58/80) reported ≥150 minutes of moderate-intensity PA/week. Overall, 41% of young survivors were at least moderately concerned about their BC coming back, with concern varying numerically by surgery (65% post-BCS, 50% post-UM, 29% post-BM, p=0.053). Conclusions: BC recurrence concerns were frequent among young DCIS patients, particularly among those with remaining breast tissue. BM decisions were largely patient-driven and made with high confidence, reflecting preferences towards surgical prevention. While adherence to survivorship lifestyle guidelines was high, including not smoking, consumption of ≤7 drinks/week, and engaging in PA, tamoxifen use was low, even when offered by a provider. Young DCIS survivors appear motivated to lower future BC risk through surgery and maintenance of healthy behaviors, and less so with tamoxifen; such values should be considered during treatment and survivorship counseling. Citation Format: Megan E. Tesch, Julia S. Wong, Laura Dominici, Kathryn J. Ruddy, Rulla Tamini, Lidia Schapira, Virginia F. Borges, Ellen Warner, Steven E. Come, Karen Sepucha, Laura C. Collins, Ann H. Partridge, Shoshana M. Rosenberg. Breast cancer (BC) risk reduction in young women with ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR009.

ObjectiveTo assess barium esophagram (BAS) as a diagnostic marker for patients with Killian Jamieson diverticula (KJD).MethodsProspective, multicenter cohort study of individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative. Patient demographics, comorbidities, radiographic imaging reports, laryngoscopy findings, patient‐reported outcome measures (PROM), and operative reporting were abstracted from a REDCap database and summarized using means, medians, percentages, frequencies. Paired t‐tests and Wilcoxon Signed Rank test were used to test pre‐ to post‐operative differences in RSI, EAT‐10, and VHI‐10 scores. Diagnostic test evaluation including sensitivity, specificity, positive, and negative predictive value with 95% confidence intervals were calculated comparing BAS findings to operative report.ResultsA total of 287 persons were enrolled; 13 (4%) patients were identified with confirmed KJD on operative reports. 100% underwent open transcervical excision. BAS has a 46.2% (95% confidence interval [CI]: 23.2, 70.9) sensitivity and 97.8% (95% CI: 95.3, 99.0) specificity in detecting a KJD and 50% (95% CI: 25.4, 74.6) positive predictive value but 97.4% (95%CI: 94.8, 98.7) negative predictive value. Preoperatively, patients reported mean (SD) RSI and EAT‐10 of 19.4 (9) and 8.3 (7.5) accordingly. Postoperatively, patients reported mean (SD) RSI and EAT‐10 as 5.4 (6.2) and 2.3 (3.3). Both changes in RSI and EAT‐10 were statistically significant (p = 0.008, p = 0.03).ConclusionKJD are rare and represent <5% of hypopharyngeal diverticula undergoing surgical intervention. Open transcervical surgery significantly improves symptoms of dysphagia. BAS has high specificity but low sensitivity in detecting KJD.Level of Evidence4 Laryngoscope, 133:2110–2115, 2023