Mary Beth

Study Aim: Patients with high-risk Ewing sarcoma (ES) have dismal outcomes despite aggressive multimodal therapy. This phase II, single-institution study evaluated the response rate to two up-front cycles of irinotecan, temozolomide, and temsirolimus (ITT) and assessed the tolerability of maintenance therapy following standard treatment in high-risk ES. Methods: Eligible patients had newly diagnosed high-risk ES (age ≥14 years old, metastatic disease, or primary pelvic tumor). The therapy included two cycles of window therapy (ITT) followed by interval-compressed chemotherapy (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and maintenance therapy (cyclophosphamide, sorafenib, and bevacizumab). A two-stage sequential design was employed to assess a >50% WHO response (CR or PR) with 80% power. Patients who required emergent radiation were excluded from receiving window therapy. Results: Sixteen patients (median age 12.2 years; range 4.8–23.6 years) were enrolled (12 evaluable for overall response, 10 for primary tumor response). Only three achieved a PR to window therapy, leading to study closure. All evaluable patients demonstrated a decline in their primary tumor volume (mean decline: 32.5%, standard deviation: 17.6%, p-value: 0.0005) and SUV peak (mean decline: 49.9%, standard deviation: 21.1%, p-value: 0.002). Maintenance therapy was well tolerated, with only 2/13 patients discontinuing due to toxicity. Conclusions: ITT did not achieve the prespecified response rate of 50%, according to WHO criteria; however, all patients exhibited decreased volume and metabolic activity, highlighting the limitations of conventional response assessments. Maintenance therapy was feasible and well tolerated. Although limited by small sample size, heterogeneous disease presentations, and the absence of a control arm, this study supports further evaluation of ITT and a maintenance approach in larger, randomized trials for high-risk ES.

Background: Performance of daily activities (Activities of Daily Living [ADLs] and Instrumental ADLs [IADLs]) is key to independent functioning in dementia, and greater I/ADL dependence contributes to burden in caregivers. We investigated how domains of daily living activities predict previously defined factors of the Zarit Burden Interview (ZBI). Methods: Caregiver and care recipient data for 389 dyads were extracted from outpatient memory clinic records. Results: Four previously defined factors of the ZBI (‘Impact on Life’, ‘Guilt/Uncertainty’, ‘Embarrassment/Frustration’, ‘Overwhelm’) were used in regression analyses, which demonstrated that ADLs predicted Impact on Life and Embarrassment/Frustration while IADLs predicted only Embarrassment/Frustration. Conclusions: Areas of decline in daily performance may differentially contribute to facets of dementia caregiver burden, with ADLs potentially having greater impact than IADLs.

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

To facilitate treatment decisions in people at risk of Cardiovascular Disease (CVD), several risk equations such as the Pooled Cohort Equations and Predicting Risk of Cardiovascular Disease Events (PREVENT) equations have been developed to estimate CVD risk for primary prevention patients. However, it is unclear whether these equations achieve high predictive accuracy and fairness in patients with type 2 diabetes (T2D), and whether a T2D-specific risk equation is needed. Accordingly, we developed a Weibull Accelerated Failure Time (AFT) survival model for predicting the 3-year CVD risk in 23,795 patients with T2D from the All of Us dataset, using sociodemographic information, physical measurements, medication, and CVD history. Among patients without CVD history, our Weibull AFT (vs. PREVENT) achieved a greater C-index (0.646 vs. 0.465), greater Concordance Fractions (0.610–0.674 vs. 0.541–0.600), and comparable Concordance Imparity (0.006 vs. 0.002) across sex and race/ethnicity (0.065 vs. 0.058) subgroups. Our findings highlight the need for a T2D-specific CVD risk equation and demonstrate the value of diverse datasets for developing fair and accurate predictive models.

Background/Objectives: Photobiomodulation Therapy (PBMT) is widely used in musculoskeletal rehabilitation. Although its clinical use continues to expand, the dose-dependent metabolic responses on specific musculoskeletal cell populations remain undefined. This study assessed the effects of 1064 nm PBMT on primary human tenocytes and bursa-derived cells across varying fluence and irradiance. Methods: Primary tenocytes and bursa-derived cells were cultured in 24-well plates and exposed to Hiro TT 1064 nm laser at fluences ranging from 1.5 to 6.0 J/cm2 and irradiance levels of 90 or 125 mW/cm2. Treatments were administered once daily for three consecutive days. Cellular activity was assessed using an XTT assay and bright field microscopy was performed to assess cell morphology and confluency. Statistical analysis was compared to evaluate dose-dependent effects. Results: PBMT demonstrated tissue-dependent effects on cellular metabolic activity and proliferation. In tenocytes, moderate fluence (4.5–6.0 J/cm2) significantly increased metabolic activity compared with control. In contrast, bursa-derived cells exhibited smaller magnitude changes, with most treatment groups demonstrating neutral or modest deviations from control. Conclusions: PBMT of 1064 nm wavelenght produced distinct dose-dependent responses in musculoskeletal cell types, with tenocytes demonstrating a threshold-dependent response and bursa-derived cells showing attenuated effects. These findings support the need for tissue-specific parameters when applying PBMT in clinical tendon-related applications.

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