Citations

TPS2101 Background: Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective therapy and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination treatment that utilizes a drug, aminolevulinic acid HCL (SONALA-001), and a device, the Exablate 4000 Type 2.0, to deliver non-ablative MR-guided focused ultrasound (MRgFUS) to tumor. Preclinical studies have shown that SDT-induced sonoluminescence activates protoporphyrin IX (PpIX), which in turn generates reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that SONALA-001 SDT was well-tolerated and not associated with off-target cellular or radiographic effects, and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). Methods: SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of 10 mg/kg iv SONALA-001 in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Treatments take place every 4 weeks. In phase 1, sonication energy escalation utilizes an accelerated titration design with a single subject for dose level 1, followed by cohorts 2 and 3 with 3+3 design for additional dose escalation. SONALA-001 is administered 6 to 12 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of SONALA-001 SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Clinical trial information: NCT05370508 .

Purpose To report the rate of anterior cruciate ligament (ACL) graft failure by physis status (open, closing, closed) and to analyze which factors were associated with higher risk of ACL graft failure. Methods Patients younger than 18 years who underwent transphyseal ACL reconstruction (ACLR) between 2000 and 2018 at a single institution were reviewed at minimum 2 years after ACLR. Patient records were reviewed for anthropometrics, surgical techniques, and ACL graft failure. Patients were subsequently stratified based on physis status (open, closing, closed) and analyzed. Results A total of 272 patients (mean age of 15.4 ± 1.3 years) were assessed. The transtibial technique was used in 63.6% of cases. A hamstring autograft was used exclusively in the open physis group. A patellar tendon autograft was used in 65.9% of patients with a closing physis and 80.9% of patients with a closed physis. The overall graft failure rate was 13.2%, with a contralateral ACL injury rate of 11.0%. Kaplan‐Maier analysis by physis status showed different injury free from ACL reinjury ( P < .001). An open physis was associated with increased risk of ACL reinjury (hazard ratio, 5.2; P < .001) when compared to a closed physis. A closing physis presented a higher hazard ratio but was not statistically significant (hazard ratio, 2.6; P = .08). Hamstring graft type ( P = .03) and lower graft diameter ( P = .04) were significantly related to higher ACL reinjury after adjusting for physis status. Conclusions Transphyseal ACLR is a safe procedure in pediatric patients. The rate of reinjury was 13.2%. This rate decreases with skeletal maturity, use of patellar tendon autograft, and a larger graft diameter. Level of Evidence Level III, retrospective cohort study.

9508 Background: Outcomes for pts with mMEL remain sobering despite access to available immunotherapies as the majority of pts are resistant or become refractory to checkpoint blockade with no approved treatments. CXCR1 and CXCR2 (CXCR1/2) signaling mediate myeloid immunosuppression and MEL growth, inversely correlating with anti-PD-1 response and pt survival. SX-682 is an oral allosteric inhibitor of CXCR1/2. As a single agent, SX-682 increases tumor CD8+ T cell infiltration and inhibits tumor growth in mouse MEL. Methods: This phase 1 dose-escalation with expansion trial (NCT03161431) evaluated pem and escalating doses of SX-682 (25 - 400 mg orally BID) in pts with mMEL in a 21-day cycle. Pts must have had progressive disease (PD) on prior anti-PD-1. Mucosal MEL and asymptomatic brain metastases were allowed. Escalation cohorts had a 21-day SX-682 monotherapy (MONO) run-in. Response assessment by RECIST 1.1 was every 2 cycles during combination (COMBO) treatment. Primary endpoint was safety: adverse events (AEs), dose-limiting toxicity (DLT) and maximally-tolerated dose (MTD). Secondary endpoints included objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + PR + stable disease [SD]) and overall survival (OS). Results: As of October 2023, 51 pts were enrolled and treated; median age of 65 (range 24-91), 55% male, 61% elevated LDH, 39% BRAF mutated. All pts received prior anti-PD-1, 37 (73%) received combined anti-PD-1 and anti-CTLA-4, and 23 (45%) had ≥ 3 prior therapies. Steady-state blood SX-682 was dose-proportional. No MONO DLT or MTD was identified. The 200 mg dose cohort was expanded in COMBO based on safety and pharmacodynamics: mg BID dose (n) = 25 (3), 50 (3), 100 (6), 150 (8), 200 (31). Any grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 75% and 43%, respectively, and discontinuation (DC) due to TRAEs in 20% (when uncomplicated neutropenia, a permitted effect from CXCR2 inhibition on bone-marrow trafficking, was excluded there were 25% grade 3/4 TRAEs and 12% DC [rash, transaminitis]). There was no infectious signal. At the 200 mg dose, the ORR was 21% in 19 evaluable pts (4 PR + 0 CR) and the DCR was 63% (8 SD + 4 PR). DCR significantly depended on SX-682 dose ( P vs. ≤100 mg): 0% (0/9) at ≤100 mg, 50% (3/6) at 150 mg ( P = 0.0440) and 63% (12/19) at 200 mg ( P = 0.0028). All 15 pts with disease control had progressed on anti-PD-1 and anti-CTLA-4. Median OS was longer in pts in the 200 mg cohort (14.7 months; 95% CI, 10.5 – NR [not reached], n = 31) than in pts treated with ≤100 mg SX-682 (7.4 months; 95% CI, 5.0 – NR; n = 10). Conclusions: SX-682 combined with pem had a tolerable safety profile and activity reflected by objective responses and clinically meaningful disease control in heavily pretreated mMEL pts with progression on anti-PD-1 and anti–CTLA-4. Clinical trial information: NCT03161431 .

Abstract Generative artificial intelligence (AI) holds immense potential for medical applications, but the lack of a comprehensive evaluation framework and methodological deficiencies in existing studies hinder its effective implementation. Standardized assessment guidelines are crucial for ensuring reliable and consistent evaluation of generative AI in healthcare. Our objective is to develop robust, standardized guidelines tailored for evaluating generative AI performance in medical contexts. Through a rigorous literature review utilizing the Web of Sciences, Cochrane Library, PubMed, and Google Scholar, we focused on research testing generative AI capabilities in medicine. Our multidisciplinary team of experts conducted discussion sessions to develop a comprehensive 32‐item checklist. This checklist encompasses critical evaluation aspects of generative AI in medical applications, addressing key dimensions such as question collection, querying methodologies, and assessment techniques. The checklist and its broader assessment framework provide a holistic evaluation of AI systems, delineating a clear pathway from question gathering to result assessment. It guides researchers through potential challenges and pitfalls, enhancing research quality and reporting and aiding the evolution of generative AI in medicine and life sciences. Our framework furnishes a standardized, systematic approach for testing generative AI's applicability in medicine. For a concise checklist, please refer to Table S or visit GenAIMed.org .

Abstract Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objectives By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate genome-wide association study and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n = 1,278) and adults from the UKBiobank (n = 369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP (hedgehog interacting protein), DSP, and NPNT as potential molecular targets based on colocalization of their expression. A higher dysanapsis genetic risk score was associated with obstructive spirometry among 5-year-old children and among adults in the fifth, sixth, and seventh decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development, and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endophenotype link between the genetic variations associated with lung function and COPD.

Abstract Background Physiatry is a specialty with high rates of burnout. Although organizational strategies to combat burnout are key, it is also important to understand strategies that individual physiatrists can use to address burnout. Objective To identify changes that resulted in improvement of occupational well‐being of physiatrists over a 6‐ to 9‐month period. Design We employed two quantitative surveys spaced 6 to 9 months apart to identify physiatrists who experienced meaningful improvement in occupational burnout and/or professional fulfillment between the two survey timepoints. These physiatrists were subsequently recruited to participate in a qualitative study using semi‐structured interviews to identify changes that respondents felt contributed to improvements in burnout and professional fulfillment. Setting Online surveys and interviews. Participants Physiatrists in the American Academy of Physical Medicine and Rehabilitation (AAPM&R) Membership Masterfile. Main Outcome Measure Burnout and professional fulfillment were assessed using the Stanford Professional Fulfillment Index. Results One hundred twelve physiatrists responded to the baseline and follow‐up surveys. Of these, 35 were eligible for interviews based on improvements in the Stanford Professional Fulfillment Index, and 23 (64%) agreed to participate. Themes from the qualitative interviews highlighted the importance of personal lifestyle choices, approaches to improve professional satisfaction, and strategies to foster work‐life harmony. Personal lifestyle strategies included investing in wellness and mental health. Efforts to improve professional satisfaction included decreasing work intensity, prioritizing meaningful aspects of work, and building relationships with colleagues. Fostering work‐life harmony also included making trade‐offs in both domains, setting boundaries at work, setting expectations at home, and overcoming personal challenges. Conclusion Our findings illustrate that, in addition to organizational strategies demonstrated to be effective, there are actions that individual physiatrists can take to recover from burnout and foster professional fulfillment.

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

Abstract Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer’s Disease Neuroimaging Initiative, n = 53) and who had Alzheimer’s disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer’s Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer’s disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.