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10032 Background: Identifying clinical and biological factors associated with outcomes in localized Ewing sarcoma (ES) will enable risk-stratified clinical trials with the goal of improved outcomes for high-risk patients and decreased treatment toxicity for low-risk patients. The specific aims of this analysis in localized ES patients were 1) to classify extraosseous (EO) primary tumors with subdivisions into deep (viscera, glands, body cavities, muscle, nerves) and superficial (cutaneous and subcutaneous) sites, and 2) to understand the relationship between baseline clinical factors (age, sex, primary tumor site, size (maximum dimension and volume)) and event-free survival (EFS). Methods: The analytic cohort included ES patients treated with ICC on AEWS0031 and AEWS1031. Primary tumor sites were defined as pelvic, non-pelvic, and EO (deep vs. superficial). Post-enrollment EFS was the primary endpoint. Univariate analyses used the Kaplan–Meier method (logrank test). Multivariable analyses used Cox proportional hazards models. To assess the impact of tumor volume as a continuous variable, a subgroup analysis was conducted using AEWS1031 only, as tumor volumes were collected prospectively on this study. Visual exploration of effects of continuous variables on EFS event hazard used restricted cubic splines with 3 knots. Tests were performed at the 5% level. Results: AEWS0031 (n = 628) and AEWS1031 Regimen B (n = 283) yielded 911 patients. In univariate analyses, difference in risk of EFS event was observed between tumor sites ( P = 0.03). EO tumors had the highest estimated EFS compared to pelvic and non-pelvic (5 year EFS 84.7% vs. 72.4% and 75.9%). Superficial EO appeared to be a very low-risk group, albeit interpretations are limited by the small group size and singular event (one second malignant neoplasm among 15 patients). In multivariable analysis of the combined cohort, sex, race, and ethnicity were not prognostic. EO tumors may be associated with decreased hazard compared with non-pelvic bone primaries (HR 0.58, P = 0.07), and tumors ≥200 mL with increased hazard (HR 1.56, P < 0.01). In the subgroup analysis, tumor volume and age were prognostic and in visualizations age was non-linearly related to the hazard of EFS event, increasing until approximately 15 years. Tumor volume was non-linearly related to the hazard of EFS event and increased until approximately 400 mL. Conclusions: Patients with ES and primary tumors ≥200 mL continue to be at higher risk of an EFS event when treated with ICC, and EO tumors may be lower risk compared with other sites. Risk of an event appears to remain constant in ES patients ≥15 years or with primary tumors ≥400 mL. These findings should be validated in prospective trials and tumor biology integrated with clinical factors to improve risk stratification for localized ES.

e13574 Background: AL (amyloid light chain) amyloidosis is associated with poor prognosis especially if diagnosis occurs with cardiac involvement. Current AL treatments target the plasma cell clone producing the light chains that misfold, aggregate and deposit in various tissues. The multi-organ manifestations of AL amyloidosis require a multidisciplinary care team of hematologist-oncologists, cardiologists, and other healthcare providers (HCPs) for comprehensive, patient-centric management. Since 2022, Amyloidosis Stakeholder Partnerships for Impact, Reach & Equity (ASPIRE), facilitated by Amyloidosis Research Consortium (ARC) has been bringing together biotech and pharmaceutical companies with the shared goal of optimizing amyloidosis patient care. Through this study, ARC-ASPIRE sought to document and share the current best practices and key barriers to patient-centric amyloidosis care at US specialized amyloidosis centers (SACs). A broad range of stakeholders in amyloidosis care – healthcare providers at SACs, patients, referring physicians, and patient advocacy group representatives – were interviewed for this study. This abstract presents findings relevant to the management of patients with AL amyloidosis. Methods: Structured interviews were conducted between December 2023 and February 2024 with 77 amyloidosis stakeholders (physicians, advanced practice providers, registered nurses from 17 SACs, patients, referring physicians, and patient advocacy group representatives), including 12 hematology-oncologists and 8 AL patients. SACs were selected to be representative of current US amyloidosis care, based on geography, amyloidosis patient volume, years since establishment, and types of amyloidosis treated. Results: Three-quarters of participating SACs treat AL patients under a single multidisciplinary amyloidosis program. Multidisciplinary care is facilitated by regular team meetings, dedicated clinic days, and informal communications across specialties. At diagnosis, collaboration between cardiology and hematology-oncology ensures AL patients are accurately diagnosed and promptly treated. Sixty percent of SACs have a centralized intake system, and patients suspected with AL are prioritized to ensure an appointment within 1 week of referral. Key barriers were delayed or missed diagnosis due to low awareness of AL amyloidosis within community oncologists, travel burden to SACs, lack of seamless medical records sharing and telehealth regulations. Conclusions: The best practices outlined in this study serve to educate AL amyloidosis and non-AL amyloidosis HCPs for better multidisciplinary collaboration and early diagnosis. The key barriers identified should be addressed to improve patient care.

2072 Background: Methylation of the MGMT gene promoter (MGMTp) is a critical biomarker to inform GBM prognosis and guide treatment decisions, including clinical trial eligibility. Rapid reporting of MGMTp methylation can help stratify patients early and facilitate clinical trial referral during the crucial post-operative period where treatment options are being considered by patients and physicians alike. Methods: We developed a probe-based ddPCR method to detect and quantify MGMTp methylation. Assay specificity was assessed using bisulfite-converted, unmethylated DNA. Assay linearity and Limit of Detection (LoD) were determined using MGMTp methylated cell line DNA samples of decreasing fractional abundances (35%, 5%, and 0.5%) and decreasing DNA inputs (30ng, 10ng, 3ng,1ng and 0.5ng). The limit of Blank (LoB) was calculated using 16 replicates of unmethylated bisulfite-converted PBMC DNA, and DNA from tonsil FFPE samples (n = 9). Reproducibility studies were conducted on two different days with two different operators. Accuracy and concordance were assessed using an in-house MGMTp methylation pyrosequencing assay as an orthogonal method to analyze11 melanoma and one glioblastoma cell line. Preliminary clinical validation was conducted via analysis of FFPE tumor DNA from 34 GBM patients with clinical MGMTp methylation pyrosequencing results. Results: The MGMTp methylation ddPCR assay demonstrated 100% specificity to detect promoter methylation. The method linearly quantified both total DNA and methylated DNA along a range of input DNAs with conserved fractional abundances. The LoB was 0.036% and 0.034% using PBMC and tonsil FFPE DNA, respectively. The LoD was 0.075%. The bisulfite conversion and assay were highly reproducible, with a coefficient of variation < 20%. Among the 12 cell lines analyzed by both pyrosequencing and ddPCR the concordance was 100%. Ten of 11 GBM tumor samples identified as MGMTp methylated by the clinical pyrosequencing assay were also identified as methylated by the ddPCR assay. Five of 23 clinically unmethylated tumors were positive in the ddPCR assay with generally very low fractional abundances (0.08%, 0.12% 0.3%, 0.97% and 10.11%). Conclusions: We report preliminary validation of a highly sensitive and specific ddPCR assay to detect MGMTp methylation. Given the minimal sample requirements and rapid turnaround time for ddPCR assays, this test could eventually be utilized in clinical laboratories to quickly report MGMTp methylation status for GBM patient management.

AbstractPatients with resectable Ewing sarcoma (ES) in select sites, such as the pelvis or chest wall, have a higher risk of positive microscopic margins following surgery. AEWS1031 was the first North American/Australasia ES cooperative group trial allowing standardized preoperative radiotherapy, intended to minimize the morbidity of combined modality local tumor control as well as improve the likelihood of clear surgical margins. In this study, we found that the use of low‐dose preoperative radiation to a smaller target volume resulted in a high rate of R0 resection. The robust pathologic response rate strengthens existing evidence illustrating the radiosensitivity of Ewing sarcoma.

Abstract The Alzheimer's disease (AD) scientific field continues to make significant advances in early detection and treatments, which importantly rest on advances in our fundamental understanding of AD pathobiology and its contribution to cognitive decline. Clinical readouts of monoclonal antibodies against various forms of the amyloid beta (Aβ) protein indicate that the impact of these treatments may extend beyond reduction in amyloid plaques. The Alzheimer's Association Research Roundtable meeting held on May 17 and 18, 2022, reviewed our understanding to date of the impact of treatments targeting various species of Aβ; its impact on other related pathophysiology including tau; and ultimately, its effects on neurodegeneration and clinical decline, driven by the latest available data. Participants discussed the current evidence for a causal relationship among amyloid accumulation, tau alteration, and cognitive decline; the effect of anti‐amyloid therapies on clinical and biomarker endpoints; and how we can accelerate the pathway to therapeutic approval and what should guide us for the near future. Highlights The Alzheimer's Association Research Roundtable convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic “Current Understanding of AD Pathophysiology & Impact of Amyloid‐beta Targeted Treatments on Biomarkers and Clinical Endpoints.” The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on the relationship between amyloid beta (Aβ), amyloid, tau, and cognitive impairment is helping our understanding of the downstream effects and overall importance of lowering amyloid plaque load. Based on data from multiple phase 2 and 3 clinical trials of anti‐amyloid monoclonal antibodies, there is strong evidence to support that a sufficiently large reduction in amyloid plaque load to near‐normal levels is associated with positive changes in tau biomarkers and clinical endpoints. Reduction of Aβ plaque, measured easily by plasma amyloid biomarkers, is reasonably likely to predict benefit in clinical outcome measures.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

ABSTRACTBackgroundRenal medullary carcinoma (RMC) is an aggressive tumor associated with sickle cell trait. Despite treatment advances for other rare renal tumors, RMC survival remains poor. We aimed to describe the contemporary management and survival of children and adults with RMC.ProcedureIn this multicenter retrospective cohort study, Pediatric Surgical Oncology Research Collaborative sites searched their databases for patients diagnosed with RMC (2000–2022). Descriptive statistics were calculated and survival analyses performed using Kaplan–Meier and Cox regression.ResultsThirty‐four patients with RMC were identified. Median age was 19 years (IQR: 15–28; range: 7–52). Most were male (24/34; 71%), Black (27/32; 84%), had sickle cell trait or disease (30/33; 91%), presented with metastatic disease (27/34; 79%), and were symptomatic at presentation (32/34; 94%). Median overall survival (OS) was 24 months from diagnosis (16 months for children, 28 months for adults, p = 0.6). Receipt of platinum‐based chemotherapy (23/34; 68%) was associated with significantly higher OS than other regimens (35 vs. 5 months, p < 0.001). Nephrectomy (24/34; 71%) was associated with significantly improved OS compared with non‐operative management (34 vs. 7 months, p = 0.001). Immunotherapy, targeted therapy, or radiation therapy were not associated with significant differences in OS, nor were age, sex, race, sickle cell status, SMARCB1/INI‐1, stage, nephrectomy approach, retroperitoneal lymph node dissection, gross residual disease, margins, or tumor size.ConclusionsRMC survival remains poor despite newer therapies. Nephrectomy and platinum‐based chemotherapy should be considered in locally advanced and metastatic disease. Coordinated international cooperative group studies are needed to meaningfully improve RMC survival.

Abstract Introduction The new preference-informed allocation (PIA) system introduced for the 2024 UK cohort Foundation Programme (UKFPO) marks a shift away from the traditional meritocratic ‘ranking’ used in previous years. Instead of appointment to Foundation Programme places, PIA is a computer-generated allocation and deanery preferencing system. This change has raised numerous concerns among both students and clinicians. Aims To investigate the opinions of medical students on the new UKFPO PIA system. Methodology An online questionnaire was distributed to medical students graduating in 2024, 2025, or 2026 across the UK. Results In total, 2297 responses were collected and 2288 were included in the study. Overall, 51.6% (n = 1183) of respondents felt the PIA system was unfair, 76.3% (n = 1746) felt they had lost control of their application, and 46.3% (n = 1049) had noticed a negative effect on their physical or mental health. Notably, 48.2% (n = 1094) of students who responded are now considering a career outside the National Health Service (NHS). Conclusions Overall, the PIA system falls short of students’ expectations and has led to record numbers of students considering careers outside the NHS. Further changes to this system are needed and should aim to address fairness and equity while rewarding students for their hard work. According to these data, the PIA system risks further deteriorating workforce morale and attrition rates.

Abstract Background Preexisting diabetes (PDM) increases the risk of maternal and perinatal mortality and morbidity. Reduction of maternal hyperglycemia prior to and during pregnancy can reduce these risks. Despite compelling evidence that preconception care (PCC), which includes achieving strict glycemic goals, reduces the risk of congenital malformations and other adverse pregnancy outcomes, only a minority of individuals receive PCC. Suboptimal pregnancy outcomes demonstrated in real-world data highlight the need to further optimize prenatal glycemia. New evolving technology shows promise in helping to achieve that goal. Dysglycemia is not the only driver of poor pregnancy outcomes in PDM. The increasing impact of obesity on pregnancy outcomes underscores the importance of optimal nutrition and management of insulin sensitizing medications during prenatal care for PDM. Objective To provide recommendations for the care of individuals with PDM that lead to a reduction in maternal and neonatal adverse outcomes. Methods The Guideline Development Panel (GDP) composed of a multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 10 clinically relevant questions related to the care of individuals with diabetes before, during and after pregnancy. The GDP prioritized randomized controlled trials (RCTs) evaluating the effects of different interventions (eg, PCC, nutrition, treatment options, delivery) during the reproductive life cycle of individuals with diabetes, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Systematic reviews queried electronic databases for publications related to these 10 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and develop recommendations. The approach incorporated perspectives from 2 patient representatives and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. Results In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest asking a screening question about pregnancy intention at every reproductive, diabetes, and primary care visit. Screening for pregnancy intent is also suggested at urgent care/emergency room visits when clinically appropriate (2 | ⊕OOO). This was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced glycated hemoglobin (HbA1c) at the first prenatal visit and congenital malformations. In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest use of contraception when pregnancy is not desired (2 | ⊕⊕OO). This was suggested based on indirect evidence in women with diabetes, where PCC—including contraception as a key component—showed a clinically significant association with improvements in first-trimester HbA1c and the rate of congenital malformations, together with indirect evidence from the general population regarding the reduction of unplanned pregnancies and pregnancy terminations with the use of contraception. In individuals with T2DM, we suggest discontinuation of glucagon-like peptide-1 receptor agonist (GLP-1RA) before conception rather than discontinuation between the start of pregnancy and the end of the first trimester (2 | ⊕OOO). This was suggested based on limited data on risk of exposure to GLP-1RA receptor agonists during pregnancy. In pregnant individuals with T2DM already on insulin, we suggest against routine addition of metformin (2 | ⊕OOO). This was suggested based on the GDP judgment that the benefit of adding metformin to insulin to achieve decrease in rates of large for gestational age infants did not outweigh the potential harm of increasing the risk of small for gestational age infants or adverse childhood outcomes related to changes in body composition. In individuals with PDM, we suggest either a carbohydrate-restricted diet (&lt;175 g/day) or usual diet (&gt;175 g/day) during pregnancy (2 | ⊕OOO). This was suggested based on the GDP judgment that the available evidence was limited and very indirect, resulting in significant uncertainty about the net benefits or harms. As such, the evidence was insufficient to support a recommendation either for or against a carbohydrate intake cutoff of 175 g/day. In pregnant individuals with T2DM, we suggest either the use of a continuous glucose monitor (CGM) or self-monitoring of blood glucose (SMBG) (2 | ⊕OOO). There is lack of direct evidence supporting superiority of CGM use over SMBG for T2DM during pregnancy. There is indirect evidence supporting improved glucometrics with the use of CGM for individuals with T2DM outside of pregnancy, substantial improvements in neonatal outcomes for individuals with T1DM using CGM during pregnancy and the potential for decreasing adverse pregnancy outcomes with improved glucometrics in individuals with T2DM. In individuals with PDM using a CGM, we suggest against the use of a single 24-hour CGM target &lt;140 mg/dL (7.8 mmol/L) in place of standard-of-care pregnancy glucose targets of fasting &lt;95 mg/dL (5.3 mmol/L), 1-hour postprandial &lt;140 mg/dL (7.8 mmol/L), and 2-hour postprandial &lt; 120 mg/dL (6.7 mmol/L) (2 | ⊕OOO). This was suggested based on indirect evidence that associated adverse pregnancy outcomes with a fasting glucose &gt; 126 mg/dL (7 mmol/L). In individuals with T1DM who are pregnant, we suggest the use of a hybrid closed-loop pump (pump adjusting automatically based on CGM) rather than an insulin pump with CGM (without an algorithm) or multiple daily insulin injections with CGM (2 | ⊕OOO). This was suggested based on a meta-analysis of RCTs which demonstrated improvement in glucometrics with increased time in range (MD +3.81%; CI −4.24 to 11.86) and reduced time below range (MD −0.88%; 95% CI: −2.04 to 0.27) with the use of hybrid closed-loop pump technology. In individuals with PDM, we suggest early delivery based on risk assessment rather than expectant management (2 | ⊕OOO). This was suggested based on indirect evidence that risks may outweigh benefits of expectant management beyond 38 weeks gestation and that risk assessment criteria may be useful to inform ideal delivery timing. In individuals with PDM (including those with pregnancy loss or termination), we suggest postpartum endocrine care (diabetes management), in addition to usual obstetric care (2 | ⊕OOO). As the postpartum period frequently overlaps with preconception, this was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced HbA1c at the first prenatal visit and congenital malformations. Conclusion The data supporting these recommendations were of very low to low certainty, highlighting the urgent need for research designed to provide high certainty evidence to support the care of individuals with diabetes before, during, and after pregnancy. Investment in implementation science for PCC is crucial to prevent significant mortality and morbidity for individuals with PDM and their children. RCTs to further define glycemic targets in pregnancy and refinement of emerging technology to achieve those targets can lead to significant reduction of harm and in the burden of diabetes care. Data on optimal nutrition and obesity management in pregnancy are lacking. More research on timing of delivery in women with PDM is also needed.

Abstract Background Primary aldosteronism (PA), a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands, is a common cause of hypertension. It is associated with an increased risk of cardiovascular complications compared with primary hypertension. Despite effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated. Objective To develop an updated guideline that provides a practical, clinical approach to identifying and managing PA to improve diagnosis rates and encourage targeted treatment. Methods The Guideline Development Panel (GDP), composed of a multidisciplinary panel of clinical experts and experts in systemic review methodology, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to define 10 questions related to the diagnosis and treatment of PA. Systematic reviews were conducted for each question. The GDP used the GRADE Evidence to Decision (EtD) framework to consider contextual factors, such as stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and the potential impact on health equity. Results We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio, and that subsequent clinical care be guided by the results. We suggest that individuals with PA receive PA-specific therapy, either medical or surgical. In individuals who screen positive for PA, we suggest (1) commencement of PA-specific medical therapy in individuals who do not desire or are not candidates for surgery and in situations where the probability of lateralizing PA (excess aldosterone produced by one adrenal) is low based on screening results; and (2) aldosterone suppression testing in situations when screening results indicate an intermediate probability for lateralizing PA and individualized decision making confirms a desire to pursue eligibility for surgical therapy. In those who test positive by aldosterone suppression testing, and in those in whom screening results show a high probability of lateralizing PA (obviating the need for aldosterone suppression testing), we suggest adrenal lateralization with computed tomography scanning and adrenal venous sampling prior to deciding the treatment approach (medical vs surgical). In all individuals with PA and an adrenal adenoma, we suggest performing a 1-mg overnight dexamethasone suppression test. We suggest the use of mineralocorticoid receptor antagonists (MRAs) over epithelial sodium-channel (ENaC) inhibitors in the medical treatment of PA. We suggest the use of spironolactone over other MRAs, given its lower cost and greater availability; however, all MRAs, when titrated to equivalent potencies, are anticipated to have similar efficacy in treating PA. Thus, MRAs with greater mineralocorticoid receptor specificity and fewer androgen/progesterone receptor-mediated side effects may be preferred in some situations. In individuals receiving MRA therapy, we suggest monitoring renin and, in those whose hypertension remains uncontrolled and renin is suppressed, titrating the MRA to increase renin. Conclusion These recommendations provide a practical framework for the diagnosis and treatment of PA. They are based on currently available literature and take into consideration outcomes that are important to key stakeholders. The goal is to increase identification of individuals with PA and, by initiating PA-specific medical or surgical therapy, improve blood pressure control and reduce PA-associated adverse cardiovascular events. The guidelines also highlight important knowledge gaps in PA diagnosis and management.