Citations

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P < 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.

Summary: Breast cancer is a common malignancy, and treatment often involves mastectomy. For oncological safety, the anterior and lateral cutaneous branches of the third through fifth intercostal nerves are routinely resected during nipple-sparing mastectomies, leading to loss of nipple sensation. The current gold standard for nipple neurotization uses nerve allografts to connect the nipple with a remaining stump of an intercostal nerve. Despite the convenience of off-the-shelf solutions, this study explored a novel approach using intercostal nerves as autografts or for direct repair to restore nipple sensation. Six patients underwent nipple-sparing mastectomy and opted for nipple neurotization. Three patients underwent neurotization with an intercostal nerve autograft, whereas in 3 patients, long intercostal nerves allowed nipple neurotization directly without the need for an autograft. Meticulous dissection of the intercostal nerves enabled a length of approximately 9 cm (±1.5) per nerve. The acquired nerve length allowed tension-free coaptation of direct nipple neurotization in 3 patients and utilization as an autograft in the other 3 patients. No postoperative complications were observed, whereas sensory outcomes are yet to be evaluated. The study highlighted the feasibility of using intercostal nerves either as autologous intercostal nerve grafts or for direct neurotization. Using an intercostal nerve as an autograft is a cost-effective and time-efficient strategy to avoid the need for an allograft without additional donor-site morbidity. This technique offers a practical and globally accessible solution for improving patient access to state-of-the-art postmastectomy breast reconstruction.

Objective: To evaluate the first 3 years of compliance with the American College of Surgeons Commission on Cancer (CoC) Operative Standards. Background: CoC implemented evidence-based standards to improve the quality of sentinel lymph node biopsy and axillary lymph node dissection for breast cancer (operative standards 5.3 and 5.4), wide local excision for melanoma (5.5), colectomy for colon cancer (5.6), proctectomy for rectal cancer (5.7), and pulmonary resection for lung cancer (5.8) at ∼1400 programs treating >74% of US cancer patients. Each operative standard defines a technical element of the operation and structured documentation. Methods: Compliance data are from site visits conducted between January 1, 2022, and December 31, 2024 (implementation/site visits began in 2021/2022 for 5.7 and 5.8 and 2023/2024 for 5.3–5.6). Compliance with each operative standard was determined by evaluation of 7 operative (5.3–5.6) or pathology (5.7, 5.8) reports. Deficiency in technical performance, documentation, or both was considered noncompliance. Results: Reviewers conducted 974 site visits of Comprehensive Community (44%), Community (23%), Academic Comprehensive (16%), network (12%), NCI-Designated Comprehensive (4%), and other (1%) cancer programs. Program compliance rates ranged from 53% to 88%. Documentation noncompliance was more common for standards 5.3 to 5.6 (based on operative reports), and technical noncompliance was more common for 5.7 and 5.8 (based on pathology reports). Compliance significantly (P=0.006) varied by program type for 5.8 (highest: 66% at NCI-designated Comprehensive programs; lowest: 37% at Community Cancer programs). Conclusions: Early compliance with CoC operative standards varied, indicating local and large-scale national quality improvement efforts are needed.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

9503 Background: Neoadjuvant ± adjuvant immunotherapy improves event-free survival relative to adjuvant immunotherapy alone for patients with high-risk resectable stage III melanoma. However, the optimal regimen balancing efficacy and tolerability is not known. T-cell immunoglobulin and ITIM domain (TIGIT) is a promising immune checkpoint but its therapeutic potential in stage III melanoma is underexplored. Methods: In this phase II trial, patients with resectable, macroscopic stage III melanoma received four 21-day neoadjuvant cycles of 1200mg IV atezolizumab (atezo, anti-PD-L1) + 600mg IV tiragolumab (tira, anti-TIGIT), followed by therapeutic lymph node dissection (TLND) and eight 21-day adjuvant cycles of 1200mg IV atezo. Primary endpoints were pathologic response (of all patients initiating neoadjuvant therapy) and recurrence-free survival (RFS) from the time of TLND in patients who were operated on per protocol and received adjuvant therapy. Secondary endpoint was adverse events (AEs); exploratory endpoints included event-free survival (EFS) and distant metastasis-free survival (DMFS). Results: Thirty-four patients, median age 59 years, were accrued and initiated neoadjuvant atezo/tira. 76.5% had >1 metastatic lymph node involved at baseline and 73.5% presented with Stage IIIC disease. All 34 patients were evaluable for AEs, pathologic response and EFS. Four patients were diagnosed with metastatic disease during neoadjuvant treatment, while 30 had TLND per protocol and 28 received adjuvant treatment and were evaluable for RFS and DMFS. Major pathologic responses (MPR, ≤10% viable tumor) were observed in 16/34 patients (47.1%, Table). With 19.9 months median follow-up from registration, 12-month EFS was 72.0% (95% CI 57.9 to 89.5%). With 16 months median follow-up from operation, 12-month RFS was 73.3% (n=28, 95% CI 56.9 to 94.5%), while 12-month DMFS was 86.0% (n=28, 95% CI 72.2 to 100%). In the 16 patients with an MPR, 2 did not receive adjuvant treatment and were followed for 33.3 and 10.8 months without recurrence/death. In the remaining 14 patients, 12-month RFS and 12-month DMFS were both 91.7% (95% CI 77.3 to 100%). 5 patients (14.7%) experienced any grade 3+ AE with 2 (5.9%) at least possibly related to the neoadjuvant regimen. Conclusions: Among patients with high-risk resectable stage III melanoma, neoadjuvant atezo/tira was a promising regimen with a favorable safety profile and warrants further study. Identification of predictive biomarkers will allow for optimization of neoadjuvant therapy for individual patients. Clinical trial information: NCT03554083 . Pathologic response. N=34 Major Pathologic Response 16 (47.1%) Pathologic complete response (no viable tumor) 13 (38.2%) Near-pathologic complete response (0.1−10% viable tumor) 3 (8.8%) Pathologic partial response (>10.0−50% viable tumor) 2 (5.9%) Pathologic non-response (>50% viable tumor) 12 (35.3%) No per protocol operation 4 (11.8%)

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

AbstractINTRODUCTIONWe compare the stability of phosphorylated tau (p‐tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p‐tau217/Aβ42 at different storage temperatures.METHODSTen ethylenediaminetetraacetic acid–plasma sample aliquots stored at frozen, refrigerated, and ambient temperatures were tested at various timepoints up to 30 days. The mean percent change from baseline was calculated.RESULTSAβ42 and Aβ40 concentrations decreased by >15% after 6 hours at ambient temperature and after 24 hours refrigerated, while p‐tau217 remained stable over 72 hours with < 10% deviation from baseline at either storage temperature. The Aβ42/40 ratio remained relatively constant as each analyte concentration decreased concurrently, while the p‐tau217/Aβ42 ratio deviated from baseline over time. All biomarkers were stable up to 30 days frozen.DISCUSSIONDifferences in the stability of Aβ42 and p‐tau217 may lead to altered p‐tau217/Aβ42 ratio results if samples are not handled properly during the pre‐analytical testing phase. Ideally, samples should be frozen promptly and sent to the laboratory frozen.Highlights Plasma phosphorylated tau (p‐tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p‐tau217/Aβ42 stability was assessed. P‐tau217 was stable, but Aβ42 and Aβ40 started decreasing by 6 hours at ambient temperature. The analyte stability differences led to falsely increased p‐tau217/Aβ42 ratios. Increases > 15% were seen in p‐tau217/Aβ42 after 6 hours at ambient temperature or 24 hours at 4°C.

AbstractIntroductionActive learning engages learners in constructing knowledge through interactive strategies such as simulation, small‐group discussion, and peer instruction. Although recognized as a superior approach to traditional passive learning, its adoption has been inconsistent. Barriers include reliance on traditional lectures, lack of training, and limited time to develop materials. Simulation educators have a unique skill set that may inform and support active learning initiatives.MethodsFifteen emergency medicine simulation experts convened to define the unique skill set of simulation educators and identify transferable simulation‐based medical education (SBME) skills and concepts to promote effective active learning beyond the simulation lab. Workgroup members are simulation education directors who have undergone specialized training in SBME. During biweekly meetings over 6 months, workgroup members reviewed primary literature in SBME and active learning, along with relevant simulation educator training materials. Objectives were achieved through iterative review, group conceptualization, and expert consensus.Unique treatmentThe increasing prevalence of SBME in medical education, along with the growth of simulation fellowships, has produced a group of education experts with shared competencies. Simulation educators acquire expertise in psychological safety, facilitation, communication, and debriefing, through specialized training and extensive experience. These skills are critical for active learning environments where learners benefit from structured, engaging, and psychologically safe experiences.Implications for educatorsKey transferable SBME topics were identified for use in active learning environments outside of the simulation lab: (1) psychological safety, (2) facilitation strategies, and (3) communication techniques. Transferable tools and concepts were identified to promote efficacy and learner engagement during active learning in diverse environments. Simulation educators’ expertise is an underutilized resource for faculty development initiatives aimed at advancing active learning. This work advocates for leveraging simulation educators’ skills to close the active learning implementation gap, enhance learner outcomes, and meet the evolving needs of contemporary medical education.

Background Parkinsonism following hypoxic ischemic damage of the basal ganglia is an uncommon phenomenon that has been infrequently reported. However, only a few cases have noted improvement of symptoms with dopaminergic therapy. We report the clinical and imaging features of five patients with post-anoxic parkinsonism responsive to dopamine supplementation. Objective To describe a retrospective case series of five cases of dopamine-responsive post-anoxic parkinsonism. Methods We identified all the cases using the Mayo Clinic Data Management System utilizing advanced data explorer search engine for any patients evaluated for post anoxic parkinsonism and its associated acronyms from 2000–2024. Clinical features, neuroimaging, medication trials, and responses were obtained from chart review of identified patients. Results Five patients met the inclusion criteria. All patients underwent anoxic events followed by development of parkinsonism. Patients exhibited parkinsonism described as combinations of bradykinesia, rigidity, tremor, and postural instability. All patients underwent evaluation by a neurologist, MRI imaging, and treatment by dopaminergic agents. Of the five patients, four received carbidopa/levodopa whereas one received a dopamine agonist. All patients were clinically followed for a median of approximately 4 years and showed improvement in parkinsonism. Conclusions Parkinsonism following a hypoxic ischemic insult is a rare occurrence but response to dopaminergic therapy in those cases is even more scarcely described. Our cases series provides important implications for treatment options for patients with post anoxic parkinsonism.

Abstract Breast cancer is the leading cause of cancer death among women worldwide. Most cases occur in those without identifiable modifiable risk factors, highlighting critical gaps in our understanding of breast cancer biology including the influence of the gut microbiome. Here we studied the gut microbiome with shallow shotgun metagenomic sequencing from preoperative stool samples in a well-characterized clinical cohort of 131 women, median age 59 years, undergoing breast-conserving surgery for benign (n=23), high-risk (n=47), or malignant (n=61) breast disease. Taxonomic profiling was performed with Sourmasth 4.2.4 with GTDBv202 as reference database; functional profiling of metagenomic data employed HUMAnN 3.6 with identified gene families mapped to MetaCyc pathways. Differences in alpha diversity in terms of species richness were observed across diagnosis groups (benign, high-risk, malignant) and was lowest for high-risk lesions (p=0.031). Decreased alpha diversity was also associated with higher body mass index (BMI) (Shannon p=0.12, Inverse Simpson p=0.025). Significant beta diversity differences across diagnosis groups also were seen (Bray-Curtis p=0.044, Jaccard p=0.013) as were differences in association with BMI (Bray-Curtis, Jaccard, both p=0.002). No significant diversity differences associated with age, mammographic breast density or menopausal status were observed. Functional pathway profiling stratified by BMI showed a correlation between increasing BMI and greater relative abundance of genes in nicotinamide adenine dinucleotide (NAD) biosynthesis, folate metabolism, and aromatic amino acid metabolism pathways (p=0.0279, 0.0667 and 0.0860, respectively) - pathways implicated in breast cancer detection, survival and prognosis. Cross-referencing our significantly (FDR &lt;5%) differentially abundant taxonomic findings with these functional pathway data identified enrichment of several Blautia species, linked to NAD biosynthesis via tryptophan metabolism, in patients with higher BMI. We also noted enrichment of Dorea formicigenerans, a species associated with increased breast cancer risk in obese women due to its pro-inflammatory effects, in individuals with a higher BMI. Here we report significant differences in gut microbiome diversity, taxonomy and functional pathway signals in association with BMI in women with breast disease. Differentially abundant species seen with rising BMI may contribute to functional pathways that drive increased breast cancer risk and may provide an actionable target for risk reduction independent of conventional risk reduction strategies. Citation Format: Jack W. Sample, Matteo Redaelli, Stephen Johnson, Tanya L. Hoskin, Marina R. Walther-Antonio, Jun Chen, Tina J. Hieken. Obesity alters cancer-related microbial pathways in women with benign and malignant breast disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2213.