Citations

TPS1107 Background: ALP (α-selective PI3K inhibitor and degrader) is approved with FUL for pts with PIK3CA-mut HR+, HER2− ABC. HG is a known on-target effect of PI3K inhibition, manageable with oral anti-HG agents such as MET and dose interruptions/modifications of ALP and reversible upon discontinuation of ALP. Although HG management guidelines were refined throughout the SOLAR-1 and BYLieve studies evaluating ALP + FUL/letrozole, there remains a need for optimized strategies beyond initial MET therapy that offers earlier and more sustained improvement of HG, particularly for pts at an increased risk for severe HG. In preclinical models, the addition of a SGLT2 inhibitor to ALP (+/− MET) reduced HG while maintaining ALP efficacy. The aim of this study is to evaluate the safety and efficacy of prophylactic MET XR +/− the SGLT2 inhibitor DAPA in reducing severe HG in pts with PIK3CA-mut HR+, HER2− ABC on ALP + FUL with an increased risk for severe HG (grade ≥ 3) on ALP. Methods: EPIK-B4 is a Phase II, randomized (1:1), open-label, active-controlled study assessing the efficacy and safety of MET XR +/− DAPA (starting at Cycle 1 Day 1 [C1D1]) with ALP (300 mg orally [PO], once daily [QD], starting at C1D8) + FUL (500 mg intramuscularly on C1D1, C1D15, and D1 of subsequent cycles) in pts (N ≈ 132) with HR+, HER2–, PIK3CA-mut ABC after progression on/after endocrine-based treatment (Tx). MET XR is administered PO starting at 500 mg QD (titrated up to 2 g QD) and MET XR + DAPA starting at 500 mg and 5 mg QD (titrated up to 2 g and 10 mg QD), respectively. Eligible pts include adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mut ABC and ≥ 1 risk factor for severe HG (diabetes [fasting plasma glucose (FPG) ≥ 126 mg/dL and/or HbA1c ≥ 6.5%], prediabetes [FPG ≥ 100 to < 126 mg/dL and/or HbA1c 5.7% to < 6.5%], obesity [BMI ≥ 30], age ≥ 75 years); prior endocrine-based Tx (eg, FUL or oral SERD) was permitted. Randomization is stratified by baseline diabetes status. Key exclusion criteria include > 1 line of Tx in the metastatic setting; prior chemotherapy (metastatic setting) or PI3K, mTOR, or AKT inhibitor; type I or II diabetes requiring Tx; or antecedent of pancreatitis or severe cutaneous reaction. The primary endpoint is the occurrence of severe HG (grade ≥ 3 [glucose > 250 mg/dL] based on laboratory assessments) over the first 8 weeks of ALP + FUL. Secondary endpoints include progression-free survival, overall response and clinical benefit rates with confirmed response, safety, and tolerability. A biomarker analysis is planned as an exploratory objective. Recruitment is ongoing with enrollment planned in 56 sites across 8 countries; completion of primary data collection is anticipated in 2023. Clinical trial information: NCT04899349; EUDRACT#2021-001908-15.

3134 Background: Mucinous breast cancer (MuBC) is a rare subtype of invasive ductal carcinoma (IDC) that accounts for less than 2% of all breast cancers and is associated with a favorable prognosis. Since MuBCs are rare in clinical trials, current treatment guidelines are extrapolated from IDC-no special type (IDC-NST). To provide better understanding of MuBCs and factors contributing to their clinical behavior, we examined the transcriptomic profiles of MuBCs in our FLEX study. Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III breast cancer patients who receive MammaPrint (MP)/BluePrint (BP) testing and consent to full transcriptome and clinical data collection. For this study, histologically confirmed MuBCs (n = 102) in the FLEX database were included. All patients examined were ER+/HER2- by immunohistochemistry and Luminal by BP. MuBC was compared with IDC matched for Age, MP, and BP index (n = 97). Differential gene expression analyses (DGEA) were performed with R package ‘limma’ and differentially expressed genes (DEGs) were considered significant if they had an adjusted p < 0.05 and fold change ≥ 2. Results: DGEA comparing MuBC (n = 102) with IDC (n = 97) revealed 60 DEGs, regardless of the genomic risk, of which 42 genes were upregulated and 18 were downregulated in MuBC relative to IDC. Genes associated with MuBC, such as MUC2, TFF1, CARTPT were among the upregulated genes. Of the 102 MuBC patients, 56 were Luminal A (MP Low Risk-LR) and 46 were Luminal B (MP High Risk-HR) by MammaPrint and BluePrint. Comparison of LR MuBC with LR IDC revealed 111 DEGs. Functional enrichment showed upregulation of pathways involved in estrogen response (early & late) and androgen response and a downregulation of the epithelial to mesenchymal transition (EMT) and E2F pathways in LR MuBC compared to LR IDC. DGEA between HR MuBC and HR IDC revealed only 22 DEGs with immune pathways being downregulated in HR MuBC. DGEA comparing LR MuBC with HR MuBC resulted in 63 DEGs, indicating LR and HR MuBC are biologically distinct types. Interestingly in LR MuBC, the tumor suppressor marker SCUBE2 is upregulated. Over expression of SCUBE2 is associated with better prognosis. Conclusions: Although MuBCs are often expected to have low clinical risk, MP revealed that half of the MuBCs examined in this study were MP High Risk (Luminal B). MP low risk MuBC is biologically different from MP low risk IDC, and downregulation of E2F and EMT pathways might lead to favorable prognoses in MP low risk MuBC. MP high risk MuBC showed limited DEGs compared to high-risk IDCs indicating these tumor types are highly genomically similar and likely to benefit from chemotherapy. The downregulation of immune pathways in MP high risk MuBC may lead to immune surveillance escape resulting in metastasis and further investigation is needed. Clinical trial information: NCT03053193.

Abstract Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

ABSTRACT. Global health education programs should strive continually to improve the quality of education, increase access, create communities that foster excellence in global health practices, and ensure sustainability. The COVID-19 pandemic forced the University of Minnesota’s extensive global health education programs, which includes a decade of hybrid online and in-person programing, to move completely online. We share our experience, a working framework for evaluating global health educational programming, and lessons learned. Over the decades we have moved from a predominantly passive, lecture-based, in-person course to a hybrid online (passive) course with an intensive hands-on 2-week requirement. The pandemic forced us to explore new active online learning models. We retained our on-demand, online passive didactics, which used experts’ time efficiently and was widely accessible and well received. In addition, we developed a highly effective synchronous online component that we felt replaced some of the hands-on activities effectively and led us to develop new and innovative “hands-on” experiences. This new, fully online model combining quality asynchronous and synchronous learning provided many unanticipated advantages, such as increasing access while decreasing our carbon footprint dramatically. By sharing our experience, lessons learned, and resources, we hope to inspire other programs likewise to innovate to improve quality, access, community, and sustainability in global health, especially if these innovations can help decrease negative aspects of global health education such as its environmental impact.

SummaryIn young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front‐line setting. Recently, time‐to‐event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post‐autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six‐month [hazard ratio (HR) = 7·68], 12‐month (HR = 6·68), and 18‐month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non‐relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high‐risk group with inferior post‐relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up‐front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.

Background: Data regarding opioid prescribing patterns following pediatric orthopaedic procedures is limited. The aim of this work was to evaluate the effects of tiered guidelines for discharge opioid prescriptions following common pediatric orthopaedic procedures. Methods: Quality improvement project conducted at a single academic institution. Guidelines for discharge opioid prescriptions were implemented January 2018 and established 4 tiers of increasing invasiveness for 28 common pediatric orthopaedic procedures. Patients who underwent these procedures in 2017 comprised the preguideline cohort (N=258), while patients treated in 2019 comprised the postguideline cohort (N=212). Opioid prescriptions were reported as oral morphine equivalents (OMEs). Univariate tests were performed to assess statistically significant differences before and after implementation of the guidelines. Results: There was a significant decrease in OME prescribed between preguideline and postguideline cohorts (median OME 97.5 vs. 37.5). When analyzed according to procedure tiers, tiers 1, 2, and 4 showed significant decreases in OME prescribed between 2017 and 2019. The rate of no opioids prescribed at discharge increased from 13% to 23% between preguideline and postguideline cohorts. The 30-day refill rate did not significantly change. After implementation of guidelines, 91% of all prescriptions were within the guideline parameters, and there was a significant reduction in prescription variability. In tier 4 procedures, median OME prescribed decreased from 375 preguideline to 188 postguideline, but was associated with greater opioid refills within 30 days of discharge (10.2% preguideline vs. 28.8% postguideline). Conclusions: Tiered guidelines for discharge opioid prescriptions following pediatric orthopaedic procedures can significantly decrease the quantity of opioids prescribed. Furthermore, we noted excellent adherence and no overall increase in the rates of narcotic refills. Such guidelines may improve pediatric orthopaedists’ ability to responsibly treat postoperative pain while limiting the distribution of unneeded opioids. Level of Evidence: Level IV—quality improvement project.

» The incidence of brachial plexus birth injury (BPBI) in the United States is declining and now occurs in <1 per 1,000 births. » The gold standard for predicting the need for early intervention remains serial examination. » Early treatment of BPBI with reconstructive surgery requires the ability to perform both interposition nerve grafting and nerve transfers. » Given the heterogeneity of lesions, the evidence is largely limited to retrospective comparative studies and case series.