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Background: The prognosis for advanced/metastatic triple negative breast cancer (TNBC) remains poor and novel therapeutic strategies are urgently needed to improve outcomes. Insulin resistance and obesity contribute to cancer progression and are independent predictors of worse survival after TNBC diagnosis. Chemotherapy worsens insulin resistance, body mass index, and multiple other metabolic parameters which can paradoxically limit treatment efficacy and survival. Methionine aminopeptidase 2 (MetAP2/p67) is overexpressed in many tumor types and MetAP2 inhibitors exhibit broad anti-tumor activity. Additionally, MetAP2 inhibitors improve insulin resistance, reduce adiposity, and normalize levels of adipokines, attenuating the effects of metabolic dysfunction on tumor growth. Evexomostat (SDX-7320) is a second-generation MetAP2 inhibitor designed to improve drug-like properties and minimize central nervous system toxicities. Evexomostat improved insulin sensitivity, reduced fat mass and normalized adipokine levels in preclinical models of obesity, and reduced tumor growth in preclinical models of TNBC. In phase 1 trials, MetAP2 inhibition combined with chemotherapy was safe and well tolerated, while evexomostat monotherapy partially restored insulin sensitivity, reduced angiogenic factors as well as adipokines and showed anti-metastatic effects in patients with advanced solid tumors. The goal of this phase 2 study is to test whether evexomostat in combination with eribulin chemotherapy prevents worsening of insulin resistance and augments tumor response in patients with metastatic TNBC and concomitant metabolic dysfunction. Methods: This is a single-center, placebo-controlled phase 2 randomized control trial of evexomostat, a MetAP2 inhibitor, in combination with eribulin chemotherapy. Eligible patients must have histologically confirmed metastatic TNBC, measurable disease or ≥1 predominantly lytic bone lesion, baseline metabolic dysfunction defined as hemoglobin A1c >5.5% and/or BMI ≥30 kg/m2, have received ≤2 prior lines of therapy in the advanced/metastatic setting, have ECOG performance status ≤1, and adequate organ function. Patients with uncontrolled or insulin-dependent type II diabetes, or who require combination antihyperglycemic therapy are excluded. During the safety run-in period, 15 patients will be assigned to receive evexomostat 49 mg/m2 every 2 weeks in combination with eribulin 1.4 mg/m2 administered on days 1 and 8 of a 21-day cycle. Upon safety confirmation, an additional 40 patients will be randomized 2:1 to receive evexomostat or placebo in combination with eribulin. The primary endpoint is metabolic efficacy assessed by change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Secondary endpoints include objective response rate, progression-free survival, duration of response, safety and tolerability, patient-reported outcomes, changes in metabolic markers, and changes in body composition parameters. Historically, HOMA-IR scores double during chemotherapy, and this trial will test whether evexomostat will attenuate the expected rise in HOMA-IR. Specifically, the trial will have >90% power to detect a difference between a 1.5-fold change in HOMA-IR in the control arm versus no change in the investigational arm while controlling the Type I error at 5%. This trial opened to accrual in July 2022. A total accrual of 61 patients is planned with a goal of 55 evaluable patients. For any inquiries/questions, please contact Sherry Shen at shens1@mskcc.org. Clinical trial registry number: pending Funding, study drug evexomostat and other support provided by: SynDevRx, Inc. Citation Format: Sherry Shen, Anna Whalen, Mark E. Robson, Larry Norton, Tiffany A. Traina, Neil M. Iyengar. The ARETHA Study: A phase 2 randomized control trial of Eribulin with Evexomostat (SDX-7320) or placebo for patients with metastatic triple-negative breast cancer and metabolic dysfunction [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-17-02.

Background: Diet is a modifiable risk factor for breast cancer risk and mortality. Current guidelines recommend a diet that provides a diverse array of nutrients, comprised predominantly of fruits/vegetables and whole grains, with limited added sugar. The Healthy Living Program (HLP) is a clinical program at Memorial Sloan Kettering Cancer Center for patients with early-stage breast cancer that offers longitudinal, personalized lifestyle management starting at the time of diagnosis. Here, we report dietary patterns among the HLP cohort and association with baseline body mass index (BMI). Methods: We included all patients enrolled in the HLP from September 2020-February 2022. At the time of enrollment, participants complete a survey containing the National Cancer Institute (NCI) Dietary Screener Questionnaire (DSQ), which consists of consumption frequency questions for 26 food items over the past month. Total daily intake equivalents are calculated for foods from every diet factor group according to standard NCI DSQ scoring as follows: 1) Total daily cup equivalents of fruits/vegetables, which includes fruit, fruit juice, salad, potatoes, beans, other vegetables, tomato sauce, salsa, and pizza; 2) Total daily ounce equivalents of whole grains, which includes cereal, whole grain bread, whole grain rice, and popcorn; 3) Total teaspoon (tsp) equivalents of added sugars from candy, doughnuts, cookies/cake/pie, cereal, ice cream, and sugar-sweetened beverages including soda, fruit drinks, and sugar/honey in coffee/tea. Adherence to recommended daily intake of fruits/vegetables, whole grains, and added sugars was assessed as per the 2020-2025 Dietary Guidelines, the American Institute for Cancer Research, and the World Health Organization guidelines. Patient and tumor characteristics were abstracted from medical records. Results: Among the 399 patients included, the median age at diagnosis was 58 and median baseline BMI was 26.1 kg/m2. 45 patients had carcinoma in situ (11.3%), 296 had stage I disease (74.2%), 51 had stage II disease (12.8%), and 7 had stage III disease (1.8%). 316 had hormone-receptor positive disease (89.3%), 24 had HER2-positive disease (6.8%), and 26 had triple-negative disease (7.3%). 106 participants (27%) met the guideline recommendation of ≥4-5 cup equivalents of fruits/vegetables daily and 3 participants (0.8%) met the guideline recommendation of ≥3 ounces equivalents of whole grains daily. All patients in the cohort met the guideline recommendation of < 6 tsp equivalents of added sugars daily. Only 2 patients (0.5%) met guidelines for all three diet factors. Baseline BMI was significantly higher among patients who did not meet the recommended fruit/vegetable intake than among those who did (26.9 kg/m2 vs. 24.5 kg/m2, p=0.016). There were no significant differences in BMI between those who did and did not adhere to the other diet factor guidelines and no significant association between tumor stage or histology and dietary guideline adherence. Conclusion: Most patients with early-stage breast cancer did not meet the recommended daily intake of fruits/vegetables or whole grains. Participants who did not meet the fruit and vegetable intake guideline had significantly higher BMI at diagnosis. These findings indicate that lifestyle assessment near the time of breast cancer diagnosis identifies patients that could benefit from personalized dietary interventions to optimize prognostic factors such as BMI. Citation Format: Bethina Liu, Sherry Shen, Erica Salehi, Yuan Chen, Nicolas Toumbacaris, Johnny Allsop, Cara Anselmo, Stacie Corcoran, Bridget Kelly, Rocco Magnoli, Andrea Smith, Melissa Emerzian, Julia Brockway-Marchello, Doreen Bacotti, Mark E. Robson, Neil M. Iyengar. Dietary patterns among women with early-stage breast cancer from the Healthy Living Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-07.

Background: Evidence-based recommendations support a dietary pattern rich in whole grains, fruits, and vegetables with limited consumption of added sugars to improve cancer risk and mortality. The Optimal Living Program (OLP) is a prospective multiparametric lifestyle intervention that engages early-stage breast cancer patients at the time of diagnosis in risk-stratified, personalized lifestyle management. Here, we report baseline dietary patterns among women enrolled in the OLP. Methods: Upon enrollment, patients complete a questionnaire that incorporates the National Cancer Institute (NCI) Dietary Screener Questionnaire (DSQ), which queries the consumption frequency of 26 food items over the past month. Based on standard NCI DSQ scoring procedures, we calculated total daily serving equivalents of all food items within a dietary factor group. This included: 1) total daily cup equivalents of fruit and vegetables from fruit, fruit juice, salad, potatoes, beans, other vegetables, tomato sauce, salsa, and pizza, 2) total daily ounce equivalents per day of whole grains from cereal, whole grain bread, popcorn, and whole grain rice, and 3) total daily teaspoon (tsp) equivalents of added sugars from cookies/cake/pie, doughnuts, ice cream, candy, cereals, and sugar-sweetened beverages including soda, fruit drinks, and sugar/honey in coffee/tea. Results: There were 100 patients enrolled in the OLP for whom baseline DSQ data were available. The median age at diagnosis was 58 and median BMI was 27.4 mg/m2. 69 patients were white (69.0%), 14 were Black (14.0%), and 7 were Asian (7.0%). 62 patients had stage I disease (62.0%), 22 patients had stage II disease (22.0%), and 15 patients had ductal carcinoma in situ (15.0%). 74 patients had hormone receptor-positive disease (74.0%), 3 had HER2-positive disease (3.0%), and 7 had triple-negative disease (7.0%). Daily frequency of consumption of dietary factor groups are shown in Table 1. Only 29 patients (29.0%) met the current dietary guideline of 4-5 cup equivalents of fruits and vegetables per day and no patients (0%) met the guideline of more than 3 ounce equivalents of whole grains per day. Added sugar intake ranged from 0 to 4.8 teaspoon equivalents per day. Conclusion: Most women in this cohort with newly diagnosed early-stage breast cancer did not consume the recommended daily intake of fruits, vegetables, and whole grains per the 2020-2025 Dietary Guidelines and the American Institute for Cancer Research. Our findings identify these dietary factors as important targets of intervention with personalized dietary guidance at the time of breast cancer diagnosis. Table 1.4/dayFruits and vegetables (cup equivalents)6 (6.0%)23 (23.0%)28 (28.0%)14 (14.0%)29 (29.0%)Whole grains (ounce equivalents)63 (63.0%)29 (29.0%)8 (8.0%)0 (0%)0 (0%)Added sugar (tsp equivalents)32 (32.0%)35 (35.0%)22 (22.0%)6 (6.0%)5 (5.0%)Sugar-sweetened beverages (tsp equivalents)62 (62.0%)21 (21.0%)15 (15.0%)2 (2.0%)0 (0%) Citation Format: Sherry Shen, Johnny Allsop, Erica Salehi, Cara Anselmo, Stacie Corcoran, Jill Clayton, Andrea Smith, Melissa Emerzian, Mark Robson, Neil Iyengar. Baseline dietary patterns among women with newly diagnosed early-stage breast cancer enrolled in the Optimal Living Program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-05.

Hyperinsulinemia is an independent risk factor for cancer mortality. Insulin-lowering dietary strategies such as calorie restriction (CR), low-carbohydrate or ketogenic diets (KD), and intermittent fasting (IF) are aimed at reducing systemic stores of nutrients utilized by cancer cells, attenuating insulin-related growth signaling, and improving obesity-related metabolic parameters. In this narrative review, we searched the published literature for studies that tested various insulin-lowering diets in metastatic cancer in preclinical and clinical settings. A total of 23 studies were identified. Of these, 14 were preclinical studies of dietary strategies that demonstrated improvements in insulin levels, inhibition of metastasis, and/or reduction in metastatic disease burden in animal models. The remaining nine clinical studies tested carbohydrate restriction, KD, or IF strategies which appear to be safe and feasible in patients with metastatic cancer. These approaches have also been shown to improve serum insulin and other metabolic parameters. Though promising, the anti-cancer efficacy of these interventions, such as impact on tumor response, disease-specific-, and overall survival, have not yet been conclusively demonstrated. Studies that are adequately powered to evaluate whether insulin-lowering diets improve cancer outcomes are warranted.

Endometrial cancer incidence and mortality are rising among all ethnic groups. Carboplatin plus paclitaxel is the established frontline treatment for advanced/recurrent disease; however, subsequent treatment with traditional cytotoxic chemotherapy is challenging. The molecular characterization of endometrial cancer has provided important insights into the biological drivers of carcinogenesis, which has allowed for the development of newer precision immunotherapies and targeted therapies, including pembrolizumab, dostarlimab, and lenvatinib. Until recently, platinum rechallenge was often considered at the time of recurrence, given the lack of other available therapeutic options; however, "platinum sensitivity" in endometrial cancer is subjective and largely based on expert opinion and/or practitioner experience. Small retrospective studies have tried to provide guidance on the utility of platinum rechallenge, but they are limited by variable patient characteristics and small sample sizes. The applicability of these retrospective studies to contemporary clinical practice is difficult in the setting of changing patient demographics, a better understanding of endometrial cancer drivers, and the recent approvals of immune checkpoint inhibitors and the combination of lenvatinib plus pembrolizumab in the second-line setting. The primary focus of this review is to distill the available data regarding platinum-doublet chemotherapy rechallenge and highlight recent pivotal developments in endometrial cancer treatment, as well as future directions.

Context Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. Evidence Acquisition Pubmed literature search using combinations of “obesity,” “breast cancer risk,” “diet,” “exercise,” “weight gain,” “weight loss,” “adipose tissue inflammation,” “crown-like structure,” “immune markers,” “metformin,” “gliflozins,” “SGLT-2i,” “GLP1-RA,” and related terms. Evidence Synthesis Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor–positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk. Conclusion Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

The COVID-19 pandemic has been particularly severe in New York City, resulting in a rapid influx of patients into New York-Presbyterian Hospital/Columbia University Irving Medical Center. The challenges precipitated by this pandemic have required urgent changes to existing models of care. Internal medicine residents are at the forefront of caring for patients with COVID-19, including the critically ill. This article describes the exigent restructuring of the New York-Presbyterian Hospital/Columbia University Internal Medicine Residency Program. Patient care and educational models were fundamentally reconceptualized, which required a transition away from traditional hierarchical team structures and a significant expansion in the program's capacity and flexibility to care for large numbers of patients with disproportionately high levels of critical illness. These changes were made while the residency program maintained the priorities of patient care and safety, resident safety and well-being, open communication, and education. The process of adapting the residency program to the demands of the pandemic was iterative given the unprecedented nature of this crisis. The goal of this article is to share the experiences and lessons learned from this crisis, communicate the solutions that were designed, and inform others who may be facing the prospect of creating similar disaster response measures.

The problematic term “citizen science” continues to circulate in scholarly circles and points to challenges with how researchers may conceptualize who takes part in community-engaged inquiry. Emerging from experiences with a research team intentionally comprised of students who are undocumented, political asylees, and those belonging to mixed status families, we seek to center how immigration status can inform justice-oriented research processes. By focusing on students experiencing liminal status, we note both the structural barriers they face as well as their agency. Through a critical reflexive process, we outline four key tensions that address skills, authenticity, inclusivity, and possibilities relevant to mixed status teams conducting community-engaged research. By exploring how citizenship status impacts research at epistemological and applied levels, we arrive at more inclusive and just possibilities for community-engaged research.

TPS1113 Background: Breast cancer is the most common malignancy among women in the U.S. and is a leading cause of cancer-related death. Among women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, 45% harbor activating mutations in the PIK3CA gene , which induces hyperactivation of phosphatidylinositol 3-kinase (PI3K) and drives cell growth and survival. The SOLAR-1 trial found that the combination of alpelisib, a PI3K inhibitor, and fulvestrant, an endocrine therapy, significantly improved progression-free survival compared to fulvestrant alone, leading to Food and Drug Administration approval in PIK3CA-mutated metastatic breast cancer. While PI3K inhibition induces apoptosis of cancer cells, inhibition of this pathway in the liver and skeletal muscle impairs physiologic insulin signaling leading to hyperglycemia. This affects > 60% of patients, results in grade 3-4 hyperglycemia in 36% of patients, and is a major cause of interrupted/reduced dosing or discontinuation. In preclinical models, application of a very low carbohydrate (ketogenic) diet or a sodium-glucose cotransporter 2 inhibitor (SGLT2i), a commonly used diabetes medication, minimized hyperglycemia and improved the anti-tumor efficacy of PI3K inhibition. These interventions are safe and feasible in cancer patients but have not been studied for the prevention of PI3K inhibitor-associated hyperglycemia. Methods: We are conducting a multicenter phase II clinical trial (NCT05090358) in patients receiving standard-of-care alpelisib plus fulvestrant to test the efficacy of three interventions (n = 106): 1) ketogenic diet, 2) low-carbohydrate diet, or 3) canagliflozin (a SGLT2i) in preventing alpelisib-associated hyperglycemia. The goal of this study is to mitigate a major toxicity of PI3K inhibitors and maximize their clinical efficacy. Eligible patients must be postmenopausal and have histologically confirmed HR-positive, HER2-negative metastatic breast cancer, ≥1 activating PIK3CA mutations, measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion, recurrence or progression during or after endocrine-based therapy, ECOG performance status of 0-1, hemoglobin A1c < 8%, and fasting blood glucose < = 140mg/dL. Prior CDK4/6 inhibitor use is allowed. The primary endpoint is the grade 3-4 hyperglycemia-free rate at 12 weeks. Secondary endpoints include the 6- and 12-month overall response rate, 6- and 12-month progression-free survival, alpelisib adherence, changes in systemic hormones and metabolites related to glucose homeostasis, changes in body composition, and quality of life. The first patient was enrolled on October 15, 2021. Participating sites include Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, and the Ohio State University Wexner Medical Center. Clinical trial information: NCT05090358.

5584 Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States. Human epidermal growth factor 2 (HER2) overexpression or gene amplification occurs in 10-60% of EC. The addition of trastuzumab to carboplatin-paclitaxel chemotherapy improves survival in women with HER2-positive serous EC. However, criteria for assessment of HER2 status in EC are not standardized, and furthermore, intratumor heterogeneity may impact therapeutic efficacy. We aimed to identify factors associated with treatment response and survival outcomes in a retrospective cohort of ECs treated with anti-HER2 therapy. Methods: Patients with advanced/recurrent EC treated with trastuzumab or trastuzumab emtansine alone or in combination with chemotherapy from 2013-2021 at our institution were identified. Clinical and treatment information were retrieved from medical records. Central pathology review, HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) were performed. HER2 IHC was scored using modified ASCO/CAP 2007 guidelines for breast cancer. HER2 expression heterogeneity was defined as a 2-degree difference in staining intensity in ≥5% of tumor cells or discordant IHC score on different specimens. HER2 amplification (tumor/normal fold change) was also estimated from targeted next-generation sequencing (NGS). Best response was assessed by RECIST v1.1 as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with clinical benefit defined as CR/PR/SD. Results: Among 39 patients included, median age was 69. Histologic subtypes included serous (n = 18, 46%), carcinosarcoma (n = 7, 18%), high-grade EC with ambiguous features (n = 13, 33%) and low-grade endometrioid carcinoma (n = 1, 3%). HER2 IHC results were 0 or 1+ (n = 2, 5%), 2+ (n = 17, 46%), 3+ (n = 18, 49%), with HER2 heterogeneity in 15 cases. By FISH, the HER2/CEP17 ratio was ≥2.0 in 34 (92%) and < 2.0 in 3 (8%); HER2 copy number (CN) was ≥6.0 in 25 (68%) and < 6.0 in 12 (32%). HER2 copy number ≥6.0 was significantly correlated with HER2 amplification by NGS ( p< 0.001). 18 (49%) patients had a co-existing somatic PIK3CA mutation. Amongst parameters assessed, only higher level of HER2 amplification by NGS was significantly associated with clinical benefit ( p= 0.036). None of these features were associated with progression-free survival. Notably, 2 patients with IHC 0/1+ had PD and 1 patient with IHC 3+, but non-amplified by FISH, achieved PR. Conclusions: In our cohort of EC patients treated with anti-HER2 therapy, higher level of HER2 amplification was associated with clinical benefit. Further studies with larger sample sizes are needed to determine whether any additional characteristics are associated with treatment response and survival.

1016 Background: For women with metastatic hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer, the combination of alpelisib and fulvestrant improves progression-free survival in those with PIK3CA mutations. Hyperglycemia is a major toxicity of PI3K inhibitors including alpelisib, which limits the clinical efficacy of these drugs due to interrupted/reduced dosing and discontinuation. In the SOLAR-1 trial that led to the Food and Drug Administration (FDA) approval of alpelisib, over 60% of patients developed hyperglycemia of any grade, and over 36% developed grade 3-4 hyperglycemia. Here we describe the incidence and treatment of alpelisib-associated hyperglycemia in a single center cohort. Methods: Patients with metastatic breast cancer who received alpelisib on a clinical trial or as part of standard care from 2013-2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Patient and tumor characteristics and pre-treatment body mass index (BMI), hemoglobin A1c, and serum glucose levels were abstracted from medical records. Alpelisib dose interruptions, reductions, or discontinuation was recorded as well as endocrinology consultation and use of anti-hyperglycemic agents. Date of progression and/or death were recorded where applicable. Results: 247 patients were included in this study, among whom 245 (99.1%) were female and 198 (80.1%) were white. 100 (40.5%) were treated on a clinical trial. Median baseline BMI was 25.4 kg/m2. Among 164 patients with baseline hemoglobin A1c levels available, 93 (56.7%) patients had normal hemoglobin A1c, 54 (32.9%) had prediabetes, and 17 (10.4%) had diabetes. 152 patients (61.5%) developed hyperglycemia of any grade; 56 (22.7%) developed grade 3 and 16 (6.5%) developed grade 4 hyperglycemia. The median time to onset of hyperglycemia was 16 days. BMI ≥25 kg/m2 or hemoglobin A1c ≥5.7% were strongly predictive of development of any-grade hyperglycemia ( p= 0.036 and p< 0.001, respectively) and grade 3-4 hyperglycemia ( p< 0.001 for both). Among those who developed hyperglycemia, 101 (40.9%) received treatment; 69 patients (27.9%) required only 1 anti-hyperglycemic agent whereas 9 (3.6%) required ≥3 anti-hyperglycemic agents. 49 (19.8%) were referred for endocrinology consult. In 66 patients (26.7%), alpelisib was held until resolution of hyperglycemia; 42 patients (17%) required dose reductions, and 11 (4.5%) discontinued alpelisib due to hyperglycemia. There was no significant difference in progression-free survival by hyperglycemia status or severity of hyperglycemia. Conclusions: Overweight BMI and hemoglobin A1c in the prediabetes or diabetes range were strongly predictive of developing alpelisib-associated hyperglycemia. Management of these co-morbidities prior to alpelisib treatment should be strongly considered.

Background: Recent data suggest that subcutaneous adiposity represents an independent prognostic marker in cancer. We aimed to determine whether subcutaneous adiposity estimated by the subcutaneous adiposity tissue index (SATI) was associated with mortality in esophageal cancer. Methods: We conducted a retrospective analysis of a prospectively enrolled cohort from 2009 to 2015 with esophageal cancer at two major cancer centers. CT scans for initial staging were used to quantify adiposity and skeletal muscle areas. Subjects were categorized as above or below median SATI using sex-specific values. Sarcopenia was defined using previously established skeletal muscle area cutoffs. Cox proportional hazards modeling was performed to determine associations between SATI and all-cause mortality. Results: Of the original 167 patients, 78 met inclusion criteria and had CT images available. Mean age was 67 years, 81.8% had adenocarcinoma, and 58.9% had stage 3 or 4 disease. Median follow-up time was 29.5 months. Overall 5-year survival was 38.9% [95% confidence interval (CI), 26.8–50.7]. Lower body mass index, higher Charlson comorbidity score, and more advanced stage were independently associated with low SATI. Patients with low SATI had increased mortality (unadjusted HR 2.23; 95% CI, 1.20–4.12), even when adjusted for sarcopenia or for percent weight loss. In a multivariable model including age, histology, stage, and receipt of curative surgery, the association between low SATI and mortality was attenuated (adjusted HR 1.64; 95% CI, 0.81–3.34). Conclusions: Low subcutaneous adiposity as estimated by SATI may be associated with increased mortality in esophageal cancer. Impact: Interventions to reduce loss of subcutaneous fat may improve survival in esophageal cancer.

PURPOSE: Although aromatase inhibitors (AIs) prolong survival in postmenopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results. METHODS: We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I–III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0–10). RESULTS: Among the 249 participants, 139 had BMI

Highlights • Endometrial mesonephric-like adenocarcinoma (MLA) is a rare and aggressive subtype of epithelial endometrial cancer. • KRAS mutations are characteristic in patients with endometrial MLA. • We report two cases of KRAS-mutated endometrial MLA with excellent and durable responses to lenvatinib and pembrolizumab. • Tumors with KRAS mutations may be particularly sensitive to lenvatinib, but this warrants further study.

BACKGROUND Cardiovascular disease (CVD) is the leading cause of death among patients with early-stage breast cancer (BC), but adherence to cardiovascular disease risk factor (CVD-RF) medications is reported to be poor in BC survivors. The objective of the current study was to determine the association between nonadherence to CVD-RF medications and cardiovascular events in BC survivors. METHODS The authors included patients with stages I to III BC from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database who had Medicare part D coverage and who were taking at least 1 CVD-RF medication prior to their BC diagnosis (2008-2013). Logistic regression was performed to define factors associated with nonadherence. Cox regression was used to calculate the association between nonadherence and new cardiac events after treatment. RESULTS Among 15,576 patients included in the current analysis, 4797 (30.8%) were nonadherent to at least 1 category after the initial BC treatment period. Black race, greater comorbidity burden, more advanced cancer stage, hormone receptor-negative status, and receipt of chemotherapy were found to be associated with nonadherence. Nonadherence after treatment demonstrated a trend toward an increased risk of a subsequent cardiac event (hazard ratio [HR], 1.15; 95% CI 1.00-1.33 [P = .06]). This effect size increased with nonadherence to a greater number of medications (P

TPS12126 Background: The undertreatment of pain in patients with advanced or metastatic cancer is well described in cancer research. Overcoming barriers that prevent successful use of opioid analgesics for cancer pain requires a clear understanding of how individuals use oral medications at home. The Proteus Discover is a digital medicine program (DMP) consisting of an FDA-approved ingestible sensor made of dietary minerals co-encapsulated with patients’ medications, a wearable sensor patch, and a mobile device app that enables patients to electronically transmit their medication adherence patterns. Use of the DMP has demonstrated improved clinical outcomes vs. usual care in patients with diabetes and hypertension, shown superiority over directly-observed therapy in tuberculosis and has been studied in the treatment of patients with hepatitis C, HIV, cancer and severe mental illness, but it has not been previously studied with opioids or in monitoring cancer-related pain. Methods: We are conducting a multicenter pilot study at SWOG NCORP sites to test the feasibility of using the DMP to monitor opioid use in the treatment of metastatic cancer pain. Eligible patients must have a diagnosis of metastatic cancer, have a baseline Brief Pain Inventory worst pain score of ≥3, be deemed by their physician to need initiation or up-titration of oxycodone-acetaminophen for pain control, and be able to read English. Primary outcomes include: (1) study accrual of 60 patients within six months of study activation at all participating sites; (2) patient retention defined as ≥50 patients completing the study, and; (3) adherence to the DMP defined as ≥66% of patients wearing the sensor patch for ≥28 days of the 42-day observation period. Secondary outcomes include change in Brief Pain Inventory pain scores, opioid medication consumption, number of safety alert triggers for high consumption, hospital or emergency room visits for pain, activity levels, and frequency of changes to the pain control regimen. The study will enroll patients at six sites; the first patient was enrolled on 1/20/2020. If successful, this study will inform design of a randomized controlled trial of the DMP vs. usual care in optimizing medication utilization and controlling cancer-related pain. Clinical trial information: NCT04194528 .

Background Cardiovascular disease is the primary cause of death among patients with breast cancer. However, the association of cardiovascular-disease risk factors (CVD-RFs) with long-term survival and cardiac events is not well studied. Methods We examined SWOG (formerly the Southwest Oncology Group) breast cancer trials from 1999 to 2011. We identified baseline diabetes, hypertension, hypercholesterolemia, and coronary artery disease by linking trial records to Medicare claims. The primary outcome was overall survival. Patients with both baseline and follow-up claims were examined for cardiac events. Cox regression was used to assess the association between CVD-RFs and outcomes. Results We identified 1,460 participants older than 66 years of age from five trials; 842 were eligible for survival outcomes analysis. At baseline, median age was 70 years, and median follow-up was 6 years. Hypertension (73%) and hypercholesterolemia (57%) were the most prevalent conditions; 87% of patients had one or more CVD-RF. There was no association between any of the individual CVD-RFs and overall survival except for hypercholesterolemia, which was associated with improved overall survival (hazard ratio [HR], 0.73; 95% CI, 0.57 to 0.93; P = .01). With each additional CVD-RF, there was an increased risk of death (HR, 1.23; 95% CI, 1.08 to 1.40; P = .002), worse progression-free survival (HR, 1.12; 95% CI, 1.00 to 1.25; P = .05), and marginally worse cancer-free survival (HR, 1.15; 95% CI, 0.99 to 1.34; P = .07). The relationship between baseline CVD-RFs and cardiac events was analyzed in 736 patients. A strong linear association between the number of CVD-RFs and cardiac event was observed (HR per CVD-RF, 1.41; 95% CI, 1.17 to 1.69; P < .001). Conclusion Among participants in clinical trials, each additional baseline CVD-RF was associated with an increased risk of cardiac events and death. Efforts to improve control of modifiable CVD-RFs are needed, especially among those with multiple risk factors.

To report the phenotypes caused by a novel mutation in the PDE6B gene in a family with two affected siblings and one affected cousin with a 2-year follow-up.Three patients from a family with a history of retinitis pigmentosa underwent clinical evaluations. The affected patients' DNA was analyzed using next-generation sequencing and segregation analyses were performed for the family.Edward S. Harkness Eye Institute, New York Presbyterian Hospital.Two siblings, one cousin, and five unaffected family members.Macular appearance assessed by funduscopy, autofluorescence imaging, spectral-domain optical coherence tomography and visual function assessed by electroretinography.The proband, brother, and cousin had rod-cone degeneration with cystoid macular edema. Fundus autofluorescence showed hyperautofluorescent ring constriction over time. Spectral-domain optical coherence tomography revealed retinal pigment epithelium atrophy, loss of external limiting membrane, retinal layer thinning, and reduction in ellipsoid zone length over time. Next-generation whole exome sequencing revealed a homozygous c.1923_1969ins6del47 nonsense PDE6B mutation, which has not been previously described, that segregated with the disease in the family.The homozygous PDE6B mutation causes retinitis pigmentosa. Acetazolamide treatment improved visual acuity but rod degeneration continued. Despite having the same mutation and living in the same environment, the proband's brother progressed at a faster rate starting at a younger age, suggesting that gene modifiers may influence the expressivity of the phenotype. Next-generation sequencing, used to discover this mutation, is a practical new technology that can detect novel disease-causing alleles, where previous arrayed primer extension (APEX) technology could not.

It has long been assumed that in retinitis pigmentosa, disease presentation and progression are symmetrical. This study investigated whether hyperautofluorescent ring size, one known marker of disease progression, is symmetrical in typical RP patients.A total of 88 patients with typical retinitis pigmentosa were enrolled in the study. Each presented with a hyperautofluorescent ring when imaged at baseline with fundus autofluorescence (AF). Vertical and horizontal diameters were analyzed according to mode of inheritance and age group. Seven of 88 patients had data missing in one eye and were excluded from further analysis.There was no significant relationship between hyperautofluorescent ring diameter and inheritance mode. There was a tendency toward smaller ring size with age and 3.7% of subjects displayed marked asymmetry in ring size between right and left eyes, although their electroretinogram results did not differ. Overall, when patients were considered as a group, there was a high correlation between right and left eyes' horizontal and vertical diameters (r=0.99, p0.0001; r=0.98, p0.0001). Comparing individual patients' eyes, and accounting for measurement error, a smaller majority of patients displayed symmetry of the hyperautofluorescent ring in both dimensions (85.7% in the vertical dimension, 87.3% in the horizontal dimension).This study confirmed the highly symmetrical nature of the hyperautofluorescent ring in RP patients, except in a small subgroup. AF results, which provide less variability per image, and are consistently interpreted between different observers, may be a more sensitive and reliable method for testing symmetry than many functional tests.

Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emphasis on the development work which led to this effective process.

A scalable process for the preparation of 4,4,5,5-tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane from trimethylsilylpropyne, isopropyl pinacol borate, and n-butyllithium is described. Problems associated with implementing a typical aqueous workup and batch process into production due to borolane “ate” equilibration and protonolysis are presented. To address these issues, a continuous-flow and distillation process was developed which efficiently produced 297 kg of the key propargylation reagent.

A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.

A new chiral sulfinyl transfer auxiliary derived from readily available phenylglycine was developed. This auxiliary is utilized to synthesize a diverse array of alkyl- and arylsulfinamides and sulfinylferrocenes in high yields and excellent ee's. The desired products are produced in a one-pot sequence from the oxathiazolidine 2-oxide by two sequential nucleophilic additions that proceed in a stereospecific manner.

Separation of an aromatic amine is presented using Chirosil RCA(+), which consists of a chemically bonded crown ether tetracarboxylic acid stationary phase. To separate this amine, we used as mobile phase aqueous-organic mobile phases consisting of 0.1% HClO4 in water and acetonitrile or methanol. Plots of ln k′ vs. the volume fraction of the organic modifier showed a non-linear behavior which prompted us to investigate non-chromatographic techniques. In particular, we pursued vibrational circular dichroism in order to elucidate the interactions between the chiral amine and the crown ether tetracarboxylic acid. The enantiomeric separation of several other aromatic amino alcohols molecules was also performed. The relationship between the retention, enantioselectivity and the structure of the molecules is discussed.

Enantiomeric separation of two aromatic α-substituted alanine esters was achieved on two commercially available polysaccharide-based chiral stationary phases (CSPs): amylose tris(3,5-dimethylphenylcarbamate) (ADMPC) and cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC). The interactions between enantiomeric analytes and the CSPs were investigated using chromatographic methods and vibration circular dichroism (VCD). The two analytes differ on the aromatic portion of the molecules where one analyte has a π-acceptor aromatic ring (1) while the other has a π-donor aromatic ring (2). When an ADMPC CSP was employed, an increase in the polarity of the mobile phase leads to a reversal of the elution order for the two enantiomers of 1. The elution order of compound 2 was not affected by the polarity of the mobile phase. In order to gain an understanding of these phenomena, the enantiomeric separation of 1 and 2 was also performed on the CDMPC CSP. Interestingly, no reversal of elution order was observed upon the chromatographic separation of both pairs of enantiomers of compounds 1 and 2 upon increasing the solvent polarity when a CDMPC CSP was utilized. To understand the underlying mechanism governing these chiral separations, VCD was applied to study the structure of the ADMPC and CDMPC polymers and their conformational behaviors under chromatographic conditions. For the first time the conformations of the side chains of both polymers were revealed based on the VCD spectra along with DFT calculations. Furthermore, the interactions between the two analytes and the two CSPs were directly probed by VCD. By comparing the spectral differences of the two CSPs in the presence of the two analytes, the detailed interactions involving different functional groups associated with the chiral recognition were elucidated and thus explained the unusual reversal of elution order associated with increasing solvent polarity.

A fast enantiomeric separation of a chiral aromatic amine was achieved, using ultra high pressure liquid chromatography and highly sulfated beta-cyclodextrin (S-beta-CD) as a chiral additive in the mobile phase. The stationary phase consisted of a core-shell support with a particle size of 2.7mum. Under these conditions the base-line separation was obtained within 2.5min. The influence of the concentration of the additive, along with the thermodynamics of the separation, was studied. Vibrational circular dichroism (VCD) spectroscopy was applied to assess the absolute configuration of the two enantiomeric analytes, as well as the interaction of these enantiomers with the S-beta-CD. The VCD results revealed that S-beta-CD undergoes a temperature-induced conformational change. Further, VCD experiments indicate that the interactions of the two enantiomers with the S-beta-CD occur through an inclusion of the aromatic part of the analyte, as well as through electrostatic interaction between the protonated amine and the sulfate groups located at the narrow part of the S-beta-CD. Molecular mechanics calculations performed according to the VCD results are consistent with experimental data, providing further evidence of these interactions.

Racemization of chiral imidazolines with base has been studied for the first time following an unexpected finding in the synthesis of chiral imidazoline ligands. Amine bases do not cause racemization. Strong inorganic bases can induce racemization, yet this occurs only when the nitrogen is unsubstituted, in agreement with a symmetry-allowed thermal disrotatory ring opening and closure from a diazapentadienyl anion. Surprisingly, even with electron-withdrawing N-substituents, no racemization is observed. Conditions which allow for the racemization-free manipulations of this important compound class have been defined and developed.

Separation of amino alcohols on two types of commercially available crown ethers stationary phases (Crownpak CR (+) and Chirosil RCA (+)) is presented. The difference between the two types of crown ether columns is that the Crownpak CR (+) column contains a large non-polar aromatic moiety, while the Chirosil RCA (+) consists of an immobilized crown ether tetracarboxylic acid. The interactions between the amino alcohols and the two stationary phases were characterized by their thermodynamic parameters. The influence of the organic modifier on the retention time and the enantioselectivity was studied using IR experiments. The IR spectra revealed that at a low concentration of organic modifier, Crownpak CR (+) self-interacts through its aromatic moieties, while Chirosil RCA (+) exists in both monomeric and dimeric state. At a higher concentration of organic modifier Crownpak CR (+) exits predominantly as a monomer, while Chirosil RCA (+) exists predominantly as a dimer.

Separation of twelve substituted anilines in less than ten minutes is reported. A C18 hybrid stationary phase and a mobile phase consisting of pure water was used for separation. To separate the analytes a temperature program between 160°C and 200°C with 5°C/min was used. Under isothermal conditions van't Hoff plots were constructed between 150°C and 200°C. All the plots were straight lines indicating only one type of interaction between the analytes and the stationary phase. The compounds were detected using either UV or simultaneous UV and FID detection.

A novel ruthenium carbene-catalyzed epimerization of vinylcyclopropanes is reported. The reaction rate strongly depends on the presence of ruthenium ligands in solution. When the first-generation Grubbs catalyst is employed, a 5.3:1 equilibrium ratio of epimers is established quickly, but when a first-generation Hoveyda catalyst is employed, epimerization is observed only if an additional phosphine or nitrogen ligand is added. NMR and kinetic studies suggest that the isomerization reaction occurs through the intermediacy of a ruthenacyclopentene. The observation suggests that cyclopropylmethylidene ruthenium carbenes of synthetic utility may be accessible via ruthenacyclopentenes obtained via other routes.

[reaction: see text] Diisobutylaluminum hydride (DIBAL-H) and triisobutylaluminum have been found to be outstanding reductants for secondary phosphine oxides (SPOs). All classes of SPOs can be readily reduced, including diaryl, arylalkyl, and dialkyl members. Many SPOs can now be reduced at cryogenic temperatures, and conditions for preservation of reducible functional groups have been found. Even the most electron-rich and sterically hindered phosphine oxides can be reduced in a few hours at 50-70 degrees C. This new reduction has distinct advantages over existing technologies.

An efficient and chromatography-free approach for synthesis of a new class of LFA-1 inhibitors was developed. A copper(I) chloride-promoted intramolecular cyclization of thiohydantoins 7a–b serves as a key step to highly functionalized bicyclic guanidines 5a–b, that were subsequently converted to 1H-imidazo[1,2-a]imidazol-2-one LFA-1 inhibitors. This process has been successfully implemented in the pilot plant to produce multikilogram quantities of LFA-1 inhibitors such as 1a–b.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron–zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1–0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.

Background: Esophageal cancer survival rates remain extremely low and factors influencing outcomes for this malignancy are not well understood. Tumor cachexia is a poor prognostic factor for certain tumor types, but is not well-studied in esophageal cancer. Weight loss in esophageal cancer is likely multifactorial; it can be due to tumor cachexia as well as dysphagia from obstructing tumors. In this present study, we aimed to investigate the relationship between weight loss and overall survival in a cohort of esophageal cancer patients and to determine whether these associations differed with tumor size. Methods: We prospectively enrolled subjects with recently diagnosed esophageal cancer at two tertiary care centers. Using a baseline questionnaire, we assessed demographics, medical history, medication use, and lifestyle factors. We recorded self-reported height and weight one year prior to and at diagnosis, which we used to calculate body mass index (BMI) and percent weight change, categorized by tertile. We ascertained from the medical records tumor characteristics including T stage (T1/2 or T3/4), location, pathology, and metastasis status, and collected follow-up data on treatment, imaging, and death. We used Cox regression to assess the association between percent weight loss and all-cause mortality. Results: We included 134 subjects in the analyses, the majority of whom were male (81.3%) and had adenocarcinoma (82.1%). The median BMI one year prior to diagnosis was 28.3 (IQR 24.4 - 31.0) and median percent weight loss was 4.7% (IQR 0 - 10.9%). There was no association between BMI one year prior and all-cause mortality (HR 0.98, 95% CI 0.93 - 1.03). Increasing percent weight loss was associated with increased risk of all-cause mortality (unadjusted HR 2.74 for highest vs. lowest tertile, 95% CI 1.34 - 5.58, Ptrend = 0.005) and this remained significant when adjusted for BMI one year prior (HR 2.87 for highest vs. lowest tertile, 95% CI 1.40 - 5.89, Ptrend = 0.003). We found significant interaction between weight loss and T stage. Percent weight loss was significantly associated with all-cause mortality, adjusted for BMI one year prior, among patients with T stages 1 or 2 (HR 6.49 for highest vs. lowest tertile, 95% CI 1.30 - 32.4, Ptrend = 0.012), but not T stages 3 or 4 (HR 1.42 for highest vs. lowest tertile, 95% CI 0.54 - 3.71). In the final multivariable model, there remained a significant association between percent weight loss and all-cause mortality among patients with T stages 1 or 2 (HR 6.34 for highest vs. lowest tertile, 95% CI 1.22 - 33.1, Ptrend = 0.022). Conclusions: In this cohort of esophageal cancer patients, we found that pre-diagnosis weight loss was associated with increased risk of all-cause mortality in patients with earlier stage tumors, independent of baseline BMI. We suspect that weight loss in early stage esophageal cancer may be due to tumor cachexia, a potential marker of more aggressive disease and worse prognosis. Citation Format: Sherry Shen, James L. Araujo, Nasser K. Altorki, Joshua R. Sonett, Adriana Rodriguez, Kivilcim Sungur-Stasik, Alfred I. Neugut, Julian A. Abrams. Impact of pre-diagnosis weight loss on outcomes in a prospective cohort of esophageal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2637.

The first report of monitoring the kinetics of racemization in solution by online vibrational circular dichroism (VCD), chemometrics, and density functional theory (DFT) calculations is presented. The activation energy for the racemization of an imidazoline based on the experimental VCD was determined, and the detailed mechanism of the process utilizing DFT calculations was elucidated. This study demonstrates the utility of VCD for the determination of reaction mechanisms in asymmetric transformations.

Phosphine boranes have been found to hydrophosphinate internal, unactivated alkynes at room temperature under basic conditions without the need for catalysts or radical initiators. The use of air-sensitive secondary phosphines is avoided in this facile process. Broad scope in both the phosphine borane and alkyne partners leads to excellent diversity in the phosphine products. Asymmetric hydrogenation of these species then provides one of the shortest possible routes to chiral monodentate phosphines. Hydrophosphination of allenyl phosphine oxides under similar conditions followed by hydrogenation of the exomethylene moiety yields a wide variety of bis-phosphine derivatives.

A fast enantiomeric separation of a chiral aromatic amine was achieved, using ultra high pressure liquid chromatography and highly sulfated beta-cyclodextrin (S-beta-CD) as a chiral additive in the mobile phase. The stationary phase consisted of a core-shell support with a particle size of 2.7mum. Under these conditions the base-line separation was obtained within 2.5min. The influence of the concentration of the additive, along with the thermodynamics of the separation, was studied. Vibrational circular dichroism (VCD) spectroscopy was applied to assess the absolute configuration of the two enantiomeric analytes, as well as the interaction of these enantiomers with the S-beta-CD. The VCD results revealed that S-beta-CD undergoes a temperature-induced conformational change. Further, VCD experiments indicate that the interactions of the two enantiomers with the S-beta-CD occur through an inclusion of the aromatic part of the analyte, as well as through electrostatic interaction between the protonated amine and the sulfate groups located at the narrow part of the S-beta-CD. Molecular mechanics calculations performed according to the VCD results are consistent with experimental data, providing further evidence of these interactions.

Four unknown trace impurities (7–10) were observed in the capsule formulation of the HIV drug Tipranavir® after prolonged storage at 30 °C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug substance. The structures were ultimately confirmed by total synthesis with final purification by chiral, preparative supercritical fluid chromatography. A novel Favorskii rearrangement to furnish butyrolactones was also uncovered during the synthesis. Copyright © 2005 John Wiley & Sons, Ltd.