Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers.

m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins.

A Short Measure of the Big Five Aspects: Development and Validation of the BFAS-40.

We present psychometric evidence for the BFAS-40, an abbreviated measure of the Big Five Aspects Scale (DeYoung et al., 2007). In Study 1, we developed the BFAS-40 using metaheuristic algorithms and cross-validated the factor structure of the shortened measure. In Study 2, we demonstrated that the BFAS and BFAS-40 correlate with external criteria in similar ways. In Studies 3 and 4, we provide convergent validity evidence by examining correlations between the BFAS-40 and other measures of typical and clinically relevant personality. Finally, in Study 5, we provide evidence of test-retest reliability as well as additional construct validity evidence. Across these five studies, we demonstrate that the BFAS-40 is a short, reliable, and valid measure of the Big Five Aspects.

Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Does Scalp Cooling Have the Same Efficacy in Black Patients Receiving Chemotherapy for Breast Cancer?

LESSONS LEARNED: Despite U.S. Food and Drug Administration approval to reduce alopecia, data on efficacy of scalp cooling in Black patients with cancer are limited by lack of minority representation in prior clinical trials. Scalp cooling devices may have less efficacy in Black patients; additional studies are required to explore the possible causes for this, including hair texture and cap design. BACKGROUND: The Paxman scalp cooling (SC) device is U.S. Food and Drug Administration (FDA)-approved for prevention of chemotherapy-induced alopecia. Studies report 50%-80% success rates and high patient satisfaction, yet there have been no studies of SC in Black patients. We conducted a phase II feasibility study of Paxman SC with a planned enrollment of 30 Black patients receiving chemotherapy for stage I-III breast cancer. METHODS: Black patients who planned to receive at least four cycles of chemotherapy with non-anthracycline (NAC) or anthracycline (AC) regimens were eligible. Alopecia was assessed by trained oncology providers using the modified Dean scale (MDS) prior to each chemotherapy session. Distress related to alopecia was measured by the Chemotherapy Alopecia Distress Scale (CADS). RESULTS: Fifteen patients enrolled in the intervention before the study was closed early because of lack of efficacy. Median MDS and CADS increased after SC, suggesting increased hair loss (p < .001) and alopecia distress (p = .04). Only one participant was successful in preventing significant hair loss; the majority stopped SC before chemotherapy completion because of grade 3 alopecia (>50% hair loss). CONCLUSION: SC may not be efficacious in preventing alopecia in Black women. Differences in hair thickness, hair volume, and limitations of cooling cap design are possible contributing factors.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

PURPOSE: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years. METHODS: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. RESULTS: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. CONCLUSIONS: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

Trainability of Cricoid Pressure Force Application: A Simulation-Based Study.

BACKGROUND: Aspiration of gastric contents is a leading cause of airway management-related mortality during anesthesia practice. Cricoid pressure (CP) is widely used during rapid sequence induction to prevent aspiration. National guidelines for CP suggest a target force of 10 N before and 30 N after loss of consciousness. However, few studies have rigorously assessed whether clinicians can be trained to consistently achieve these levels of force. We hypothesized that clinicians can be trained effectively to deliver 10-30 N during application of CP. METHODS: Clinicians (attending anesthesiologist, anesthesiology residents, certified registered nurse anesthetists, or operating room nurses) applied CP on a Vernier force plate simulator with measurements taken at 4 time points over 60 seconds, 2 measurements before and 2 measurements after loss of consciousness. A successful cycle required all 4 time points to be within the target range (10 ± 5 and 30 ± 5 N, respectively). After baseline assessment (n = 100 clinicians), a subset of 40 participants volunteered for education on recommended force targets, underwent self-regulated practice, and then performed 30 1-minute cycles of high-frequency simulation analyzed by cumulative sum analysis to assess their change in performance. RESULTS: At baseline, 5 cycles (1.3% [confidence interval {CI}, 0.3%-2.50%]) out of 400 were successful. Performance improved after education and self-regulated practice (16% successful cycles [CI, 7.8%-25%]), and performance during the last 4 of 30 cycles was 45% (CI, 33%-58%). The odds of success increased over time (odds ratio, 1.1; P < .001). By cumulative sum analysis, however, no subject crossed the h0 line, indicating that no one achieved proficiency of the predefined target forces. CONCLUSIONS: At baseline, performance was poor at achieving target forces specified by national guidelines. Simulation-based training improved the success rate, but no participant achieved the predefined threshold for proficiency.

Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer.

Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS.

Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States (US) Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases. OBJECTIVES: Using a US military cohort who receives equal and open access to healthcare, we sought to examine demographic, clinical features and outcomes with NSCLC. DESIGN AND PARTICIPANTS: We conducted a retrospective cohort analysis of 4,751 patients, aged ≥ 18 years and diagnosed with a first primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD) cancer registry. MAIN MEASURES: Differences by patient and disease characteristics were compared using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed overall survival. RESULTS: The mean age at diagnosis was 66 years, 64 % were male, 72 % were Caucasian, 41 % were diagnosed at early stage, 77 % received treatment and 82 % had a history of tobacco use. Mean age at diagnosis was highest among Caucasians (67 years) and lowest among African Americans (AA; 62 years). Asian/Pacific Islanders (PI) were more likely to be female (p < 0.0001), have adenocarcinoma histology (p = 0.0003) and less likely to have a history of tobacco use (p < 0.0001) compared to other racial/ethnic groups. In multivariable survival analysis, older age, male gender, increasing stage, not receiving treatment, and tobacco history were associated with higher mortality risk. Untreated patients exhibited a 39 % higher mortality risk compared to treated patients (HR = 1.39; 95%CI = 1.23-1.57). Compared to Caucasian patients, Asian/PIs demonstrated a 20 % lower risk of death (HR = 0.80; 95%CI = 0.66-0.96). There was no difference in mortality risk between AAs and Hispanics compared to Caucasians. CONCLUSION: The lack of significant outcome disparity between AAs and Caucasians and the earlier stage at diagnosis than usually seen in civilian populations suggest that equal access to healthcare may play a role in early detection and survival.

Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial.

BACKGROUND: Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine). METHODS: In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278). FINDINGS: Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection. INTERPRETATION: Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer. FUNDING: Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.

Racial/ethnic differences in breast cancer survival by inflammatory status and hormonal receptor status: an analysis of the Surveillance, Epidemiology, and End Results data.

BACKGROUND: Compared to non-inflammatory breast cancer (non-IBC), inflammatory breast cancer (IBC) has less favorable survival and is more likely to be estrogen receptor (ER) and progesterone receptor (PR) negative. ER-/PR- tumors, regardless of histology, have less favorable survival. While black women are more likely to have IBC and ER-/PR- tumors than white women, it is unclear whether the racial disparity in survival is explained by these factors. The objective of this study was to assess racial/ethnic differences in breast cancer survival by inflammatory status and hormone receptor status. METHODS: This study examined breast cancer mortality among non-Hispanic white (NHW), Hispanic white, black, and Asian/Pacific Islander (API) women diagnosed between 1990 and 2004 using the National Cancer Institute's Surveillance, Epidemiology, and End Results data. Kaplan-Meier survival curves and Cox proportional hazard ratios (HRs) assessed the relationship between race/ethnicity and survival. RESULTS: Black women had significantly poorer survival than NHW women regardless of inflammatory status and hormone receptor status. Compared to NHWs, the HRs for black women were 1.32 (95 % confidence interval (CI) 1.21-1.44), 1.43 (95 % CI 1.20-1.69), and 1.30 (95 % CI 1.16-1.47) for IBC, IBC with ER+/PR+, and with ER-/PR-, respectively. Similar HRs were found for non-IBC, non-IBC with ER+/PR-, and non-IBC with ER-/PR-. API women had significantly better survival than NHW women regardless of inflammatory status and hormone receptor status. CONCLUSION: Compared to NHW women, black women had poorer survival regardless of inflammatory status and hormone receptor status and API women had better survival. These results suggest that factors other than inflammatory status and hormone receptor status may play a role in racial/ethnic disparities in breast cancer survival.

Understanding Perceptions of Care Coordination and Chronic Illness Management among Black Breast and Prostate Cancer Survivors and Providers: Findings from a Quality Improvement Study.

Navigating cancer care is complex and is exacerbated by pre-existing comorbidities managed by multiple providers. In this quality improvement study, we evaluated changes in perceived care coordination, navigation, and chronic illness care with community health worker (CHW) and mHealth support among Black breast cancer and prostate cancer patients with hypertension and/or diabetes. We collected patient and provider surveys on chronic illness care coordination at baseline and six months and found improvements in multiple domains. These findings support engaging CHWs to improve care coordination among cancer patients with comorbidities and demonstrate a use case of importance with emerging navigation reimbursement policies.

Designing and Developing a Medical-Legal Partnership to Address Cancer Patients' Health-Harming Legal Needs.

The Georgetown University's Cancer Legal Assistance and Well-being Project launched in 2020 as a medical-legal partnership that works with health care providers at a Washington, D.C. safety-net hospital to treat the health-harming legal needs of historically and intentionally marginalized patients with cancer.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Effect of ASCO/CAP guidelines for determining ER status on molecular subtype.

BACKGROUND: Determination of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status is standard for predicting prognosis and determining treatment options for patients with breast cancer. In 2010, the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) issued guidelines that tumors with ≥1% positively staining cells should be considered ER positive. Here, we determined how this cutoff relates to molecular subtype. METHODS: Clinicopathological characteristics were compared between ER-negative, ER-positive, and low-ER-staining (1-10%) tumors using chi-square analysis with P<0.05 defining statistical significance. Gene expression data were generated for 26 low-ER-staining tumors, and their intrinsic subtype determined. Immunohistochemistry (IHC)-defined surrogate subtypes, using the threshold of positivity defined by ASCO/CAP guidelines, were compared with molecular subtypes. RESULTS: Low-ER-staining tumors were clinicopathologically more similar to ER-negative than to ER-positive tumors; 88% of low-staining tumors were basal like or HER2 enriched. Only those tumors expressing 10% ER-positive cells were classified as luminal A subtype. CONCLUSIONS: Under ASCO/CAP guidelines, tumors with 1-10% ER staining would be classified as ER positive, yet most are basal like or HER2 enriched and have pathological features similar to ER-negative tumors. Clinical trials seeking to treat tumors of ER-negative basal-like and/or HER2-enriched subtypes should thus not preclude enrollment based solely on results of ER immunohistochemistry. As ER status is a critical element in the choice of treatments for patients with breast cancer, it is imperative that the most effective method for classifying tumors be developed.

P-REALITY X: A Real-World Analysis of Palbociclib Plus an Aromatase Inhibitor in HR+/HER2- Metastatic Breast Cancer-A Podcast.

Stringent enrollment criteria can limit the diversity of patient populations in clinical trials and, consequently, the generalizability of clinical trial data to real-world clinical practice. In this podcast, we discuss how real-world data in heterogeneous patient populations can complement clinical trial data in informing treatment decision making for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer. Specifically, our focus is on P-REALITY X, an observational retrospective analysis that was recently published in npj Breast Cancer. P-REALITY X used real-world data from the Flatiron database to compare the effectiveness of palbociclib plus an aromatase inhibitor versus an aromatase inhibitor alone as first-line treatment for patients with HR+/HER2- metastatic breast cancer. After stabilized inverse probability treatment weighting to control for observed confounders, both overall survival and real-world progression-free survival were significantly prolonged with palbociclib plus an aromatase inhibitor versus an aromatase inhibitor alone. Furthermore, overall survival and real-world progression-free survival benefits were observed across most subgroups examined. We discuss the clinical implications of P-REALITY X data, including how these results add to data from prior randomized clinical trials and real-world studies in supporting the use of first-line palbociclib plus an aromatase inhibitor as a standard-of-care treatment for patients with HR+/HER2- metastatic breast cancer. We also provide an example of how to integrate and describe key information about the P-REALITY X study in plain language when discussing palbociclib as a therapeutic option with patients.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Overcoming congressional inertia on obesity requires better literacy in obesity science.

Obesity-focused health policies, including the landmark Treat and Reduce Obesity Act, have stalled at the federal level over the past decade. Congressional inaction on obesity reflects both misconceptions of obesity as a lifestyle choice and limited awareness for the burden obesity imposes on our health care system. Given these challenges, we argue that health professionals must bolster their efforts to partner with public figures with obesity and to directly educate the public. These strategies may help destigmatize obesity and build awareness of obesity as a disease. Furthermore, we suggest that these strategies may empower patients to flex their unrealized political muscle and demand more from their elected leaders. A bold, multilevel approach that elicits a public demand for change can propel obesity policy into the 21st century.

BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS: From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS: One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

A randomized, controlled trial on dexmedetomidine for providing adequate sedation and hemodynamic control for awake, diagnostic transesophageal echocardiography.

OBJECTIVE: Transesophageal echocardiography (TEE) has become established as a sensitive and accurate diagnostic method for the rapid assessment of myocardial function. It was theorized that dexmedetomidine (Precedex; Hospira, Inc, Lake Forest, IL) might prove to be useful for sedating patients while undergoing TEE. DESIGN: A prospective, randomized trial was designed comparing dexmedetomidine versus standard therapy (eg, midazolam and opioids) for sedation. SETTING: This trial was performed in a tertiary care, single-institution university hospital. PARTICIPANTS: Males and females, American Society of Anesthesiologists I to IV, ages 18 to 65 years, requiring diagnostic TEE. Patients were excluded if pregnant, if they had taken benzodiazepines or opioids within 24 hours, or if they were deemed to be too unstable to receive any kind of sedation. INTERVENTIONS: Patients were randomized to standard therapy or dexmedetomidine infusion groups. Sedation was assessed at 6 time points. Pulse oximetry, electrocardiogram, heart rate, noninvasive blood pressure, and respiratory rate were monitored. Additional variables measured were the amount of each drug given, the time of the TEE procedure, and the time to recovery. MEASUREMENTS AND MAIN RESULTS: A survey about the quality of sedation, the level of comfort, and whether or not they would accept this type of sedation again was administered after recovery from sedation. Demographic data and patient questionnaire responses were reported as means and standard errors or percents and were analyzed with the t test and chi-square test. Twenty-two patients were enrolled. Hemodynamics were statistically different between the two groups at several time points. Both systolic and diastolic blood pressures (BP) were elevated in the standard therapy group, whereas the dexmedetomidine group had a lower BP. Heart rate was elevated significantly in the standard therapy group compared with the dexmedetomidine group. There was no statistical or clinical difference between the groups in terms of oxygenation or respiratory rate. CONCLUSIONS: The authors concluded that dexmedetomidine appears equivalent in achieving adequate levels of sedation without increasing the rate of respiratory depression or decreasing oxygen saturation compared with standard therapy, and it may be better in achieving desired hemodynamic results.