Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer.

Importance: National Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration. Objective: To examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making. Design, Setting, and Participants: Patients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022. Exposure: New and/or previous diagnosis of breast cancer. Main Outcomes and Measures: Disease management recommendations that were changed as a result of genetic testing results are reported. Results: Clinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]). Conclusions and Relevance: In this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.

Resection of Cavity Shave Margins in Stage 0-III Breast Cancer Patients Undergoing Breast Conserving Surgery: A Prospective Multicenter Randomized Controlled Trial.

OBJECTIVE: Single-center studies have demonstrated that resection of cavity shave margins (CSM) halves the rate of positive margins and re-excision in breast cancer patients undergoing partial mastectomy (PM). We sought to determine if these findings were externally generalizable across practice settings. METHODS: In this multicenter randomized controlled trial occurring in 9 centers across the United States, stage 0-III breast cancer patients undergoing PM were randomly assigned to either have resection of CSM ("shave" group) or not ("no shave" group). Randomization occurred intraoperatively, after the surgeon had completed their standard PM. Primary outcome measures were positive margin and re-excision rates. RESULTS: Between July 28, 2016 and April 13, 2018, 400 patients were enrolled in this trial. Four patients (2 in each arm) did not meet inclusion criteria after randomization, leaving 396 patients for analysis: 196 in the "shave" group and 200 to the "no shave" group. Median patient age was 65 years (range; 29-94). Groups were well matched at baseline for demographic and clinicopathologic factors. Prior to randomization, positive margin rates were similar in the "shave" and "no shave" groups (76/196 (38.8%) vs. 72/200 (36.0%), respectively, P = 0.604). After randomization, those in the "shave" group were significantly less likely than those in the "no shave" group to have positive margins (19/196 (9.7%) vs. 72/200 (36.0%), P < 0.001), and to require re-excision or mastectomy for margin clearance (17/196 (8.7%) vs. 47/200 (23.5%), P < 0.001). CONCLUSION: Resection of CSM significantly reduces positive margin and re-excision rates in patients undergoing PM.

An Investigation of the Stability of Patients' Treatment Preferences Over the Course of a Clinical Trial.

OBJECTIVES: The usefulness of discrete choice experiments (DCEs) to inform clinical guidelines rests on the assumption that patients facing the same treatment choice at different points in time will express the same preferences. This study provides the first investigation, to our knowledge, to specifically focus on the stability of patients' treatment preferences over the course of a clinical trial. METHODS: The same DCE was completed by participants at baseline and final post-treatment assessment in a trial of the efficacy of alternative topical treatments for actinic keratosis as a means for the prevention of skin cancer. The study assesses both the consistency of stated treatment choices and the stability of population-level preference parameter estimates and analyzes how the former is influenced by design aspects of the DCE. RESULTS: No evidence was found of population-level preference parameter instability over the course of the trial despite only a moderate strength of choice consistency. Choice consistency is negatively related to task difficulty with weak evidence of the existence of ordering effects over the sequence of choice tasks. CONCLUSIONS: The results provide no evidence that the timing of a DCE within a clinical trial significantly influences population-level treatment preference estimates.

Randomized Double-Blind Placebo-Controlled Biomarker Modulation Study of Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer (SWOG S0812).

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of -9.8 versus -1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.

Instructional design affects the efficacy of simulation-based training in central venous catheterization.

BACKGROUND: Simulation-based learning is a common educational tool in health care training and frequently involves instructional designs based on Experiential Learning Theory (ELT). However, little research explores the effectiveness and efficiency of different instructional design methodologies appropriate for simulations. The aim of this study was to compare 2 instructional design models, ELT and Guided Experiential Learning (GEL), to determine which is more effective for training the central venous catheterization procedure. METHODS: Using a quasi-experimental randomized block design, nurse anesthetists completed training under 1 of the 2 instructional design models. Performance was assessed using a checklist of central venous catheterization performance, pass rates, and critical action errors. RESULTS: Participants in the GEL condition performed significantly better than those in the ELT condition on the overall checklist score after controlling for individual practice time (F[1, 29] = 4.021, P = .027, Cohen's d = .71), had higher pass rates (P = .006, Cohen's d = 1.15), and had lower rates of failure due to critical action errors (P = .038, Cohen's d = .81). CONCLUSIONS: The GEL model of instructional design is significantly more effective than ELT for simulation-based learning of the central venous catheterization procedure, yielding large differences in effect size.

Four-year results using balloon-based brachytherapy to deliver accelerated partial breast irradiation with a 2-day dose fractionation schedule.

PURPOSE: We present 4-year results from a Phase I/II trial using balloon-based brachytherapy to deliver accelerated partial breast irradiation in 2 days. MATERIALS/METHODS: Forty-five patients received breast-conserving surgery followed by adjuvant radiation therapy using a balloon-based brachytherapy applicator delivering 2800 cGy in four fractions over 2 days. Outcomes analyzed include toxicities scored using the NCI Common Toxicity Criteria v3.0 scale, ipsilateral breast tumor recurrence, regional nodal failure, distant metastasis, disease-free survival, cause-specific survival, and overall survival. RESULTS: Median age was 66 years (range, 48-83 years) and median tumor size was 0.6 cm (range, 0.2-2.3 cm). Five percent of patients were node positive (n=2), whereas 73% was estrogen receptor positive (n=33). Median followup was 3.7 years (2.4-7.0 years) with greater than 2 years of followup for all patients. Only Grades 1 and 2 chronic toxicities were noted with fat necrosis (18%) and asymptomatic seromas (42%) being the most common toxicities. Seven percent of patients developed ipsilateral rib fractures (n=3), although this was not statistically associated with maximum rib dose (p=0.31). Ninety-eight percent of patients had a good or excellent radiation-related cosmetic outcome at the time of last followup. There were no ipsilateral breast tumor recurrences or regional nodal failures; however, 2 patients developed distant metastases. Four-year actuarial disease-free survival, cause-specific survival, and overall survival were 96%, 100%, and 93%, respectively. CONCLUSIONS: Treatment of early-stage breast cancer patients with breast-conserving therapy using a 2-day radiation dose schedule resulted in acceptable chronic toxicity and similar clinical outcomes as standard 5-day fractionation.

Emergency cricothyrotomy in confined space airway emergencies: a comparison.

INTRODUCTION: In confined-space airway emergencies, prehospital personnel may need to perform cricothyrotomy when conventional airway techniques cannot be utilized or have failed. This study is a prospective, cross-over, randomized controlled trial that compares two widely-known techniques using two commercially available kits. METHODS: Twenty residents at Palmetto Health Richland Department of Emergency Medicine participated in the study. Their performance was assessed using the time required to placement and correctness of placement for each device. The residents performed the procedures on an Air-Man™ manikin that had been situated in a confined space.The residents also indicated which kit they would prefer in a confined-space, emergency airway situation. RESULTS: All of the devices were placed in the airway. The mean time to placement for the Melker™ and Quicktrach™ kits was 108.5 seconds and 23.9 seconds, respectively. This yielded a mean difference of 84.5 seconds, which provided a t-statistic of 8.88 (p < 0.0001).There was no evidence of a carry-over effect (p = 0.292) or a period effect (p = 0.973). All residents preferred using the Quicktrach™ kit. CONCLUSIONS: Use of the Quicktrach™ kit resulted in the fastest time to placement, was placed correctly in the airway, and was preferred by each of the residents. Its small, simple,and sturdy design, with few parts and easy manipulation, allow the Quicktrach™ to be a valuable option in prehospital situations involving confined spaces. The Melker™ kit, with its many parts, and need for greater manipulation, is not as easily utilized or preferred in a confined space scenario.

Biochemical characterization of the enterotoxigenic Escherichia coli LeoA protein.

Enterotoxigenic Escherichia coli (ETEC) causes enterotoxin-induced diarrhoea and significant mortality. The molecular mechanisms underlying how the heat-labile enterotoxin (LT) is secreted during infection are poorly understood. ETEC produce outer-membrane vesicles (OMVs) containing LT that are endocytosed into host cells. Although OMV production and protein content may be a regulated component of ETEC pathogenesis, how LT loading into OMVs is regulated is unknown. The LeoA protein plays a role in secreting LT from the bacterial periplasm. To begin to understand the function of LeoA and its role in ETEC H10407 pathogenesis, a site-directed mutant lacking the putative GTP-binding domain was constructed. The ability of wild-type and mutant LeoA to hydrolyse GTP in vitro was quantified. This domain was found to be responsible for GTP binding; it is important to LeoA's function in LT secretion, and may play a modest role in the formation and protein content of OMVs. Deletion of leoA reduced the abundance of OmpX in outer-membrane protein preparations and of LT in OMVs. Immunoprecipitation experiments revealed that LeoA interacts directly with OmpA, but that the GTP-binding domain is non-essential for this interaction. Deletion of leoA rendered ETEC H10407 non-motile, through apparent periplasmic accumulation of FliC.

Susceptibility of human enterotoxigenic Escherichia coli isolates to growth inhibition by porcine intestinal epithelial cells.

Growth of human, but not porcine enterotoxigenic Escherichia coli (ETEC) isolates is inhibited during incubation with porcine intestinal epithelial cells and by a constitutively produced factor(s) present in unstimulated cell supernatants. The inhibitory factor(s) is heat stable, not produced by serum-starved cells, and is present in a diverse number of cultured epithelial cell lines of animal, but not of human origin. Susceptibility to porcine intestinal epithelial cells appears to be restricted to ETEC and not E. coli O157:H7 disease isolates.