Citations

Background There is evidence that center-volume of cases affects outcomes for both carotid endarterectomy (CEA) and stenting (CAS). We sought to evaluate the effect of center-volume by site on complication rates in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Methods In CREST, the primary composite endpoint was any stroke, myocardial infarction, or death within 30 days or ipsilateral stroke in follow-up. Certification was achieved by 477 surgeons performing more than 12 procedures per year with complication rates less than 3% for asymptomatic patients and less than 5% for symptomatic patients; 224 interventionists were certified after a rigorous training and credentialing process that included a lead-in registry. CREST centers were divided into tertiles based on the number of patients enrolled into the study, with Group 1 composed of 82 sites each enrolling <25 patients, Group 2 with 24 sites enrolling 25-51 patients and Group 3 with 10 sites enrolling >51 patients. Differences in periprocedural event rates for the primary composite endpoint and its components were compared using logistic regression adjusting for age, sex, and symptomatic status within site-volume level. Results The safety of CAS and CEA did not vary by site-volume during the periprocedural period as indicated by occurrence of the primary endpoint (p=0.54) or by stroke and death (p=0.87). Conclusion Complication rates (as indicated by the primary endpoint and its components) were low in CREST and were not associated with center-volume. The data are consistent with the value of rigorous training and credentialing in trials evaluating endovascular devices and surgical procedures; because of ongoing entry of new interventionalists and surgeons into CREST, operator experience independent of center-volume cannot be addressed.

Cardiac I Kr is a critical repolarizing current in the heart and a target for inherited and acquired long QT syndrome. Biochemical studies show that native I Kr channels are heteromers composed of both hERG 1a and 1b subunits, yet our current understanding of I Kr functional properties derives primarily from studies of homo-oligomers of the original hERG 1a isolate. The hERG 1a and 1b subunits are identical except at the amino (NH2) terminus, which in hERG 1b is much shorter and has a unique primary sequence. We compared the biophysical properties of currents produced by hERG 1a and 1a/1b channels expressed in HEK-293 cells at near-physiological temperatures. We found that heteromeric hERG 1a/1b currents are much larger than hERG 1a currents and conduct 80% more charge during an action potential. This surprising difference corresponds to a two-fold increase in the apparent rates of activation and recovery from inactivation, which reduces rectification and facilitates current rebound during repolarization. Kinetic modeling shows these gating differences account quantitatively for the differences in current amplitude between the two channel types. Depending on the action potential model used, loss of 1b predicts an increase in action potential duration of 27 ms (7%) or 41 ms (17%), respectively. Drug sensitivity was also different. Compared to homomeric 1a channels, heteromeric 1a/1b channels were inhibited by E-4031 with a slower time course and a corresponding four-fold positive shift in the IC 50 . Differences in current kinetics and drug sensitivity were modeled by “NH2 mode” gating with conformational states bound by the amino terminus in hERG 1a homomers but not 1a/1b heteromers. The importance of hERG 1b in vivo is supported by the identification of a 1b-specific A8V missense mutation in 1/269 unrelated genotype-negative LQTS patients and absent in 400 control alleles. Mutant 1bA8V expressed alone or with hERG 1a in HEK-293 cells nearly eliminated 1b protein. Thus, mutations specifically disrupting hERG 1b function are expected to reduce cardiac I Kr , prolong QT interval and enhance drug sensitivity, thus representing a potential mechanism underlying inherited or acquired LQTS.

Introduction: Careful selection and timely activation of clinical sites in multicenter clinical trials is critical for successful enrollment, subject safety, and generalizability of results. Methods: In the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2), a multidisciplinary Site Selection Committee evaluated applicants referred via participation in CREST, CREST principal investigators (PIs) and other investigators, StrokeNet and industry partners. Data for consideration included performance metrics in CREST and other carotid trials and a site selection questionnaire containing information on the investigators as well as quantitative data on carotid procedures performed. Any FDA warning letters were reviewed. Results: The Committee met bi-weekly for 36 months (n=64 meetings). Applications from 176 sites between March 2014 and July 2016 were evaluated: 153 were approved, 7 are under Committee review, 5 were approved but withdrew, 5 were placed on a waiting list, and 6 were rejected. One-hundred-four sites have completed the regulatory and training requirements to randomize: 51 (49%) academic medical centers, 31 (30%) private hospital-based centers, 16 (15%) private office-based practices, and 6 (6%) Veterans Administration medical centers. The mean times from application-to- approval was 5.2 weeks (interquartile range, 1.9, 6.2), and from approval-to-randomization status was 46.7 weeks (interquartile range, 35.4, 51.7). Specialties of the 104 site PIs are vascular surgery for 35 (33.7%), cardiology for 30 (28.8%), neurology for 25 (24%), neurosurgery for 8 (7.7%), interventional radiology for 4 (3.8%), and interventional neuroradiology for 2 (1.9%). Conclusions: Careful site selection is time-consuming for prospective sites and for trial leadership. Times from application-to-site-approval were modest (mean = 5.2 weeks), in contrast to the times for completing regulatory and training requirements (mean = 46.7 weeks). However, subject enrollment by teams from a wide range of medical centers led by a multi-disciplinary cohort of PIs will promote the generalizability of trial results.

Background: Concern for underrepresentation of minorities in clinical trials has focused on enrollment proportions and generalizability. The interplay of trial event-rates with diversity has not been emphasized. Methods: The Carotid Revascularization Endarterectomy vs Stent Trial (CREST) randomized 2502 patients and compared them by race, ethnicity, baseline characteristics, and primary outcome (any peri-procedural stroke, death or MI and subsequent ipsilateral stroke up to 10 years); those with unknown race or ethnicity were excluded. Proportional hazards models adjusting for age, sex, symptomatic status and treatment were used to test for a treatment by race/ethnicity interaction. Results: One-hundred-nine patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other by self-report, and 18 (0.7%) unknown; 90 (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. Compared to whites, racial minorities were younger (mean age 67±8.9 vs 69±8.8, p=0.004), more often female (44% vs 34%, p=0.01), symptomatic (63 vs 52%, p=0.01), and diabetic (51% vs 29%, p<0.0001), but less often dyslipidemic (76% vs 85%, p=0.004), current smokers (19% vs 27%, p=0.04), or had a history of cardiovascular disease (34% vs 46%, p=0.007). Hispanics were more often diabetic (48% vs 30%, p=0.0002). The rate of the primary endpoint was 10.9%±0.9% at 10 years, and did not differ by race or ethnicity (p inter >0.24). In the context of this low rate, even if minority recruitment were increased to represent 50% of study participants, and if the treatment difference in one race were a greater hazard of HR = 1.49 (anticipated alternative hypothesis), then the hazard ratio in the other group would need to be <0.73, or >3.31, to have 90% power of detection. Conclusions: The proportion of racial and ethnicity participation in CREST was suboptimal at < 10%. Primary outcomes did not differ by minority or ethnic status. However, in low event-rate trials very high and even unrealistic enrollment goals for diversity, for example ≥50%, may still be insufficient for detection of outcome differences by race or ethnicity.

The American Academy of Pediatrics (AAP) recommends that all breastfed infants be supplemented with 400 IU of vitamin D daily, beginning soon after birth. We surveyed all Family Medicine providers at a single, academic medical institution regarding their perceptions and practices of infant vitamin D supplementation. Of 99 surveys solicited, 56 (57%) responded. Respondents were aware of the AAP recommendation with 52 (93%) correctly identifying the AAP’s recommended dose. The self‐reported median (interquartile range) proportion of visits in which the provider recommended supplementation to exclusively or partially breastfed infants were 80% (50 ‐ 97%) and 50% (25 ‐ 80%), respectively. The most common reason (82%) for recommending supplementation was “to follow the AAP recommendations.” Thirty (54%) reported recommending vitamin D supplementation within the first two weeks of life. Of all respondents, 49 (88%) recommend infant vitamin D drops as the route of supplementation. Finally, 49 (88%) respondents would prefer to supplement the mother instead of the infant or offer the parents a choice if this were an adequate and safe option for vitamin D supplementation, and 17 (30%) would prefer monthly to daily supplementation. In conclusion, Family Medicine providers are aware of current AAP recommendations, but vary in their practices; they are open to maternal vitamin D supplementation as an alternative option.

Pulse Decomposition Analysis (PDA) offers new insights into factors altering the arterial pressure pulse contour. PDA premise is that peripheral arterial pressure pulse envelope consists of distinct component pressure pulses, a left ventricular ejection and its reflections. Two PDA parameters appear to be particularly useful in quantifying the pulse contour. P2P1 is the ratio of second component pulse and primary ejection pulse amplitudes. T13 is the temporal delay between the third component pulse and the primary ejection pulse. P2P1 and T13 parameters were used to examine pressure pulse contour changes in 81 healthy subjects (18–27 yrs; BMI 27.5 ± 2.6) undergoing a Stroop mental stress test, cycle ergometer stress tests (3 min; 50W and 100W), and post‐exercise recovery. Digital pressure pulse contours were recorded/quantified using PDA formalism. Relative to baseline, P2P1 increased 8% post‐Stroop (individual variation 0% to 15%), T13 increased 4%, (individual variation 0% to 8%). Exercise decreased P2P1 21 ± 14%, while the T13 change was 19 ± 15%. PDA‐based pulse propagation model quantifies physical changes that arterial pulse reflection sites undergo. Peripheral arterial pressure pulse appears to be due to the primary ejection pulse and two major reflections. Two reflection sites in the central arteries appear to be responsible for the “reflected” wave part of the pulse contour.

TPS3151 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved in combination with trastuzumab (Tras) and capecitabine (Cape) for HER2 overexpressed/amplified (HER2+) metastatic breast cancer (BC), based on a statistically significant and clinically meaningful PFS, OS, and ORR benefit over Tras and Cape. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. While various HER2-directed agents have been evaluated in HER2+ and HER2-mut tumors, there are no approved HER2 therapies outside of breast and gastric cancers. The SGNTUC-019 basket study is evaluating TUC combined with Tras in patients (pts) with HER2+ or HER2-mut locally-advanced unresectable or metastatic solid tumors. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase 2 study. Eligible pts must have progressed on or after the last systemic therapy for advanced disease. Metastatic cervical cancer: must have received platinum-based chemotherapy ± bevacizumab; hormone receptor positive (HR+) HER2-mut BC: must have received a prior CDK4/6 inhibitor. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulation, and cardiac function, and no prior HER2-directed therapy (except Tras for uterine serous carcinoma). For eligibility, HER2 alterations can be demonstrated by HER2+ in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts with HER2+ disease will be enrolled in cohorts for cervical, uterine, biliary tract, and urothelial cancers, non-squamous NSCLC, and other solid tumors (except GEC, BC, and CRC). Pts with HER2-mut disease will be enrolled in cohorts for non-squamous NSCLC, BC, and other solid tumors. Except for solid tumor and BC cohorts, 12 RECIST 1.1 evaluable pts will be enrolled in each cohort. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Other solid tumor and BC cohorts will enroll 30 pts in a single stage. If justified, additional HER2+ or HER2-mut disease-specific cohorts may be opened. Approximately 162-270 pts are planned. The primary objective is antitumor activity in each cohort, with confirmed ORR per investigator as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. HR+ BC pts will also receive fulvestrant 500 mg IM every 4 weeks and C1 D15. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. TUC PK will be evaluated in all pts in Cycles 2-6. QoL is evaluated q2 cycle using EQ-5D-5L. Sites are open in the US; EU and Asia will be opened. Enrollment began in Dec 2020. Clinical trial information: NCT04579380.

Abstract Context Nutritional rickets results from the interaction of low vitamin D status and limited calcium intake. Serum alkaline phosphatase (AP) activity is a biomarker of impaired mineralization in rickets. Objective To assess the performance of serum AP activity in identifying nutritional rickets in calcium-deprived Nigerian children. Methods We reanalyzed data from a case-control study of children with active rickets and matched control subjects without rickets, using a multivariate logistic regression to assess the odds of rickets associated with AP activity, adjusting for age, sex, and weight-for-age z-score. Results A total of 122 children with rickets and 119 controls were included. Rachitic children had a mean (±SD) age of 54 ± 29 months, and 55 (45.1%) were male. Cases and controls had low dietary calcium intakes (216 ± 87 and 214 ± 96 mg/day, respectively). Serum AP activity levels in cases and controls were 812 ± 415 and 245 ± 78 U/L, respectively (P &lt; 0.001). AP was negatively associated with 25-hydroxyvitamin D values (r = −0.34; P &lt; 0.001). In the adjusted model, the odds ratio (95% CI) receiver operating characteristic curve was 0.978. AP &gt; 350 U/L identified nutritional rickets in Nigerian children with sensitivity 0.93, specificity 0.92, positive likelihood ratio 11.3, and negative likelihood ratio 0.07. Conclusion An AP &gt; 350 U/L effectively discriminated between Nigerian children with and without nutritional rickets. AP is a low-cost biochemical test that could be used to screen for nutritional rickets, but cutoff values require validation in other populations, and laboratory values need to be standardized for widespread population studies.