Citations

Background: Optimum management of carotid stenosis, both symptomatic (sx) and asymptomatic (asx), remains controversial despite clinical trials evaluating Carotid Endarterectomy (CEA) and Carotid Stenting (CAS). Objective: We compared attitudes in management of carotid stenosis between experts in Europe (EU), and North America (NA). Methods: From April 2011 to July 2012, a 3-round, email-Delphi survey was sent to members of the European Stroke Organisation (n=390) and to a list of NA stroke neurologists developed at the University of Texas at Houston Stroke Program (n=289). Those completing the survey were shown all responses broken down by EU/NA after each of the first 2 survey rounds. Continent specific consensus was defined a priori to be > 80% agreement. Results: 100 (15%, of which 73% EU) participated in all 3-Delphi rounds, 19% of all EU vs 9% NA (χ2=11.62, p=0.0007): 76% male; 69% treating between 1-8 new cases of carotid stenosis per month. In the final round, EU reached consensus in 7/11 statements (3 reached in phase-I), while NA did in 4/11 (1 reached in phase-I).Ninety-percent of EU vs 70% of NA (χ2=8.09, p=0.017) disagreed that CAS and CEA are equivalent treatments for sx carotid stenosis, and stated that CEA is superior. There remains a significant difference between EU and NA when considering ipsilateral stroke and death < 30 days as primary outcome (χ2=12.18, p=0.007). Sixty-nine-percent of NA agreed that there is a stronger indication for CAS over CEA in patients < 65 years for sx carotid stenosis whereas 55% of EU (χ2=11.39, p=0.023) disagreed with the statement. When asked how likely they would recommend CEA for an asx carotid stenosis, 81% of EU and 80% of NA said ‘sometimes’. When asked how likely they would recommend CAS for an asx carotid stenosis, 62% of NA said ‘sometimes’ vs 60% of EU said ‘never’(χ2=3.54, p=0.06). Conclusion: There are several clear differences in attitudes regarding the management of carotid stenosis between EU and NA: EU has a stronger attitude towards superiority of CEA while in NA there is more equipoise between the two treatments. Areas of lack of consensus may provide direction for future clinical trials.

Introduction: Estrogens have been associated with risk of stroke in both men and women. Estradiol and estrone are synthesized from testosterone via the aromatase enzyme in both men and postmenopausal women. Genetic variation affecting function of the aromatase gene (CYP19A1) has been linked to elevated estradiol levels. We tested the hypothesis that these variants, as well as a modifying gene, are associated with ischemic stroke in three cohorts: the Vitamin Intervention for Stroke Prevention trial (VISP), Women’s Health Initiative (WHI), and Genetic Susceptibility to Early-Onset Stroke study (GEOS). Methods: Genomic data for individuals of European descent with ischemic stroke was compared against an equal number of controls: VISP (1723 cases - 65% men), WHI (436 cases - all postmenopausal women), GEOS (557 cases - all men age <55). Genotyping was funded through the Genomics and Randomized Trials Network (GARNET) and Gene Environment Association Studies (GENEVA) consortia. All cohorts used the Illumina Omni1-Quad chip for genotyping with imputation as needed. Eight candidate single nucleotide polymorphisms (SNPs) in CYP19A1 on chromosome 15 and an additional regulatory SNP in a modifier locus on chromosome 8 were chosen for analysis due to coding status or previous association with estradiol levels. Analyses were adjusted for age, hormone therapy use (women), and the top three principal components. Association results were determined as odds ratios for individual SNPs (effect allele = minor), with significance level of p<0.05. Results: GWAS results are tabulated. There were no significant differences in allele frequency for four SNPs in CYP19A1 among stroke patients and controls. The additional four SNPs were monomorphic in all three populations. The modifier gene SNP (rs1864729) was less common among young men with prior stroke in GEOS, but not men in VISP or in women. Conclusions: Aromatase genetic variation was not associated with risk of stroke in these three cohorts. One SNP that modifies aromatase function was less common among young, but not older men with stroke. Replication in other studies is necessary.

Background: Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy Syndrome (TS) with severe QT prolongation, cardiac hypertrophy, syndactyly, facial dysmorphisms, developmental delay, and sudden death by impaired channel inactivation and increase peak current. Recently, a small number of patients with CACNA1C mutations with only long QT syndrome (LQTS) have been described. Objective: To explore whether CACNA1C mutations associated with TS were mechanistically and clinically distinct from CACNA1C-mediated LQTS. Methods/Results: Illumina HiSeq 2000 platform-based whole exome sequencing with variant alignment using HGSC Mercury analysis and Atlas2 revealed a novel variant CACNA1C-L762F that co-segregated with affected patients of a large, multi-generational family with LQTS and sudden death. The proband presented at 3 years of age with out-of-hospital cardiac arrest and demonstrated QTc of 530. The mutation localized to the DII/DIII intracellular linker domain of the channel in a highly conserved region in close proximity to the 6th DI transmembrane domain. Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased late current indicating its gain-of-function cellular electrophysiological phenotype. Comprehensive review and topological mapping of all described CACNA1C mutations associated with TS or LQTS revealed disease-specific hotspots. TS-associated mutations localized to cytoplasmic aspects of transmembrane domains while LQTS-associated mutations localized to cytoplasmic N- and C-terminal domains and linker regions. Probands hosting TS mutations demonstrated markedly prolonged QTc values compared to LQTS (618 vs 486 ms, p<0.001) and were younger at presentation (2.7 vs 20.1 years, p<0.002). Supporting these associations, the L762F mutation localized closer to the CACNA1C transmembrane domain than any other LQTS mutation and are associated with a QTc and age of diagnosis reflective of TS-associated mutations. Conclusions: The CACNA1C-L762F mutation is associated with biochemical and clinical features which highlight a molecular and clinical distinction between TS- and LQTS-associated CACNA1C mutations.

AbstractThe efficacy of COVID‐19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID‐19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7‐ and 28‐day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non‐intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7‐ and 28‐day death rates, respectively, compared to those non‐intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non‐intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

Abstract Introduction: Breast cancer treatments can impair fertility via direct gonadotoxicity (chemotherapy) as well as by introducing delays in childbearing that allow natural ovarian aging. Guidelines strongly recommend fertility counseling and consideration of fertility preservation techniques for premenopausal women who have not completed their desired childbearing at the time of cancer diagnosis. Prior studies have identified high rates of fertility concern but relatively low rates of fertility counseling and use of fertility preservation techniques. We sought to investigate rates of fertility counseling, use of fertility preservation techniques, and how fertility concerns impact cancer treatment decisions in a modern cohort of patients with breast cancer at a large academic medical center in the United States. Methods: All patients seen at Mayo Clinic Rochester with a new diagnosis (within the year prior) of stage 0-4 breast cancer were invited (by mail or in person) to participate in the Mayo Clinic Breast Registry. After informed consent, participants were asked to complete a baseline survey and annual follow-up surveys. On baseline and one-year surveys, patients were queried about desire for future children and fertility concerns. Nurse chart abstraction was used to collect information about tumor subtype, stage, and treatments received. We examined survey data from women diagnosed under the age of 50 who expressed an interest in having future biological children on either the baseline or year 1 survey between February 2015 and October 2020. Descriptive statistics were used to summarize the degree of fertility concern in this population, the impact of that concern on cancer treatment decisions, and steps taken to preserve fertility. Results: Between February 2015 and October 2020, 865 women under age 50 at diagnosis consented to the registry. Of these women, 627 completed a baseline and/or 1-year survey and 100 answered either “yes” or “unsure” to the question: “At the present time, do you wish to have any more biological children in the future?” on one or both surveys. Among the 100 women expressing interest in future child-bearing, 92% were white, 27% had node-positive and one had distant metastatic disease at diagnosis. The age at diagnosis ranged from 19 to 49 years, with a mean age of 33.8 years. Of the 75 who reported a desire for future children at baseline, 28% felt “somewhat concerned” about their future fertility and 40% felt “very concerned.” Of the 70 who reported a desire for future children on the year 1 survey, 17% felt “somewhat concerned” and 59% felt “very concerned.” For those “very concerned” about future fertility at year 1, 65% reported that this concern had a major impact on their treatment decisions. Often, that treatment modification entailed using endocrine therapy for less than 5 years; 52% of those who specified the type of treatment modification they had made indicated this option. Of note, six women who reported no desire for future biological children at baseline were “unsure” at year 1. At year 1, 93% of women recalled a discussion about fertility with their doctor prior to starting treatment, and 49% had taken steps to preserve fertility (32.5% with embryo cryopreservation, 20% with oocyte cryopreservation and 65% with a GnRH agonist; some selected multiple options). Conclusion: We found a reassuringly high rate of patient-reported fertility counseling and use of reproductive endocrinology technologies to preserve fertility in women who reported a desire for additional children at or soon after diagnosis with breast cancer. Consistent with prior studies, fertility concerns frequently impacted breast cancer treatment decisions. It is important to err on the side of inclusivity when providing fertility counseling because desire for fertility can change over time. Citation Format: Samantha Mannion, Alexandra Higgins, Elizabeth A Stewart, Zaraq Khan, Chandra Shenoy, Nicole Larson, Hazel B Nichols, H Irene Su, Ann H Partridge, Fergus J Couch, Janet E Olson, Kathryn Ruddy. Prevalence and impact of fertility concerns in young women with breast cancer [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 P4-11-02.

Abstract Funding Source: Institutional funds at Mayo Clinic. Background: While alopecia is a common and distressing acute side effect of chemotherapy, chronic hair thinning is also reported by some survivors during endocrine therapy. The purpose of the current study was to evaluate real world experiences of late/long-term alopecia among breast cancer survivors. Methods: Breast cancer survivors participating in the ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR) were mailed a survey six years after diagnosis, between June and November 2020. Respondents were asked to report how bothered they are by hair thinning and hair loss over the last year on a scale from 0 “not at all” to 4 “extremely”. They were also asked whether they used any hair thickening or regrowth products. Results: 552/899 survivors responded (response rate 61%); 403 survivors’ responses were available for analysis. Respondents’ median age was 66 years, and median time since diagnosis was 78 months. Seventy patients (17%) were diagnosed with stage 0 breast cancer, 195 (48%) were diagnosed with stage 1 cancer, 104 (26%) with stage 2, 25 (6%) with stage 3; 6 (1%) had been diagnosed with metastatic or recurrent disease at the time of this survey. 139 (34%) patients had received chemotherapy. Of the patients who received chemotherapy, 82 (59%) had received doxorubicin and cyclophosphamide, 41 (29%) received docetaxel and cyclophosphamide, 77 (55%) received paclitaxel, and 27 (19%) received carboplatin. 258 (64%) received endocrine therapy. Of these patients who received endocrine therapy, 131 (51%) received Tamoxifen and 186 (72%) received aromatase inhibitors. 309 survivors (77%) were 55 years or older. 189 (47%) of all patients reported that they were bothered by chronic hair loss, and 225 (56%) reported that they were bothered by hair thinning; 71 (18%) reported use of thickening/regrowth products. There did not appear to be differences in chronic hair loss or thinning by receipt of chemotherapy: 64 patients (46%) who received chemotherapy reported hair loss and 79 (56%) reported hair thinning, compared with 123 patients (46%) who did not receive chemotherapy and reported hair loss and 142 (54%) who reported hair thinning. Hair thinning or loss did not appear to differ based upon age (Table 1). Symptoms did not appear to be more common amongst current or previous endocrine therapy recipients, with 113 (44%) of that subset bothered by hair loss and 128 (50%) by hair thinning. Conclusion: Hair loss and thinning are frequently reported as bothersome symptoms by long-term breast cancer survivors. Future investigations into treatments for chronic hair thinning during and after cancer therapy are needed. Table 1.&lt; 5555+Bothered by hair loss (n)%Bothered by hair thinning (n)%Bothered by hair loss (n)%Bothered by hair thinning (n)%Not at all5761%4649%15751%13142%Slightly1920%2426%8728%9731%Moderately77%910%3110%4113%BOTHERED BY HAIR LOSS (N)%BOTHERED BY HAIR THINNING (N)%BOTHERED BY HAIR LOSS (N)%BOTHERED BY HAIR THINNING (N)%Quite a bit77%1112%227%268%Extremely44%33%93%103%Missing00%11%31%41% Citation Format: Elizabeth Cathcart-Rake, Charles L Loprinzi, Janet E Olson, Fergus Couch, Brittany Dulmage, Maryam Lustberg, Nicole Larson, Kathryn J Ruddy. Alopecia among breast cancer survivors [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 P4-10-17.

Abstract Background: Eyebrow and eyelash loss are widely recognized as consequences of some chemotherapies, but prevalence and predictors are understudied. The purpose of this study was to evaluate real world experiences of eyebrow and eyelash loss during treatment for breast cancer. Methods: Breast cancer survivors participating in the ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR) were mailed a survey one year after diagnosis. Respondents were asked to recall their severity of eyebrow and eyelash loss since diagnosis, measured from “no loss” to “a little loss” to “a lot of loss” to “complete loss”. Results: 524 participants were mailed a survey including these questions between May 2020 and November 2020; the median time from diagnosis to survey completion was 12 months (range 6 months). Of the 265 participants whose responses were available for analysis (median age 60.8 years), 88 (33%) had received chemotherapy, including 39 (44%) who received doxorubicin and cyclophosphamide, 16 (18%) who received docetaxel and cyclophosphamide, 56 (64%) who received paclitaxel, and 11 (13%) who received carboplatin. 173 (65%) had received endocrine therapy: 56 (32%) of patients who received endocrine therapy received tamoxifen, and 115 (66%) received aromatase inhibitors. 124 (47%) reported at least a little eyebrow loss, and 22 (8%) reported complete loss. Forty-seven percent reported at least a little eyelash loss, and 27 (10%) reported complete loss (Table 1). In the subgroup of 88 patients who received chemotherapy, the rates of at least a little eyebrow and eyelash loss were 50% and 55%, respectively, and rates of complete loss were 8% and 9%. Rates of eyebrow and eyelash loss did not appear to differ significantly by age. Conclusion: Eyebrow and eyelash loss are frequently reported during breast cancer-directed therapy. Future investigations into the incidence and treatment of this side effect are needed. Table 1.&lt;55 years old55+ years oldEyebrow Loss (N)%Eyelash Loss (N)%Eyebrow Loss (N)%Eyelash Loss (N)%No Loss4551%4753%9655%9353%A Little Loss2629%2225%3922%3922%A lot of loss1011%1112%2715%2514%Complete Loss89%910%148%1810%Funding Source: Breast Cancer Research Foundation (CLL) Clinic Citation Format: Elizabeth Cathcart-Rake, Charles L Loprinzi, Fergus Couch, Janet Olson, Brittany Dulmage, Maryam Lustberg, Nicole Larson, Kathryn J Ruddy. Eyebrow/eyelash loss among survivors [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 P4-10-11.

Introduction: The Accreditation Council for Graduate Medical Education and the American Board of Psychiatry and Neurology first developed milestones for the clinical neurophysiology (CNP) fellowship in 2015. The milestones provide a comprehensive evaluation of the fellow's development based on six domains of competency. Here, we describe the development of a new set of milestones for CNP fellowship with level 1 as the incoming level, level 4 as the goal for graduation, and level 5 as the aspirational level that may not be achieved. Methods: Committee members were nominated or volunteered to participate in the milestones update. Milestone development began with the creation of a shared mental model of the ideal skills and knowledge a graduating CNP fellow should attain. Results: The CNP committee met virtually 7 times for a total of 14 meeting hours. Nine Patient Care and five Medical Knowledge milestones evolved from the seven Patient Care and six Medical Knowledge milestones that were in the first iteration. The committee incorporated 11 “Harmonized Milestones” into the revision and a supplemental guide was created. Conclusions: The revised Accreditation Council for Graduate Medical Education milestones for CNP fellowship contain important updates that program directors should review against their curricula to identify any gaps in learning. Program leadership should take note of two new Patient Care milestones for telemedicine and intraoperative monitoring. Clinical neurophysiology fellowships are not designed to provide level 4 competency across all milestones. The revised milestones should be viewed within the context of an individual program's goals.