Identifying breast cancer patients at increased risk for carrying a mutation in the BRCA1 and BRCA2 genes is an important objective in clinical practice. Although age at diagnosis, family history of breast and/or ovarian cancer, and ethnicity are all essential parameters to consider when assessing risk, there are limitations as to how well such factors accurately predict BRCA1/2 status, even when quantitative risk models are applied. Integrating information about triple negative (TN) disease may help refine these estimates. Among newly diagnosed breast cancer patients, fewer than 10% have a mutation in the BRCA1 or BRCA2 genes, and up to 20% present with TN disease. However, among BRCA1 mutation carriers at least one-third have TN breast cancers. In this paper, we review key studies that have assessed breast cancer cases with a known BRCA1/2 status and triple marker data. We also discuss how integrating such information into qualitative and quantitative risk assessments of BRCA1/2 carrier probability may improve the ability to identify women who are appropriate candidates for genetic testing. Identifying women at increased risk is critical as knowledge of mutation status may impact surgical and systemic treatment in newly diagnosed patients, as well as recommendations for ovarian cancer risk management.

Purpose To describe our methodology for implementing synchronous telemedicine during the 2019 novel coronavirus (COVID-19) pandemic. Methods A retrospective review of outpatient records at a single children’s hospital from March 21 to April 10, 2020, was carried out to determine the outcome of already-scheduled face-to-face outpatient appointments. The week leading up to the March 21, all appointments in the study period were categorized as follows: (1) requiring an in-person visit, (2) face-to-face visit that could be postponed, and (3) consultation required but could be virtual. Teams of administrators, schedulers, and ophthalmic technicians used defined scripts and standardized emails to communicate results of categorization to patients. Flowcharts were devised to schedule and implement telemedicine visits. Informational videos were made accessible on social media to prepare patients for the telemedicine experience. Simultaneously our children’s hospital launched a pediatric on-demand e-consult service, the data analytics of which could be used to determine how many visits were eye related. Results A total of 237 virtual ophthalmology consult visits were offered during the study period: 212 were scheduled, and 206 were completed, of which 43 were with new patients and 163 with returning patients. Following the initial virtual visit, another was required on average in 4 weeks by 21 patients; in-person follow-up was required for 170 patients on average 4.6 months after the initial virtual visit. None needed review within 72 hours. The pediatric on-demand service completed 290 visits, of which 25 had eye complaints. Conclusions With proper materials, technology, and staffing, a telemedicine strategy based on three patient categories can be rapidly implemented to provide continued patient care during pandemic conditions. In our study cohort, the scheduled clinic e-visits had a low no-show rate (3%), and 8% of the on-demand virtual access for pediatric care was eye related.

Inhibitor formation is a serious complication of haemophilia treatment, occurring in approximately 28% of those with severe haemophilia A [1]. Characterized as a T-cell-dependent, B-cell-mediated immune response directed against infused factor VIII (FVIII) [2], inhibitors neutralize FVIII activity and disrupt haemostasis. Treatment with bypass agents, for example, activated recombinant FVII (rFVIIa) or activated prothrombin complex concentrate, results in less predictable haemostasis and greater morbidity and mortality than in individuals without inhibitors. Thus, inhibitor prevention is a goal of haemophilia treatment. Although there are no proven strategies to prevent inhibitors, several factors may be associated with inhibitor formation. First, when early FVIII treatment is high-intensity [1], such as at the time of bleeds, surgery or trauma, inhibitor risk is 5-fold higher than when early factor is low-intensity, such as to prevent bleeds (prophylaxis). The 'danger theory' suggests that bleeds at the time of first factor exposure activates the immune system, triggering an inhibitor response to FVIII [3], but this remains unproven. Second, the recently FDA approved rFVIII fusion protein, rFVIIIFc (rFVIIIFc), Eloctate [4], contains an Fc sequence which not only increases FVIII half-life by delaying its lysosomal degradation [5], but also promotes antigenspecific tolerance to proteins to which it is fused, in this case rFVIII, by inducing regulatory T cells [6]. In preclinical studies, inhibitor titre and frequency were significantly reduced in Eloctate-treated vs. rFVIIItreated haemophilia A mice [7]. We report the development of a low-titre inhibitor in a child from an inhibitor-prone family with severe haemophilia A treated with rFVIIIFc, Eloctate, as compared to a hightitre inhibitor in his rFVIII-treated maternal cousin. Patient 1 is a child with severe haemophilia A, FVIII < 0.01 IU mL À1 , born in 2010, with a strong family history of haemophilia and inhibitor formation in his maternal grandfather. Next-generation sequencing of his F8 gene identified a pathogenic nonsense variant in exon 14, c.5177G>A, resulting in p.W12726X. At 5 months of age, with no previous bleeds or factor treatment, and to avoid inhibitor formation, he was begun on once weekly rFVIII, Kogenate, 25 IU kg À1 weekly (Fig. 1, Table 1). Although standard prophylaxis is 2-3 times weekly FVIII, he was treated once weekly to avoid port placement for venous access and associated complications. After 15 exposures, an anti-VIII inhibitor was detected at 22.4 Bethesda units (BU), confirmed as high-titre (>5.0 BU), with peak titre 43.2 BU. After confirmation, rFVIII prophylaxis was stopped, and per standard of care [8], when the anti-VIII titre fell to <10.0 BU, a port was placed and immune tolerance induction (ITI), a program of high-dose factor to suppress the inhibitor, was begun with rFVIII, Kogenate, 200 IU kg À1 daily. Bleeds were managed with bypass therapy, rFVIIa 90 mcg kg À1 . His course was complicated by recurrent port infections re...

1512 Background: Identification of colorectal cancer (CRC) cases that are due to Lynch Syndrome (LS) is important to prevent secondary malignancies or development of additional malignancies among relatives. Utilization of clinical criteria to select CRC patients for laboratory testing fails to identify a significant proportion of patients whose CRC is due to LS. Therefore, universal screening for LS among CRC patients has been advocated by the Evaluation of Genomic Applications in Practice and Prevention Working Group. However, the feasibility of routine universal screening has not been evaluated in a community-based, non-research setting. We implemented a universal screening protocol for LS as part of routine care of CRC at Norton Healthcare, a multi-institutional community-based healthcare organization. Methods: Beginning in October 2009, all resected CRC tumors automatically underwent immunohistochemistry analysis (IHC) for Lynch Syndrome-associated mismatch repair gene (MMR) expression. Selected patients who underexpressed MLH1 also underwent testing for the BRAF V600E mutation. Patients who had a BRAF V600E mutation were considered to have sporadic CRC. All other patients with abnormal IHC were automatically referred for genetic counseling. We retrospectively reviewed the outcomes of genetic counseling in all patients referred through this universal screening protocol. Results: Between October 2009 and December 2011, 388 patients underwent resection of CRC, all of whom had IHC for MMR expression. Seventy patients were identified as having abnormal IHC. Sixty-two had MLH1/PMS2 underexpression, of which 18 underwent BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6 underexpression. Nine patients have been confirmed to have LS, 31 have been found not to have LS, and 19 are in the process of evaluation. Seven patients declined genetic counseling, and 4 died before they could be adequately evaluated. Conclusions: Universal screening for CRC due to LS, using IHC with select BRAF V600E mutation testing and automated referral for genetic counseling, is feasible in the community setting. Funded in part with federal funds: NCI, NIH, Contract No. HHSN261200800001.

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