Citations

By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

AbstractFebrile infection-related epilepsy syndrome (FIRES) is a rare and devastating epileptic encephalopathy with historically abysmal neurocognitive outcomes, including a high incidence of mortality. It tends to affect children and young adults and is characterized by superrefractory status epilepticus following a recent febrile illness. Growing evidence suggests a heterogeneous etiology resulting in fulminant nonantibody-mediated neuroinflammation. For some children with FIRES, this aberrant neuroinflammation appears secondary to a functional deficiency in the endogenous interleukin-1 receptor antagonist. A precise etiology has not been identified in all FIRES patients, and current treatments are not always successful. Limited treatment evidence exists to guide choice, dosing, and duration of therapies. However, the ketogenic diet and certain targeted immunomodulatory treatments, including anakinra, appear safe and have been associated with relatively excellent clinical outcomes in some FIRES patients. Future prospective multicenter collaborative studies are needed to further delineate the FIRES heterogeneous disease pathophysiology and to determine the safety and efficacy of treatment strategies through a robust measurement of neurocognitive outcomes.

e11051 Background: Limited data exist on patient (pt) experience and work productivity (WP) in MBC. VIRGO is a prospective OCS following >1200 pts with locally advanced or MBC receiving 1st-line hormonal therapy (HT) or chemotherapy (CT) in a real-world setting. We report baseline characteristics of 277 pts from the VIRGO PRO substudy and correlations between health-related quality of life (HRQoL), symptoms, activities of daily living, and WP. Methods: Symptom severity and interference (MD Anderson Symptom Inventory [MDASI]), functional status (Activity Level Scale [ALS] from the Rotterdam Symptom Checklist) and WP (Work Productivity and Activity Impairment Questionnaire) were assessed. Pts rated their HRQoL during the past week on a scale of 0–10. Results: See table. The five most severe symptoms at baseline were fatigue, decreased sexual interest, disturbed sleep, drowsiness, and emotional distress; these were reported with less severity in the HT cohort (24%-37% vs 42%-59%). Overall MDASI severity and interference correlated with WP measures in the CT (R = 0.46 to 0.78) and HT cohorts (0.36 to 0.94). Mean of the five most severe symptoms also significantly correlated with WP indices (R = 0.47 to 0.66). HRQoL correlated (p < 0.05) with all WP measures (R = -0.46 to -0.56) in the CT cohort and with % impairment while working (R = -0.65) and % overall work impairment (R = -0.71) in the HT cohort. In univariate regression analysis, MDASI symptom interference score was the best predictor of reduced WP (R2 = 0.52 while working; R2 = 0.48 for nonwork activities). Conclusions: MBC pts receiving CT and HT report significant work impairment. Results indicate moderate correlations between WP indices, HRQoL and symptom burden. [Table: see text]

503 Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.

Objectives. The available literature on pulmonary disease in pediatric inflammatory bowel disease is limited. We evaluated the prevalence of pulmonary manifestations in pediatric inflammatory bowel disease and their association with disease severity. Methods. Patients completed the St. George’s Respiratory Questionnaire (SGRQ), a self-reported measure of quality of life in patients with pulmonary disease. Chart review provided demographic information and Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index scores. Regression models were utilized to evaluate associations between SGRQ score and clinical risk factors. Results. The prevalence of pulmonary manifestations was 9.62% (95% confidence interval = 5.48% to -15.36%). PCDAI scores in Crohn’s disease patients with pulmonary symptoms were significantly higher (SGRQ mean = 10.71 ± 10.94) than in patients without such symptoms. SGRQ score was also higher in patients with indeterminate colitis (8.64, 95% confidence interval = 0.72-16.57, P = .03), when compared with Crohn’s disease. Conclusions. Additional investigations including pulmonary function tests and imaging could provide further insight into this issue.

PURPOSE To provide guidelines for the accurate pathologic diagnosis of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), the preoperative evaluation of the patient with suspected BIA-ALCL, and the pathologic evaluation of the capsulectomy specimen. METHODS To better inform patients and healthcare providers about BIA-ALCL, we convened to review diagnostic procedures used in the evaluation of patients with suspected BIA-ALCL. We focused on the processing of the seroma fluid/effusion surrounding the implant, the handling of capsulectomy specimens following removal of implant(s), and the preoperative evaluation of the patient with suspected BIA-ALCL. Recommendations were based on the published literature and our experience to optimize procedures to obtain an accurate diagnosis and assess for tumor invasion and the extent of the disease. RECOMMENDATIONS Early diagnosis of BIA-ALCL is important as the disease can progress and deaths have been reported. Because the most common presentation of BIA-ALCL is swelling of the breast with fluid collection, an accurate diagnosis requires cytologic evaluation of the effusion fluid surrounding the affected implant. The first priority is cytocentrifugation and filtration of fresh, unfixed effusion fluid to produce air-dried smears that are stained with Wright-Giemsa or other Romanowsky-type stains. Preparation of a cell block is desirable to allow for hematoxylin and eosin staining and immunohistochemical analysis of formalin-fixed, paraffin-embedded histologic sections. Cell block sections can be used for polymerase chain reaction–based investigation of T-cell receptor gene rearrangement to detect clonality. Fixation and mapping of the capsulectomy specimen to select multiple representative sections are advised to assess for microscopic tumor involvement and capsular invasion. It is appropriate to assess lymph node involvement by excisional biopsy material rather than fine needle aspiration, due to propensity for focal involvement.

Objective Non-vitamin K oral anticoagulants (NOACs) require dose adjustment for renal function. We sought to investigate change in renal function over time in patients with atrial fibrillation (AF) and whether those on NOACs have appropriate dose adjustments according to its decline. Methods We included patients with AF enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry treated with oral anticoagulation. Worsening renal function (WRF) was defined as a decrease of >20% in creatinine clearance (CrCl) from baseline. The US Food and Drug Administration (FDA)-approved package inserts were used to define the reduction criteria of NOACs dosing. Results Among 6682 patients with AF from 220 sites (median age (25th, 75th): 72.0 years (65.0, 79.0); 57.1% male; median CrCl at baseline: 80.1 mL/min (57.4, 108.5)), 1543 patients (23.1%) experienced WRF with mean decline in CrCl during 2 year follow-up of −6.63 mL/min for NOACs and −6.16 mL/min for warfarin. Among 4120 patients on NOACs, 154 (3.7%) patients had a CrCl decline sufficient to warrant FDA-recommended dose reductions. Of these, NOACs dosing was appropriately reduced in only 31 (20.1%) patients. Compared with patients with appropriately reduced NOACs, those without were more likely to experience bleeding complications (major bleeding: 1.7% vs 0%; bleeding hospitalisation: 2.6% vs 0%) at 1 year. Conclusions In the US practice, about one-fourth of patients with AF had >20% decline in CrCl over time during 2 year follow-up. As a result, about 3.7% of those treated with NOACs met guideline criteria for dose reduction, but of these, only 20.1% actually had a reduction.