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e18523 Background: Noninvasive breast cancers ( e.g. ductal and lobular carcinoma in situ) are highly treatable nonobligate precursors to invasive breast cancers. However, even after treatment, some women develop second breast cancers (SBCs), increasing their mortality risk. Prognosticators may inform treatment recommendations for women at higher risk of SBC. In this study, risk factors for SBC were evaluated using deidentified data from the Hawaiʻi Tumor Registry (HTR), an NCI SEER registry. The HTR covers a uniquely multiethnic, statewide population allowing for elucidation of disparities in understudied U.S. populations. Methods: Women initially diagnosed between 1973-2017 with noninvasive (ductal and lobular) breast cancer were identified. Patient demographics, cancer characteristics, and treatment information were collected. Univariate (UVA) and multivariate (MVA) logistic regression analyses were used to identify factors associated with SBC, defined as a breast cancer diagnosis > 6 months after their prior cancer. Results: Of 7,057 women diagnosed with a first noninvasive breast cancer, 696 (10%) developed SBC. Invasive ipsilateral (iiSBC) and invasive contralateral (icSBC) disease represented 9% and 20% of patients who developed SBC, respectively. The five most prevalent ethnic groups were Chinese, Filipino, Japanese, Native Hawaiian, and White. When adjusting for confounders, women who developed iiSBC were more likely to be Native Hawaiian (odds ratio [OR] = 3.20, 95% CI = 2.07-4.94) or Filipino (OR = 1.72, 95%CI = 1.02-2.91) when compared to Whites; diagnosed between 1990-1999 (OR = 2.06, 95%CI = 1.27-3.34); and not have undergone surgical treatment (OR = 2.93, 95%CI = 1.42-6.04). Women who developed iiSBC were less likely to be > 50 years old (OR = 0.67, 95%CI = 0.49-0.90); diagnosed between 2010-2017 (OR = 0.18, 95%CI = 0.09-0.35); received lumpectomy with radiation therapy (OR = 0.54, 95%CI = 0.35-0.72); and undergone mastectomy (OR = 0.48, 95%CI = 0.32-0.72). Women who developed an icSBC were more likely to be Native Hawaiian (OR = 1.58, 95%CI = 1.06-2.35) or Filipino (OR = 1.60, 95%CI = 1.06-2.42). These women were also less likely to have been diagnosed between 2010-2017 (OR = 0.30, 95%CI = 0.17-0.53). On a subset analysis separating all patients with SBC by first course treatment type, there were no statistically significant differences for treatment type based on race/ethnicity. Conclusions: Overall, in this observational study, Native Hawaiian women, Filipino women, and younger women had increased odds of developing invasive SBC. This study highlights racial disparities in SBC development risk that was not previously appreciated among disaggregated groups of Pacific Islanders and Asian women when compared to White women. This may help oncologists understand the risk of developing SBC in these understudied populations.

5526 Background: HR-HPV DNA testing, with or without cervical cytology, provides excellent sensitivity for detection of cervical cancer (CC) and its precursors; negative test results indicate that risk of disease is extremely low and enable women to undergo reduced screening with safety. However, management of women who screen positive remains challenging as many will prove to have self-limited HR-HPV infections. DNA methylation is an early event in carcinogenesis that could enhance CC screening specificity. Methods: For discovery, DNA from 70 FFPE CC (36 squamous, 34 adenocarcinoma) tissues that were reviewed microscopically, 18 fresh frozen benign cervicovaginal (BCV) tissues collected at the time of benign hysterectomy, and 18 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with CC. Candidate MDM selection was based on area under the receiver operating characteristic curve (AUC) discrimination, methylation fold change, and low background methylation among benign controls. Candidate MDMs were re-tested using methylation-specific PCR (MSP) to confirm performance. Blinded biological validation was performed using MSP on DNA extracted from independent FFPE CC (38 squamous, 43 adenocarcinoma) and BCV (40) tissues. The performance of CC MDMs was also tested in DNA extracted from cervical dysplasia (36 adenocarcinoma in situ (AIS), 32 cervical intraepithelial neoplasia (CIN) 2/3, 11 CIN 1) FFPE tissues. Results: From RRBS discovery and technical validation via MSP, 30 candidate MDMs showed marked methylation fold changes (10 to >1000) across both CC histologies compared to BCV tissue from cancer-free women. Each of the 30 MDMs highly discriminated CC from BCV tissue with 9 MDMs having an AUC >0.90 (Table). CC MDMs also highly discriminated AIS from BCV but did not perform well in CIN 2/3 and CIN 1 (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation have yielded outstanding candidate MDMs for CC that highly discriminate CC from BCV, notably with high specificity. Performance in cervical dysplasias varied with higher positivity rates in AIS than in CIN 2/3 and CIN 1. Translation to testing these novel MDMs in lower genital tract biospecimens and the addition of HR-HPV to the CC panel are warranted.[Table: see text]

Abstract Aims Associations between growth differentiation factor-15 (GDF-15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP-1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF-15 and change in GDF-15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF-15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF-15 were more likely to be male and have more co-morbidities. After adjustment, an increase in GDF-15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF-15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF-15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF-15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF-15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF-15 trajectory in informing risk of heart failure disease progression.

AbstractBackgroundRecognizable skin findings of child physical abuse include bruises, abrasions, lacerations, bite marks, burns, and oral injuries. Self‐induced skin picking, or neurotic excoriation, can correspond to emotional stress, underlying psychiatric illness, or substance abuse. Parental neurotic excoriation injury of children has not been reported previously as a form of physical abuse.MethodsWe present a case series of five children abused via parental excoriation. All affected children were three years of age or younger and otherwise healthy. Each child presented with wounds determined to be consistent with chronic picking. Patient age, injury location, and in some cases, witness accounts confirmed the lesions were not self‐inflicted.ResultsIn three cases, caregivers reported methamphetamine use. In these cases, caregivers repeatedly picked or wiped the infants’ skin. In two cases, the caregiver demonstrated personal neurotic excoriation behavior, which was imposed upon her children resulting in similar lesions. One affected child died at 14 days of age from abusive head trauma, while the other four children were placed in foster care by Child Protective Services.ConclusionExcoriation injury places children at risk for significant scarring and other long‐term effects. We report examples demonstrating that repetitive skin injury by caregivers is a diagnostic consideration for abuse in young children.

ObjectiveTo describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America.MethodsAnalysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied.ResultsThe cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow‐up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow‐up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow‐up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow‐up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores.ConclusionThis analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long‐term remission to limit the accrual of disease‐related damage.

Diagnostic criteria to classify severity of internal carotid artery (ICA) stenosis vary across vascular laboratories. Consensus-based criteria, proposed by the Society of Radiologists in Ultrasound in 2003 (SRUCC), have been broadly implemented but have not been adequately validated. We conducted a multicentered, retrospective correlative imaging study of duplex ultrasound versus catheter angiography for evaluation of severity of ICA stenosis. Velocity data were abstracted from bilateral duplex studies performed between 1/1/2009 and 12/31/2015 and studies were interpreted using SRUCC. Percentage ICA stenosis was determined using North American Symptomatic Carotid Endarterectomy Trial (NASCET) methodology. Receiver operating characteristic analysis evaluated the performance of SRUCC parameters compared with angiography. Of 448 ICA sides (from 224 patients), 299 ICA sides (from 167 patients) were included. Agreement between duplex ultrasound and angiography was moderate (κ = 0.42), with overestimation of degree of stenosis for both moderate (50–69%) and severe (⩾ 70%) ICA lesions. The primary SRUCC parameter for ⩾ 50% ICA stenosis of peak-systolic velocity (PSV) of ⩾ 125 cm/sec did not meet prespecified thresholds for adequate sensitivity, specificity, and accuracy (sensitivity 97.8%, specificity 64.2%, accuracy 74.5%). Test performance was improved by raising the PSV threshold to ⩾ 180 cm/sec (sensitivity 93.3%, specificity 81.6%, accuracy 85.2%) or by adding the additional parameter of ICA/common carotid artery (CCA) PSV ratio ⩾ 2.0 (sensitivity 94.3%, specificity 84.3%, accuracy 87.4%). For ⩾ 70% ICA stenosis, analysis was limited by a low number of cases with angiographically severe disease. Interpretation of carotid duplex examinations using SRUCC resulted in significant overestimation of severity of ICA stenosis when compared with angiography; raising the PSV threshold for ⩾ 50% ICA stenosis to ⩾ 180 cm/sec as a single parameter or requiring the ICA/CCA PSV ratio ⩾ 2.0 in addition to PSV of ⩾ 125 cm/sec for laboratories using the SRUCC is recommended to improve the accuracy of carotid duplex examinations.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health‐care utilization. We performed a cross‐sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6‐min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow‐up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow‐up, and have increased health‐care utilization.

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Purpose To investigate the information quality on YouTube regarding rehabilitation and return to sport (RTS) after hip arthroscopy. Methods By use of private browsing and predefined search terms, 217 unique videos regarding RTS and rehabilitation after hip arthroscopy were included and systematically reviewed. A total of 164 videos were included in the final analysis. Videos were scored using 4 scoring systems: (1) Journal of the American Medical Association benchmark criteria, (2) the Global Quality Score, (3) a score for RTS after hip arthroscopy, and (4) a score for rehabilitation after hip arthroscopy. Results A large majority of the included videos provided substandard information quality, dependability, and precision. RTS videos that were uploaded by physicians had a significantly higher Journal of the American Medical Association score, Global Quality Score, and RTS score compared with commercial and personal testimony videos ( P = .0003, P = .0021, and P = .0005, respectively). Physician videos pertaining to RTS were also significantly longer than videos in other categories ( P = .0397). Conclusions The quality and reliability of video content on YouTube pertaining to rehabilitation and RTS after hip arthroscopy are generally poor. The educational content of YouTube videos produced by physicians is of significantly higher quality as compared with non‐physicians, patient testimonials, and commercials. Clinical Relevance The quality of the information patients receive on rehabilitation and RTS after hip arthroscopy is important for successful outcomes.

Background: Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroid cancer BMs remains limited. The goal of this international, multi-centered study was to evaluate the efficacy and safety of SRS for thyroid cancer BMs. Methods: From 10 institutions participating in the International Radiosurgery Research Foundation, we pooled patients with established papillary or follicular thyroid cancer diagnosis who underwent SRS for histologically confirmed or radiologically suspected BMs. We investigated patient overall survival (OS), local tumor control, and adverse radiation events (AREs). Results: We studied 42 (52% men) patients who underwent SRS for 122 papillary (83%) or follicular (17%) thyroid cancer BMs. The mean age at SRS was 59.86 ± 12.69 years. The mean latency from thyroid cancer diagnosis to SRS for BMs was 89.05 ± 105.49 months. The median number of BMs per patient was 2 (range: 1–10 BMs). The median SRS treatment volume was 0.79 cm 3 (range: 0.003–38.18 cm 3 ), and the median SRS prescription dose was 20 Gy (range: 8–24 Gy). The median survival after SRS for BMs was 14 months (range: 3–58 months). The OS was significantly shorter in patients harboring ≥2 BMs, when compared with patients with one BM (Log-rank = 5.452, p = 0.02). Two or more BMs (odds ratio [OR] = 3.688; confidence interval [CI]: 1.143–11.904; p = 0.03) and lower Karnofsky performance score at the time of SRS (OR = 0.807; CI: 0.689–0.945; p = 0.008) were associated with shorter OS. During post-SRS imaging follow-up of 25.21 ± 30.49 months, local failure (progression and/or radiation necrosis) of BMs treated with SRS was documented in five (4%) BMs at 7.2 ± 7.3 months after the SRS. At the last imaging follow-up, the majority of patients with available imaging data had stable intracranial disease (33%) or achieved complete (26%) or partial (24%) response. There were no clinical AREs. Post-SRS peritumoral T2/fluid attenuated inversion recovery signal hyperintensity was noted in 7% BMs. Conclusion: The SRS allows durable local control of papillary and follicular thyroid cancer BMs in the vast majority of patients. Higher number of BMs and worse functional status at the time of SRS are associated with shorter OS in patients with thyroid cancer BMs. The SRS is safe and is associated with a low risk of AREs.