Citations

Abstract Background: Tamoxifen therapy has been shown to have greater therapeutic benefit among women whose breast density declines subsequent to treatment than among women whose density does not decline. Although limited data suggests that endocrine symptoms after tamoxifen initiation may be associated with improved breast cancer outcomes, it is unknown whether these symptoms are associated with reductions in breast density. We therefore evaluated endocrine symptoms and change in breast density in a 12-month longitudinal study of women undergoing tamoxifen therapy for clinical indications. Methods: Cohort members (N=74) were aged 30-74 years in the Ultrasound Study of Tamoxifen at Karmanos Cancer Institute and Henry Ford Health Systems (Detroit, MI). Endocrine symptoms and breast density were both assessed prior to tamoxifen initiation (T0) and at 1-3 months (T1), 4-6 months (T2), and approximately 12 months (T3) post-tamoxifen initiation. Treatment-associated endocrine symptoms included treatment-emergent or increasing vasomotor and/or joint symptoms. Endocrine symptom severity was also assessed with a Likert scale for symptom frequency and categorized as no symptoms (score=0), low/moderate symptoms (score=1-5), and high symptoms (score=6+). Sound speed (m/s), a surrogate of volumetric breast density, was measured with whole breast ultrasound tomography. Change in breast density was calculated as density at T1-T3 minus density at T0. We used multivariable linear regression to estimate mean change in density by endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline sound speed. Generalized estimating equations were used to account for within-subject correlations over time. Results: Women with treatment-associated endocrine symptoms had an overall greater mean reduction in breast density compared with women without symptoms (mean change [95% CI]: -1.97 m/s [-3.80, -0.13]; -0.27 m/s [- 3.50, 2.95], respectively; p=0.22). Longitudinal trends in breast density significantly differed for women with versus without treatment-associated endocrine symptoms (p-interaction=0.02). Significant declines in breast density over time were observed among women with treatment-associated endocrine symptoms (p-trend=0.005), but not among women without symptoms (p-trend=0.16). Similar trends in breast density decline were observed among women with higher symptom severity (p-trends for no symptoms=0.53; low/moderate symptoms=0.04; high symptoms=0.008). Conclusions: These findings suggest that treatment-associated endocrine symptoms may be associated with a significant decline in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations can predict clinical outcome, and if confirmed, both treatment-associated endocrine symptoms and observed reductions in breast density may be useful for patients and providers to improve adherence. Citation Format: Cody Ramin, Ruth Pfeiffer, Shaoqi Fan, Maeve Mullooly, Roni T. Falk, Mark A. Sak, Michael S. Simon, David H. Gorski, Haythem Ali, Peter Littrup, Nebojsa Duric, Mark E. Sherman, Gretchen L. Gierach. Treatment-associated endocrine symptoms and change in ultrasound tomography measures of breast density after tamoxifen therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5805.

Abstract Introduction Elevated mammographic density (MD) is a strong and independent risk factor for breast cancer, though underlying mechanisms are unclear. Prior studies have suggested that increased cumulative exposure to sex-steroid hormones and growth factors may impact both MD and MD-related breast cancer risk; however, most studies have only evaluated individual hormones. In this study, we simultaneously explored the relationship between 29 circulating hormones and growth factors with MD among postmenopausal women undergoing diagnostic breast biopsy. Methods We used data from 89 postmenopausal women, aged 44-65, who had complete measurements of 29 serum hormones from a single pre-biopsy blood draw (i.e., sex-steroid hormones: 15 estrogen/estrogen metabolites, 7 progesterone/progesterone metabolites; and non-sex hormones: insulin-like growth factor I and binding proteins (IGFBPs) 2-7). Volumetric MD (% fibroglandular volume) was assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Sufficient dimension reduction methods were used to compute a composite marker score that accommodates correlations among hormones and their relationship to MD. Backward elimination was applied to select log-transformed hormones contributing to the score at α=0.05; multivariable linear regression was used to further examine associations between selected hormones and MD within a single model, adjusting for age and BMI. Results Pearson correlations between hormones were moderate-to-strong. Dimension reduction methods identified 6 hormones as associated with MD (p<0.05): estradiol, 2-hydroxyestradiol, 2-methoxyestrone, 16-ketoestradiol, IGFBP-2, and 17α-hydroxyprogesterone, in models that considered MD as either continuous or dichotomous (>median vs. ≤median); BMI was consistently identified as the most significant predictor of MD (P <0.0001). In a multivariable linear regression model that included these 6 hormones, in addition to age and BMI, higher levels of 2-methoxyestrone, IGFBP-2, and 17α-hydroxyprogesterone were significantly associated with increased MD, whereas higher levels of age and BMI were significantly associated with lower MD. Conclusions We identified 6 out of 29 correlated hormones that were significantly associated with MD among postmenopausal women. For several, the directions of their associations with MD were comparable to those observed in prior studies that have separately evaluated these hormones in relation to breast cancer risk. We plan to further explore how circulating hormones concurrently affect MD in premenopausal women, accounting for menstrual cycle phase. Incorporation of dimension reduction methods in studies of multiple correlated hormones can help uncover new etiologic insights into the role of hormones and growth factors in MD and breast carcinogenesis and inform strategies for prevention. Citation Format: Shaoqi Fan, Ruth M. Pfeiffer, Manila Hada, Roni T. Falk, Maeve Mullooly, Hannah Oh, Berta Geller, Pamela Vacek, Donald Weave, John Shepherd, Jeff Wang, Sally Herschorn, Louise A. Brinton, Xia Xu, Mark E. Sherman, Britton Trabert, Gretchen L. Gierach. Associations of circulating hormones with mammographic density in postmenopausal women referred to diagnostic breast biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3488.

Background: Racial disparity in pathological consequences in skull growth may impact the treatment plan for different patient populations. This study attempts to explore the differences between Asian and Caucasian cranial morphology in Crouzon syndrome. Method: Ninety-one computed tomographic scans were included (Asian Crouzon syndrome, n = 12; Asian controls, n = 22; Caucasian Crouzon syndrome, n = 16; Caucasian controls, n = 41), and measured using Mimics and 3-matics software. Results: The entire cranial base length was reduced 11.92 mm (P = 0.004) in Asian Crouzon patients, and 14.58 mm (P < 0.001) in Caucasian Crouzon patients, compared to respective controls. The cranial base angle on the facial side of basicranium was more narrowed in Crouzon syndrome in both races, with similar changes of degrees (9.61°, P = 0.002, in Asian Crouzon; 9.20°, P = 0.019, in Caucasian Crouzon). However, the intracranial side was statistically more narrowed only in the Asian group (9.86°, P = 0.003). Both Asian and Caucasian Crouzon patients developed reduced posterior fossa volume, by 15% (P = 0.034) and 17% (P = 0.004), respectively. However, Caucasian Crouzon patients developed a more shortened anterior and middle cranial base, than that of Asian patients. The separation of lateral pterygoids was only significantly increased in Caucasian patients (5.49°, P < 0.001). Conclusion: Crouzon syndrome causes a shortened, widened, and kyphotic cranial base across both races. It also restricts the development of the posterior cranial fossa. However, the skull malformation is not the same between populations: Asian Crouzon patients developed more narrowed cranial base angulation on the intracranial side of basicranium, while Caucasian Crouzon patients developed more widened lateral pterygoids.

ABSTRACT Background Implementation of checklists has been shown to be effective in improving patient safety. This study aims to evaluate the effectiveness of implementation of a checklist for daily care processes into clinical practice of pediatric intensive care units (PICUs) with limited resources. Methods Prospective before–after study in eight PICUs from China, Congo, Croatia, Fiji, and India after implementation of a daily checklist into the ICU rounds. Results Seven hundred and thirty-five patients from eight centers were enrolled between 2015 and 2017. Baseline stage had 292 patients and post-implementation 443. The ICU length of stay post-implementation decreased significantly [9.4 (4–15.5) vs. 7.3 (3.4–13.4) days, p = 0.01], with a nominal improvement in the hospital length of stay [15.4 (8.4–25) vs. 12.6 (7.5–24.4) days, p = 0.055]. The hospital mortality and ICU mortality between baseline group and post-implementation group did not show a significant difference, 14.4% vs. 11.3%; p = 0.22 for each. There was a variable impact of checklist implementation on adherence to various processes of care recommendations. A decreased exposure in days was noticed for; mechanical ventilation from 42.6% to 33.8%, p &lt; 0.01; central line from 31.3% to 25.3%, p &lt; 0.01; and urinary catheter from 30.6% to 24.4%, p &lt; 0.01. Although there was an increased utilization of antimicrobials (89.9–93.2%, p &lt; 0.01). Conclusions Checklists for the treatment of acute illness and injury in the PICU setting marginally impacted the outcome and processes of care. The intervention led to increasing adherence with guidelines in multiple ICU processes and led to decreased length of stay.

Abstract Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3–T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.

Background: Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest. Several BrS or ECG traits-related single-nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in white patients. We aimed to validate these SNPs in BrS patients in the Taiwanese population, assessing the cumulative effect of risk alleles and the BrS-polygenic risk score in predicting cardiac events. Methods: We genotyped 190 unrelated BrS patients using the TWB Array, and Taiwan Biobank was used as controls. SNPs not included in the array were imputed by IMPUTE2. Cox proportional hazards model was used to evaluate the associations between each particular SNP, the collective BrS-polygenic risk score, and clinical outcomes. Results: Of the 88 previously reported SNPs, 22 were validated in Taiwanese BrS patients ( P <0.05). Of the 22 SNPs, 2 (rs10428132 and rs9388451) were linked with susceptibility to BrS, 10 were SNPs previously reaching genome-wide significance, and 10 were SNPs associated with ECG traits. For the 3 most commonly reported SNPs, disease risk increased consistently with the number of risk alleles (odds ratio, 3.54; P trend =1.38×10 −9 for 5 risk alleles versus 1). Similar patterns were observed in both SCN5A mutation+ (odds ratio, 3.66; P trend =0.049) and SCN5A mutation− (odds ratio, 3.75; P trend =8.54×10 −9 ) subgroups. Furthermore, BrS patients without SCN5A mutations had more risk alleles than BrS patients with SCN5A mutations regardless of the range of polygenic risk scores. Three SNPs (rs4687718, rs7784776, and rs2968863) showed significant associations with the composite outcome (sudden cardiac arrest plus syncope, hazard ratio, 2.13, 1.48, and 0.41; P =0.02, 0.006, and 0.008, respectively). Conclusions: Our findings suggested that some SNPs associated with BrS or ECG traits exist across multiple populations. The cumulative risk of the BrS-related SNPs is similar to that in white BrS patients, but it appears to correlate with the absence of SCN5A mutations.

AbstractObjectiveThe study sought to describe the literature related to the development of methods for auditing the Unified Medical Language System (UMLS), with particular attention to identifying errors and inconsistencies of attributes of the concepts in the UMLS Metathesaurus.Materials and MethodsWe applied the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach by searching the MEDLINE database and Google Scholar for studies referencing the UMLS and any of several terms related to auditing, error detection, and quality assurance. A qualitative analysis and summarization of articles that met inclusion criteria were performed.ResultsEighty-three studies were reviewed in detail. We first categorized techniques based on various aspects including concepts, concept names, and synonymy (n = 37), semantic type assignments (n = 36), hierarchical relationships (n = 24), lateral relationships (n = 12), ontology enrichment (n = 8), and ontology alignment (n = 18). We also categorized the methods according to their level of automation (ie, automated systematic, automated heuristic, or manual) and the type of knowledge used (ie, intrinsic or extrinsic knowledge).ConclusionsThis study is a comprehensive review of the published methods for auditing the various conceptual aspects of the UMLS. Categorizing the auditing techniques according to the various aspects will enable the curators of the UMLS as well as researchers comprehensive easy access to this wealth of knowledge (eg, for auditing lateral relationships in the UMLS). We also reviewed ontology enrichment and alignment techniques due to their critical use of and impact on the UMLS.

Background and Aims Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. Approach and Results EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end‐stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol‐associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 1011/mL) compared to healthy controls (4.38 × 1010/mL; P < 0.0001), heavy drinkers (1.28 × 1011/mL; P < 0.0001), ESLD (5.35 × 1010/mL; P < 0.0001), and decompensated AC (9.2 × 1010/mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End‐Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high‐EV group and 90.0% in the low‐EV group (log‐rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. Conclusions Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90‐day survival permitting dynamic risk profiling.