tbuckley/cabot-search huggingface dataset:
Abstract P178: Age-Related Gender and Ethnic Variations of Pulse Pressure and Pulsatile Stress
Authors: Sarina Sachdev, Landai Nguyen, Hassan Tahir, Bassam Omar, Farnoosh Rahimi, G. Mustafa Awan, Christopher Malozzi
Journal: Circulation (2019)

Background: Aging causes significant widening of pulse pressure (PP), which has been associated with increased incidence of heart failure, especially diastolic with preserved ejection fraction (HFpEF). Pulsatile stress (PS; the product of PP and heart rate, HR) is a measure of the pulsatile load (per minute) on the cardiovascular system of the beat-to-beat PP, also associated with negative outcomes. Methods: Encounters from university-based cardiology clinic with broad referral base were analyzed; 400 encounters were reviewed for PP and PS; with a total of 100 in each of the categories (WM, WF, AAM and AAF). Each group was individually analyzed for PP and PS in young patients (Young; &lt; 60 years of age) versus old patients (Old; ≥ 60 years of age), using a Student’s t-test. PP is reported in mmHg, PS in mmHg/min (PP in mmHg x HR in beats per minute) and mean age in each category is reported in years. Results: PP in Young WM (mean age 50; n = 41) was 48 ± 15 mmHg, and in Old WM (mean age 69; n = 59) was 55 ± 19 mmHg (7 mmHg difference; P = NS). PS in Young WM was 3395 ±1158 mmHg/min, and in Old WM was 3805 ± 1386 mmHg/min (410 mmHg difference; P = NS). PP in Young WF (mean age 52; n = 27) was 45 ± 9 mmHg, and in Old WF (mean age 70; n = 73) was 59 ± 21 mmHg (14 mmHg difference; P &lt; 0.05). PS in Young WF was 3319 ± 891 mmHg/min, and in Old WF was 4159 ± 1486 mmHg/min (840 mmHg difference; P &lt;0.05). PP in Young AAM (mean age 50; n = 47) was 51 ± 14 mmHg, and in Old AAM (mean age 70; n = 53) was 56 ± 17 mmHg (6 mmHg difference; P = NS). PS in Young AAM was 3623 ± 1102 mmHg/min, and in Old AAM was 3855 ± 1447 mmHg/min (232 mmHg difference; P = NS). PP in Young AAF (mean age 48; n = 42) was 50 ± 18 mmHg, and in Old AAF (mean age 68; n = 58) was 58 ± 21 mmHg (8 mmHg difference; P &lt; 0.05). PS in Young AAF was 3760 ± 1441 mmHg/min, and in Old AAF 4043 ± 1638 mmHg/min (283 mmHg difference; P= NS). Conclusion: The elderly suffer from mostly isolated systolic hypertension , with elevated pulse pressure, an independent predictor of cardiac events. Here, PP was higher in elderly compared with young patients, but the increase was significant only in females. PS was non-significantly changed with age in males. In females PS became non-significantly changed with age in AAF, but was statistically higher in older WF. These differences may help explain the increased incidence of HFpEF in older women compared to men and older white patients compared to blacks. The reason for this variation is unclear, but may be in part related to post-menopausal hormonal changes in older females. These observations are important as they identify significant gender and ethnic-related changes in pulse pressure and pulsatile stress with age affecting females, especially white females, who have elevated cardiovascular risk post-menopause.
Abstract P360: Blunted Hemodynamic Response to Acute Mental Stress Among African Americans With Coronary Heart Disease
Authors: Shakia T Hardy, Samaah Sullivan, Muhammad Hammadah, Lisa Elon, Lian Li, J. Douglas Bremner, Arshed Quyyumi, Viola Vaccarino
Journal: Circulation (2019)

Introduction: Racial differences in cardiovascular disease morbidity and mortality are well established by middle age with African Americans contributing to higher rates of cardiovascular disease. In addition to traditional risk factors, African Americans experience greater exposure to stressful life events. Both an enhanced and a blunted hemodynamic reactivity to acute psychological stress have been associated with worse cardiovascular health status and may contribute to these disparities. Methods: We studied 920 patients with stable coronary artery disease (CAD) and 109 controls without CAD. Systolic blood pressure (SBP), heart rate (HR), and rate-pressure product (RPP) were measured prior to, and following a public speaking stress task. We examined the association between race and hemodynamic reactivity to stress using mixed linear regression models adjusting for cardiovascular disease severity, medication usage and psychosocial, demographic and lifestyle factors. Results: Of the 920 patients (mean age 59 years), 39% were African American. African Americans had a more adverse socioeconomic and cardiometabolic profile (hypertension, diabetes, and body mass index) compared to white Americans. In response to mental stress, African American patients exhibited a lower increase in SBP (23 vs 27 mmHg; p &lt;.0001), HR (11 vs 13 beats/minute; p =0.008) and RPP (3205 vs 3718 mmHg x beat/min; p =0.004) compared to white Americans, after adjusting for demographics, lifestyle and medical risk factors. Among controls (41% African American), there were no significant differences in hemodynamic reactivity to mental stress by race, and among CAD patients, there were also no differences in the hemodynamic reactivity to an exercise stress test by race. Conclusions: African Americans with CAD exhibit a blunted hemodynamic response to mental stress compared to white Americans. Further research is needed to clarify the determinants of such differences and whether they contribute to race disparities in cardiovascular disease risk.
Association of p53-ness with chemo-resistance in urothelial cancers treated with neoadjuvant gemcitabine plus cisplatin.
Authors: Roland Seiler, Woonyoung Choi, Lucia L.C. Lam, Nicholas Erho, Christine Buerki, Elai Davicioni, George N. Thalmann, David James McConkey, Peter C. Black
Journal: Journal of Clinical Oncology (2015)

4512 Background: Recent genomic analyses demonstrated that muscle-invasive bladder cancers can be grouped into intrinsic basal and luminal subtypes. Within the luminal subtype, tumors with “p53-like” gene expression were resistant to neoadjuvant chemotherapy (NAC) with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). We investigated the response of these subtypes to gemcitabine plus cisplatin (GC), the other major frontline NAC regimen in this disease setting. Methods: Fifty-two bladder cancer patients received neoadjuvant GC followed by cystectomy. At diagnosis 44 (85%) and 36 (69%) patients had extravesical extension of the primary tumors and were clinically node-positive, respectively. At cystectomy, 37 (71%) patients did not respond to NAC (ypT ≥ 2 or any ypN1-3). RNA was isolated from pre-NAC transurethral resection (TUR) specimens and post-NAC cystectomy specimens using the RNeasy FFPE kit (Qiagen), amplified with the Ovation WTA FFPE system (NuGen) and hybridized to GeneChip Human Exon 1.0 ST microarrays (Affymetrix). A one nearest neighbor (oneNN) prediction model was used with the RNA normalized gene expression values to assign the tumors to intrinsic subtypes. Results: Unsupervised hierarchical clustering separated the tumors into clusters characterized by non-overlapping expression of basal or luminal biomarkers. Assignment of pretreatment TUR tumors to subtypes yielded the expected ratios of basal, p53-like, and luminal tumors. Rates of pathological down staging ( < ypT2), disease specific (p = 0.013), and overall survival (p = 0.003) were lower in the p53-like tumors compared to the other subtypes. An immune signature was enriched in the basal tumors that responded to NAC, although this did not reach statistical significance. Analyses of matched tumors before and after therapy revealed enrichment for p53-like tumors at cystectomy. Conclusions: Patterns of response and resistance to neoadjuvant GC appear to be very similar to those observed with MVAC, with p53-like tumors displaying chemo-resistance. If these results are confirmed prospectively, patients with p53-like tumors should not be treated with cisplatin-based chemotherapy.
Abstract P408: Ischemic Stroke Risk Factor Differences and Their Changes Over Time Among Young (45 Years or Less) Persons in a Rural State: 2012-2017
Authors: Kristin Weeks, James C Torner
Journal: Circulation (2019)

Introduction: A positive public health trend in Iowa in the last decade has been the decreasing mortality by stroke. However, there has been an alarming trend in the increased occurrence of stroke in the younger population (≤45 years) in Iowa from 2010-2018. The risk factors responsible for the rising incidence in the young need attention for prevention. Hypothesis: This analysis examines whether over time young persons with stroke will have a different frequency and distribution of some cardiovascular risk factors at the time of their stroke. Additionally, we analyze if the risk factor prevalence varies by age cohort and if risk factor prevalence differs from the general age-matched population in Iowa. Methods: Using the Iowa Stroke Registry, data from 22,652 patients from 2012-2017 was collected from 32 hospitals. We investigated demographics, medical, social, and family histories by age (≤45, &gt;45) across time (2012-2017) for ischemic strokes. Statistical analysis was done to determine if for each age cohort a factor varied significantly over time, and if factor prevalence varied between age groups. Comparisons were using Chi-Square tests for categorical variables and ANOVA for continuous variables with an alpha=0.05. Trend of change over time was analyzed. We used Iowa Behavioral Risk Factor Surveillance System data from 2015 to compare prevalence of risk factors among stroke patients and the population. Results: Compared to over 45 years old stroke patients, 45 or less years old stroke patients in Iowa in 2012-2018 have a higher prevelance at the time of their stroke of obesity, morbid obesity, drug abuse, migraines, a family history of stroke and a smoking history (p=&lt;0.05). There was a lower prevalance of past cardiovascular event, dyslipidemia, hypertension, atrial fibulation, antiplatelet medication use, anticoagulant medication use, and antihypertension medication use (p=&lt;0.05). Dyslipidemia and hypertension decreased in prevelance among stroke patients over years (R 2 0.45, 0.44). Also in comparison to their age-matched Iowa counterparts, Iowa stroke patients have a higher prevelance of smoking, diabetes, prior stroke, prior MI, hypertension, high cholesterol. They have lower diagnosed depression and no difference in obesity. Conclusions: Younger persons with strokes experience risk factors at different proportions than older patients with strokes and the prevalence of these risk factors are changing over time. The ≤45 year old stroke patients vary from their overall age-matches state counterparts in their risk factor prevalence. Overall, these findings highlight the need for increased screening and preventive interventions by public health and health care providers.
Clinical and genetic determinants of toxicity and quality-of-life (QOL) outcomes for SBRT in Asian prostate cancer.
Authors: Janice Ser Huey Tan, Sheena Xue Fei Tan, Youquan Li, Jeffrey Kit Loong Tuan, Terence Wee Kiat Tan, Michael Lian Chek Wang, Kae Jack Tay, Lui Shiong Lee, Jonathan Yi Hui Teh, Melvin Lee Kiang Chua
Journal: Journal of Clinical Oncology (2019)

95 Background: There is limited data on clinical and patient-reported quality of life (PRO-QOL) outcomes after stereotactic body radiotherapy (SBRT) in Asian men with localised prostate cancer. Demographic differences with regard to PRO-QOL outcomes may be due to variation in germline genetics. We therefore conduct a single-institution prospective phase II trial of prostate SBRT in Asian men with intermediate-risk prostate cancers (IR-PCa). Additionally, we investigated association of dosimetric and genetic factors with outcomes. Methods: Patients with biopsy-proven NCCN-defined IR-PCa were recruited. SBRT was delivered at 36.25 Gy/5fr using a Linac-based RapidArc technique. Adverse events (AEs) were assessed with CTCAEv4.0 and IPSS; PRO-QOL assessed using the EPIC instrument at baseline, 1 and 2-year post-SBRT. Germline genetics were profiled by whole exome sequencing (30X). Results: 65 patients were recruited over the period of 2014-2016 (median follow-up = 30 mo). We observed 4 acute ≥G2 gastrointestinal (GI) events (3 fecal urgency, 1 diarrhea). Longitudinal assessment of acute genitourinary (GU) events by IPSS showed worsened symptoms that peaked at 1 wk post-SBRT (44.6% vs 6.2% at 1 mo for men reporting scale upgrade). There was no significant association between acute GU effects (by IPSS) and dosimetric parameters of the irradiated urethra and bladder. PRO-QOL scores demonstrated minimal change over time across all domains; however, sexual bother in the top 50 th percentile subgroup at baseline indicated ≥20% worsening of scores for 10/32 (31%) at 12 mo and 5/12 (42%) at 24 mo; which was not associated with Dose max to the penile bulb (P = 0.1). We observed a high frequency of germline mutations in DNA repair genes (N = 10; 15.4%), including two BRCA2 stop-gain and frameshift mutations. In particular, BRCA2 mutations were detected in 2 of 4 cases with ≥G2 GI effects, independent of rectal dose. Conclusions: While prostate SBRT is well tolerated in our Asian cohort, there appears to be demographic differences in sexual bother compared to Caucasian cohorts. Interestingly, we observed a higher than expected prevalence for germline mutations in DNA repair genes, which may predict treatment response. Clinical trial information: NCT02313298.
Higher blood–brain barrier penetration of [<sup>14</sup>C]apalutamide and [<sup>14</sup>C]enzalutamide compared to [<sup>14</sup>C]darolutamide in rats using whole-body autoradiography.
Authors: Christian Zurth, Steffen Sandman, Dagmar Trummel, Dietrich Seidel, Reinhard Nubbemeyer, Hille Gieschen
Journal: Journal of Clinical Oncology (2019)

156 Background: Darolutamide ([ 14 C]Daro) is an investigational oral androgen receptor antagonist, structurally distinct from enzalutamide ([ 14 C]Enza) and apalutamide ([ 14 C]Apa). In a retrospective analysis of the ARADES database, central nervous system (CNS)-related adverse events (AEs) were not linked with Daro (Fizazi, et al. 2015). CNS-related AEs have been observed with Enza and Apa, eg, fatigue, mental impairment, and seizure (Hussain et al, 2018; Smith et al, 2018). In preclinical studies, low blood–brain barrier (BBB) penetration of Daro was observed, suggesting low impact on the CNS. To understand the different CNS effects, we report in vivo tissue distribution data in rats with [ 14 C]-labeled Apa compared to previously presented [ 14 C]Enza and [ 14 C]Daro distribution data (Zurth, ASCO GU 2018) using quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [ 14 C]Apa under similar experimental conditions as previously reported for [ 14 C]Daro or [ 14 C]Enza, prior to QWBA. One animal was sacrificed at each timepoint: (t max ) 3h, 8h, and 24h post-dose. Timepoint selection was based on a single oral Apa dose pharmacokinetic study in rats. Results: Apa displayed good absorption and homogeneous distribution throughout the body early post-dose, comparable to previous observations for Enza and Daro. As observed for [ 14 C]Enza, [ 14 C]Apa remained constant in the body (t 1/2 ~4h vs ~3h) up to 8h post-dose, whereas [ 14 C]Daro was eliminated from all tissues (t 1/2 ~1h). High concentrations of [ 14 C]Apa persisted in the brain for up to 8h, although concentrations were ~2-fold lower than previously reported for [ 14 C]Enza. [ 14 C]Daro brain concentrations were near the lower limit of quantification, and ~26x and 46x lower than [ 14 C]Apa and [ 14 C]Enza brain concentrations, respectively. Conclusions: The current preclinical study demonstrated moderate BBB penetration for Apa, similar to the previous Enza data, whereas Daro displayed &gt; 25-fold lower BBB penetration, suggesting that Daro may be less likely to induce CNS-related AEs, which is expected to be confirmed by data from the ARAMIS study.
Immunophenotypic Patterns of Bone Marrow Eosinopoiesis in Patients with Hypereosinophillic Syndrome and Systemic Mastocytosis
Authors: Christopher Trindade, Xiaoping Sun, Dragan Maric, Chunjie Jiang, Christopher S. Hourigan, Dean D. Metcalfe, Amy Klion, Irina Maric
Journal: Blood (2018)
Diastolic dysfunction in patients treated with doxorubicin for early stage breast cancer.
Authors: Megan Veresh Caram, Monika Leja, Jeffrey B. Smerage, Cui Guo, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2015)

e17619 Background: Heart failure with preserved ejection fraction (EF) accounts for half of the cases of heart failure in the community and diastolic dysfunction is a precursor to heart failure with preserved EF. Diastolic dysfunction is commonly seen in patients as they age, with a prevalence as high as 40% in women over 65 years of age and 16% in women aged 55-64 years. The consequences of premature diastolic dysfunction are poorly understood and not previously studied in patients who received anthracyclines as part of their breast cancer treatment. Methods: We evaluated the prevalence of elevated cardiac biomarkers (serum brain natriuretic peptide (BNP), N-terminal (NT)-proBNP, troponin, and urine NT-proBNP) and the echocardiographic findings of the women who had an abnormal cardiac biomarker in a sample of patients treated with doxorubicin for early stage breast cancer at least 12 months before enrollment. Extensive medical record review was conducted to control for age, cumulative dose of doxorubicin, diabetes, hypertension, left-sided radiation therapy, and other factors that could affect the risk of developing premature diastolic dysfunction. Results: Among the 246 patients who completed participation in the study, 166 underwent an echocardiogram based on the presence of an abnormal cardiac biomarker; 11 echocardiograms were not sufficient to report on diastolic function. The median age of the 155 women who had complete echocardiograms was 56 years and 48% had some degree of diastolic dysfunction. Age, body mass index, and hypertension were strongly associated with diastolic dysfunction. None of the biomarkers were associated with the presence of diastolic dysfunction, raising the possibility that there may have been additional patients with normal biomarkers who did not undergo echocardiography who may also have diastolic dysfunction. Conclusions: While diastolic dysfunction is a common finding in women with hypertension and with advancing age, our relatively young patient sample experienced a higher than expected rate of diastolic dysfunction, approaching the incidence expected of women in the eighth decade of life, suggesting that anthracyclines may play a part in premature aging of the myocardium.
Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: Nationwide survey in Japan.
Authors: Teruo Inamoto, Haruhito Azuma, Mototsugu Oya, Yoko Hamada, Hideyuki Akaza
Journal: Journal of Clinical Oncology (2019)

565 Background: The average age of the patients (pts) with renal cell carcinoma (RCC) are getting older year by year, hence the baseline comorbidity should be considered when pts have tyrosine kinase inhibitor treatments. However, the safety and efficacy data of these agents in pts with cardiovascular disease (CVD) are limited. In this study, we analyzed the data which were prospectively collected practical use of sorafenib amongst all RCC pts in Japan, and investigated whether baseline comorbidity of CVD would provide any affection for the safety and efficacy on sorafenib treatment using propensity-matched analysis. Methods: A total of 3,255 pts with advanced RCC were enrolled and 770 pts selected by propensity score were matched for CVD (n=385) and non-CVD pts (n=385). Dose modification, tumor response, progression free survival (PFS), and adverse events (AEs) were analyzed. Results: After matching the patient’s demographics were well balanced except for BMI (22.47 ± 3.37 vs. 23.13 ± 3.59, p=0.019) between non-CVD and CVD group, respectively. The median starting dose (800mg vs. 800mg), median daily dose (484.8mg vs. 500mg), and median duration of treatment (7.26 months vs. 7.89 months) were not significantly different. Objective response rate (CR+PR) was comparable in both groups (27.1 and 29.4%). The hazard ratio (HR) of overall PFS was similar between two groups (HR: 1.005, 95% CI: 0.838-1.206). When stratified according to IMDC risk classification, the risk of PFS was not significantly different in any IMDC risk groups (favorable; HR: 0.883, 95% CI: 0.600-1.300, intermediate; HR: 1.11, 95% CI: 0.885-1.3920, and poor ; HR 0.972, 95% CI: 0.513-1.842). Safety was analyzed for 766 pts, and any grade AEs observed ≥20% were hand-foot skin reaction (59.5%), hypertension (40.0%), rash (26.9%), lipase/amylase increased (26.5%), and diarrhea (24.2%). The frequency of any grade AEs were similar between the groups, but lipase/ amylase increased was significantly higher in CVD group than that in non-CVD group (p=0.0042). Conclusions: The present study suggests that sorafenib can be used with clinical benefit for RCC pts regardless of baseline cardiovascular comorbidities. Clinical trial information: NCT01411423.
Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study
Authors: Aksam Yassin, Ahmad Haider, Karim S. Haider, Monica Caliber, Gheorghe Doros, Farid Saad, W. Timothy Garvey
Journal: Diabetes Care (2019)

Type 2 diabetes (T2D) is a public health threat. Prediabetes represents a window of opportunity for intervention to prevent T2D. Men with T2D and prediabetes often have low testosterone. Since testosterone improves glycemic control in T2D, we investigated whether testosterone therapy (TTh) in men with hypogonadism and prediabetes prevents progression to T2D.Three hundred and sixteen men with prediabetes (defined as HbA1c 5.7-6.4%) and total testosterone levels ≤12.1 nmol/L combined with symptoms of hypogonadism were analyzed. Two hundred and twenty-nine men received parenteral testosterone undecanoate (T-group), and 87 men with hypogonadism served as untreated control subjects. Metabolic and anthropometric parameters were measured twice yearly for 8 years.HbA1c decreased by 0.39 ± 0.03% (P < 0.0001) in the T-group and increased by 0.63 ± 0.1% (P < 0.0001) in the untreated group. In the T-group, 90% achieved normal glucose regulation (HbA1c <5.7%). In the untreated group, 40.2% progressed to T2D (HbA1c >6.5%). TTh was also associated with significant improvements in fasting glucose, triglyceride:HDL ratio, triglyceride-glucose index, lipid accumulation product, total cholesterol, LDL, HDL, non-HDL, triglycerides, and Aging Males' Symptoms (AMS) scale. Significant deterioration in all these parameters was seen in the untreated group. Mortality was 7.4% in the T-group and 16.1% in the untreated group (P < 0.05). The incidence of nonfatal myocardial infarction was 0.4% in the T-group and 5.7% in the untreated group (P < 0.005).Long-term TTh completely prevents prediabetes progression to T2D in men with hypogonadism and improves glycemia, lipids, and AMS score. TTh holds tremendous potential for the large and growing population of men with prediabetes and hypogonadism.