tbuckley/cabot-search huggingface dataset:
Assessment of intratumor heterogeneity using imaging texture features in clear cell renal cell carcinoma.
Authors: Durga Udayakumar, Durgesh Dwivedi, Ze Zhang, Yin Xi, Tao Wang, Ananth J Madhuranthakam, Payal Kapur, Michael Fulkerson, Alberto Diaz de Leon, Matthew Lewis, Jeffrey A Cadeddu, Vitaly Margulis, James Brugarolas, Aditya Bagrodia, Ivan Pedrosa
Journal: Journal of Clinical Oncology (2019)

663 Background: Intratumoral heterogeneity (ITH) relates to aggressiveness in clear cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of kidney cancer. Percutaneous biopsies have high diagnostic accuracy. However, ITH lowers their reliability in larger, heterogeneous tumors. Haralick texture features extracted from a gray level co-occurrence matrix (GLCM) is a robust method to assess intrinsic tumor imaging characteristics. Some of these features, including entropy as a measure of ITH, have recently been used in differentiating malignant from benign tumors in various organs. We aim to understand how tumor entropy extracted from magnetic resonance (MR) imaging correlate with tumor grade (aggressiveness) and gene expression heterogeneity in ccRCC. Methods: This IRB-approved, prospective study included T2-weighted (T2W) and arterial spin labeled (ASL) MR images of 62 patients with ccRCC. The GLCM was constructed for regions-of interest (ROI) within the tumor and 13 Haralick texture features were estimated. Correlations between texture features and tumor grade were evaluated by logistic regression and quantified by the area under the receiving operating characteristic (ROC) curve (AUC). RNA sequencing of 182 tumor samples in 49 resected tumors was performed. Entropy was correlated with standard deviation (SD) of normalized gene expression levels in multiple samples from the same tumor. Spearman correlation (rho) was computed for each gene. False discovery rate q values &lt; 0.05 were considered statistically significant. Results: Entropy was higher in high-grade than low-grade tumors (11.28 ± 0.52 vs. 10.95 ± 0.65) on T2W (q = 0.028) and ASL (10.45 ± 1.15 vs. 9.65 ± 1.29) (q = 0.013). Entropy had an AUC of 0.70 (T2) for high-grade prediction and was weakly correlated with tumor size (R 2 = 0.2). Higher T2 and ASL entropy correlated with higher SD of gene expression. Gene ontology analysis of top correlated genes revealed strong enrichment of genes in metabolic processes. Conclusions: Higher MRI entropy predicts high tumor grade and correlates with increased heterogeneity in gene expression of metabolic processes.
DNA damage and repair markers to improve accuracy of prostate cancer diagnosis and identification of aggressive disease.
Authors: Amit Mohan Algotar, Anne Cress, Ray Nagle, Mitchell Sokoloff, Roxanna Behnejad, Daniel Drinkwitz, Naran Lodhia, Patricia Thompson, Steven Paul Stratton
Journal: Journal of Clinical Oncology (2015)

e16012 Background: Prostate biopsy is the gold standard test for diagnosing prostate cancer (PCa). However, it is associated with sampling error. Using markers associated with DNA damage and repair, this study attempts to improve the diagnostic accuracy of prostate biopsies in men at high risk for PCa. Methods: Data were obtained from men participating in a randomized chemoprevention trial designed to investigate the effects of selenium on PCa incidence in men at high risk for PCa and had a negative prostate biopsy. 699 men were randomized to receive placebo, 200 ug Se/d, 400 ug Se/d and were followed every 6 months for up to five years. 73 subjects were diagnosed with PCa on repeat biopsy. Prostate biopsy samples from 73 subjects and 146 matched controls were stained immunohistochemically for RAD51 and H2AX. Image analysis was conducted using ScanScope and Spectrum software from Aperio Technologies and statistical analysis using Stata12. Results: Subjects diagnosed with PCa demonstrated higher expressions of both H2AX (mean(SD), 33.8(17.7) and 19.4(14.5)) as well as RAD51 (55.8(24.1) and (44.7(26.5)). As compared to the model containing baseline PSA, age and race, model containing RAD51 and H2AX data showed improved positive predictive value, negative predictive value and area under the curve (70%, 78.9%, 0.77 and 80%, 87.06%, 0.90 respectively, p = 0.025). The above also holds true when data from subjects diagnosed with low grade disease are compared with those having high grade disease (100%, 80%, 0.72 and 100%, 85%, 0.82, p = 0.07). Conclusions: Results of this study indicate that markers associated with DNA damage and repair can potentially improve diagnostic accuracy for PCa as well as for aggressive disease.
Predictors of positive lesions in 18F-fluciclovine PET/CT.
Authors: Helen Y Hougen, Nadine Mallak, Yiyi Chen, Catherine Degnin, Ryan P Kopp, Jen-Jane Liu, Sudhir Isharwal, Arthur Hung
Journal: Journal of Clinical Oncology (2019)

231 Background: The 18F-Fluciclovine (FACBC) PET/CT scan has higher sensitivity than traditional imaging modalities for detection of prostate cancer (PCa) recurrence. We aim to identify the PSA characteristics as predictors of positive FACBC scan. Methods: Seventy-eight patients who underwent FACBC scan in 2018 at our institution were identified. Patient demographics, prior PSA, clinical information including prior treatment was recorded. Scans were deemed positive if definitive lesions were noted at the prostate bed, pelvic lymph nodes, or skeletal level. Detection rate was the ratio of positive over total scans and was calculated for PSA ranges. PSA velocity (PSAV) was calculated for patients who did not initiate androgen-deprivation therapy 12 months prior to the scan. The baseline PSA and PSAV were modeled as predictors of having a positive scan using logistic regression. Results: The median baseline PSA is 2.7 (range 0.2 - 226.5). The rates of positivity increased with increasing baseline PSA (Table 1). Positive scans had higher median baseline PSA (3.0, range 0.2-226.5 vs. 1.2, range 0.2-26.0; p = 0.0015) and higher PSAV (median 2.3, range -0.6-1478.7 vs. 1.0, range -0.5-31.9; p = 0.025). Baseline PSA (AUC = 0.712) was better predictor than PSAV (AUC = 0.656) of a positive scan. Combining the two variables does not improve their predictive ability (AUC = 0.719). There is a 50% detection rate in post-radical prostatectomy (RP) patients (Table 2). Conclusions: FACBC PET’s detection rate increases with increasing baseline PSA. While higher PSAV is associated with higher rate of positive scan, it did not increase the predictive ability of baseline PSA for a positive scan in prostate cancer recurrence patients. [Table: see text][Table: see text]
Abstract 10893: Dietary Nitrate Supplementation With Beetroot Juice Enhances Cardiac Autophagy Markers AMBRA-1 (Activating Molecule in Beclin-1-regulated Autophagy) and ATG-5 (Autophagy-related Gene 5): Protective Role Against Doxorubicin Cardiotoxicity
Authors: Chang Yin, Shabina Rehman, Rakesh C Kukreja, Lei Xi
Journal: Circulation (2015)

Background: Beetroot juice (BRJ) is a dietary supplement containing high levels of nitrate and other nutrients. We previously reported that oral intake of BRJ protects against cardiotoxicity of doxorubicin (DOX) - a widely used anticancer drug. BRJ diminished cell injury (indicated by significantly lower serum levels of cardiac troponin I) and ventricular dysfunction caused by DOX. However, it remains unknown if BRJ modulates cardiac autophagy - a critical endogenous cellular quality control and damaged organelles removal mechanism, particularly under DOX-induced cardiototoxic stress. Therefore, the current study is designed to determine if cardioprotective dose of BRJ affects cardiac autophagy. Methods: Adult male CF-1 mice were divided into 4 groups (n=3-4/group) to receive: 1) Saline (0.2 ml, IP); 2) DOX (15 mg/kg, IP); 3) BRJ (10 g BRJ extract per liter of drinking water provided for 13 days); and 4) BRJ+DOX (BRJ for 7 days before DOX injection on Day 8 and throughout the 5-day post-DOX period. On Day 13, heart tissue samples were collected for determining the key autophagy markers with real-time PCR or Western blots. Results: Cardiac protein expression of AMBRA-1 (Fig. A) and ATG-5 (Fig. C) was significantly enhanced by BRJ with or without DOX co-treatment (P&lt;0.05). Interestingly, BRJ intake also significantly augmented mRNA levels of AMBRA-1 (Fig. B) and ATG-5 (Fig. D) in BRJ+DOX group. Furthermore, the ratio of LC3B-II/LC3B-I, another hallmark for autophagy was decreased in DOX group, but restored in BRJ+DOX group to the level of Saline control group. Conclusions: BRJ intake significantly upregulates several key molecular markers of cardiac autophagy such as AMBRA-1 and ATG-5, which may contribute to BRJ-induced protection against DOX cardiotoxicity. The autophagy-related novel molecular mechanisms revealed in this study may provide a new rationale for potential use of BRJ as a safe nutraceutical therapy in reducing cardiotoxicity caused by DOX chemotherapy.
A 17-gene genomic prostate score as a predictor of adverse pathology for men on active surveillance.
Authors: Zachary Kornberg, Matthew R. Cooperberg, Janet E. Cowan, Jeffry Simko, June M. Chan, Imelda Tenggara, Peter Carroll
Journal: Journal of Clinical Oncology (2019)

97 Background: The OncotypeDX Genomic Prostate Score (GPS) test is a RNA expression assay that can be performed on needle-core biopsies from men with prostate cancer (PCa). GPS has previously been validated as a predictor of adverse pathology in men with low-risk prostate cancer who undergo primary radical prostatectomy (RP). We sought to determine whether GPS was associated with increased risk of adverse pathology for men enrolled on active surveillance (AS) who undergo delayed RP. Methods: Of 1,662 men enrolled on AS at the University of California San Francisco (UCSF) who consented for prospective data collection, we evaluated 215 men on AS with Gleason score (GS) 3+3 and GS 3+4 PCa who underwent GPS testing at diagnostic or confirmatory biopsy (ie. within 1 year). Patients had at least 6 biopsy cores sampled and ≤ 33% positive cores, stage T1 or T2 disease, PSA &lt; 20, and clinical Cancer of the Prostate Risk Assessment (CAPRA) score &lt; 6. The primary outcome was adverse pathology at delayed RP, defined as GS ≥ 4+3, stage ≥ pT3a or pN1. We performed Cox proportional hazards regression, and inverse probability censored weights (IPCW) models to evaluate association between GPS and adverse pathology, adjusting for CAPRA score. Results: 72 percent (N=154) of the cohort had GS 3+3, and 28 percent (N=61) had GS 3+4. 83 percent of men (N=179) were low risk, and 17 percent of men (N=36) were intermediate risk by CAPRA scoring. Median GPS was 26.4 (interquartile range [IQR]: 18.8, 34.6). Median time from diagnosis to RP was 23 months (IQR: 15, 40). 121 men had adverse pathology on delayed RP at a median time of 27 months (IQR 16, 43) to prostatectomy. In a Cox-proportional hazards regression adjusted for CAPRA, GPS was associated with increased risk of adverse pathology at delayed RP (Hazard Ratio [HR] per 5 units: 1.12, 95 Confidence Interval [CI]: 1.05, 1.20, p &lt; 0.01). CAPRA score was not associated with adverse pathology (p=0.09). IPCW model findings were very similar to Cox results. Conclusions: In patients who undergo RP after a relatively short period of AS, a higher GPS is associated with increased risk for adverse pathology on delayed RP.
Factors influencing prognosis for occupational hand eczema: new trends
Authors: C.M. Olesen, T. Agner, N.E. Ebbehøj, T.K. Carøe
Journal: British Journal of Dermatology (2019)

Variables traditionally reported to influence the prognosis of occupational hand eczema (OHE) are atopic dermatitis (AD) and contact sensitization. However, recent studies indicate that lifestyle factors may be of major importance. To identify factors influencing the prognosis in a cohort of patients with recognized OHE. In this register‐based cohort study, individuals with hand eczema recognized as occupational disease in the period January 2010–December 2011 were identified using files from Labor Market Insurance Denmark and included in the study. At baseline, information on sex, age, occupation, wet work, AD and contact sensitization was collected. In 2015 participants received a questionnaire with questions about lifestyle factors, current occupation and healing of OHE. In total, 2703 patients received the questionnaire; 1491 responded to the question about healing of OHE and were included in the study. Altogether, 19·3% of patients reported complete healing at follow‐up. Current tobacco smoking and a high level of stress were factors inversely associated with healing of hand eczema (P < 0·001 and P = 0·030, respectively), while a high level of exercise was significantly related to healing of eczema (P = 0·011). Change of profession was a favourable prognostic factor, while age, sex, AD, contact sensitization and education did not significantly influence prognosis. Traditionally important risk factors such as AD and contact sensitization had no marked influence on prognosis, while lifestyle factors were of major importance. Our findings indicate that risk factors may vary over time, allowing for new perspectives on prevention. What's already known about this topic? Occupational hand eczema has a relapsing course and a poor overall prognosis. Atopic dermatitis and contact sensitization have previously been reported as risk factors for a poor prognosis. What does this study add? The results indicate that lifestyle factors are of importance for the prognosis of occupational hand eczema. Traditionally reported risk factors such as atopic dermatitis and contact sensitization do not currently influence prognosis.
Abstract MP71: Female Community Health Volunteer-Led Lifestyle Intervention is a Highly Cost-Effective, Low-Cost and Scalable Solution for Blood Pressure Control in Nepal
Authors: Dinesh Neupane, Anirudh Krishnan, Per Kallestrup, Arjun Karki, Michael H Olsen, Eric A Finkelstein
Journal: Circulation (2019)

Introduction: Cardiovascular disease (CVD) has become the leading cause of death worldwide, accounting for 32% of global deaths in 2016. Hypertension, which can be mitigated through diet, exercise and adherence to medication, is the greatest risk factor for CVD. However, public spending on CVD prevention remains low in many low- and middle-income countries partly due to a lack of evidence of low-cost, scalable, cost-effective and evidence-based CVD prevention programs. The goal of this study was to quantify the scalability and cost effectiveness of an evidence-based community-based hypertension management study (COBIN) in Nepal. Hypothesis: A community health worker-led BP monitoring and lifestyle counseling intervention is a cost-effective solution to achieving greater BP control in Nepal. Methods: We conducted a cost-effectiveness (CE) and budget impact (BI) analysis of a community health worker-led hypertension prevention and management intervention in Nepal that has previously been shown to reduce BP. Costs were retrospectively collected to estimate per capita and total costs of a national scale-up focusing on three scenarios: (A) hypertensives only; (B) prehypertensives and hypertensives; and (C) all adults aged 25-65 years. The primary CE measure was incremental cost per CVD disability-adjusted life year (DALY) averted. Both CE and BI analyses were conducted for each scenario. One-way sensitivity analyses were conducted to assess the impact of uncertainty in key parameter values on the primary CE measure. Results: The first-year BI was estimated to be an average of US$0.88 per participant: a total of US$2,698,181, US$5,667,503, and US$10,832,403 in scenarios A, B, and C respectively. In subsequent years costs are roughly half as much. In the base-case CE analysis, scenarios A, B, and C resulted in an incremental cost-effectiveness ratio (ICER) of US$185, US$340, and US$303/DALY respectively. One-way sensitivity analyses around the base-case analysis for scenario C show that the ICER was most sensitive to uncertainty in the estimate of SBP reduction among normotensives, varying the ICER between US$225 and US$465/DALY. Conclusions: The program is highly cost effective in all three scenarios compared to the WHO threshold of US$835/DALY for Nepal. This work presents the first evidence from Nepal that a community-based hypertension prevention and management program can be a cost-effective, low-cost, and scalable solution to control blood pressure nationwide.
Phosphatidylinositol-3,4-Bisphosphate-Akt Signaling Pathway Promotes Platelet Activation
Authors: Jasna Marjanovic, Brad Rumancik, Luke Weber, Felix Wangmang, Dane Fickes, Dmitri Postnov, Dung Nguyen, Yoon Lee, Richard Ngo-Lam, Monita Wilson
Journal: Blood (2018)
Monitoring of serum carcinoembryonic antigen levels after curative resection of colon cancer: Setting of cutoff values in accordance with preoperative values.
Authors: Gota Saito, Sotaro Sadahiro, Kazutake Okada, Akira Tanaka, Toshiyuki Suzuki
Journal: Journal of Clinical Oncology (2015)

e14509 Background: Serum carcinoembryonic antigen (CEA) is a representative tumor marker for colorectal cancer and has been used for postoperative surveillance. In clinical practice, however, we often encounter patients without recurrence in whom serum CEA does not become negative after surgery or patients in whom serum CEA transiently increases after surgery. We hypothesized that setting the cutoff value according to whether preoperative serum CEA levels was positive or negative before initial surgery may help the precise diagnosis of recurrence. Methods: We studied 783 patients with colon cancer in whom serum CEA levels were measured before and 1 to 6 months after curative surgery between 2005 and 2013. If serum CEA was measured multiple times 1 to 6 months after surgery, the highest value was selected. We set the cutoff values at 5 ng/ml before surgery, and 5 ng/ml and 10 ng/ml during 1 to 6 months after surgery. Results: 677 (86.5%) had no recurrence (NR group) and 106 (13.5%) had recurrence (R group). The serum CEA was 5 ng/ml or higher in 48.0% in the NR group and 67.9% in the R group before surgery. (p = 0.0002) If the cutoff value after surgery was set at 5 ng/mL, the false positive rate in the NR group was 19.6% and the false negative rate was 34.9% in the R group. If the cutoff value after surgery was set at 10 ng/mL, the false positive rate in the NR group was 3.2% and the false negative rate in the R group was 52.8%. When the cutoff value of the postoperative serum CEA level was set at 5 ng/ml, the rate of correct diagnosis for recurrence was 89.1% in patients whose preoperative serum CEA level was less than 5 ng/ml and only 58.4% in patients whose preoperative serum CEA level was 5 ng/ml or higher. However, in patients who had a preoperative serum CEA level of 5 ng/mL or higher before surgery, the rate of correct diagnosis rate for recurrence increased to 79.3% when the cutoff value of the postoperative serum CEA level was set at 10 ng/ml. Conclusions: For the postoperative surveillance of colon cancer, the postoperative cutoff value of serum CEA should be set separately according to whether preoperative serum CEA level was negative or positive to increase the diagnostic accuracy for recurrence.
Pembrolizumab in men with heavily treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Matthew D Tucker, Jason Zhu, William R. Berry, Sundhar Ramalingam, Tian Zhang, Michael Roger Harrison, Yuan Wu, Patrick Healy, Daniel J. George, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2019)

172 Background: Pembrolizumab is approved for patients with metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors who have progressed on prior therapy and have no satisfactory treatment options. However, very few men with PC were included in these initial studies. We evaluated the clinical activity of pembro in a cohort of men with mCRPC and their responses based on molecular genotype. Methods: We performed a retrospective, IRB-approved review of all men with mCRPC in the Duke Cancer Center who were treated with pembro in order to define the duration of therapy, time to PSA-progression, and imaging responses according to prior/concurrent therapy and by molecular subtypes. Results: We identified 51 men who received ≥1 cycle of pembro for mCRPC. Of these, 86% (44/51) had ≥3 prior lines of therapy after ADT, including abiraterone (88%), docetaxel (86%), enzalutamide (enza, 80%), and sipuleucel-T (74%). Somatic tumor sequencing was available in 18/51 men (35%). We found that 16% (8/51) had a ≥50% confirmed PSA decline with pembro, with 8% (4/51) having ≥90% PSA decline. Two of 4 had mutations in LRP1b, one of whom also had MSH2loss and was MSI-H and TMB-high; of the other 2 patients, one had no actionable mutations and the other had no genetic testing available. Fifty-nine percent (30/51) of men were treated with concurrent therapy with pembro (most commonly enza); however, all patients with PSA responses who were concurrently treated with enza had prior documented PSA progression on enza. Overall, the median time to discontinuation of treatment was 5.8 months (mo), median PSA-PFS, defined as a 25% increase in PSA from baseline, was 1.4 mo, and median OS was 6.7 mo. Among patients with ≥50% PSA decline, duration of response ranged from 3.7 to 16.3 mo with 5 patients with ongoing responses. Conclusions: In a heavily pre-treated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 16% (8/51) of men, including a dramatic ≥90% PSA response in 8% (4/51), two of whom harbored LRP1b mutations, one also with MSH2loss and a MSI-H tumor. Large prospective studies with genomic testing are needed to identify men with the greatest chance for response to immunotherapy.