tbuckley/cabot-search huggingface dataset:
Digital holography can differentiate between bladder cancer grades.
Authors: Miki Haifler, Almog Yogev, Ofer Goldstein, Amnon Zisman, Natan T Shaked
Journal: Journal of Clinical Oncology (2019)

413 Background: Treatment of high grade non-muscle invasive bladder cancer (HG NMIBC) is controversial with BCG instillation and early cystectomy as viable options. However, accurate predictive markers for HG NMIBC are lacking. Refractive index (RI) is an optical feature of tissues and has been shown to be correlated with various oncologic outcomes in prostate and breast cancers. The role of RI in NMIBC has not been explored yet. The aim of this study is to measure and compare RI values of benign and malignant low and high grade NMIBC. Methods: After IRB approval, tissue samples were obtained from high and low grade NMIBC patients. Measurements were performed on non-stained slides using digital holography. Areas of benign and malignant tissues were marked by a fellowship trained GU pathologist. The average RI (RI avg ) and RI variance (RI var ) over malignant and benign cell nuclei were measured. Comparison between benign and malignant tissue and between low and high grade tumors was performed with the Student's t-test. Results: Multiple nuclei of LG and HG patients were measured . Mean difference of RI avg between malignant and benign cells was 0.03 in HG patients (p &lt; 0.001). Mean difference of RI var between malignant and benign tissues was 0.016 in HG patients (p &lt; 0.001). In LG tissues, there was no significant difference in RI avg or RI var between benign and malignant cells. Finally, there was a significant difference in RI avg between HG and LG cells (p &lt; 0.001). Conclusions: For the first time, RI was measured in bladder cancer tissue by digital holography. The RI values and variance were different between malignant and benign cells in HG tissues. Furtheremore, we found a significant difference in RI values between HG and LG cells. This technology may assist in the future in tissue diagnosis and classification of bladder tumor.
Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome
Authors: Federico Innocenti, Fang-Shu Ou, Xueping Qu, Tyler J. Zemla, Donna Niedzwiecki, Rachel Tam, Shilpi Mahajan, Richard M. Goldberg, Monica M. Bertagnolli, Charles D. Blanke, Hanna Sanoff, James Atkins, Blasé Polite, Alan P. Venook, Heinz-Josef Lenz, Omar Kabbarah
Journal: Journal of Clinical Oncology (2019)

CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS.Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested.Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability-high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/KRAS/BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors (P < .001).In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.
Abstract P143: Late Success in Weight Loss Trials: Do Participants Start Losing Weight After 6 Months?
Authors: Gerald J Jerome, Arlene T Dalcin, Deborah R Young, Janelle W Coughlin, Kimberly A Gudzune, Nola Durkin, Nae-Yuh Wang, Hsin C Yeh, Gail L Daumit, Lawrence J Appel
Journal: Circulation (2019)

Background: Weight loss programs often start with an initial phase of intensive lifestyle coaching to facilitate early weight loss, with a typical weight loss goal of ≥ 5%. While early weight loss is associated with long-term weight loss success, less is known about those who do not lose weight in the initial phase. This study examines those without initial weight loss success, but lose weight later. Methods: Analyses included 346 obese adults from the POWER Hopkins weight loss trial and 673 overweight to obese adults from the PREMIER hypertension control trial. Mutually exclusive categories are based on weight loss success (≥ 5% reduction from baseline) at 6m and 12m: continued success (success 6m and 12m); regainer (success 6m then regained 12m); no success (no success 6m or 12m); and late success (12m success only). Results: No success (NS) was the most common category among control and intervention participants in both studies (see table). There were low rates of late success (LS) in POWER (intervention 5%, control 7%, p=.25) and PREMIER (intervention 5%, control 8%, p=.75). Within the POWER intervention, LS and NS were similar in age, sex, race, and baseline weight. Coaching contact rates were similar at 1-6m (LS 64%, NS 57%, p=.49) and 7-12m (LS 45%, NS 46%, p=.89). Within the PREMIER intervention LS had a lower baseline weight than NS (89 vs 99 kg, p=.01), but were similar in age, sex, and race. Coaching contact rates are similar at 1-6m (LS 77%, NS 72%, p=.23) and 7-12m (LS 66%, NS 62%, p=.58). Conclusion: Given the small fraction of intervention participants with late success (only 5%), alternative strategies are needed to address the large fraction of persons without initial weight loss success.
ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Karim Fizazi, Neal D. Shore, Teuvo Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas, Murilo Luz, Boris Y. Alekseev, Iris Kuss, Christian Kappeler, Amir Snapir, Toni Sarapohja, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2019)

140 Background: Delaying metastases for nmCRPC patients, while minimizing the risk of adverse events, is an important treatment goal. Darolutamide, a structurally unique androgen receptor (AR) antagonist, is being evaluated for the treatment of advanced prostate cancer. The ARAMIS trial studied the efficacy and safety of darolutamide in nmCRPC patients. Methods: This double-blind, placebo-controlled phase III trial randomized nmCRPC patients in a 2:1 ratio to receive darolutamide 600 mg (two 300 mg tablets) twice-daily or placebo, while continuing androgen deprivation therapy. Patients were stratified by prostate-specific antigen doubling time (≤6 months or &gt;6 months) and use of osteoclast-targeted therapy. The primary endpoint was metastasis-free survival (MFS), with independent central review of radiographic imaging every 16 weeks. Secondary endpoints include overall survival (OS), times to pain progression (assessed by Brief Pain Inventory), first cytotoxic chemotherapy and first symptomatic skeletal event, as well as safety profile. Results: In total, 1,509 patients were randomized (955 to darolutamide, 554 to placebo). Median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; 2-sided p&lt;0.0001). OS showed a trend in favor of darolutamide (HR 0.71, 95% CI 0.50–0.99, 2-sided p=0.045), as did time to pain progression (HR 0.65; 95% CI 0.53–0.79; 2-sided p&lt;0.0001). Other secondary and exploratory efficacy endpoints also favored darolutamide. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency or grade 3–5 were comparable between darolutamide and placebo arms; none except fatigue occurred in &gt;10%. Discontinuation rates due to AEs were 8.9% with darolutamide and 8.7% with placebo. Grouped terms for AEs noted with other AR inhibitors (including fracture, falls, seizures, weight decrease, hypertension, and cognitive disorder) showed minimal or no difference in incidence between study arms. Conclusion: Among men with nmCRPC, MFS was significantly longer with darolutamide than with placebo with a low incidence of treatment-related AEs in this asymptomatic patient population. Clinical trial information: NCT02200614.
3D Bioprinting of Functional Islets of Langerhans in an Alginate/Methylcellulose Hydrogel Blend
Authors: Sarah Duin, Kathleen Schütz, Tilman Ahlfeld, Susann Lehmann, Anja Lode, Barbara Ludwig, Michael Gelinsky
Journal: Advanced Healthcare Materials (2019)

Transplantation of pancreatic islets is a promising strategy to alleviate the unstable blood-glucose control that some patients with diabetes type 1 exhibit and has seen many advances over the years. Protection of transplanted islets from the immune system can be accomplished by encapsulation within a hydrogel, the most investigated of which is alginate. In this study, islet encapsulation is combined with 3D extrusion bioprinting, an additive manufacturing method which enables the fabrication of 3D structures with a precise geometry to produce macroporous hydrogel constructs with embedded islets. Using a plottable hydrogel blend consisting of clinically approved ultrapure alginate and methylcellulose (Alg/MC) enables encapsulating pancreatic islets in macroporous 3D hydrogel constructs of defined geometry while retaining their viability, morphology, and functionality. Diffusion of glucose and insulin in the Alg/MC hydrogel is comparable to diffusion in plain alginate; the embedded islets continuously produce insulin and glucagon throughout the observation and still react to glucose stimulation albeit to a lesser degree than control islets.
Exploratory endpoints in a FARETES study of the efficacy of testosterone in metastatic renal cell carcinoma (mRCC) patients.
Authors: Ilya Tsimafeyeu, Pavel Borisov, Ruslan Zukov, Kristina Zakurdaeva, Anastasia Bondarenko, Yulia Tishova
Journal: Journal of Clinical Oncology (2019)

574 Background: In multicenter randomized phase 2 study (FARETES) we showed that male patients with mRCC receiving targeted therapy had significantly less fatigue and better symptom control with testosterone undecanoate (T) (MASCC 2018, LBA004). Here we described exploratory endpoints in FARETES study. Methods: Sixty male patients with clear cell mRCC, normal PSA level, low testosterone level and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either T (Nebido, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Exploratory endpoints included rate of adverse events (AE) of targeted therapy, duration of targeted therapy, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of the data cutoff on October 17, 2018, median (range) follow-up was 15.2 (9.9 -16.5) months. No unexpected toxicity of T was observed. Grade 3-4 targeted therapy-related AE occurred in 11 (37%) and 3 (10%) patients in the control group and T group, respectively. Discontinuation due to AE was observed in 3% (1/30) of patients in the T group and in 17% (5/30) of patients in the control group. ORR and PFS were significantly better in the T group (all P &lt; 0.05, Table). Median OS was not reached in either group. Clinical trial information: NCT03379012. Conclusions: T therapy could decrease rate of serious AE of targeted therapy. Male mRCC patients receiving T had longer duration of targeted therapy, better PFS and ORR. Larger trials are needed to evaluate efficacy of T in this group of patients.[Table: see text]
Abstract P023: Lifetime Risk of Atrial Fibrillation by Race and Socioeconomic Status: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Liping Mou, Faye Norby, Lin Chen, Wesley O'Neal, Tene Lewis, Laura Loehr, Elsayed Soliman, Alvaro Alonso
Journal: Circulation (2018)

Background: The lifetime risk of atrial fibrillation (AF) has been previously reported in whites, but not in African Americans. Moreover, we lack current estimates of lifetime risk of AF that take into account recent trends in the incidence of this arrhythmia. Lifetime risk of AF by socioeconomic status has not been investigated before. Methods: We studied 15,343 whites and African Americans in the Atherosclerosis Risk in Communities study who were followed for an average of 21 years (maximum 27 years). Total family income was categorized as &lt;$25,000, $25,000-$49,999, and ≥$50,000, and education as &lt; high school graduate, high school graduate, and at least some college. Incident AF was ascertained from study electrocardiograms, hospital discharge records, and death certificates. Lifetime risk of AF was estimated by a modified Kaplan-Meier method that accounted for the competing risk of death. Results: We identified 2760 AF cases during follow-up. Lifetime risk of AF was 36% (95% CI: 32-38%) in white men, 30% (26-32%) in white women, 21% (13-24%) in African American men, and 22% (16-25%) in African American women (Figure). Regardless of race and sex, incidence rates of AF decreased from the lowest to highest categories of income and education. In contrast, lifetime risk of AF increased in individuals with higher income and education in most sex-race groups. Cumulative incidence of AF was lower in those with higher income and education compared to their low socioeconomic status counterparts through earlier life, but was reversed after age 80. Conclusion: Lifetime risk of AF in a contemporary cohort in the United States was approximately 1 in 3 among whites and 1 in 5 among African Americans. Socioeconomic status was inversely associated with cumulative incidence of AF before the last decades of life.
αIIb(R990W), a Gain-of Function Mutation of αIIbβ3, Knock-in Mice Show Moderately Impaired Thrombopoiesis
Authors: Keigo Akuta, Kazunobu Kiyomizu, Hirokazu Kashiwagi, Shinji Kunishima, Fumiaki Banno, Koichi Kokame, Nobuko Nishiura, Hisashi Kato, Shigenori Honda, Yuzuru Kanakura, Toshiyuki Miyata, Yoshiaki Tomiyama
Journal: Blood (2018)
The oral α and β tubulin inhibitor, VERU-111, for the treatment of metastatic castration-resistant and androgen blocking agent-resistant prostate cancer in nonclinical toxicity studies.
Authors: Robert H. Getzenberg, Mario A. Eisenberger, Mark Christopher Markowski, Gary Barnette, Darryl Patrick, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2019)

299 Background: A dose limiting toxicity of taxane chemotherapy, including docetaxel and cabazitaxel, is neutropenia. VERU-111 is a novel, oral aand btubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. Nonclinical toxicity studies were recently performed in order to assess the effects of daily, high-dose administration of orally dosed daily VERU-111. Methods: Toxicity of VERU-111 was evaluated in a 28-day oral dosing toxicity study which was conducted in both rats and dogs. These studies were performed at an independent facility under GLP conditions. Results: In both species evaluated, at oral doses of ≤3 mg/kg/day (rat) and ≤8 mg/kg/day (dog) there were no significant observed findings of neutropenia, myelosuppression, or abnormal liver function. Conclusions: In contrast to cabazitaxel and docetaxel, which are given once every 3 weeks IV, VERU-111 given oral, daily for 28 days in toxicity studies in dog and rat did not result in neutropenia, and myelosuppression. Furthermore, VERU-111 orally each day did not affect liver function tests. These nonclinical toxicity studies provide the basis for progressing VERU-111 into a Phase 1b/2 study which targets men with metastatic castration and androgen blocking agent (abiraterone and enzalutamide) resistant prostate cancer.
BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population
Authors: N.C. Turner, E. Alarcón, A.C. Armstrong, M. Philco, Y.A. López Chuken, M.-P. Sablin, K. Tamura, A. Gómez Villanueva, J.A. Pérez-Fidalgo, S.Y.A. Cheung, C. Corcoran, M. Cullberg, B.R. Davies, E.C. de Bruin, A. Foxley, J.P.O. Lindemann, R. Maudsley, M. Moschetta, E. Outhwaite, M. Pass, P. Rugman, G. Schiavon, M. Oliveira
Journal: Annals of Oncology (2019)

BackgroundBEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1–3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+).Patients and methodsBEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2− metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population.ResultsCapivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups.ConclusionsCapivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2− advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.
Homologous recombination (HR) deficiency, tumor <i>BRCA1/2</i> mutations (tmBRCA) and association with response and outcome following platinum monotherapy in high grade serous ovarian cancer (HGSOC).
Authors: Robert Brown, Kirsten Timms, James Paul, Elisha Hughes, Mona El-Bahrawy, Jennifer H Steel, Saritha Kalva, Xinxue Liu, Yuepeng Wang, Nona R Rama, Charlotte Wilhelm-Benartzi, Alexander Gutin, Liz-Anne Lewsley, Nadeem Siddiqui, Naina Patel, Jerry S. Lanchbury, Hani Gabra, Euan A Stronach
Journal: Journal of Clinical Oncology (2015)

5576 Background: Response to DNA-damaging agents, including platinum, is associated with defects in BRCA1/2 and other HR pathway genes. The HRD score is a sum of three previously described metrics (Abkevich et al, Birkbak et al, Popova et al), and is significantly associated with both tmBRCA and response to DNA damaging agents. This study examined whether HR deficiency (HRD score ≥ 42 or tmBRCA positivity) was predictive of response or prognostic in a carboplatin monotherapy treated HGSOC cohort from the SCOTROC4 phase 3 trial (Bannerjee et al 2013). Methods: DNA from formalin-fixed archival tumor from 165 HGSOC patients treated with first-line single-agent carboplatin was analyzed for HRD scores and tmBRCA. Cox proportional hazards analysis was used to test CA125 response, HR deficiency, and tmBRCA for associations with progression free survival (PFS) and overall survival (OS). HR deficiency and tmBRCA were evaluated as predictors of CA125 complete response using logistic regression. Results: BRCA1/2 mutations were detected in 26/165 (16%) of primary HGSOC. HR deficiency was present for 53/151 (35%) tumors analyzed. Patients with CA125 complete response (n = 64) had significantly improved PFS (p = 6.6x10-7) and OS (p = 3.3x10-7) compared to no or partial CA125 response (n = 45). HR deficiency predicted CA125 complete response in all evaluable patients (p = 0.0033, n = 96) and in the BRCA1/2 wild type subset (p = 0.034, n = 75). TmBRCA trended but was not significantly associated with CA125 response (p = 0.079, n = 107). HR deficiency and tmBRCA were associated with improved PFS (p = 0.00058; 0.012 respectively) and OS (p = 0.0040; 0.026 respectively) in an independent manner from known prognostic clinical factors. Conclusions: HR deficiency and tmBRCA were significantly associated with outcome in HGSOC patients treated with platinum monotherapy. HR deficiency was also significantly associated with complete CA125 response in the entire cohort, and importantly, in BRCA1/2 wild type tumors. Pending validation evaluation of HR deficiency and tumor BRCA status should be considered in the development of platinum combination therapies.
Abstract P129: Racial Differences in Cardiovascular Disease Outcomes after Myocardial Infarction: A REGARDS Study
Authors: J. Walker Blackston, Matthew Mefford, Elizabeth Pruitt, George Howard, Virginia J Howard, Monika Safford, David C Naftel, Emily B Levitan
Journal: Circulation (2019)

Introduction: Although prognosis following myocardial infarction (MI) has improved overall, it is unclear whether improvements are similar for blacks and whites. Methods: We followed black and white participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study from their first adjudicated MI to first occurrence of a composite CVD endpoint (stroke, MI, CVD death). REGARDS includes 30,239 individuals ≥45 years of age across the US. Results: We studied 1,056 participants (38% black; 45% female; mean age 73 ± 9 years) with adjudicated MI who survived at least one day. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) comparing blacks to whites, adjusting for demographic and pre-MI clinical covariates. Blacks had higher demographic-adjusted rates of CVD after MI compared to whites (HR 1.28, 95% CI 1.08-1.51) which attenuated after full adjustment (HR 1.00, 95% CI 0.89-1.32) for clinical characteristics. Conclusion: Blacks had higher risk of post-MI CVD than whites, which was explained by pre-MI health status. Figure 1. Unadjusted=race*CVD; Predisposing factors = age + sex; Need = model 1 + marital status, income, educational attainment, health insurance status, rural or urban residential status; Enabling = model 2 + smoking, BMI, eGFR, ACR (urinary albumin-to-creatine ratio), diabetes, history of stroke, hypertension; In-hospital = model 3 + peak troponin level, ECG status, heart failure, revascularization