tbuckley/cabot-search huggingface dataset:
Evaluation of cardiovascular health in sarcoma survivors.
Authors: Laurence H. Baker, Venkatesh Locharla Murthy, Richard Lawrence Weinberg, Jose Jalife, Todd Herron
Journal: Journal of Clinical Oncology (2017)

e21579 Background: Heart disease is the most common and serious chronic illness observed in sarcoma survivors treated with doxorubicin. Now the commonest heart disease in theses survivors is coronary artery disease (CAD). We established a Sarcoma Survivorship Program to include patients at high risk of chronic illness including exposure to doxorubicin who are at least 2 years free of disease post treatment. Methods: Every 6 months patients electronically complete NIH’s PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaires (on Anxiety, Depression, Mobility, Pain Interference, Sleep Disturbance, and Physical Function). Detailed family history is documented. Chemotherapy doses are abstracted from original medical records. Data collected includes: blood pressure, lipid profile, high-sensitivity C-reactive protein (hs-CRP), basic metabolic panel, chemistries, renal and pulmonary function, expert echocardiography. All patients signed an IRB approved informed consent. Results: All patients had normal left ventricular ejection fractions (median = 60%) yet 8 (N = 24) patients had an elevated hs-CRP suggesting increased risk of early CAD. 10 patients had untreated hypertension. More than half of our patients have a BMI &gt; 25 and self-declare that they do not exercise. Our high rate of family history of heart disease (58%) raises the issue of genetic predisposition both to heart disease and sarcoma. We compared standardized cardiac risk assessments with mediastinal calcification and epicardial fat on serial chest CT scans. A 39 y.o. man had a coronary calcium score &gt; 400 Agatston units and scattered calcifications were found in 4 additional patients under the age of 40. Conclusions: This survivorship phase of oncologic care represents a unique opportunity to improve the health and quality of life for sarcoma survivors as well as a new focus for translational research to understand mechanisms driving premature aging and chronic heart disease. We assess cardiomyocyte function (cell viability, organization, fibrosis, electrical coupling and contractility) for survivors and matched sibling controls with cells from skin biopsy using 3D bioengineering techniques to culture and mature the phenotype from human stem cells.
A phase II trial of abiraterone acetate (AA) without prednisone in castration resistant prostate cancer (CRPC).
Authors: Rana R. McKay, Lillian Werner, Alexandra Jones, Atish Dipankar Choudhury, Mark Pomerantz, Christopher Sweeney, Glenn J. Bubley, Susan F. Slovin, Michael J. Morris, Philip W. Kantoff, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2017)

5040 Background: AA blocks CYP17 and suppresses adrenal androgens and glucocorticoids. Given the risk of mineralocorticoid excess (ME), AA is administered with corticosteroids. In this phase II multicenter, single-arm study, we assess the safety of AA without steroids in CRPC. The primary objective is to determine the proportion of men requiring prednisone to manage ME. Methods: Eligible patients had CRPC with controlled blood pressure (BP) ( &lt; 140/90 on ≤3 agents) and a normal or ≥3.5 mmol/L potassium. Patients initially received AA (1000 mg daily) alone. Patients who developed a BP ≥ 140/90 were treated with anti-hypertensives (HTN) and/or a mineralocorticoid antagonist (MA) prior to steroids. Hypokalemia was treated with supplementation or a MA. Patients with persistent or severe ME were initiated on prednisone (5 mg twice daily). To assess response to steroids, prednisone was added to AA at PSA progression. Therapy was continued until radiographic progression, toxicity, or withdrawal. Results: 60 patients were enrolled of whom 51 (83%) had metastases 16 (27%) received prior chemotherapy, 6 (10%) enzalutamide, and 4 (7%) ketoconazole. Grade (G) 3-4 adverse events (AEs) of interest included HTN (G3 n = 8, 13%; G4 n = 1, 2%), hypokalemia (G3 n = 4, 7%; G4 n = 0), fatigue (G3 n = 1, 2%; G4 n = 0). There was no G ≥3 edema. 9 patients (15%) initiated prednisone for toxicity: HTN (n = 3, 5%), hypokalemia (n = 4, 7%), fatigue (n = 2, 3%). Baseline PSA was 15.4 ng/mL. Time to nadir PSA was 2.5 months (IQR 1.4, 6.3) and median nadir PSA was 2.1 ng/mL. 67% of patients (n = 40) experienced a ≥50% PSA decline and 35% (n = 21) experienced a ≥90% decline. 19 patients (32%) initiated prednisone for PSA progression. Median time to prednisone initiation in patients with PSA progression was 6.1 months (IQR 4.9, 11.7); 5 patients (8.3%) had a PSA decline and 1 achieved a ≥50% decline. Levels of corticosteroids will be reported. Conclusions: In CRPC, AA without steroids is feasible, however clinically significant AEs, particularly HTN, can occur in a minority of patients. HTN and hypokalemia can be treated with anti-HTN agents or potassium without steroids in the majority. Use of AA without prednisone needs to be balanced with the potential risk of toxicity. Clinical trial information: NCT02025010.
Acalabrutinib combined with PI3Kδ inhibitor ACP-319 in patients (pts) with relapsed/refractory (R/R) B-cell malignancies.
Authors: Paul M. Barr, Stephen Douglas Smith, Mark J. Roschewski, Susan Mary O'Brien, Jeff Porter Sharman, Jason M. Melear, Ahmed M. Hamdy, Raquel Izumi, J. Greg Slatter, Nataliya Chernyukhin, Elena Bibikova, Ming Yin, Tianling Chen, Stephen Edward Forbes Spurgeon
Journal: Journal of Clinical Oncology (2018)

7518 Background: Acalabrutinib, a selective, covalent inhibitor of Bruton tyrosine kinase (BTK), was evaluated in combination with the PI3Kδ inhibitor ACP-319 in pts with R/R B-cell malignancies. Methods: Pts with ≥1 prior therapy & ECOG PS ≤2 received oral acalabrutinib 100 mg bid and ACP-319 in escalating doses (25/50/100 mg bid; Part 1) or 50 mg bid (expansion cohort; Part 2) until progressive disease or unacceptable toxicity. The primary endpoint was safety (including dose-limiting toxicity [DLT; Part 1]). Secondary endpoints were PK/PD, overall response rate (ORR), duration of response (DOR) & progression-free survival (PFS). Results: Part 1 pts (8 CLL/SLL, 3 FL, 3 MCL, 3 diffuse large B-cell lymphoma [DLBCL], 1 WM) had median age 65 y (range 48-77) & ECOG PS ≤1. One pt had a DLT in the ACP-319 50-mg group (maculopapular rash [MR]); 2 had DLTs in the 100-mg group (MR; febrile neutropenia, diarrhea & pneumonitis). The maximum tolerated dose for Part 2 was ACP-319 50 mg bid with acalabrutinib 100 mg bid. Pts with CLL/SLL were switched to acalabrutinib monotherapy in 2016 due to reduced benefit:risk ratio with added ACP-319. Herein, 25 DLBCL pts (3 in Part 1, 22 in Part 2) were analyzed; by IHC (Hans algorithm), 9 had germinal center B-cell (GCB) & 16 had non-GCB DLBCL. Median age was 70 y (range 55-90); median no. of prior therapies was 2 (range 1-5). Common AEs (≥40%) were increased AST/ALT (48%/52% [Grade ≥3, 28%/20%]), diarrhea (52% [12%]), fatigue (40% [0%]) & rash (40% [12%]); 22 pts discontinued (5/7 due to AEs with acalabrutinib/ACP-319); no deaths were due to AEs. ORR is in Table. ACP-319 exposure was dose proportional with higher/variable exposure to an inactive metabolite. Acalabrutinib exposure was slightly higher at ACP-319 100 (vs 25/50) mg. Median BTK occupancy at trough was 95%; p-AKT inhibition was ACP-319 dose dependent. Conclusions: The combination of acalabrutinib + ACP-319 was tolerable with manageable AEs; in DLBCL, response rate was high in non-GCB pts. Clinical trial information: NCT02328014. DLBCL GCB n=9 Non-GCB n=16 ORR (≥ PR), n (%) 0 10 (63) 95% CI 35, 85 CR 0 4 (25) PR 0 6 (38) Median, mo Time on study (range) 2.4 (0.8, 10.4) 4.0 (0.8, 29.7) DOR (95% CI) – NR (1.8, NR) range, 0.03+ – 18.4+ PFS (95% CI) 1.8 (1.7, 10.4) 5.5 (1.6, NR) +Censored
TCT-96 Predicting angina-limited exercise capacity using coronary physiology
Authors: Christopher Cook, Yousif Ahmad, James Howard, Matthew Shun-Shin, Amarjit Sethi, Gerald Clesham, Kare Tang, Sukhjinder Nijjer, Paul Kelly, John Davies, Iqbal Malik, Raffi Kaprielian, Ghada Mikhail, Ricardo Petraco, Takayuki Warisawa, Firas Al-Janabi, Grigoris Karamasis, Reto Gamma, Rasha Al-Lamee, Thomas Keeble, Jamil Mayet, Sayan Sen, Darrel Francis, Justin Davies
Journal: Journal of the American College of Cardiology (2018)
Analysis of efficacy and safety of POM as a replacement therapy for lenalidomide for relapsed/refractory multiple myeloma pts refractory to a lenalidomide-containing combination regimen.
Authors: James R. Berenson, Alexa Cohen, Tanya M. Spektor, Ashkan Lashkari, Roy Mackintosh, Alberto Bessudo, Michael Oren Robinson, Haresh S. Jhangiani, Nashat Y. Gabrail, Ibrahim Nakhoul, Samir V. Kubba, Jeffrey D. Neidhart, Tina Maluso, Regina A. Swift, Robert A. Vescio, Shahrooz Eshaghian
Journal: Journal of Clinical Oncology (2017)

e19528 Background: Pomalidomide (POM) is a third –generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) for patients (pts) previously treated with bortezomib and lenalidomide (LEN) and in combination with dexamethasone it has been shown to overcome resistance in RRMM. In this phase 2 trial, we are evaluating the efficacy, safety and tolerability of POM as a replacement therapy for LEN for pts who have progressed receiving a LEN combination regimen. Methods: This is a phase 2, multicenter, open-label and non-randomized study. Pts who have failed a combination regimen containing LEN were treated with POM along with all of the other drugs previously used in the regimen. POM administered orally (dose is determined based on the previous regimen) on days 1-21 of a 28-day cycle, whereas other drugs are administered using the same schedule(s), dose(s) and drug combination as the last LEN-containing regimen that the patient received and failed. The planned enrollment on the study will be 45 pts. Results: To date, a total of 29 pts have been enrolled, 25 pts are evaluable and 12 pts have discontinued treatment. Of the evaluable pts, 9 (36%) and 16 (64%) received 3mg and 4mg of POM, respectively. The median age of all pts was 72 years (range, 52-81), and 17 (68%) were males. Pts have received a median of 3 prior treatments (range, 1-7). The median follow-up time for all pts is 3.1 months (range, 0.2-8.1). Amongst evaluable pts, 5 (23.8%) pts achieved at least a minimal response, 10 (47.6%) pts showed stable disease while 6 (28.6%) pts exhibited disease progression. At the time of data cutoff, only 17 pts have completed more than 1 full cycle of treatment; and, thus, the overall response and clinical benefit rates are fairly low (14.3% and 23.8%, respectively) but expected to improve with further follow up. The median PFS for the cohort was 7.6 months. Common ≥ Gr3 adverse events were neutropenia (8%), hypomania (4%) and leukopenia (4%). Conclusions: We show thatPOM appears to be promising replacement therapy for LEN in RRMM pts who have progressed within receiving a LEN combination regimen.
Predicting outcomes in renal cell cancer: The role of single nucleotide polymorphisms (SNPs).
Authors: Carmen Garrigos, Marta Espinosa, Ignacio Osman, Rainiero Ávila, Rafael Medina, Ricardo Melendez, Ana Salinas, Begoña Pérez-Valderrama, Ignacio Duran
Journal: Journal of Clinical Oncology (2017)

e16074 Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined mostly using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of RCC patients (pts) [localized and advanced] RCC treated at our institution. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). Sixty-four SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). Statistically significant SNPs were validated in an external cohort by individual assays. The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS) and response to treatment (RR). SPSS v20 was utilized for statistical analyses. Results: In pts with localized RCC, 2 SNPs in 2 genes involved in angiogenesis showed a protective effect (VEGFR2: rs2071559, PDGFRA: rs4358459) and others SNPs predicted for worse DFS (VEGFR2: rs10013228, rs1870377, PDGFRA: rs2228230) and shorter OS (VEGFR2: rs2305948, rs10013228; VEGFR3: rs6877011, rs307826) (p &lt; 0.05). In the advanced setting, 6 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics were statistically implicated in OS (IL8: rs2227543, PDGFA: rs9800958, PDGFRB: rs2302273 (p≤0.05)) and RR (VEGFA: rs699947, rs3025010, VEGFB: rs594942 (p &lt; 0.03)). These 14 SNPs are currently being validated in an external cohort of 80 patients with RCC and this data will be presented. Conclusions: These SNPs in genes critical to angiogenesis and metabolism of antiangiogenics might be used as potential prognostic/predictive biomarkers. Prospective validation is ongoing.
Establishment and verification of detecting multiple biomarkers for ovarian cancer by suspensionarray technology and clinical validation for ovarian cancer.
Authors: Li Li, Bingice Zhao
Journal: Journal of Clinical Oncology (2018)

e24256 Background: Establish and validation of combined detecting of CCL18, CXCL1, C1D,TM4SF1, FXR1, TIZ suspension array technology and investigates the diagnostic value for ovarian cancer. Methods: (1) CCL18, CXCL1 monoclonal antibody and C1D, TM4SF1, FXR1, TIZ protein were coupled with polyethylene microspheres.(2)To compare the diagnostic efficiency and diagnostic accuracy of Suspension array technology and ELISA. (3) Suspension array was used to detect six biomarkers in 120 cases of healthy women, 204 cases of patients with benign pelvic tumors, 119 cases of pelvic malignant tumor patients, and 40 cases with breast cancer, lung cancer or liver cancer, respectively. Constructed diagnosis model of combined detection six biomarkers for diagnosis of ovarian malignant tumor. Constructed diagnosis model of combined detection autoantibodies to diagnose epithelial ovarian cancer. Analysed the value of detecting six biomarkers for diagnosis of ovarian malignant tumor and detecting autoantibodies for diagnosis of epithelial ovarian cancer. Compared diagnostic value of detecting six biomarkers in diagnosis of tissue types and pathologic grading with that of CA125. Results: The diagnostic accuracy of two methods was statistically significant. The diagnostic accuracy of suspension array technology was superior to those of ELISA method (all P < 0.05). Sensitivity and specificity of detecting six biomarker to diagnose ovarian malignant tumor was 90.6% and 98.7%. Sensitivity and specificity of detecting autoantibodies to diagnose epithelial ovarian cancer was 75.8% and 96.7%. Combined detection for six biomarkers to diagnose serous and mucinous ovarian cancer was statistically no better than those of CA125 (P = 0.196 and P = 0.602, respectively); there was significantly difference in diagnosis of ovarian cancer (P = 0.023), and there was no significantly difference in diagnosis of different pathological grading (P = 0.089 and P = 0.169, respectively). Conclusions: Combined detection six biomarkers to diagnose serous and mucinous ovarian tumors is betterthan that of CA125.
Final overall survival (OS) analysis of first-line (1L) FOLFOX-4 ± cetuximab (cet) in patients (pts) with <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 3 TAILOR trial.
Authors: Shukui Qin, Weijian Guo, Jian-Ming Xu, Qi Li, Ying Cheng, Tian Shu Liu, Jiongjie Chen, Wen-Feng Chen, Jin Li
Journal: Journal of Clinical Oncology (2018)

3521 Background: The survival advantage conferred by the addition of cet to FOLFOX chemotherapy was verified in TAILOR, the first prospective, randomized, phase 3 study of the addition of cet to 1L FOLFOX in pts with RAS wt mCRC. We previously presented the primary analysis of the TAILOR trial, with fewer OS events. Here, we provide the final OS results for this trial. Methods: TAILOR was an open-label, randomized, multicenter, phase 3 trial with a modified intention-to-treat (mITT) population of 393 pts from China that evaluated FOLFOX-4 ± cet in RAS wt mCRC. The primary endpoint was progression-free survival (PFS) time; secondary endpoints include OS time, overall response rate (ORR), and safety/tolerability. Results: An updated analysis (performed after 84% of events occurred) verified the survival advantage of the addition of cet to FOLFOX-4 (Table). Additionally, > 77% of pts in the cet + FOLFOX-4 arm reached ≥ 80% dose intensity of cet, confirming that cet + FOLFOX-4 has high compliance. There were no new or unexpected safety findings. Finally, 59.6% and 56.0% of pts in the cet + FOLFOX-4 and FOLFOX-4 arms, respectively, received subsequent anticancer therapy after treatment discontinuation (54.4% and 49.5% received any chemotherapy, and 17.6% and 27.0% received any targeted therapy). Clinical trial information: NCT01228734. Conclusions: The TAILOR study met all its endpoints, confirming cet in combination with FOLFOX-4 as an effective standard-of-care 1L treatment regimen for pts with RAS wt mCRC. We acknowledge that OS findings for the mITT population are likely influenced by the low percentage of pts who received further lines of treatment after progression on their 1L regimen, suggesting regional differences in access to anticancer therapy. Efficacy outcome Cet + FOLFOX-4 (n = 193) FOLFOX-4 (n = 200) OS # events 156 174 Median, months 20.8 16.5 95% CI 16.3-23.5 14.8-19.5 HR (95% CI); p value 0.763 (0.614-0.949); p = .015 PFS by investigator # events 165 142 Median, months 9.2 7.4 95% CI 8.8-10.9 5.8-7.5 HR (95% CI); p value 0.629 (0.498-0.794); p < .001 Response rate by investigator, % ORR 66.3 40.5 95% CI 59.2-72.9 33.6-47.7 OR (95% CI); p value 2.893 (1.918-4.363); p < .001
Targeting the Hedgehog signalling pathway in triple negative breast cancer.
Authors: Mun Ngah Hui, Aurelie Cazet, Benjamin Elsworth, Daniel Roden, Thomas Cox, Jessica Yang, Andrea McFarland, NianTao Deng, Chia-Ling Chan, Sandra O'Toole, Alexander Swarbrick
Journal: Journal of Clinical Oncology (2018)

e24216 Background: Paracrine Hedgehog (Hh) signalling occurs in ~30% of all triple negative breast cancers (TNBCs) and confers worse overall survival. The tumour stroma has been shown to facilitate chemoresistance in TNBC. In this study, we investigated the impact of inhibiting paracrine Hh signalling to sensitise tumours to chemotherapy. Methods: For therapeutic studies, NSG mice bearing Hh expressing TNBC (PDX) were randomised to treatment with placebo, Hh Smoothened inhibitor (LDE-225), docetaxel, and combination LDE-225 + docetaxel. Treatment continued until ethical endpoint (tumour size > 2cm, excessive toxicities or metastatic burden). At endpoint, tumours were harvested for tissue analysis. For sequencing studies, Hh expressing murine TNBCs (M6-Hh) were dissociated into neoplastic and stromal cell populations followed by bulk and single cell RNA-sequencing (SCRS). Results: RNA sequencing of neoplastic and stromal cell populations from M6-Hh tumours revealed that the former was enriched for stemness genes and the latter for genes that encode the extracellular matrix. The resulting stromal gene signature predicts worse prognosis in basal TNBC in The Cancer Genome Atlas breast cancer cohort. Using SCRS, cancer-associated fibroblasts (CAFs) were found to be the stromal cell type that respond to Hh ligand stimulation. CAF activation led to collagen remodelling and stromal FGF secretion which in turn increased the number of cancer stem cells (CSCs). CSCs inherently chemoresistant and constitute a subset of cells involved in the initial steps of metastasis. Therapeutic targeting of CAFs using an inhibitor of Smoothened (LDE-225), the key effector molecule of the Hh pathway sensitised PDXs to the effect of docetaxel. Pathway inhibition in tumour CAFs reduced FGF secretion and collagen deposition resulting in a significant reduction in tumour stem cells. This in turn translated to tumour stasis, marked reduction in metastatic burden and improved survival. Conclusions: CAFs remodel the tumour stroma to form a niche for cancer cells to evade the therapeutic effects of chemotherapy. Targeting CAFs leads to multiple downstream changes including alterations in stromal and stem cell composition which ultimately improves TNBC outcome.
Abstract 11046: Chronic Obstructive Pulmonary Disease and Sudden Cardiac Death in Hypertensive Patients: The LIFE Study
Authors: Peter M Okin, Sverre E Kjeldsen, Richard B Devereux
Journal: Circulation (2015)

Background: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular (CV) disease and CV mortality. A recent large, population-based study suggested that COPD is associated with an increased risk of sudden cardiac death (SCD). However, whether COPD predicts SCD in hypertensive patients during aggressive blood pressure (BP) lowering has not been examined. Methods: Risk of SCD was examined in relation to a history of COPD in 9193 hypertensive patients with ECG left ventricular hypertrophy (LVH) who were randomly assigned to losartan- or atenolol-based treatment. A history of COPD was present in 385 patients (4.2%). SCD, a prespecified secondary endpoint in LIFE, was defined as death that was sudden and unexpected, including observed arrhythmic deaths and those not attributable to myocardial infarction (MI), intractable heart failure (HF) or other identifiable cause, occurring within 24 hours of symptom onset or when the subject was last seen alive if unwitnessed SCD. Results: During mean follow-up of 4.8±0.9 years, 178 patients (2.4%) had SCD, with a higher incidence rate per 1000 person-years in those with COPD: 9.0; 95% CI, 6.1-11.9 vs 3.8; 95% CI, 3.4-4.2; p=0.001. In a univariate Cox model, COPD was associated with a &gt; 2-fold increased risk of SCD (HR 2.36, 95% CI 1.42-3.95, p=0.001). In a multivariable Cox regression model that adjusted for other predictors of SCD in this population (randomized treatment, age, gender, race, history of atrial fibrillation, stroke or transient ischemic attack, baseline serum creatinine and glucose entered as standard covariates and incident MI, incident HF and in-treatment diastolic pressure, heart rate, QRS duration, HDL cholesterol, and use of hydrochlorothiazide or a statin entered as time-varying covariates), COPD remained associated with a nearly 2-fold increased risk of SCD (HR, 1.82; 95% CI, 1.04-3.18, p=0.035). Conclusions: COPD is associated with an increased risk of SCD in hypertensive patients. The higher SCD risk in COPD patients persists after adjusting for the higher prevalence of risk factors in COPD patients, in-treatment blood pressure, incident MI and HF, and the established predictive value of in-treatment ECG LVH and heart rate for SCD in this population.