tbuckley/cabot-search huggingface dataset:
Clinical and biochemical parameters as predictors of response to checkpoint inhibitors (CPI): A single institution experience.
Authors: Shipra Gandhi, Manu Pandey, Nischala Ammannagari, Katy Wang, Karen L Vona, Jill Nestico, Lamya Hamad, Grace K. Dy, Marc S. Ernstoff
Journal: Journal of Clinical Oncology (2017)

e14590 Background: The benefit of CPI is limited to a subgroup of patients. Significant toxicity and financial burden make it imperative to identify biomarkers predictive of clinical benefit. We aimed to analyze if immune related adverse events (irAE), laboratory parameters (besides PD-L1 status), prior chemotherapy and concomitant medication use could predict response to CPI. Methods: 216 consecutive patients treated at RPCI with single/multiple CPI from 2011 to 2016 were identified. Demographics, irAE (CTCAE v4.03), concomitant medication use, response (RECIST v1.1) and laboratory parameters were recorded. Progression free (PFS) and overall survival (OS) were calculated. Clinical benefit (responder) was defined as objective response or stable disease with PFS ≥ 6 months. Statistical analysis was performed using SAS v9.4. Results: 185/216 patients (86%) had clinical outcomes with first CPI available (55.7% melanoma, 28.1% lung, 10.8% kidney, 3.8% bladder, 1.6% others), 14% died before disease assessment. Median age was 61 years; 64% were males. 31% were responders (R); 69% non-responders (NR). Median PFS and OS for R were not reached and for NR were 4.7/7 months (p &lt; 0.001). 26% R developed rash vs. 12% NR (p = 0.02). irAE diarrhea was associated with better OS (p = 0.03); rash with better PFS (p = 0.007) and OS (p = 0.05). Concomitant beta-blocker/NSAID use was noted in 35%/28% R vs 20%/12% NR (p = 0.04; p = 0.01). Higher median absolute eosinophil (AEC) and absolute lymphocyte count (ALC) were noted in R (400 and 2000/µl in R vs. 300 and 1600/µl in NR; p = 0.008 and 0.024). NR were noted to have a higher median lactate dehydrogenase (LDH) of 565 vs. 503 (p &lt; 0.001). AEC &gt; 100/µl and ALC &gt; 1000/ µl were associated with better OS (P = 0.03; P = 0.001). Absolute neutrophil count (ANC) &gt; 7500/µl and leucocyte count &gt; 8750/ µl were associated with inferior PFS (p = 0.005; P = 0.02) and OS (p = 0.002; p = 0.03). Pre-CPI chemotherapy did not correlate with response to CPI. Conclusions: Among irAE, diarrhea and rash predicted improved outcomes. Eosinophilia, lymphocytosis, neutrophilia, leukocytosis and LDH could serve as potential prognostic biomarkers to CPI. Prospective studies are warranted to validate these findings.
Effect of chemoradiation for cervical cancer on transient decrease and variable expansion in T-cell infiltrate and diversity of T-cell repertoire.
Authors: Lauren Elizabeth Colbert, Stephanie Dorta-Estremera, Rebecca A. Previs, Patricia J. Eifel, Anuja Jhingran, Lois M. Ramondetta, Stephen M. Hahn, James William Welsh, Amir A. Jazaeri, Michael M. Frumovitz, Jagannadha Sastry, Ann Klopp
Journal: Journal of Clinical Oncology (2017)

11557 Background: The effect of fractionated radiation on intratumoral immune infiltrate is unclear. The purpose of this study was to characterize local immune changes and treatment response during chemoradiation (CRT). Methods: Cervical cancer patients underwent cisplatin based CRT over 5 weeks with brachytherapy. Cervical DNA swabs and cytology brushings were collected at baseline, one week, three weeks and five weeks. Deep T cell receptor β sequencing (TCR; Adaptive, Seattle WA) and multiparametric flow cytometry (MPFC) were performed for each time point. T cell density (TCD) and productive clonality (PC) were analyzed. Cells separated from the tumor brushings were stained and fixed with antibodies to T cell subsets with activation and suppressor markers including CD3, CD4, CD8, Ki67, PD-1, CTLA-4, and ICOS. Changes in T cell subsets were evaluated as percentage of live lymphocytes. Results: Eight patients were evaluated using MPFC. CD4 and CD8 percentages were lowest at one week and subsequently expanded. The percentage of proliferating CD4 (CD4+ Ki67+) was highest at week 5 (1.19%). There was no change in percentage of CD8+ cells expressing PD1, CTLA4 or ICOS over the course of treatment. TCR diversity was assessed for 9 patients. At baseline, week 1, week 3 and week 5, median TCD for all patients were 0.046 (IQR 0.008 to 0.097), 0.021 (IQR 0.005 to 0.043), 0.035 (IQR 0.015 to 0.083), and 0.033 (IQR 0.017 to 0.110). Median productive clonality at each point was 0.05 (IQR 0.06 to 0.02), 0.03 (IQR 0.06 to 0.02), 0.04 (IQR 0.05 to 0.02) and 0.03 (IQR 0.01 to 0.05). PC fold count increased (1.69, SD 1.3) for complete response (CR) patients and decreased 0.3 (SD 0.008) for patients with recurrent (REC) disease (p = 0.1). One TCR sequence was common in 4/9 patients at the end of treatment and six sequences were common in 3/9 patients. Conclusions: Chemoradiation induces a transient decline in tumor infiltrating CD8+ and CD4+ cells, followed by a variable expansion in T-cells at the end of treatment with an increase in proliferation phenotypes. TCR sequencing revealed increase in productive clonality during radiation for patients with a complete response to treatment.
Circulating vitamin D during neoadjuvant therapy in high-risk rectal cancer.
Authors: Hanna Abrahamsson, Alina C Porojnicu, Jonas C Lindstrøm, Svein Dueland, Kjersti Flatmark, Knut H Hole, Therese Seierstad, Johan Moan, Kathrine Røe Redalen, Sebastian Meltzer, Anne Hansen Ree
Journal: Journal of Clinical Oncology (2018)

e15532 Background: Following curative intention neoadjuvant therapy in locally advanced rectal cancer, metastatic progression is still dominant. We investigated if patient’s circulating 25-hydroxyvitamin D [25(OH)D] level was associated with outcome. Methods: Serum 25(OH)D concentration was assessed in samples collected from 84 patients at baseline, completion of the neoadjuvant therapy, and treatment evaluation before surgery, and analyzed with respect to the season of diagnosis, disease presentation, and treatment effects. Results: In the cohort of patients residing at latitude 58-62°N, baseline 25(OH)D levels differed significantly over the seasons, with highest measures (mean of 71.2±5.6 nmol/L) in summer and lowest (48.7±4.5 nmol/L) in spring, and changed over the three-month neoadjuvant period till response evaluation solely owing to season. Patients with slightly reduced performance status or anemia, as well as those with T4 disease that did not respond to the neoadjuvant therapy (ypT4 cases), had significantly lower baseline 25(OH)D levels ( < 50 nmol/L) than T4 cases with response (ypT0-3) and T2-3 cases ( > 60 nmol/L). A third of patients with T4 disease had particularly low 25(OH)D ( < 35 nmol/L). Compared to the T4 patients with levels > 50 nmol/L, regarded as adequate for bone health, those presenting levels below had significantly heightened risk of disease progression (mainly metastasis) and death, with hazard ratio of 3.21 and 17.5, respectively. Conclusions: Rectal cancer T4 cases had high risk of metastatic progression and death if circulating 25(OH)D levels were insufficient but obtained short-term and long-term outcome to neoadjuvant treatment no worse than patients with T2-3 disease when 25(OH)D was sufficient. Clinical trial information: NCT00278694.25(OH)D, nmol/L T2-3 cases T4 cases < 50 ≥50 p1 < 50 ≥50 p1 PFS No. at risk 18 35 14 17 No. of events 4 12 9 6 Multivariable HR (95% CI)2 0.548 (0.176-1.71) Referent 0.30 3.21 (1.08-9.54) Referent 0.036 OS No. at risk 18 35 14 17 No. of events 2 5 7 1 Multivariable HR (95% CI)2 0.594 (0.110-3.22) Referent 0.55 17.5 (1.98-155) Referent 0.010 PFS = progression-free survival, OS = overall survival, HR = hazard ratio, CI = confidence interval 1 Estimated by Cox proportional hazard model 2 Adjusted for age, sex, and body mass index
TCT-664 Twelve-Month Clinical Outcomes Comparing Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Coronary Stents in Patients With De Novo Native Coronary Artery Lesions: The meriT-V Randomized Trial
Authors: Alexandre Abizaid, Ricardo Costa, Roberto Botelho, Pedro A. Lemos, Elvin Kedhi, Jacques J. Koolen, Alexander Ijsselmuiden, Luc Janssens, Farzin Fath-Ordoubadi, Suneel Talwar, Monica Masotti, Andrejs Erglis, Sasko Kedev, Ota Hlinomaz, Petr Kala, Krzysztof Milewski, Sripal Bangalore
Journal: Journal of the American College of Cardiology (2018)
Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC): A phase 1/2 clinical trial.
Authors: Jorge A. Garcia, Robert Dreicer, Allan J. Pantuck, Naomi B. Haas, Ulka N. Vaishampayan, Niranjan Sathyanarayana Rao, Louis J. Denis, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2017)

5041 Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase that selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction. Methods: This Phase (Ph) 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While Ph 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Ph 2. Endpoints include maximum dose (MTD) and dose limiting toxicities, recommended Ph 2 dose, PK, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 26 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, constipation and nausea. At 400mg, two pts experienced asymptomatic, reversible Gr 3 ALT/AST elevation, but no recurrence when retreated at 300mg. Enrollment of ABI/ENZA naïve patients continues at lower doses to further evaluate safety and efficacy. Testosterone decrease to below quantifiable limits and DHEA decrease of up to 80% was observed. Systemic exposure was high (C max , AUC and T 1/2 at 300 mg QD were 6.7 µM, 80 µM.h and 21.5 h, respectively). Stable disease up to 18+ months has been observed despite prior ABI and ENZA exposure. PSA decline of &gt; 50% (up to 93% decline) and up to 37+ wks duration was observed in 3 of 4 ABI/ENZA naïve patients at starting doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated. Prednisone co-administration was not needed. Encouraging preliminary evidence of efficacy is reflected by PSA declines in evaluable mCRPC pts not pretreated with ABI or ENZA and by durable disease stabilization in refractory disease. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.
Goals and aggressiveness of care in metastatic lung cancer.
Authors: Francois Goldwasser, Pascale Vinant, Olivier Huillard, Lucas Morin
Journal: Journal of Clinical Oncology (2016)

10026 Background: Early integration of palliative care for patients with metastatic lung cancer was found to improve quality of life, survival and to reduce care aggressiveness near the end-of-life. We examined the association between the timing of palliative care diagnosis and the aggressiveness of end-of-life care. Methods: We used the French national hospital registry to identify all hospitalized adults ( ≥ 20 years) who died from metastatic lung cancer in France between 2010 and 2013. We compared the use of care and treatments near the end of life between patients whose palliative care needs were first identified during the 3rd month, 2nd month, 4th to 3rd weeks, 2nd week and last week before death and patients whose palliative care needs were never identified. A propensity score-weighting method was used to control for potential confounders. Results: A total of 64,950 patients died from metastatic lung cancer and were included. 6,716 (10.3%) patients had palliative care needs first identified during the 3rd month before death, 10,361 (16.0%) during the 2nd month before death, 11,721 (18.1%) during the 4th to 3rd week before death and 17,046 (26.2%) during the last 2 weeks before death. 19,106 (29.4%) patients had no identified palliative care needs until death. After propensity score-weighting, patients whose palliative care needs were first identified during the 3rd month before death had the earliest and most progressive decrease in the use of anticancer treatments. During the last week of life, patients whose palliative care needs were never identified were more likely to die in intensive care units (OR = 11.0, 95%CI = 8.2-13.9), to receive chemotherapy (OR = 1.9, 95%CI = 1.7 to 2.1), radiation therapy (OR = 1.5, 95%CI = 1.3-1.8), blood transfusion (OR = 1.3, 95%CI = 1.2-1.5), invasive ventilation (OR = 6.9, 95%CI = 5.4-8.9), CPR (OR = 15.7, 95%CI = 6.5-51.6), hemodynamic support (OR = 5.9, 95%CI = 4.7-7.5) or dialysis (OR = 5.6, 95%CI = 3.4-9.7), compared with patients whose palliative care needs were first identified during the 3rd month before death. Conclusions: The aggressiveness of end-of-life care is dependent on the time of introduction of palliative care: the earlier is the integration, and the earlier and the greater is the benefit.
Abstract 18480: A Novel Cardiac Biomarker Algorithm For Endothelial Injury Identifies Patients With Lower Estimated Global Risk For Cardiovascular Disease And Discordantly High 5-year Risk For Acute Coronary Syndrome
Authors: Masood Younus, Wenjun Fan, Doug S Harrington, Nathan D Wong
Journal: Circulation (2017)

Introduction: Traditional global risk assessment for cardiovascular disease (CVD) fails to identify a significant percentage of the population at high risk for acute coronary syndrome (ACS). We exa...
Which is better in CD19 CAR-T treatment of r/r B-ALL, CD28 or 4-1BB? A parallel trial under the same manufacturing process.
Authors: Peihua Lu, Xin-an Lu, Xian Zhang, Min Xiong, Jianping Zhang, Xiaosu Zhou, Feifei Qi, Junfang Yang, Ting He
Journal: Journal of Clinical Oncology (2018)

3041 Background: Second-generation CARs have been shown to improve the overall functional activity and persistence of CAR-T cells. KYMRIAH and YESCARTA used 4-1BB and CD28 co-stimulatory signaling domains, respectively. Methods: A parallel trial under the same manufacturing process to compare the CD28 and 4-1BB CD19 CAR-T. Results: This study enrolled 47 relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) patients, including 19 patients in CD28 group and 28 patients in 4-1BB group. 47 patients who received at least one infusion treatment and one clinical evaluation were available for assessing safety and efficacy. The overall objective response rate (ORR) was 96%. The ORR of 4-1BB group (100%) was higher than that of CD28 group (89%). All of the patients achieving objective response were MRD negative. CAR-T cell expansion in peripheral blood was detected by Flow cytometry, and the peak of CAR-T cells of 4-1BB group was significantly higher than that of CD28 group. Different degrees of cytokine release syndrome (CRS) occurred in 45 of 47 patients (95%). 5 patients who had grade III-IV of CRS were all in CD28 group. Cytokine release peak in CD28 group was significantly higher than that of the 4-1BB group. 9 patients experienced different levels of neurotoxicity (19%). 5 patients who had grade III-IV of neurotoxicity were all in CD28 group, too. All adverse events were effectively controlled within 1 month. Conclusions: The study illustrates that 4-1BB CAR-T cells show enhanced safety, efficacy, and expansion than CD28 CAR-T cells, suggesting a superior therapeutic strategy in the treatment of relapsed or refractory CD19-positive B-ALL patients. Clinical trial information: NCT03173417.
Association between treatment facility volume and mortality in patients with glioblastoma (GBM): A large national analysis.
Authors: Sonikpreet Aulakh, Michelle DeDeo, Joseph Free, Kyle Berdeguez, Steven Rosenfeld, Alfredo Quinones-Hinojosa, Asher Alban Akmal Chanan-Khan, Sikander Ailawadhi
Journal: Journal of Clinical Oncology (2018)

2026 Background: Glioblastoma (GBM) is an aggressive primary malignancy of the brain, treated with surgical resection and chemo-radiotherapy, yet it has a dismal prognosis of 12-14 month overall survival (OS). Optimal outcomes require an experienced team providing multidisciplinary management. We explored the association of treatment facility volume and mortality in patients with GBM. Methods: We identified incident GBM (ICD-O-3 code: 9440/3) cases from the National Cancer Database (NCDB) (2004-2013) and utilized Cox-regression to determine the facility volume-outcome (volume = quartiles; Q) relationship, adjusting for year of diagnosis, demographic (sex, age, race, ethnicity), socio-economic (income, education, insurance type), geographic (area of residence, treatment facility location, travel distance) and co-morbidity factors (Charlson-Deyo score). Results: There were 114,467 patients (median age 60 years, range: 18-90) with GBM treated at 1207 facilities of which, 54.8% were men. Median annual facility volume was 5 patients/year (range: 0.1-136.4). The top 14 (1.2%) facilities treated > 60 patients/year (10%). Median overall survival (OS) was 15 months There were significant differences (all p < 0.001) in patient characteristics by facility volume (Table). Unadjusted median OS by facility volume (months) was Q1: 29.1, Q2: 32.9, Q3: 36.4, Q4: 48.2 (p < 0.0001). Multivariate analysis showed facility volume to be independently associated with all-cause mortality (Reference Q4; Q3 HR: 1.30, 95% CI 1.28-1.33; Q2 HR: 1.36, 95% CI 1.36-1.43; Q1 HR: 1.58 95% CI 1.50-1.67). OS disparity by facility volume is persistent but not worsening in recent years (2010-2013 vs 2004-2005). Conclusions: In GBM, facility-volume independently affects OS of the patients. Attempts should be made to address modifiable factors and get patients access to high-volume centers earlier in the disease course. Characteristic Lower Quartile (Q1, Q2, Q3) Higher Quartile (Q4) Patients seen/year < 1-12.2 12.2-136.4 Academic centers 7.3% 48.9% Median age (years) 63 58 Median travel distance to facility (miles) 7.2 14.7 Private Insurance 41.2% 50.4% Medicare/Medicaid 51% 40.7% Income > $46000 38.7% 43.6%
New primary lung cancers after a head and neck cancer: The impact of radiation therapy and latency period on risk.
Authors: Chetan Jeurkar, Tiffany Pompa, Jessica Ruth Bauman, Maneesh Rajiv Jain, Kristine Marie Ward, Michael Styler
Journal: Journal of Clinical Oncology (2017)

10015 Background: Patients with head and neck cancer (HNC) have an increased risk of developing a new primary lung cancer (NPLC). Our objective was to assess the critical latency period after HNC when the risk for a NPLC was highest and to see if radiation therapy (XRT) had an impact on this risk. Methods: This was a population based study of patients with HNC in the Surveillance, Epidemiology, and End Results (SEER) database. The risk of NPLC was calculated using standardized incidence ratios (SIR) and from this, the number needed to screen (NNS) was extrapolated. The cohort was separated by delivery of XRT and latency period of the NPLC. Results: There were a total of 4,209 NPLC from the cohort of 85,154 HNC patients. The SIR, NNS, observed/expected number of NPLC for both the no XRT and XRT groups are shown in table 1. As compared to the no XRT group, the XRT group had higher SIR and lower NNS values across all latency periods. The highest SIR for both the no XRT and XRT groups came between 1 and 3 years. Conclusions: In patients with HNC, the risk of developing a NPLC is associated with receiving XRT. This risk is highest within 10 years of the initial HNC diagnosis. The NNS was especially low for the XRT group, less than 100 for most latency periods. Since low dose computed tomography scans for lung cancer screening in smokers has a NNS of 217, screening for these patients should be considered, especially within 10 years of the primary HNC diagnosis. This may contribute to better survivorship care in these patients. [Table: see text]
TCT-390 Impact of Strut Thickness on Radial Force and Late Vascular Recoil of a Novel Thin-Strut Ultra High Molecular Weight PLLA Sirolimus-Eluting Bioresorbable Coronary Scaffold
Authors: Nicolas Isaza, Marco Ferrone, Gilberto Melnick, Yanping Cheng, Jenn McGregor, Kamal Ramzipoor, Chang Lee, Gerard Conditt, Grzegorz Kaluza, Juan Granada
Journal: Journal of the American College of Cardiology (2018)
Abstract 14577: Kvβ1.1 Binds Pyridine Nucleotides and Alters Cardiac Action Potential
Authors: Jared Tur, Sachin L Badole, Kalyan C Chapalamadugu, Srinivas M Tipparaju
Journal: Circulation (2015)

Introduction: Kvβ1 subunits demonstrate a unique ability to bind pyridine nucleotides and alter Kv channel function. Pyridine nucleotide levels are altered in cardiovascular diseases resulting in higher NADH levels. Therefore coupling of the Kvβ1 subunit with Kv channels may be important in how the repolarization is modulated in presence of NADH. Hypothesis: The Kvβ1 subunits are highly expressed in the heart and bind to multiple Kv channels (Kv4.x and Kv1.x) and regulate Kv channel activity. Therefore, we evaluated pyridine nucleotide changes in cardiovascular disease in the presence and absence of Kvβ1 and how they modulate Kv channel activity. Methods: Wild type (WT) and Kvβ1 knockout (KO) mice hearts (n=7 each group) using the ex-vivo Langendorff system were exposed to both acute and chronic alterations of lactate to induce an increase in NADH levels. Cardiac monophasic action potentials (MAPs) were measured before and 10 min after perfusion of the lactate, for chronic alterations mice were injected with isoprenaline to induce cardiac hypertrophy and demonstrated significant NADH increase. In addition we performed pull-down assays to identify binding partners of Kvβ1.1 in the heart. Results: We observed that, lactate exposure (10mmole/L) ( p &lt;0.05) prolonged left ventricular MAP duration in WT (9.4±0.7 vs. 15.6±1.2* at APD50) however KO mice demonstrated no significant difference (10.9±0.5 vs. 11.7±1.1). NADH levels in lactate exposed hearts demonstrated a 3 fold increase compared with control Krebs buffer. Lactate prolonged MAP durations in WT hearts, which was reversal by adding pyruvate (20mmole/L) to its control (pre-lactate; 8±0.5 vs. 13.6±0.6* vs. 8.4±0.6). The chronic model, MAP duration significantly ( p &lt;0.01) prolonged in the WT (9.7±0.7 vs. 15.3±1.1*) mouse hearts after isoprenaline infusion but not KO mouse (12.4±1.8 vs. 14.4±1). Immunoprecipitation experiments indicate that Kvβ1.1 interacts with Kv4.2 and Kv1.5 from mouse heart. Conclusions: Results obtained from this study suggested that the Kvβ1.1 subunit has the ability to sense redox changes including NAD/NADH alterations and modulate MAP through Kv activity. This study highlights the physiological role Kvβ1.1 plays in cardiac repolarization physiology and cardiac disease.