tbuckley/cabot-search huggingface dataset:
Prostate specific antigen doubling time (PSADT) in patients with hormone refractory prostate cancer (HRPC) undergoing docetaxel chemotherapy as a predictor of overall survival
Authors: R. K. Pachynski, C. King, S. Srinivas
Journal: Journal of Clinical Oncology (2007)

15556 Background: Few data correlating PSADT and overall survival(OS) in patients with HRPC undergoing chemotherapy exist. Docetaxel has recently been shown to significantly improve OS in patients with HRPC, but with significant toxicities. The decision of when to initiate chemotherapy is not well defined, but the presence of symptoms or narcotic use has widely been used to indicate this. The current retrospective study aims to identify a specific PSADT that independently correlates with OS in HRPC patients receiving docetaxel. Methods: A retrospective review of all patients with HRPC receiving docetaxel from 2001 to 2006 was performed. Androgen independent prostate cancer (AIPC) was defined as the time of a rising PSA despite castrate levels of testosterone. Variables evaluated from time of AIPC to initiation of chemotherapy included PSA, PSADT, hemoglobin, alkaline phosphatase, Gleason score. Time to AIPC was also evaluated. Patients who had pain or were on narcotics at the time of chemotherapy initiation were considered symptomatic. OS was calculated for both time from AIPC to death or last follow-up, and for time from chemotherapy to death or last follow-up. Results: 50 patients treated with docetaxel for HRPC were evaluated. Median OS was 32 months, and median survival from start of docetaxel was 14 months. There was no difference in OS between symptomatic or asymptomatic patients. A PSADT of &gt;2 mos was significantly correlated with improved median OS (p= 0.005). Univariate analyses of all other factors were not significant. Furthermore, in patients with a favorable outcome ( &gt;14 mos) from start of docetaxel, a PSADT of &gt;2 mos was a significant predictor of improved survival (p=0.02). Conclusions: This is the first study to evaluate PSADT in HRPC patients receiving docetaxel exclusively. Our data shows that a shorter PSADT (&lt;2 mos) significantly predicts shorter OS. Symptoms or narcotic use did not correlate with OS. Taken together, these data suggest that a PSADT of &lt;2 mos may be a better predictor of when to initiate chemotherapy than symptoms or narcotic use. The lack of significant correlation between the other variables and OS may further suggest the robustness of PSADT as a predictive variable. No significant financial relationships to disclose.
Abstract P160: Contributing Factors to Prolonged Length of Hospital Stay After Readmission Among Patients With Cardiovascular Diseases in Rural Appalachia
Authors: Hadii M Mamudu, Sylvester Orimaye, Manul Awasthi, Arsham Alamian, Liang Wang, David Stewart, Adeola Awujoola, Adekunle Oke, Fenose Osedeme, Nonna Stepanov, Timir K Paul
Journal: Circulation (2020)

Introduction: The Appalachian region has a disproportionate rate of morbidity and mortality related to cardiovascular diseases (CVD), compared to other regions in the United States. Readmission after initial hospitalization for CVD is a major health and economic burden. However, little is known about the factors that contribute to a prolonged length of hospital stay (LOS) after readmission for CVD in rural Appalachia. This study aimed to identify factors associated with prolonged LOS after readmission of patients with CVD in rural Appalachian region. Hypothesis: It is hypothesized that certain demographic and CVD risk factors would be positively and significantly associated with prolonged LOS after readmission of patients with CVD. Methods: Study population consisted of 2,063 patients from Central Appalachia who were diagnosed with ≥1 CVD-related medical comorbidities (diabetes, hypertension, hypercholesterolemia, depressive symptoms, coronary artery disease, stroke, and heart failure) and readmitted between 2010 and 2016 to a large health system. The average LOS was assessed and the Cox Proportional Hazard Ratios (HR) were calculated to identify factors associated with prolonged LOS (defined as a LOS of six or more days) after readmission among CVD patients. The median LOS and probability of prolonged LOS for different sociodemographic risk groups in the study population were calculated. Results: The average LOS was 13.44±45.77 days. A one-year increase in the age of CVD patients tended to increase the risk of prolonged LOS by 0.6% (95% CI: 1.00-1.01; p=0.04). Additionally, being male was found to be associated with increased risk of prolonged LOS (HR: 1.20; 95% CI: 1.08-1.34; p&lt;0.001). Similarly, having at least one CVD related comorbid condition increased the risk of prolonged LOS by 23.3% (95% CI: 1.03-1.47; p=0.02). Our findings also showed that both underweight and obese CVD patients were at 58.2% (95% CI: 0.52-0.65; p&lt;0.0001) and 53.6% (95% CI: 0.50-0.56; p&lt;0.0001) higher risk of having a prolonged LOS, respectively. Conclusions: In conclusion, increasing age, being male, having ≥1 comorbidities of CVD, and being underweight or obese were positively associated with prolonged LOS after hospital readmission in this rural population. These findings suggest that preventing and treating comorbid conditions and CVD risk factors may lower the likelihood of a prolonged LOS after readmission.
An overview of SELECTTION: Survey of European lung cancer evaluating choice of treatment and tolerability in observed second-line non-small cell lung cancer (NSCLC)
Authors: E. F. Smit, A. Vergnenegre, J. Arellano, K. Kraaij, A. Kral, F. Langer, C. Visseren-Grul
Journal: Journal of Clinical Oncology (2007)

18204 Background: In addition to established second-line treatments for NSCLC in Europe, docetaxel and pemetrexed; erlotinib, has recently been approved. The only study directly comparing alternative options in second-line NSCLC showed no significant difference in efficacy between docetaxel and pemetrexed (median survival 7.9 vs 8.3 months, p = 0.226) but significant differences in toxicity profile (Hanna et al, 2004). It is of interest to observe how different second-line treatment options are used in real life settings, particularly length of therapy, reasons for discontinuation and its impact on patient’s outcomes. Methods: In observational studies patients are not assigned to different treatments at random and physicians and patients decide on treatment. A careful design is paramount to ensure the correct interpretation of data obtained. SELECTTION is the first observational, non-interventional, prospective study to be carried out in Europe in second-line NSCLC treatment. The primary objective of SELECTTION is to assess the time from treatment initiation to treatment discontinuation. Secondary objectives are to observe the reasons for treatment discontinuation and assess its impact on patient’s outcomes. A total of 13 countries will participate including: France, Portugal, Germany, Denmark, and UK with approximately 200 sites enrolling 950 patients. Information regarding patients and disease characteristics and treatment history are collected. Patients may be enrolled if they have received first-line chemotherapy for locally advanced or metastatic NSCLC, and have subsequently progressed, are at least 18 years old and are about to initiate second line treatment. Treatment cohorts will be constructed based on the distribution of patients across second-line treatments by physician decision. Results: At this stage details about design and analyses planned as well as evolution of the study, will be presented. Conclusions: SELECTTION will provide a unique set of data on how patients with stage IIIb\/IV NSCLC previously treated with chemotherapy, are treated in routine clinical practice. No significant financial relationships to disclose.
Abstract 17341: Novel Lipid Markers of Calcific Aortic Valve Stenosis
Authors: Pascal E Bogaert, Andrea L Edel, Arun Surendran, Michael Raabe, Shubhkarman Sandhawalia, Davinder Jassal, Amir Ravandi
Journal: Circulation (2018)

Introduction: Calcific aortic valve stenosis (CAVS) is the most prevalent cardiac valvular pathology, leading to a high incidence of morbidity and mortality if left untreated. The exact pathophysiology of CAVS is largely undefined. Genetic studies have shown a strong correlation of the Lp(a) gene to developing CAVS. Lp(a) is known to be the carrier of plasma Oxidized Phosphatidylcholine and results in Lysophosphatidic acid (LPA) accumulation. The focus of the present study was to determine if OxPC and LPA in calcific human aortic valves relate with echocardiographic markers of CAVS. Methods: Aortic valves (n=98) were obtained from patients undergoing AVR. OxPC and LPA were extracted from pulverized aortic valves and analyzed using a targeted mass spectrometry approach. Lipid values are represented relative to an internal standard and normalized by homogenate and leaflet weights. The severity of calcification and aortic stenosis were measured anatomically by Echocardiographic calcification (ECC) score and hemodynamically by mean AV pressure gradient. Results: One-palmitoyl-2-(9-oxo)-nonanoyl- sn- glycero-3-phosphocholine (PONPC) was the most abundant OxPC among 58 OxPC molecules detected (49.3±3.8ng), in AV tissue. When valves were graded by ECC score, scores of 1 (no calcification) had observably attenuated amounts of mean total OxPC’s (135.3±39.3ng) compared to those with a score of 4 (severe calcification) (310.1±34.8 ng). Total valvular OxPC increased linearly with increased ECC score. Total non-fragmented OxPC’s were also significantly lower in valves with ECC scores of 1 and 2 compared to a score of 4 ( P =0.03). Six LPA species were also identified with 16:0 and 18:1 being the most prevalent. Mean AV pressure gradient had a significant, positive correlation with Total LPA amounts (r 2 =0.580, p &lt;0.001), suggesting that elevated LPA concentrations in CAVS tissue is associated with disease severity. Conclusions: Our study is the largest lipidomics study of human aortic valve tissue demonstrating that OxPC and LPA molecules play a significant role in the etiology of CAVS and provides a novel therapeutic target for mitigating disease progression.
Feasibility of sequential fixed S-1 followed by paclitaxel for the treatment of advanced or recurrent gastric cancer
Authors: M. Ohashi, T. Kanda, K. Yajima, H. Honma, S. Kosugi, K. Hatakeyama, T. Kobayashi, M. Hayami
Journal: Journal of Clinical Oncology (2007)

15113 Background: First-line chemotherapy for advanced/recurrent gastric cancer has limited efficacy, achieving a median survival time (MST) of about 7 months, while addition of second-line and subsequent chemotherapy may prolong MST to about 11.5 months. In practice, however, about half of patients failing with first-line chemotherapy are unable to receive second-line chemotherapy because of worsening of their performance status (PS), disease progression, or toxicities during protracted first-line chemotherapy. We studied the feasibility of a sequential fixed regimen devised to ensure prompt initiation of second-line chemotherapy after first-line failure. Methods: Between December 2002 and December 2006, patients with advanced or recurrent gastric cancer were enrolled who met the following requirements: 1) major organ function preserved; 2) PS 0–2; 3) presence of at least one evaluable lesion; and 4) written informed consent. The treatment regimen consisted of 3 courses of single-agent S-1 or S-1/cisplatin combination followed by weekly paclitaxel (wPTX). The endpoints of the study were entry to the second-line treatment, time to failure (TTF), and MST. Results: Of 39 patients enrolled, 37 completed first- line S-1. Twenty-eight patients (76%) then received wPTX, 2 non-wPTX chemotherapy, and 6 surgery; only 1 received no additional treatments. Second-line wPTX was followed by a third-line treatment in 23/28 patients (82%). The TTF with the sequential fixed regimen was 7 months. The MST and the 1- and 2-year survival rates in the 37 completing first-line treatment were 14.6 months, 61% and 25%, while those in the 28 switched over to wPTX were 12.5 months, 51% and 17%. Conclusions: Patients with advanced/recurrent gastric cancer treated sequentially with a fixed number of courses of S-1 followed by wPTX may have a good chance of treatment continuation. A sequential fixed regimen may further improve survival of patients with advanced/recurrent gastric cancer only with combinations of currently available drugs. No significant financial relationships to disclose.
Inhibition of poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies: Results of a phase 0 trial
Authors: S. Kummar, R. Kinders, M. Gutierrez, L. Rubinstein, R. E. Parchment, L. R. Phillips, J. Low, A. J. Murgo, J. E. Tomaszewski, J. H. Doroshow
Journal: Journal of Clinical Oncology (2007)

3518 Background: Inhibition of PARP activity sensitizes tumor cells to the effects of DNA damaging agents. We conducted a phase 0 pharmacokinetic (PK) and pharmacodynamic (PD) study of ABT-888, an oral inhibitor of PARP. Methods: The objectives were to determine a dose range at which ABT-888 inhibits PARP in tumor tissue and in peripheral blood mononuclear cells (PBMC); and the PK of ABT-888. Patients with advanced solid tumors refractory to at least one line of therapy were eligible; patients with CLL or follicular lymphomas were also eligible if standard therapy was not currently indicated. A single oral dose of ABT-888 was administered per patient, dose escalations were planned in cohorts of 3 patients each (10 mg, 25 mg, 50 mg, 100 mg, and 150 mg). PBMC and tumor sampling were performed before and after drug administration for real time PK and PD analyses. All patients underwent PBMC sampling; tumor biopsies were planned once significant inhibition of PARP activity in PBMCs was seen in 1 of 3 patients in a cohort or plasma Cmax of 210 nM was achieved in at least 1 patient. Tumor biopsies were performed at baseline in the week prior to drug administration and then 3–6 hours post drug administration. Significant inhibition of PARP activity was defined as at least 0.69 reduction on the log scale, which also satisfied statistical significance. Results: A total of 6 patients have been studied so far, 3 each for the 10 mg and 25 mg cohorts. No treatment related adverse events have been observed. Target Cmax was exceeded in the first cohort, all patients in the next cohort underwent tumor biopsies in addition to PBMC sampling. A trend towards inhibition of PARP activity in PBMCs was observed in the first cohort. Significant inhibition of PAR levels was observed in tumor biopsies from all 3 patients in the second cohort (92%, 99%, 100% reductions respectively, as compared to baseline). Greater than 85% reduction of PAR levels was observed in PBMCs from 2 of the 3 patients in the second cohort (one patient was not evaluable). Conclusions: ABT-888 is orally bioavailable and inhibits PARP activity in PBMCs and tumor cells. Target assay feasibility was established in human samples. Funded in part by NCI Contract N01-CO-12400 No significant financial relationships to disclose.
Teaching students how to critically evaluate information from drug companies
Authors: Eleanor M J White, Alexander W Lawrence
Journal: BMJ (2020)

Moynihan and colleagues propose ways to produce trustworthy evidence without industry influence.1 The evidence is clear—exposure to the marketing tactics of drug companies negatively affects healthcare professionals’ prescribing and treatment habits.2 Not enough is being done to tackle harmful marketing practices, and more attention must be given to the commercial influences targeting medical students …
Abstract P369: Polypharmacy, Adverse Outcomes, and Treatment Effectiveness in Elderly Patients With Atrial Fibrillation
Authors: Aniqa Alam, Nemin Chen, Pamela L Lutsey, Richard MacLehose, J'Neka Claxton, Lin Yee Y Chen, Alanna M Chamberlain, Alvaro Alonso
Journal: Circulation (2020)

Background: Polypharmacy is highly prevalent in elderly individuals with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly AF patients remains unaddressed. Methods: We studied 338,810 AF patients ≥75 years of age with 1,761,660 active prescriptions [mean (SD), 5.1 (3.8) per patient] enrolled in the MarketScan Medicare Supplemental database in 2007-2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis based on outpatient pharmacy claims. AF treatments (oral anticoagulation, rhythm and rate control) and cardiovascular endpoints (ischemic stroke, bleeding, heart failure) were defined based on inpatient, outpatient and pharmacy claims. Multivariable Cox models were used to estimate associations of polypharmacy with cardiovascular endpoints and the interaction between polypharmacy and AF treatments in relation to cardiovascular endpoints. Results: Prevalence of polypharmacy was 52% (176,007 of 338,810). Patients with polypharmacy had increased risk of major bleeding [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.12, 1.20] and heart failure (HR 1.33, 95%CI 1.29, 1.36), but not of ischemic stroke (HR 0.96, 95%CI 0.92, 1.00), compared to those not with polypharmacy (Table). Polypharmacy status did not consistently modify the effectiveness of oral anticoagulants. However, rhythm control (vs. rate control) was more effective in preventing heart failure hospitalization in patients not with polypharmacy (HR 0.87, 95%CI 0.76, 0.99) than among those with polypharmacy (HR 0.98, 95%CI 0.91, 1.07, p for interaction = 0.02). Conclusion: Polypharmacy is frequent among elderly patients with AF, associated with adverse outcomes, and potentially affecting the effectiveness of AF treatments. Optimizing management of polypharmacy in elderly AF patients may lead to improved outcomes.
Randomized phase II study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer (NSCLC)
Authors: T. J. Lynch, D. W. Fenton, V. Hirsh, D. J. Bodkin, E. Middleman, A. Chiappori, B. Halmos, H. Liu, O. Eton, W. F. Shepherd
Journal: Journal of Clinical Oncology (2007)

7680 Background: Treatment options for previously treated NSCLC are limited, warranting consideration of novel combinations. This study evaluated the activity and toxicity of erlotinib with bortezomib, a proteasome inhibitor. Dosing was based on the approved indication for erlotinib and on phase I data for the combination. Methods: Patients (pts) with Stage IIIB/IV NSCLC who progressed following one prior line of chemotherapy, with no prior exposure to an EGF-receptor inhibitor and ECOG performance status 0 or 1 were randomly assigned to erlotinib 150 mg po daily alone (arm A) or in combination with bortezomib 1.6 mg/m 2 iv on days 1 and 8 (arm B) of a 21-day cycle. Response was evaluated by RECIST and toxicity was graded using NCI CTCAE 3.0. A Simon optimal two-stage design was used to evaluate anti-tumor activity in response-evaluable pts. Results: Fifty pts were treated at 17 sites (January-June 2006); baseline characteristics and treatment intensity were comparable in both arms. Among 24 response-evaluable pts in each arm, there were 3 partial responses (PR) and 1 complete response in arm A and 2 PR in arm B. Median progression-free survival (PFS) was 2.7 and 1.4 months in arms A and B, respectively. The study was halted as required at the planned interim analysis due to insufficient clinical activity in arm B. Activity and toxicity in arm A were consistent with published reports for erlotinib alone. Adverse-event profiles were as expected in both arms, with no significant additivity. In arm B, one pt died of pneumonia. The most common grade 3 treatment-related toxicity was skin rash (12% arm A and 8% arm B), and rash severity correlated with PFS: grades 2/3, 2.8 months PFS (20 pts); grades 0/1, 1.4 months PFS (28 pts), p=0.032. In arm B, one pt each had grade 3 anorexia, hypokalemia, and worsened peripheral sensory neuropathy compared with baseline. There were no grade 4 treatment related toxicities in either arm. Conclusions: The combination of erlotinib and bortezomib in the doses and schedules used in this trial was well tolerated but did not show sufficient activity at this dose and schedule to warrant further development. No significant financial relationships to disclose.
Association Between Second Progression-free Survival (PFS2) and Overall Survival in Metastatic Castration-resistant Prostate Cancer
Authors: David Lorente, Elena Castro, Rebeca Lozano, Javier Puente, Nuria Romero-Laorden, Alejo Rodríguez-Vida, Nuria Lainez, Rosa Villatoro, Casilda Llácer, Carlo Cattrini, Amaia Hernández, Montserrat Domenech, Francisco Zambrana, Elena Almagro, Raquel Luque, Esther Martinez, Fernando López-Campos, Belen Gonzalez, Maria Jose Méndez-Vidal, Ana Medina, Josep Maria Piulats, David Olmos
Journal: European Urology (2020)
Preclinical development of GRN163L, a telomerase inhibitor for cancer therapy
Authors: Robert J. Tressler, Allison C. Chin, Sergei Gryaznov, Calvin B. Harley
Journal: Cancer Research (2005)

4326  Telomerase is an enzyme required for maintenance of telomeric DNA “capping” of the ends of eukaryotic chromosomes. Without telomerase, telomeres shorten to a critical length, resulting in chromosomal instability, and cell cycle arrest or death. Human telomerase is repressed in most normal somatic cells, transiently inducible in certain stem or progenitor cells, and constitutively activated in germline and tumor cells. There is a strong correlation between tumorigenesis and telomerase activation, therefore telomerase is considered a promising therapeutic target for the treatment of cancer. GRN163L is a lipid-conjugated thio-phosphoramidate (N3’-P5’) oligonucleotide being developed as the first specific telomerase inhibitor for the treatment of cancer. GRN163L binds tightly to the template region of the RNA component of telomerase, blocking the active site of the enzyme. GRN163L inhibition of telomerase activity results in the slowing of tumor cell growth and progression in vitro as well as inhibiting tumor growth in various in vivo tumor models, including myeloma, hepatocellular, ovarian, and lung cancer. Additionally, combination studies with various cytotoxics, including melphalan, Velcade and taxol in selected tumor models, including melanoma, myeloma and ovarian carcinoma models have demonstrated increased efficacy of GRN163L and chemotherapy co-treatment over either agent alone. Preclinical safety studies indicate that GRN163L generally has a toxicity profile that is similar to that typically observed for the oligonucleotide class of molecules, with a clear relationship between plasma concentration and acute toxicity effects, and are readily managed by dose and infusion time. ADME and pharmacodynamic studies support an intermittent treatment schedule at drug levels that should achieve efficacious concentrations of GRN163L in cancer patients. GRN163L has been manufactured under GLP and GMP conditions, yielding sufficient drug substance to support preclinical toxicity, safety pharmacology, and pharmacokinetic studies, as well as Phase I clinical studies. Selection of the clinical indication(s) and design for Phase I and subsequent clinical studies are in progress with guidance from ongoing preclinical safety, pharmacodynamic and efficacy studies.
Re: Multi-institutional Re-evaluation of Prognostic Factors in Chromophobe Renal Cell Carcinoma: Proposal of a Novel Two-tiered Grading Scheme
Authors: Alessia Cimadamore, Liang Cheng, Riuko Ohashi, Marina Scarpelli, Antonio Lopez-Beltran, Holger Moch, Rodolfo Montironi
Journal: European Urology (2020)