tbuckley/cabot-search huggingface dataset:
Global drug development in cancer: A cross-sectional study of clinical trial registries
Authors: P. Hertz, B. Seruga, L. W. Le, I. F. Tannock
Journal: Journal of Clinical Oncology (2009)

2520 Background: Clinical trials are increasingly funded by industry. High costs of drug development may lead to attempts to develop new drugs in more ‘profitable’ (i.e., more prevalent) as compared to ‘less profitable’ (i.e., more deadly) cancers. Here we determine the focus of current global drug development. Methods: We determined characteristics of phase II and III clinical trials evaluating new drugs in oncology, which were registered with WHO International Clinical Trial Registries between 01/2008 and 06/2008. Estimates of incidence, mortality, and prevalence in the more- and less-developed world (MDW, LDW) were obtained from GLOBOCAN 2002. Simple correlation analysis was performed between the number of clinical trials and incidence, mortality and prevalence per cancer site after log transformation of variables. Results: We identified 399 newly registered trials. Of 374 trials with information about recruitment, 322 (86.1%) and 39 (10.4%) recruited patients only from the MDW and LDW, respectively, while 13 (3.5%) had worldwide recruitment. 229 (58%) of trials were sponsored by industry and 324 trials were phase II (81%). Most trials (and most phase III trials) evaluated treatments for globally prevalent cancers: breast, lung, prostate, and colorectal cancer (Table). Prevalence of a particular cancer type in both the MDW and LDW correlated significantly with the number of clinical trials (Pearson r = 0.63 and 0.55; p = 0.01 and 0.03, respectively). In contrast, mortality in the MDW (Pearson r = 0.73; p= 0.002), but not in the LDW (Pearson r = 0.38; p= 0.17), correlated significantly with the number of clinical trials. Conclusions: Global drug development in cancer predominates in globally prevalent cancers, which are a more important cause of mortality in the MDW than in the LDW. Cancer sites that are major killers globally, and especially in the LDW (e.g., stomach, liver, and esophageal cancer) should receive priority for clinical research. [Table: see text] No significant financial relationships to disclose.
Impact of early molecular response to nilotinib (NIL) or imatinib (IM) on the long-term outcomes of newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): Landmark analysis of 4-year (y) data from ENESTnd.
Authors: Giuseppe Saglio, Timothy P. Hughes, Richard A. Larson, Surapol Issaragrilsil, Anna G. Turkina, Juan Luis Steegmann, Jose L. Lopez, Chiaki Nakaseko, Matt E. Kalaycio, Francoise Huguet, Charisse N. Kemp, Xiaolin Fan, Hans D. Menssen, Hagop M. Kantarjian, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2013)

7054^ Background: ENESTnd demonstrated the superiority of NIL to IM in pts with newly diagnosed CML-CP, such as higher rates of molecular response (MR) and reduced risk of progression to accelerated phase (AP)/blast crisis (BC). This landmark analysis of ENESTnd is based on BCR-ABL transcript levels at 3 mo, with 4 y of follow-up. Methods: Rates of major MR (MMR; BCR-ABL IS ≤ 0.1%), MR 4.5 (BCR-ABL IS ≤ 0.0032%), progression to AP/BC, overall survival (OS), and progression-free survival (PFS) in pts in the NIL 300 mg twice daily (BID; n = 282) and IM 400 mg once daily (QD; n = 283) arms of ENESTnd were evaluated based on 3-mo BCR-ABL levels (≤ 10% vs &gt; 10%). Results: More pts treated with NIL than IM achieved BCR-ABL ≤ 10% at 3 mo (91% vs 67%; Table). Other factors associated with MR at 3 mo included Sokal risk, spleen size, chromosomal abnormalities, white blood cell count, and median dose intensity (for NIL). On both arms, pts with BCR-ABL ≤ 10% at 3 mo had significantly higher rates of MMR and MR 4.5 and significantly improved PFS and OS than pts with BCR-ABL &gt; 10% at 3 mo. Of the pts with BCR-ABL &gt; 10% at 3 mo, 2 on NIL (8%) and 14 on IM (16%) progressed to AP/BC on study. Half of these progressions occurred between 3 and 6 mo. Analyses of outcomes based on BCR-ABL levels at 6 mo were similar to findings based on 3-mo data. Conclusions: BCR-ABL levels ≤ 10% at 3 mo were associated with superior outcomes, including higher rates of MR 4.5 by 4 y and lower risk of disease progression. More pts treated with NIL than IM achieved this early level of MR. Clinical trial information: NCT00471497. [Table: see text]
Phase I study of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed malignant tumors
Authors: H. Rubie, D. Frappaz, A. Defachelles, A. Ndiaye, N. Dias, I. Aerts, J. Gentet, L. Djafari, M. Jaworski, G. Vassal, B. Geoerger
Journal: Journal of Clinical Oncology (2008)

13553 Background: New drugs are strongly needed in childhood cancers, particularly in metastatic tumors. Temozolomide (TMZ) and Topotecan (TPT) have shown activity in several pediatric cancers. Resistance to alkylating agents due to MGMT expression, MMR deficiency or microsatellite instability may be overcome through the combination with topoisomerase I inhibitors. The combination of TPT with TMZ has never been given in patients and our objective was to determine the recommended dose (RD) in children. Methods: The study was conducted in 9 centers of the SFCE Pharmacology Group. TMZ was administered orally followed by TPT as a 30 minutes intravenous infusion for 5 consecutive days every 28 days. Dose escalation was performed in a classical 3+3 methodology starting at 100 mg/m2 TMZ and 0.75 mg/m2 TPT. Dose-limiting toxicity (DLT) was evaluated after the first cycle. Pharmacokinetic parameters were studied during the 1st cycle Results: Sixteen patients, median age 8.5 years (range 3–19), were enrolled between February and October 2007. Eight had neuroblastoma, 2 osteosarcoma and 6 other tumors. All had received prior chemotherapy (median 3 lines, range1–5) of whom 5 high-dose regimens. Main toxicity was hematologic and manageable. No DLT was observed in 3 patients at the first dose level. One of 6 had G3 thrombocytopenia >7 days at 150 mg/m2 TMZ and 0.75 mg/m2 TPT (level 2). Two of 3 patients had G3 thrombocytopenia with G4 neutropenia >7 days in one at 150 mg/m2 TMZ and 1.0 mg/m2 TPT (level 3). Of 4 additional patients treated at the RD (level 2), 1 experienced G3 thrombocytopenia. Pharmacokinetic data are pending. Conclusion: TMZ-TPT combination is well tolerated with hematological toxicity being the limiting toxicity. The RD is 150 mg/m2 TMZ and 0.75 mg/m2 TPT. A phase II study in metastatic/refractory pediatric tumors is in preparation. No significant financial relationships to disclose.
Abstract 18200: Impact of Pulse Pressure on the Progression of Aortic Valve Calcification in Patients with Aortic Stenosis
Authors: Lionel L Tastet, Romain Capoulade, Jean G Dumesnil, Eric Larose, Mylène Shen, Marie-Annick Clavel, Abdellaziz Dahou, Marie Arsenault, Elisabeth Bédard, Patrick Mathieu, Philippe Pibarot
Journal: Circulation (2014)

Introduction: Hypothesis: We hypothesized that elevated arterial pulse pressure (PP=systolic blood pressure - diastolic blood pressure) increases mechanical stress on aortic valve cusps, which may, in turn accelerate the mineralization of the valve. The aim of this study was thus to determine the impact of pulse pressure on the progression of aortic valve calcification in patients with AS. Methods: AVC was prospectively measured by Multidetector Computed Tomography (MDCT) in 75 patients at baseline and every 2 years during follow-up. AVC progression rate was assessed by the annualized increase in AVC. Results: Patients with high PP (i.e.>60 mmHg) had faster AVC progression rate compared to those with low PP (≤60 mmHg) (annualized AVC: +64 [6 - 223] AU/yr vs. +13 [-14 - 46] AU/yr; p=0.002). In multivariate analysis adjusted for age, gender, metabolic syndrome, hypertension, creatinine level, baseline AVC, PP was an independent predictor of faster AVC progression rate (p=0.001). Conclusions: This study show...
Docetaxel, cisplatin and leucovorin/fluorouracil in first-line advanced gastric cancer and adenocarcinoma of the esophagogastric junction: Results of the phase II GASTRO-TAX-1 trial
Authors: S. Lorenzen, N. Weigert, V. Heinemann, M. Hentrich, T. Schuster, T. Seroneit, N. Röthling, C. Peschel, F. Lordick
Journal: Journal of Clinical Oncology (2007)

4561 Background: Phase II and III trials combining docetaxel, cisplatin and fluorouracil (DCF) every 3 weeks (wks) have shown superior efficacy but high rates of hematological toxicity in advanced gastric cancer. To reduce toxicity while containing the efficacy of DCF, we conducted a protocol using split doses of docetaxel (T), cisplatin (P), leucovorin (L), fluorouracil (F) (T-PLF). Methods: Chemo-naive patients (pts) with advanced gastroesophageal adenocarcinomas received T 50 mg/m 2 , P 50 mg/m 2 day 1, 15, 29 and L 500 mg/m 2 plus F 2,000 mg/m 2 d1, 8, 15, 22, 29, 36 qd49. Because significant reductions to &lt;80% of initial drug doses became necessary in 80% of pts, the regimen was amended after the first 15 pts. After the amendment the agents were administered as follows: T 40 mg/m 2 , P 40 mg/m 2 , L 200 mg/m 2 , F 2,000 mg/m 2 . The primary objective was the overall response rate (ORR) according to RECIST. Results: From 03/04 to 08/05 we included 60 pts: median age 53 yrs, (26–76); 24 pts had locally advanced tumors (LA) and 36 pts had metastatic disease (MET). Pts received a median of 2 (range 0–4) cycles. Reductions to &lt;80% of drug doses were reported in 80% versus 60% of pts pre/post amendment. Reported adverse events were: neutropenia 23%, febrile neutropenia 5%, diarrhea 20%, nausea 8%, emesis 8% and fatigue 20%. The ORR according to RECIST was 46.6% (95%CI 33.3–61.4). Only 6.6% were primarily progressive. 23/24 pts with LA underwent secondary resection (96%). Complete resections (R0) were achieved in 87%. After a median follow-up of 25.5 months, median overall survival (OS) is 17.9 months (95%CI 11.5 -24.3). Median TTP is 9.4 months (95% CI 8.3–10.5). For pts with MET, median TTP is 8.1 months and median OS is 15.1 months. Conclusion: The T-PLF regimen is highly active, safe and has a favorable toxicity profile. [Table: see text]
Abstract 13540: Left Atrial Appendage Dysfunction in Acute Cerebral Embolism Patients with Sinus Rhythm. Correlation with Pulse Wave Tissue Doppler Imaging
Authors: Kazuyoshi Kaneko, Hiroyuki Tezuka, Tetsuya Takahashi, Hiroki Saitou, Nobuyuki Kiribayashi, Koki Omi, Shigeo Sugawara, Isao Kubota
Journal: Circulation (2012)
EGFR over-expression in squamous cell carcinoma of the penis
Authors: L. Wood, N. Lavens, R. Gupta
Journal: Journal of Clinical Oncology (2008)

16029 Background: Squamous cell carcinoma of the penis (SCCP) can be an aggressive, disabling disease and a limited body of published literature exists in this area. Furthermore, standard chemotherapy drug combinations have been poorly studied and there have been no recent advances in systemic therapy. The use of targeted agents in SCCP has not been reported. Although EGFR expression is seen in normal squamous epithelium, it is typically confined to the basal cell layer. SCC from other sites overexpress EGFR and respond to EGFR targeted therapy, which leads one to consider whether the same is true for SCCP. This study was designed to examine whether EGFR is overexpressed in SCCP and could serve as a potential target for treatment. Objective: To examine EGFR expression in SCC of the penis. Materials and Methods: 17 consecutive cases of invasive SCCP (biopsy or surgical resection) collected over an 8-year period (1997 to 2004) were analyzed. Specimens were obtained from the QEII HSC pathology database after REB approval. EGFR expression was evaluated and graded (0, 1+, 2+, 3+) by a trained pathologist using guidelines outlined in the commercially available immunohistochemical system kit EGFR pharmDxTM (DakoCytomation, Carpinteria, CA). EGFR pharmDx monoclonal mouse antibody (clone 2–18C9) with controls consisting of human cell lines CAMA-1 (negative control) and HT29 (positive control) were used. Overexpression of EGFR was defined as any immunohistologic staining of tumor cell membranes above background level whether complete or incomplete circumferential staining. Results: All 17 cases overexpressed EGFR (14 cases 3+, 3 cases 2+). Of the specimens examined, 4 cases were also associated with CIS. In 2, the CIS also overexpressed EGFR, however to a lesser degree (1+) compared to the invasive component and in 2 cases, the CIS did not overexpress EGFR. In all cases, adjacent normal squamous epithelium demonstrated normal background EGFR expression. Conclusions: EGFR was overexpressed in all cases of invasive penile SCC in this study. Given this high rate of overexpression and that other SCC (eg. Head and Neck) benefit from EGFR targeted therapy, it is very reasonable that EGFR targeted agents warrant investigation in penile SCC. No significant financial relationships to disclose.
Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy.
Authors: D Kahn, R D Williams, M K Haseman, N L Reed, S J Miller, J Gerstbrein
Journal: Journal of Clinical Oncology (1998)

PURPOSE We investigated the ability of In-111-capromab pendetide to separate patients who have failed radical prostatectomy into categories of those who would versus those who would not respond to salvage radiotherapy. METHODS Prostate-specific antigen (PSA) levels in 32 men with prostate cancer who had failed radical prostatectomy and had undergone a whole-body In-111-capromab pendetide scan were followed-up for 13 months (median) after salvage radiotherapy to the pelvis. A logistic regression model was used to determine whether the scan findings, as well as other clinical variables, were associated with a durable complete response (DCR), a nondurable response (NDR), or no response (NR). RESULTS Sixteen of 23 (70%) men with a normal scan outside the prostatic fossa achieved a DCR after salvage radiotherapy versus two of nine (22%) who had a positive scan outside the prostate fossa and pelvis (P = .0225, Fisher's exact test). Predicted probability (95% confidence interval [CI]) that a DCR would be obtained with a normal scan was 0.88 (0.55 to 0.98); for men with a positive scan limited to the prostatic fossa it was 0.62 (0.42 to 0.79); and for men with a positive scan outside the pelvis it was 0.27 (0.09 to 0.58). No other variables before radiotherapy showed a significant association with the DCR rate. CONCLUSION Salvage radiotherapy is statistically more likely to lead to a durable complete PSA response in men with prostate cancer who have failed radical prostatectomy and have a negative In-111-capromab pendetide scan outside the pelvis as compared with those who have a positive scan.
Abstract 19926: Pediatric Participation in Research: Lessons Learnt from a Population-based Cardiac Biorepository
Authors: Tanya Daljevic, Mina Safi, Liz Burill, Christine Dodge, Catherine Chant-Gambacort, Laura-Lee Walter, Herschel Rosenberg, Tapas Mondal, John Smythe, Erwin Oechslin, Lynn Bergin, Elaine Gordon, Seema Mital
Journal: Circulation (2010)

Consenting minors for genetics research can be challenging given the lack of standardized guidelines for pediatric consent. We examined consent patterns during the establishment of a population-bas...
Abstract 16342: Non-invasive Analysis of Regional Myocardial Work Predicts Total Coronary Artery Occlusion in Non-ST-Elevation Myocardial Infarction Patients
Authors: Espen Boe, Russell Kristoffer, Christian Eek, Morten Eriksen, Bjornar Grenne, Harald Brunvand, Otto Smiseth, Helge Skulstad
Journal: Circulation (2012)

Introduction:  Approximately 30% of patients with non-ST-elevation myocardial infarction (N-STEMI) have acute coronary artery occlusion (CAO), which may lead to reduced regional myocardial function. In the present study we investigated if a previously validated non-invasive method for assessing segmental myocardial work (SW) can identify patients with CAO.   Methods:  Echocardiography was performed before coronary angiography (CA) in 52 patients with N-STEMI. Longitudinal strain (LS) curves were assessed by speckle tracking echocardiography for each myocardial segment in a 16-segment LV model. Left ventricular pressure (LVP) was estimated by utilizing a normalized reference curve which was adjusted according to LV isovolumic and ejection phases, as defined by timing of aortic and mitral valvular events. Systolic arterial cuff pressure was used to scale the LVP reference curve. SW was calculated as the area of the LVP-LS loop. To evaluate the ischemic region affected by a CAO, the number of segments with systolic dysfunction judged by empirical cut-off values of  · mmHg for SW and >-14% for segmental peak systolic strain (SPSS) were assessed. CAO was determined by CA. ROC analysis was performed by using the number of segments as the threshold variable. Area under the curve (AUC) (95%CI) for SW and SPSS were compared to ejection fraction (EF).   Results:  The AUCs were; SW 0.81(0.68-0.91); SPSS 0.70(0.56-0.82) and EF 0.59(0.44-0.72) (figure 1). 4 or more adjacent segments with reduced SW resulted in 67% sensitivity, 68% specificity, 70% negative predictive value and 64% positive predictive value for identifying CAO.   Conclusion:  In the present study assessment of non-invasive myocardial segmental work could predict acute coronary artery occlusion in N-STEMI patients. SW was the only predictor significantly better than EF at identifying CAO, and may therefore be an important clinical tool for selecting N-STEMI patients in need of immediate invasive treatment.
Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.
Authors: J Robert, J P Armand, S Huet, M Klink-Alakl, G Recondo, P Hurteloup
Journal: Journal of Clinical Oncology (1992)

PURPOSE 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.
Health care cost of breast cancer: A claims data analysis.
Authors: A. Z. Fu, M. Jhaveri, S. D. Sullivan, N. P. Christiansen
Journal: Journal of Clinical Oncology (2010)

6055 Background: Breast cancer (BC) is the most frequently occuring malignancy among women in the United States where one in every eight women develops BC. This study was conducted to analyze the economic burden of BC with a focus on direct health care cost in the United States. Methods: This was a retrospective matched cohort study using a large claims database from a US national commercially-insured population between January 2003 and September 2008. Women aged ≥ 18 were selected with ≥ 2 BC diagnosis (ICD-9 code: 174.xx) on different dates within 90 days, ensuring that the diagnosis code represented the actual disease condition instead of that for a regular screening. The date of the first BC diagnosis was served as the index date for case cohort. The control cohort (without BC) was selected with a 3:1 ratio by matching to the cases based on index date (same year and month), age (5 year range), region, employer, and health insurance type. Both case and control cohorts were required to have continuous enrollment for at least 6 months prior to and 12-months after the index date. Generalized linear model (GLM) with log link was applied to evaluate the 1-year post-index cost difference between cases and controls with the adjustment of demographics, comorbid conditions, and preindex total health care cost. Results: Based on the selection criteria, 140,228 patients (35,057 cases and matched 105,171 controls) were included with mean (SD) age of 52.1 (7.5) years. The total 1-year health care costs for case and control cohorts were $61,167 and $6,296, respectively (p < 0.001). GLM predicts that the adjusted incremental health care cost was $42,401 (p < 0.001) per BC patient per year, which included 12%, 86%, and 2% of the total for inpatient, outpatient, and prescription use. Conclusions: This study demonstrated that breast cancer is an expensive disease condition, which consumes an average of $40,000 more per patient within the first year of diagnosis for the U.S. health care system. The majority of the direct health care cost was spent in outpatient care settings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis sanofi-aventis