tbuckley/cabot-search huggingface dataset:
A phase I study of triapine in combination with irinotecan in refractory tumors
Authors: W. R. Schelman, K. Holen, D. Mulkerin, J. Kolesar, J. Thomas, M. Kruse, K. Oliver, R. Marnocha, J. Eickhoff, G. Wilding
Journal: Journal of Clinical Oncology (2006)

12011 Background: Triapine is a small molecule inhibitor of ribonucleotide reductase and has anti-tumor activity alone and in combination with other agents in advanced solid tumors. Based on its ability to limit DNA repair, Triapine has been postulated to act synergistically with irinotecan. This study was conducted to determine the toxicities and efficacy of Triapine with irinotecan. Correlative studies included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy. Methods: This study used standard eligibility criteria with the following exceptions: patients must have had no prior irinotecan and no G6PD deficiency. The treatment plan consisted of irinotecan on day 1 with Triapine on days 1- 3 of a 21-day cycle. Starting dose (level 1) was irinotecan (150 mg/m 2 ) and Triapine (85 mg/m 2 /day). RECIST was used to measure response. Results: 10 patients have been enrolled; 5 men, 5 women. Tumor types: 4 pancreatic, 2 cholangio, 1 esophageal, 1 sarcoma, 1 lung, 1 ovarian. Grade 3–4 toxicities at least possibly related to Triapine at any dose level were as follows: neutropenia (3), leukopenia (2), fatigue, hypoxia, nausea, vomiting, thrombocytopenia, abdominal cramping, hypocalcemia, and thrombosis. The first patient enrolled at level 1 developed a DLT (Grade 3 hypoxia). Consequently, irinotecan and Triapine doses were reduced to 100 mg/m 2 and 60 mg/m 2 /day, respectively (level -1). One of 6 patients experienced a DLT at this dose level. Further patients were then enrolled at level 1. There were 2 DLTs of 4 patients at level 1. One partial response (NSCLC) was seen. Conclusions: Unacceptable toxicities were seen at dose level 1; however, dose level -1 was well tolerated. The trial has therefore been amended in order to evaluate a higher dose of irinotecan (150 mg/m 2 ) with the level -1 dose of Triapine (60 mg/m2/day). Accrual continues at this dose level. Antitumor activity in NSCLC was noted at level 1. [Table: see text]
High CD52 mRNA Expression Is An Adverse Prognostic Factor In Fludarabine-Refractory CLL Treated With Alemtuzumab On The Gcllsg CLL2H Trial
Authors: Johannes Bloehdorn, Martin Sill, Christian Langer, Axel Benner, Dipl.Stat. Dipl.Stat., Thorsten Zenz, Andreas Bühler, Raymonde Busch, Peter Dreger, Ulrich Jäger, Michael Hallek, Hartmut Döhner, Stephan Stilgenbauer
Journal: Blood (2013)
Diethylnitrosamine-Induced Chromosome Changes in Rat Liver Cells2
Authors: Prince Masahito Hitachi, Kiyomi Yamada, Shozo Takayama
Journal: JNCI Journal of the National Cancer Institute (1974)

Donryu rats 8 weeks of age were given drinking water containing 50 ppm diethylnitrosamine (DEN), and cytogenetic studies were made on dividing cells in the livers of animals killed during and after carcinogen administration. Cytogenetic changes occurred in liver cells during DEN administration and also during the latent period before overt liver tumors appeared.
Small cell lung cancer in women: The Spanish female-specific database WORLD07.
Authors: N. Vinolas, D. Isla, E. Felip, P. Garrido, M. Majem, J. Terrasa, A. Artal, M. Garcia-Campelo, M. L. Amador, R. Rosell
Journal: Journal of Clinical Oncology (2010)

e12044 Background: Lung cancer is the leading cause of cancer mortality among women in many countries. Small cell lung cancer (SCLC) incidence has decreased during the last years and gender differences have been reported. Methods: WORLD07 is a prospective, multicenter, epidemiologic female-specific lung cancer database analyzing characteristics and treatments of women with lung cancer from several Spanish cancer centers. Inclusion criteria: women > 18 years with a diagnosis of lung cancer, regardless of being treated or not. Written informed consent was required. Results: From October 2007 to December 2009, 629 female newly diagnosed of lung cancer were included in an e-database at 36 Spanish centers. Of those, 68 (10.8%) presented with SCLC. Characteristics were the following: Median age 60 years (y) (range: 39-82); Caucasian 98.5%; marital status (%): married 54.5, unmarried 13, divorced 15, widow 16; educational level (%): basic 44, secondary 22, university 13; median age of menarche: 13 y; children: 74% (median: 2); median age of first child: 25.5 y; premenopausal 13%, postmenopausal 84%; median age of menopause: 47 y; oral contraceptive: 37%; smoking habit (%): never 13, former smoker 16, current smoker 71; family history of cancer: 47%; previous history of cancer: 15%. stage of disease: limited: 51%, extensive: 49%. Conclusions: The incidence of SCLC among women is similar to what is described in the general lung cancer population. Our results indicate that the percentage of never smokers and limited disease is slightly higher in that subgroup. No significant financial relationships to disclose.
Abstract 194: Phosphodiesterase 3 Controls Basal cGMP Levels And Regulates cGMP/cAMP Cross-talk In Adult Mouse Ventricular Cardiomyocytes
Authors: Konrad Götz, Viacheslav Nikolaev
Journal: Circulation Research (2013)

PURPOSE: cGMP is an important second messenger which is involved in the regulation of cardiac contractility and pathological hypertrophy. In cardiomyocytes, signaling by cGMP is organized in microdomains and is considered cardioprotective. Especially in adult cardiac myocytes, measurements of cGMP have been challenging and little is known about the spatio-temporal dynamics of cGMP. Here we developed a transgenic mouse model to visualize cGMP dynamis in adult cardiac myocytes. Methods: We generated transgenic mice with cardiomyocyte-specific expression of a highly sensitive fluorescence resonance energy transfer (FRET)-based cGMP biosensor red cGES-DE5 and performed FRET measurements in freshly isolated adult mouse ventricular myocytes. To analyze cGMP/cAMP crosstalk, FRET experiments were performed in cardiomyocytes isolated from mice transgenically expressing the cAMP sensor Epac1-camps. Results: Basal cytosolic cGMP levels were very low (~10 nM), but could be markedly increased by stimulation with natriuretic peptides (CNP&gt;&gt;ANP). In contrast, direct stimulation of the soluble guanylyl cyclase (sGC) with NO-donors such as SNAP showed no effect. However, constitutive activity of this cyclase contributes to basal cGMP production, since a clear decrease of basal cGMP levels was observed after stimulation with the sGC inhibitor ODQ. This basal cGMP production is regulated by phosphodiesterase (PDE) activity. Unexpectedly, PDE3 is most important in controlling basal cGMP levels, whereas PDE2 and PDE5 are much less active. We could also show that cGMP pools produced by GC-B after CNP stimulation are mainly regulated by PDE3, so that the receptor and this PDE form one functional unit important for the regulation of cGMP/cAMP cross-talk. Conclusion: In summary, we performed the first FRET-based measurements of cGMP in adult cardiomyocytes and we could highlight the key role of PDE3 in the regulation of basal cGMP levels and cGMP/cAMP cross-talk.
Time from diagnosis to treatment initiation in advanced non-small cell lung cancer (NSCLC): Time trends and racial differences
Authors: R. Martins, D. Blough, S. Ramsey
Journal: Journal of Clinical Oncology (2006)

6037 Background: Historical survival evaluation of clinical trials for advanced NSCLC suggests that median survival improved by 0.4 months over a 22 year period. Survival in clinical trails is evaluated from treatment initiation and not from diagnosis. If treatment is initiated earlier over time, this may create a lead-time effect on survival analysis and thus may explain the apparent discrepancy between trial findings and outcomes in the community. Objective: Investigate if, over time, there has been a shortening of the time between the diagnosis of NSCLC and the initiation of chemotherapy. Methods: We evaluated patients with NSCLC stages IIIB and IV between 01/01/1994 and 12/31/1999. Date of diagnosis was obtained from Surveillance, Epidemiology, and End Results (SEER). Treatment data was obtained from Medicare claims and is restricted to patients above age 65. Differences were compared using analysis of variance (ANOVA). Results: A total of 11,995 patients were identified. Patient’s characteristics: median age 74 years; 57% of patients were males; racial distribution: white (82.4%), black (9.4%), Asian (3.2%), Hispanics (1.2%), others (3.8%); stage distribution: IIIB (38%), IV (62%). Chemotherapy was given to 3,377 (28%) patients. There was an increase in chemotherapy utilization over time: 10% in 1994 to 35% in 1999. Over time there was a shortening from diagnosis to chemotherapy initiation from 1.6 months in 1994 to 1.3 months in 1999 (p = 0.0004). Among those receiving chemotherapy, median survival from diagnosis did not change over this time period. Black patients had a longer time between diagnosis and treatment initiation: 1.7 months vs. 1.4 months (p &lt; 0.01). Conclusions: Over time, there has been a shortening of the time between diagnosis and chemotherapy initiation. This difference, although small, seems to account for much of the apparent historical survival benefit observed. This finding puts additional limitation on the historical comparisons of survival between trials. Racial differences may help explain, in part, observed differences in outcome. No significant financial relationships to disclose.
Preliminary Survey of Hormonal Influences on Multicellular Architecture in Primary Cultures of Mammary Carcinoma Cells2
Authors: Howard L. Hosick, S. Nandi
Journal: JNCI Journal of the National Cancer Institute (1974)

We screened a variety of steroid and other hormones, known to influence mammary cells, for their effects on “dome” production in monolayer cell cultures from mouse mammary tumors. Fetal calf serum concentration in culture media influenced dome number but calf serum concentration did not. Insulin increased domes/plate at any given serum level (up to 15'0). The serum and insulin probably affected maintenance of cells rather than any specific differentiative activity. A variety of ccrticosteroids promoted dome formation, but other steroids were less active. Thyroxine increased the number of domes. No effect of prolactin on dome genesis was detected. Dome production was also modified by the substrate on which the cells were grown.
Comparison of efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: A meta-analysis.
Authors: G. Des Guetz, B. Uzzan, P. Nicolas, C. Kader, G. Perret, G. Sebbane, J. F. Morere
Journal: Journal of Clinical Oncology (2010)

7625 Background: In the elderly (age > 70) with advanced non-small cell lung cancer (NSCLC), the relative risk-to-benefit ratio of chemotherapy (CT) administered as single-agent or doublets (including the same single agent) is not established. We performed a meta-analysis (MA) of all published studies to clarify this issue. Methods: PubMed query: Randomized Controlled Trial, Aged, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carcinoma, NSCLC drug therapy. Articles were also obtained by cross-checking references; abstracts from ASCO and WCLC proceedings. Third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination were included. The efficacy outcomes were response rate (RR) and 1-year overall survival (OS). Hazard ratios (HRs) were calculated from the recorded events. We used EasyMA software and fixed-effect model, due to absence of statistical heterogeneity between studies. By convention, HRs < 1 corresponded to a decreased survival among the single-agent compared with the doublet. Results: Eight eligible studies included 1804 patients (mean age 73; 1362 men and 368 women; 461 stage IIIB and 1114 stage IV; 600 epidermoid cancers, 565 adenocarcinomas, 410 other pathological types). Whereas 1-year OS was similar for single-agent and doublets (HR 0.98; 95% Confidence Interval or CI: 0.92-1.05), RR was significantly improved (HR 1.31; 95 % CI 1.08-1.58; p = 0.005) and HRs for nausea/vomiting, neutropenia, thrombopenia and anaemia were significantly higher for doublets than for single agent (1.29, CI 1.13-1.46; 1.28, CI 1.17-1.41; 1.60, CI 1.26-2.02; 1.36, CI 1.19-1.55 respectively). HRs for diarrhea and stomatitis were close to 1. Concerning grade 3/4 toxicity, only the RRs for the biological side effects were significantly higher for doublets: neutropenia (1.40; 1.15-1.71), thrombopenia (2.46; 1.60-3.78) and anaemia (1.61; 1.04-2.48). Conclusions: Compared with single-agent CT, doublets improved RR, but not OS. Neutropenia, thrombopenia and anaemia were more frequent with doublets. Thus, the benefit-to-risk ratio of doublets in advanced NSCLC is not favourable. No significant financial relationships to disclose.
Abstract 18703: Fluorescence Tracking of Domain IV Voltage Sensor Motion Shows a Progressively Varying Molecular Phenotype in Long QT Syndrome Type 3 Mutants
Authors: Angela R Schubert, Alexandra B Asaro, Zoltan Varga, Jonathan R Silva
Journal: Circulation (2013)

Background: Long QT Syndrome type 3 (LQT3) is caused by mutations in SCN5a, which encodes the hNa V 1.5 α subunit; each contains 4 domains (DI-DIV) with 6 transmembrane segments (S1-S6). S1-S4 form a voltage sensing domain (VSD) that transduces membrane potential into channel gating. The molecular mechanisms that lead to LQT3 and the consequences of mutation location remain unclear, and better definition will lead to improved phenotypic precision and therapeutic targeting. We use a recent technique, voltage-clamp fluorometry (VCF), to evaluate three LQT3 mutations in the DIV VSD: R1623Q, R1626P, and previously uncharacterized, S1609W. Methods: To track the S4, a cysteine was introduced into the DIV S3-S4 linker, and conjugated to a TAMRA-MTS label. mRNA was injected into Xenopus oocytes and currents and fluorescence were recorded after 3-5 days with cut-open VCF. Results: Activation, inactivation, and recovery were similar in WT and S1609W. R1626P activation and inactivation recovery was not significantly different from WT while inactivation was left shifted. Both mutants exhibited a pro-arrhythmic delay of inactivation onset at -30mV - S1609W by 44% (0.8 ms) and R1626P by 36% (0.7 ms), when compared to onset in WT (1.9 ± 0.0 ms). DIV S4 deactivation also differed significantly among WT, S1609W, and R1626P. Exponential fitting revealed two time constants for the WT DIV S4 to return to rest of 0.23 ms and 17.44 ms with magnitudes of 0.3 and 0.7 ± 0.1, respectively. In contrast, S1609W showed a significant increase in the fast component (0.8 and 0.2 ± 0.1). A single signal from R1626P showed an intermediate phenotype (0.7 and 0.3). Further, a delay in sensor deactivation onset observed in the WT was absent from both mutants. No fluorescence was detected from R1623Q, perhaps indicating an especially severe phenotype with respect to the DIV S4 motion. Conclusion: Fluorescent kinetics from two LQT3 mutants, S1609W and R1626P showed a progressive molecular phenotype in which a slow component of recovery to the resting state was impaired by the mutation. Comparison to ionic current inactivation revealed that the reduction in this slow component corresponded to an increase in the time to peak, implying that the onset of fast inactivation is delayed by these mutations.
Analysis of HPV and ERCC1 in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Ranee Mehra, Ann Marie Egloff, Shuli Li, Donghua Yang, Lin Wang, Fang Zhu, Arlene A. Forastiere, Barbara Burtness, Athanassios Argiris
Journal: Journal of Clinical Oncology (2013)

6006 Background: We studied the association of human papillomavirus (HPV) and excision repair cross-complementation group 1 (ERCC1) tumor expression with clinical outcomes in patients (pts) with R/M SCCHN. Methods: Archival baseline specimens were obtained from pts on ECOG trials: E1395, phase III trial of cisplatin/paclitaxel (CP) vs. cisplatin/5-FU (CF), and E3301, phase II trial of docetaxel/irinotecan. HPV DNA was detected by in situ hybridization (ISH) with a wide spectrum HPV probe. Tumor p16 status was defined as positive if immunohistochemical staining for p16 was strong and present in &gt;80% of tumor cells. ERCC1 expression was measured (HistoRx PM-2000) and data analyzed using AQUA algorithms, after tissue was stained with ERCC1 ab (1:5000 HPA0297731, Sigma), and a wide-spectrum cytokeratin ab (Dako Z0622) for tumor mask. A prior determined cut point for nuclear staining was utilized. Fisher's exact test and log-rank test were used to compare categorical variables and survival. Stratified logistic regression and Cox regression model were used to estimate odds ratio (OR) and hazard ratio (HR), respectively, adjusting for potential confounding factors. p-values were two-sided. Results: Tissue was evaluable from 65 tumors (T) for HPV, 66 for p16 (E1395 and E3301), and 43 for ERCC1 expression (E1395). 11 T were HPV+ (12 p16+), and 54 were HPV-/p16-. HPV+ tumors were similarly represented in all treatment groups (p=0.58). Objective response rates (RR): 67% for HPV+, 22% for HPV- (p=0.013); 60% p16+, 22% p16- (p=0.05). RR rates were calculated excluding cases with unevaluable/unknown responses. HR for OS was 2.66 (HPV, p=0.02) and 2.27 (p16, p=0.04), favoring HPV+/p16+ pts. 18 T were ERCC1 high (H) and 25 ERCC1 low (L). HR for OS (H vs. L) was 1.96 (p=.11) RR: CF, 58% (L), 29% (H); CP, 33% (L), 56% (H). A test of ERCC1 by treatment interaction (p=0.12) suggested the effect of ERCC1 may be different for taxane vs. non-taxane regimens. Conclusions: This is the first study to show that HPV+/p16+ status is associated with a significant improvement in RR and OS among pts treated for R/M SCCHN. ERCC1 L was associated with a trend towards a better OS.
A phase II study of sorafenib in combination with tegafur/uracil (UFT) for Asian patients with advanced hepatocellular carcinoma (HCC)
Authors: Y. Shen, C. Hsu, C. Hsu, Z. Lin, P. Chen, Y. Shao, T. Huang, Y. Ding, A. Cheng
Journal: Journal of Clinical Oncology (2009)

4589 Background: Sorafenib, a multikinase inhibitor with antiangiogenic activity, has recently been approved for the treatment of unresectable HCC. Combination of sorafenib with metronomic chemotherapy has theoretic advantage in improving antitumor activity without increasing toxicities. UFT (tegafur: uracil = 4:1 in molar ratio), an oral fluoropyrimidine, is active in various gastrointestinal cancers. We conducted a phase II study to evaluate the efficacy and safety of sorafenib plus low-dose UFT in advanced HCC patients (pts). Methods: Pts with histologically or cytologically proven unresectable/metastatic HCC, ECOG PS 0–2, Child-Puch class A, platelets ≥ 100 K/μl, transaminases ≤ 5 × ULN, bilirubin ≤ 3 mg/dl, INR ≤ 2.3 and creatinine ≤ 1.5 × ULN were enrolled. Prior systemic therapy for advanced disease is not allowed. Sorafenib (400 mg bid) and UFT (125 mg/m 2 based on tegafur bid) were taken per os continuously. Tumor assessment was performed q8w by RECIST criteria. Primary endpoint is progression-free survival (PFS). Results: Between April 2007 and April 2008, 53 pts were enrolled. Baseline pts characteristics were: M/F, 47/6; median age 57 (range, 31–83); CLIP score 0–3/4, 48/5; extrahepatic spread/macroscopic vascular invasion, 33/30; and HBsAg(+)/anti-HCV(+)/both(+), 38/13/4. 89% of pts were BCLC stage C. Pts received a median of 3.7 (range 0.3- 18.9+) months of treatment. There were 3 (6%) PR and 27 (51%) SD. The median PFS and OS were of 3.7 months (95% C.I., 1.9- 5.5) and 7.4 months (95% C.I., 3.4- 11.4), respectively. Adverse events (AEs) were summarized in Table . Hand-foot skin reaction (HFSR), fatigue, and diarrhea were most common AEs. HFSR was the major AE resulting in dose reduction (19%) or treatment delay (21%). Grade 3/4 neutropenia occurred in 2 pts (4%). Conclusions: Adding metronomic UFT chemotherapy to sorafenib may improve therapeutic efficacy of the latter in pts with advanced HCC. The toxicity profile of the combination is similar to that of sorafenib alone. [Table: see text] [Table: see text]
Abstract 12839: Expression and Functional Role of The Prorenin Receptor in Human Primary Aldosteronism
Authors: Chiara Recarti, Teresa M Seccia, Brasilina Caroccia, Giulio Ceolotto, Abril Gonzales-Campos, Anna S Belloni, Lucia Petrelli, Achille C Pessina, Gian Paolo Rossi
Journal: Circulation (2013)

Hypothesis: The detection of prorenin in plasma of patients with Primary Aldosteronism (PA) suggests that prorenin plays a pathophysiologic role in PA by acting via the Pro-Renin Receptor (PRR). We therefore sought for the presence of the PRR in the normal human zona glomerulosa (ZG) and in aldosterone producing adenoma (APA), and investigated the functional response of PRR activation by prorenin on ERK1/2 phosphorylation in an adrenocortical cell line. Methods and Results: Expression levels of PRR gene were 15- and 12-fold higher than those of the housekeeping gene PBGD in the normal human adrenal cortex (n=8) and in the APAs (n=11), respectively. Similar high expression levels were found in the the H295R and HAC15 cells. The PRR protein expression was confirmed by immunohistochemistry in the human and rat normal ZG, as well as in a pure population of APA cells obtained with an immunoseparation-based technique specifically targeted to the membrane CD56. Immunoblotting, confocal and immuno-gold electron m...
Phase I trial of gefitinib with concurrent radiotherapy and fixed dose-rate gemcitabine infusion, in locally advanced pancreatic cancer
Authors: J. Maurel, M. Martin-Richard, C. Conill, M. Sanchez, L. Petriz, A. Ginés, R. Gallego, R. Cajal, S. Navarro, L. Fernandez-Cruz
Journal: Journal of Clinical Oncology (2006)

4105 Background: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor (EGFR) is over-expressed in pancreatic cancer and in vitro studies have shown that EGFR inhibitors can overcome radio- and chemo-resistance. The aim of the study was to determine the maximally tolerated dose of gefitinib, in combination with RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC). Methods: Eighteen patients with pathological proven LAPC, due to major vascular invasion based on helical computed tomography and endoscopic ultrasound, were entered. The targeted irradiated volume included the tumor and 2 cm-margin. Prophylactic irradiation of regional nodes was not allowed. Patients with &gt;500 cc of planned tumor volume (PTV) were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150 and 200 mg/m 2 /day of gemcitabine in a 2 hour infusion over weeks 1,2,3,4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers (VEGF and IL-8) was also performed. Results: Mean PTV was 293cc (range 137–462 cc). There were no dose-limiting toxicities on study. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. One patient showed a partial response of 13 months in duration, and 7 patients showed disease stabilization. Median progression free survival (PFS) was 3.7 months and median overall survival (OS) was 7.5 months. No patients have a reduction in VEGF levels &gt;50%. Reduction in VEGF serum levels &gt;25% and IL-8 levels &gt;50% had no impact on PFS and OS. Conclusion: Our results support thatthe combination of gefitinib, RT and gemcitabine showed an acceptable toxicity but with modest activity in LAPC. [Table: see text]