bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial Growth Factor Signaling Inhibitor, in Patients With Advanced Solid Tumors
Authors: Drevs Joachim , Siegert Patrizia , Medinger Michael , Mross Klaus , Strecker Ralph , Zirrgiebel Ute , Harder Jan , Blum Hubert , Robertson Jane , Jürgensmeier Juliane M. , Puchalski Thomas A. , Young Helen , Saunders Owain , Unger Clemens 
Published: July 2007

Purpose AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy. Patients and Methods In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2λz) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related. Conclusion Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.
Doctors’ and Patients’ Preferences for Participation and Treatment in Curative Prostate Cancer Radiotherapy
Authors: Stalmeier Peep F.M. , van Tol-Geerdink Julia J. , van Lin Emile N.J.Th. , Schimmel Erik , Huizenga Henk , van Daal Willem A.J. , Leer Jan-Willem 
Published: July 2007

Purpose Physicians hold opinions about unvoiced patient preferences, so-called substitute preferences. We studied whether doctors can predict preferences of patients supported with a decision aid. Methods A total of 150 patients with prostate cancer facing radiotherapy were included. After the initial consultation, without discussing any treatment choice, physicians gave substitute judgments for patients' decision-making and radiation dose preferences. Physicians knew that several weeks later, patients would be empowered by a decision aid supporting a choice between two radiation doses involving a trade-off between disease-free survival and adverse effects. Subsequently, patient preferences for decision making (whether or not they wanted to choose a radiation dose) and for treatment (low or high dose) were obtained. The chosen radiation dose actually was administered. Results Of the patients studied, 79% chose a treatment; physicians believed that 66% of the patients wanted to choose. Agreement was poor (64%; κ = 0.13; P = .11), and was better as patients became more hopeful (odds ratio [OR] = 4.4 per unit; P = .001) and as physicians' experience increased (OR = 1.09 per year; P = .02). Twenty percent of physicians' preferences, 51% of physicians' substitute preferences, and 71% of patients' preferences favored the lower dose; agreement was again poor (70%; κ = 0.2; P = .03). Conclusion Physicians had problems predicting the preferences of patients empowered with a decision aid. They slightly underestimated patients' decision-making preferences, and underestimated patients' preferences for the less toxic treatment. Counseling might be improved by first informing patients—possibly using a decision aid—before discussing patient preferences.
Phase III Randomized Controlled Trial Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma Treated With Nolatrexed or Doxorubicin
Authors: Gish Robert G. , Porta Camillo , Lazar Lucian , Ruff Paul , Feld Ronald , Croitoru Adina , Feun Lynn , Jeziorski Krzysztof , Leighton John , Knox Jennifer , Gallo José , Kennealey Gerard T. 
Published: July 2007

Purpose The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX). Patients and Methods Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) ≥ 60%, Cancer of the Liver Italian Program (CLIP) score ≤ 3, and adequate organ function. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rates, and safety. The treatment groups were well-balanced with regards to age, sex, ethnic origin, and underlying liver disease. Randomization was stratified according to KPS and CLIP score. Results At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm. Conclusion NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.
Coronary Artery Findings After Left-Sided Compared With Right-Sided Radiation Treatment for Early-Stage Breast Cancer
Authors: Correa Candace R. , Litt Harold I. , Hwang Wei-Ting , Ferrari Victor A. , Solin Lawrence J. , Harris Eleanor E. 
Published: July 2007

Purpose To compare the incidence and distribution of coronary artery disease after left-sided versus right-sided irradiation in patients treated with breast conservation for early-stage breast cancer who subsequently underwent cardiac stress testing and/or catheterization for cardiovascular symptoms. Patients and Methods The medical records of 961 stage I-II breast cancer patients treated from 1977 to 1995 at the University of Pennsylvania with conventional tangential beam radiation treatment (RT) were screened for cardiac stress tests and catheterizations performed after RT. The results of these tests were analyzed by laterality of RT and compared with baseline cardiovascular risk. Results At diagnosis, patients with left-sided and right-sided breast cancer had the same estimated 10-year risk (both 7%) of developing coronary artery disease. At a median time of 12 years post-RT (range, 2 to 24 years), 46 patients with left-sided and 36 patients with right-sided breast cancer (total, N = 82) had undergone cardiac stress testing. A statistically significant higher prevalence of stress test abnormalities was found among left (27 of 46; 59%) versus right-side irradiated patients (three of 36; 8%; P = .001). Furthermore, 19 of 27 of left-sided abnormalities (70%) were in the left anterior descending artery territory. Thirteen left-side irradiated patients also underwent cardiac catheterization revealing 12 of 13 with coronary stenoses (92%) and eight of 13 with coronary stenoses (62%) solely in the left anterior descending artery. Conclusion Patients treated with left-sided radiation as a component of breast conservation have an increased risk of late, radiation-associated coronary damage. Treatment with modern radiation techniques may reduce the risk of cardiac injury.
Randomized Trial of Laparoscopic-Assisted Resection of Colorectal Carcinoma: 3-Year Results of the UK MRC CLASICC Trial Group
Authors: Jayne David G. , Guillou Pierre J. , Thorpe Helen , Quirke Philip , Copeland Joanne , Smith Adrian M.H. , Heath Richard M. , Brown Julia M. 
Published: July 2007

Purpose The aim of the current study is to report the long-term outcomes after laparoscopic-assisted surgery compared with conventional open surgery within the context of the UK MRC CLASICC trial. Results from randomized trials have indicated that laparoscopic surgery for colon cancer is as effective as open surgery in the short term. Few data are available on rectal cancer, and long-term data on survival and recurrence are now required. Methods The United Kingdom Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (UK MRC CLASICC; clinical trials number ISRCTN 74883561) trial study comparing conventional versus laparoscopic-assisted surgery in patients with cancer of the colon and rectum. The randomization ratio was 2:1 in favor of laparoscopic surgery. Long-term outcomes (3-year overall survival [OS], disease-free survival [DFS], local recurrence, and quality of life [QoL]) have now been determined on an intention-to-treat basis. Results Seven hundred ninety-four patients were recruited (526 laparoscopic and 268 open). Overall, there were no differences in the long-term outcomes. The differences in survival rates were OS of 1.8% (95% CI, −5.2% to 8.8%; P = .55), DFS of −1.4% (95% CI, −9.5% to 6.7%; P = .70), local recurrence of −0.8% (95% CI, −5.7% to 4.2%; P = .76), and QoL (P > .01 for all scales). Higher positivity of the circumferential resection margin was reported after laparoscopic anterior resection (AR), but it did not translate into an increased incidence of local recurrence. Conclusion Successful laparoscopic-assisted surgery for colon cancer is as effective as open surgery in terms of oncological outcomes and preservation of QoL. Long-term outcomes for patients with rectal cancer were similar in those undergoing abdominoperineal resection and AR, and support the continued use of laparoscopic surgery in these patients.
Topotecan Is Active Against Wilms’ Tumor: Results of a Multi-Institutional Phase II Study
Authors: Metzger Monika L. , Stewart Clinton F. , Freeman Burgess B. , Billups Catherine A. , Hoffer Fredric A. , Wu Jianrong , Coppes Max J. , Grant Ronald , Chintagumpala Murali , Mullen Elizabeth A. , Alvarado Carlos , Daw Najat C. , Dome Jeffrey S. 
Published: July 2007

PurposeA phase II study was conducted to evaluate the activity and safety of topotecan in pediatric patients with recurrent Wilms' tumor.Patients and MethodsPatients with favorable histology Wilms' tumor (FHWT) and recurrence after at least one salvage chemotherapy regimen or with anaplastic histology Wilms' tumor (AHWT) in first or subsequent recurrence were eligible. Patients were stratified according to histology, with statistical considerations based on the FHWT stratum. Topotecan was administered intravenously over 30 minutes for 5 days on 2 consecutive weeks. Treatment dosages were adjusted to achieve a target area under the curve (AUC) of 80 ± 10 ng/mL*h. Tumor responses were measured after two cycles of treatment.ResultsThirty-seven patients (26 patients with FHWT) were enrolled and received a total of 94 cycles of topotecan (range, one to six cycles). The median topotecan dosage required to achieve the target AUC was 1.8 mg/m2(range, 0.7 to 3.2 mg/m2). Of 25 assessable patients with FHWT, 12 had partial response (PR), six had stable disease (SD), and seven had progressive disease (PD), for an overall response rate of 48% (95% CI, 27.8% to 68.7%). Of 11 assessable patients with AHWT, two had PR, one had SD, and eight had PD. The main toxicities were grade 3 and 4 neutropenia (median duration, 13 days) and thrombocytopenia (median duration, 7.5 days).ConclusionTopotecan administered on a protracted schedule is active against recurrent FHWT. Inclusion of topotecan in front-line clinical trials for patients with recurrent Wilms' tumor should be considered.
Phase I and Pharmacokinetic Study of Erlotinib for Solid Tumors in Patients With Hepatic or Renal Dysfunction: CALGB 60101
Authors: Miller Antonius A. , Murry Daryl J. , Owzar Kouros , Hollis Donna R. , Lewis Lionel D. , Kindler Hedy L. , Marshall John L. , Villalona-Calero Miguel A. , Edelman Martin J. , Hohl Raymond J. , Lichtman Stuart M. , Ratain Mark J. 
Published: July 2007

Purpose We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction. Patients and Methods Patients were assigned to one of three cohorts: cohort 1, AST ≥ 3× upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients. Results Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin ≥ 1.5× baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean ± standard deviation) was cohort dependent as follows: 1.9 ± 0.2 L/h in cohort 1; 3.7 ± 4.7 L/h in cohort 1a; 2.4 ± 1.1 L/h in cohort 2; and 4.5 ± 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017). Conclusion Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.
Comparison of Diagnostic Accuracy of Urinary Free Metanephrines, Vanillyl Mandelic Acid, and Catecholamines and Plasma Catecholamines for Diagnosis of Pheochromocytoma
Authors: Boyle James G. , Davidson D. Fraser , Perry Colin G. , Connell John M. C. 
Published: July 2007

Abstract
Context: Recent evidence suggests that plasma-free metanephrines provide a highly sensitive test in patients requiring exclusion of pheochromocytoma. The diagnostic efficacy of urinary free metanephrines, however, has not been evaluated.
Objective, Design, Setting, Patients, and Outcome Measures: We compared retrospectively the diagnostic efficacy of 24-h urinary free metanephrines with our currently available measurements of 24-h urinary vanillyl mandelic acid (VMA), urinary catecholamines, and plasma catecholamines in 159 outpatients tested in a tertiary referral center for pheochromocytoma over a 4-yr period.
Results: The sensitivity of urinary free metanephrines was 100% [25 of 25 patients; 95% confidence interval (CI) 86–100%)] compared with the sensitivity of 84% (21 of 25; 95% CI 64–95%) for urinary catecholamines; 72% (18 of 25; 95% CI 51–88%) for urinary VMA; and 76% (16 of 21; 95% CI 53–92%) for plasma catecholamines. The specificity of urinary free metanephrines was 94% (116 of 123; 95% CI 89–98%), compared with the specificity of 99% (127 of 129; 95% CI 96–100%) for urinary catecholamines; 96% (130 of 134; 95% CI 91–98%) for urinary VMA; and 88% (66 of 75; 95% CI 78–94%) for plasma catecholamines. Receiver operating characteristic curves for all test groups were generated. Pairwise comparisons of the area under the receiver operating characteristic curve for urinary free metanephrines with that of each of the other three test groups individually were: 0.993 (95% CI 0.962–0.999) vs. 0.919 (95% CI 0.862–0.957, P = 0.032) for urine catecholamines; 0.993 (95% CI 0.962–0.999) vs. 0.846 (95% CI 0.778–0.900, P = 0.002) for urine VMA; and 0.992 (95% CI 0.945–0.998) vs. 0.852 (95% CI 0.762–0.918, P = 0.009) for plasma catecholamines. Testing with urinary free metanephrines failed to misidentify a single case of pheochromocytoma, compared with four missed cases for urinary catecholamines, seven missed cases for urinary VMA, and five missed cases for plasma catecholamines.
Conclusion: Urinary free metanephrines were superior to urinary VMA, urinary catecholamines, and plasma catecholamines and can provide a valuable test for diagnosis of pheochromocytoma in adults.
Kisspeptin-54 Stimulates Gonadotropin Release Most Potently during the Preovulatory Phase of the Menstrual Cycle in Women
Authors: Dhillo Waljit S. , Chaudhri Owais B. , Thompson Emily L. , Murphy Kevin G. , Patterson Michael , Ramachandran Radha , Nijher Gurjinder K. , Amber Vian , Kokkinos Alexander , Donaldson Mandy , Ghatei Mohammad A. , Bloom Stephen R. 
Published: July 2007

Abstract
Context: Kisspeptin, the endogenous ligand of the G protein-coupled receptor 54, is a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. GPR54-null mice exhibit reproductive dysfunction, and exogenous kisspeptin potently stimulates the HPG axis in rodents, primates, and human males. The effects of kisspeptin administration to human females are unknown.
Objective: Our objective was to investigate the effects of kisspeptin on LH release during the menstrual cycle in female volunteers.
Design: Bolus sc kisspeptin-54 was administered to female volunteers, and plasma gonadotropins were measured.
Setting: The study took place at a hospital clinical research facility.
Volunteers: Subjects were healthy female volunteers with regular menstrual cycles.
Intervention: 1) Volunteers received a sc bolus injection of kisspeptin-54 (0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 nmol/kg; n = 3–4 per dose) in the follicular phase; and 2) volunteers (n = 8) received a sc bolus injection of either kisspeptin-54 (0.4 nmol/kg) or saline in random order during each phase of the menstrual cycle.
Main Outcome Measures: Plasma gonadotropins were measured.
Results: 1) Kisspeptin-54 caused a dose-dependent increase in mean LH over time at doses from 0.2–6.4 nmol/kg. 2) Kisspeptin-54 increased plasma LH compared with saline injection in all phases of the cycle. The effect of kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle [mean increase in LH over baseline (IU/liter) ± sem for follicular phase was 0.12 ± 0.17; preovulatory phase, 20.64 ± 2.91 (P &lt; 0.001 vs. follicular phase); luteal phase, 2.17 ± 0.79 (P &lt; 0.01 vs. follicular phase)].
Conclusion: Elevation of plasma kisspeptin in human females potently stimulates LH release in the preovulatory phase and provides a novel mechanism for manipulation of the HPG axis in women.
MafA Regulates Expression of Genes Important to Islet β-Cell Function
Authors: Matsuoka Taka-aki , Kaneto Hideaki , Stein Roland , Miyatsuka Takeshi , Kawamori Dan , Henderson Eva , Kojima Itaru , Matsuhisa Munehide , Hori Masatsugu , Yamasaki Yoshimitsu 
Published: July 2007

AbstractInsulin transcription factor MafA is unique in being exclusively expressed at the secondary and principal phase of insulin-expressing cell production during pancreas organogenesis and is the only transcriptional activator present exclusively in islet β-cells. Here we show that ectopic expression of MafA is sufficient to induce a small amount of endogenous insulin expression in a variety of non-β-cell lines. Insulin mRNA and protein expression was induced to a much higher level when MafA was provided with two other key insulin activators, pancreatic and duodenal homeobox (PDX-1) and BETA2. Potentiation by PDX-1 and BETA2 was entirely dependent upon MafA, and MafA binding to the insulin enhancer region was increased by PDX-1 and BETA2. Treatment with activin A and hepatocyte growth factor induced even larger amounts of insulin in AR42J pancreatic acinar cells, compared with other non-β endodermal cells. The combination of PDX-1, BETA2, and MafA also induced the expression of other important regulators of islet β-cell activity. These results support a critical role of MafA in islet β-cell function.
Functional Interaction of Hepatic Nuclear Factor-4 and Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α in CYP7A1 Regulation Is Inhibited by a Key Lipogenic Activator, Sterol Regulatory Element-Binding Protein-1c
Authors: Ponugoti Bhaskar , Fang Sungsoon , Kemper Jongsook Kim 
Published: July 2007

AbstractInsulin inhibits transcription of cholesterol 7α-hydroxylase (Cyp7a1), a key gene in bile acid synthesis, and the hepatic nuclear factor-4 (HNF-4) site in the promoter was identified as a negative insulin response sequence. Using a fasting/feeding protocol in mice and insulin treatment in HepG2 cells, we explored the inhibition mechanisms. Expression of sterol regulatory element-binding protein-1c (SREBP-1c), an insulin-induced lipogenic factor, inversely correlated with Cyp7a1 expression in mouse liver. Interaction of HNF-4 with its coactivator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), was observed in livers of fasted mice and was reduced after feeding. Conversely, HNF-4 interaction with SREBP-1c was increased after feeding. In vitro studies suggested that SREBP-1c competed with PGC-1α for direct interaction with the AF2 domain of HNF-4. Reporter assays showed that SREBP-1c, but not of a SREBP-1c mutant lacking the HNF-4 interacting domain, inhibited HNF-4/PGC-1α transactivation of Cyp7a1. SREBP-1c also inhibited PGC-1α-coactivation of estrogen receptor, constitutive androstane receptor, pregnane X receptor, and farnesoid X receptor, implying inhibition of HNF-4 by SREBP-1c could extend to other nuclear receptors. In chromatin immunoprecipitation studies, HNF-4 binding to the promoter was not altered, but PGC-1α was dissociated, SREBP-1c and histone deacetylase-2 (HDAC2) were recruited, and acetylation of histone H3 was decreased upon feeding. Adenovirus-mediated expression of a SREBP-1c dominant-negative mutant, which blocks the interaction of SREBP-1c and HNF-4, partially but significantly reversed the inhibition of Cyp7a1 after feeding. Our data show that SREBP-1c functions as a non-DNA-binding inhibitor and mediates, in part, suppression of Cyp7a1 by blocking functional interaction of HNF-4 and PGC-1α. This mechanism may be relevant to known repression of many other HNF-4 target genes upon feeding.