bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer
Authors: Miller Kathy D. , Saphner Thomas J. , Waterhouse David M. , Chen T.-T. , Rush-Taylor Anita , Sparano Joseph A. , Wolff Antonio C. , Cobleigh Melody A. , Galbraith Susan , Sledge George W. 
Published: September 2005

Abstract
Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy.
Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC&gt;T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year.
Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade ≥ 2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19.5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade ≥ 3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had ≥50% of trough concentrations &gt; 124 ng/ml (IC90 for matrix metalloproteinase-9).
Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.
Immunological Consequences of Interleukin 12 Administration after Autologous Stem Cell Transplantation
Authors: Pelloso David , Cyran Katherine , Timmons Lynette , Williams Brian T. , Robertson Michael J. 
Published: September 2005

AbstractPurpose: The purpose is to determine the immunological effects of recombinant human interleukin (rhIL)-12 therapy after autologous stem cell transplantation.Experimental Design: Twelve patients (8 non-Hodgkin’s lymphoma, 2 Hodgkin’s disease, and 2 plasma cell myeloma) were treated with rhIL-12 by bolus i.v. injection in doses of 30, 100, or 250 ng/kg starting at a median of 66 days posttransplant. Immunological assays were performed using serum and peripheral blood mononuclear cell (PBMC) samples obtained on study.Results: Dose-dependent increases in the total lymphocyte count occurred during rhIL-12 therapy. The absolute number of peripheral blood CD4 T cells increased up to 16.3-fold, CD8 T cells up to 20.5-fold, B cells up to 11-fold, and natural killer (NK) cells up to 12.3-fold during rhIL-12 administration and returned to pretreatment baseline levels after discontinuation of rhIL-12. CD56bright NK cells expanded dramatically in the blood of a patient with baseline lymphopenia before rhIL-12 therapy. In vitro proliferation of patient PBMCs in response to IL-12 was indistinguishable from that of PBMCs obtained from healthy control sub-jects. Moreover, spontaneous in vitro proliferation of patient PBMCs increased significantly during rhIL-12 therapy. Increased levels of IFN-γ and IL-18 were detected in the serum of patients treated in the 100 and 250 ng/kg dose cohorts during the first multiple dose cycle.Conclusions: Expansion of T, B, and NK cells occurs in vivo during rhIL-12 therapy after autologous stem cell transplantation for hematological malignancies. In contrast to their striking defect in IL-12-induced IFN-γ production, posttransplant patient PBMCs exhibit normal proliferative responses to IL-12 in vitro. Additional investigation of rhIL-12 for posttransplantation immunotherapy is warranted.
Malignant Mammary Cells Acquire Independence from Extracellular Context for Regulation of Estrogen Receptor α
Authors: Novaro Virginia , Radisky Derek C. , Castro Nancy E. Ramos , Weisz Alessandro , Bissell Mina J. 
Published: September 2005

Abstract
Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Alterations of these interactions can induce abnormal intracellular signaling pathways that affect the development and progression of breast tumors. One critical component of mammary gland development, as well as breast cancer progression, is the expression of estrogen receptors. In a previous study using cultured nonmalignant mammary epithelial cells, we found that the basement membrane molecules, laminin-1 and collagen-IV, were involved in maintenance of estrogen receptor (ER) α expression, and that this response could be interfered with by disrupting cell-extracellular matrix adhesion. Here we use phenotypically normal mammary epithelial SCp2 cells to dissect the promoter region of the ERα that is involved in the selective response to basement membrane. We also analyze the alteration of this response in SCg6 cells, a malignant cell line that shares a common lineage with the SCp2 cells, to provide insight into the relative overexpression of ERα and the unresponsiveness to basement membrane regulation found in those malignant cells. Evidence is presented to show the relevance of the cross-talk between different signaling pathways in the constitution of a functional tissue organization and how this integration may be disrupted in the malignant phenotype.
Cardiovascular Safety Profile of Combretastatin A4 Phosphate in a Single-Dose Phase I Study in Patients with Advanced Cancer
Authors: Cooney Matthew M. , Radivoyevitch Tomas , Dowlati Afshin , Overmoyer Beth , Levitan Nathan , Robertson Kelly , Levine Sandra L. , DeCaro Kathleen , Buchter Carol , Taylor Anne , Stambler Bruce S. , Remick Scot C. 
Published: September 2005

Abstract
Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors.
Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m2 i.v. every 21 days, and the maximal dosage was 90 mg/m2. Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc = QT/(R-R interval)1/2, and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and Cmax versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.
Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P &lt; 0.0001) and 30.8 ms (P &lt; 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P &lt; 0.01) and 15.1 bpm (P &lt; 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.
Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.
Ubiquitous Aberrant RASSF1A Promoter Methylation in Childhood Neoplasia
Authors: Wong Ivy H. N. , Chan Jacqueline , Wong Joyce , Tam Paul K. H. 
Published: September 2005

Abstract
Purpose and Experimental Design: The role of RASSF1A has been elucidated recently in regulating apoptosis and cell cycle progression by inhibiting cyclin D1 accumulation. Aberrant RASSF1A promoter methylation has been found frequently in multiple adult cancer types. Using methylation-specific PCR and reverse transcription-PCR, we investigated epigenetic deregulation of RASSF1A in primary tumors, adjacent nontumor tissues, secondary metastases, peripheral blood cells, and plasma samples from children with 18 different cancer types, in association with their clinicopathologic features.
Results: Regardless of the tumor size, ubiquitous RASSF1A promoter methylation was found in 67% (16 of 24) of pediatric tumors, including neuroblastoma, thyroid carcinoma, hepatocellular carcinoma, pancreatoblastoma, adrenocortical carcinoma, Wilms’ tumor, Burkitt’s lymphoma, and T-cell lymphoma. A majority (75%) of pediatric cancer patients with tumoral RASSF1A methylation was male. Methylated RASSF1A alleles were also detected in 4 of 13 adjacent nontumor tissues, suggesting that this epigenetic change is potentially an early and critical event in childhood neoplasia. RASSF1A promoter methylation found in 92% (11 of 12) of cell lines largely derived from pediatric cancer patients was significantly associated with transcriptional silencing/repression. After demethylation treatment with 5-aza-2′-deoxycytidine, transcriptional reactivation was shown in KELLY, RD, and Namalwa cell lines as analyzed by reverse transcription-PCR. For the first time, RASSF1A methylation was detected in 54% (7 of 13), 40% (4 of 10), and 9% (1 of 11) of buffy coat samples collected before, during, and after treatment, correspondingly, from pediatric patients with neuroblastoma, thyroid carcinoma, hepatocellular carcinoma, rhabdomyosarcoma, Burkitt’s lymphoma, T-cell lymphoma, or acute lymphoblastic leukemia. Concordantly, RASSF1A methylation was found during treatment in plasma of the same patients, suggesting cell death and good response to chemotherapy.
Conclusions: RASSF1A methylation in tumor or buffy coat did not correlate strongly with age, tumor size, recurrence/metastasis, or overall survival in this cohort of pediatric cancer patients. Of importance, epigenetic inactivation of RASSF1A may potentially be crucial in pediatric tumor initiation.
Gene-Expression Profile Changes Correlated with Tumor Progression and Lymph Node Metastasis in Esophageal Cancer
Authors: Tamoto Eiji , Tada Mitsuhiro , Murakawa Katsuhiko , Takada Minoru , Shindo Gaku , Teramoto Ken-ichi , Matsunaga Akihiro , Komuro Kazuteru , Kanai Motoshi , Kawakami Akiko , Fujiwara Yoshie , Kobayashi Nozomi , Shirata Katsutoshi , Nishimura Norihiro , Okushiba Shun-ichi , Kondo Satoshi , Hamada Jun-ichi , Yoshiki Takashi , Moriuchi Tetsuya , Katoh Hiroyuki 
Published: September 2005

Abstract
Purpose: The purpose of this research was to identify molecular clues to tumor progression and lymph node metastasis in esophageal cancer and to test their value as predictive markers.
Experimental Design: We explored the gene expression profiles in cDNA array data of a 36-tissue training set of esophageal squamous cell carcinoma (ESCC) by using generalized linear model-based regression analysis and a feature subset selection algorithm. By applying the identified optimal feature sets (predictive gene sets), we trained and developed ensemble classifiers consisting of multiple probabilistic neural networks combined with AdaBoosting to predict tumor stages and lymph node metastasis. We validated the classifier abilities with 18 independent cases of ESCC.
Results: We identified 71 genes of 1289 cancer-related genes of which the expression correlated with tumor stages. Of the 71 genes, 47 significantly differed between the Tumor-Node-Metastasis pT1/2 and pT3/4 stages. Cell cycle regulators and transcriptional factors possibly promoting the growth of tumor cells were highly expressed in the early stages of ESCC, whereas adhesion molecules and extracellular matrix-related molecules possibly promoting invasiveness increased in the later stages. For lymph node metastasis, we identified 44 genes with predictive values, which included cell adhesion molecules and cell membrane receptors showing higher expression in node-positive cases and cell cycle regulators and intracellular signaling molecules showing higher expression in node-negative cases. The ensemble classifiers trained with the selected features predicted tumor stage and lymph node metastasis in the 18 validation cases with respective accuracies of 94.4% and 88.9%. This demonstrated the reproducibility and predictive value of the identified features.
Conclusion: We suggest that these characteristic genes will provide useful information for understanding the malignant nature of ESCC as well as information useful for personalizing the treatments.
Gene Expression Profiling of Differentiated Thyroid Neoplasms
Authors: Chevillard Sylvie , Ugolin Nicolas , Vielh Philippe , Ory Katherine , Levalois Céline , Elliott Danielle , Clayman Gary L. , El-Naggar Adel K. 
Published: September 2005

Abstract
Purpose: The purpose of this research was to identify novel genes that can be targeted as diagnostic and clinical markers of differentiated thyroid tumors.
Experimental Design: Gene expression analysis using microarray platform was performed on 6 pathologically normal thyroid samples and 12 primary follicular and papillary thyroid neoplasms. Microarrays containing probes for 5,760 human full-length cDNAs were used for hybridization with total RNA from normal and tumor thyroid samples labeled with Cy3-dUTP and Cy5-dUTP, respectively. Scanned array images were recorded, and data analysis was performed. Selected sets of differentially expressed genes were analyzed using quantitative real-time reverse transcription-PCR for verification.
Results: We identified 155 genes that differentiate histologically normal thyroid tissues from benign and malignant thyroid neoplasms. Of these 75 genes were differentiated between follicular neoplasms (adenoma and carcinoma) and the follicular variant of papillary carcinoma. Purely follicular neoplasms (adenomas and carcinomas) shared many genetic profiles, and only 43 genes were distinctly different between these tumors. Hierarchical cluster analysis also differentiated conventional papillary carcinoma from its follicular variant and follicular tumors. The differentially expressed genes were composed of members of cell differentiation, adhesion, immune response, and proliferation associated pathways. Quantitative real-time reverse transcription-PCR analysis of selected genes corroborated the microarray expression results.
Conclusions: Our study show the following: (1) differences in gene expression between tumor and nontumor bearing normal thyroid tissue can be identified, (2) a set of genes differentiate follicular neoplasm from follicular variant of papillary carcinoma, (3) follicular adenoma and carcinoma share many of the differentiated genes, and (4) gene expression differences identify conventional papillary carcinoma from the follicular variant.
Expression of the ELAV-Like Protein HuR Is Associated with Higher Tumor Grade and Increased Cyclooxygenase-2 Expression in Human Breast Carcinoma
Authors: Denkert Carsten , Weichert Wilko , Winzer Klaus-Jürgen , Müller Berit-Maria , Noske Aurelia , Niesporek Silvia , Kristiansen Glen , Guski Hans , Dietel Manfred , Hauptmann Steffen 
Published: September 2005

Abstract
Purpose: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3′-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR.
Experimental Design: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry.
Results: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P &lt; 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival.
Conclusions: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.
Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies
Authors: Ryan Christopher W. , Vogelzang Nicholas J. , Vokes Everett E. , Kindler Hedy L. , Undevia Samir D. , Humerickhouse Rod , André Amy K. , Wang Qiang , Carr Robert A. , Ratain Mark J. 
Published: September 2005

Abstract
Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies.
Experimental Design: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28.
Results: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant.
Conclusions: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.
A Two-by-Two Factorial Trial Comparing Oral with Transdermal Estrogen Therapy and Fenretinide with Placebo on Breast Cancer Biomarkers
Authors: Decensi Andrea , Bonanni Bernardo , Baglietto Laura , Guerrieri-Gonzaga Aliana , Ramazzotto Francesca , Johansson Harriet , Robertson Chris , Marinucci Irene , Mariette Frederique , Sandri Maria Teresa , Daldoss Cristina , Bianco Vanda , Buttarelli Marco , Cazzaniga Massimiliano , Franchi Dorella , Cassano Enrico , Omodei Umberto 
Published: September 2005

Abstract
Purpose: Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) increase breast cancer risk, whereas the effect of transdermal estradiol (E2) and MPA is less known. Fenretinide may decrease second breast malignancies in premenopausal women but not in postmenopausal women, suggesting a hormone-sensitizing effect. We compared the 6 and 12-month changes in insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), IGF-I:IGFBP-3 ratio, sex-hormone binding-globulin, and computerized mammographic percent density during oral CEE or transdermal E2 with sequential MPA and fenretinide or placebo.
Experimental Design: A total of 226 recent postmenopausal healthy women were randomly assigned in a two-by-two factorial design to either oral CEE 0.625 mg/day (n = 111) or transdermal E2, 50 μg/day (n = 115) and to fenretinide 100 mg/twice a day (n = 112) or placebo (n = 114) for 12 months. Treatment effects were investigated by the Kruskall-Wallis test and analysis of covariance. P values were two-sided.
Results: After 12 months, oral CEE decreased IGF-I by 26% [95% confidence interval (CI), 22–30%] and increased sex-hormone binding-globulin by 96% (95% CI, 79–112%) relative to baseline, whereas no change occurred with transdermal E2 (P &lt; 0.001 between groups). Fenretinide decreased IGFBP-3 relative to placebo (P = 0.04). Percentage of breast density showed an absolute increase of 3.5% (95% CI, 2.5–4.6%) during hormone therapy without differences between groups (P = 0.39).
Conclusions: Oral CEE has more favorable changes than transdermal E2 on circulating breast cancer risk biomarkers but gives similar effects on mammographic density. Fenretinide exerted little modulation on most biomarkers. The clinical implications of these findings require additional studies.