bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imatinib Inhibits Proliferation of Ewing Tumor Cells Mediated by the Stem Cell Factor/KIT Receptor Pathway, and Sensitizes Cells to Vincristine and Doxorubicin-Induced Apoptosis
Authors: González Iranzu , Andreu Enrique J. , Panizo Angel , Inogés Susana , Fontalba Ana , Fernández-Luna José Luis , Gaboli Mirella , Sierrasesúmaga Luis , Martín-Algarra Salvador , Pardo Javier , Prósper Felipe , de Alava Enrique 
Published: September 2005

Abstract
Purpose and Experimental Design: The stem cell factor/KIT receptor loop may represent a novel target for molecular-based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines.
Results: KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWS-FLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5–20 μm) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC50, 12–15 μm). However, imatinib administered alone at doses close to IC50 for growth inhibition (10 μm) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 μm) was able to increase the antitumor in vitro effect of doxorubicin (DXR) and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15–20 and 15–36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs.
Conclusions: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor.
Identification of Peptide Vaccine Candidates Sharing among HLA-A3+, -A11+, -A31+, and -A33+ Cancer Patients
Authors: Takedatsu Hiroko , Shichijo Shigeki , Katagiri Kazuko , Sawamizu Hiromi , Sata Michio , Itoh Kyogo 
Published: September 2005

AbstractPurpose: Only a few studies have been reported on CTL epitope peptides restricted with alleles other than HLA-A2 and -A24. The HLA-A11, -A31, and -A33 alleles share similar binding motifs with HLA-A3 and -A68 alleles, and, thus, are classified as an HLA-A3 supertype. This study tried to identify CTL epitope peptides as vaccine candidates sharing by HLA-A3+, -A11+, -A31+, and -A33+ cancer patients.Experimental Design: Seven peptides possessing the ability to induce HLA-A31-restricted and tumor-reactive CTLs were examined for their ability to induce HLA-A3-, -A11-, and -A33-restricted and tumor-reactive CTLs from peripheral blood mononuclear cells (PBMCs) of 18 epithelial cancer patients. The five reference peptides all have the ability to induce CTL activity restricted with one of the HLA-A3 supertypes, and, thus, were also examined as positive controls.Results: Three peptides (2 from β-tublin5- and 1 from CGI37-derived peptides) induced tumor-reactive CTLs in PBMCs of HLA-A3+, -A11+, and -A33+ cancer patients with various frequencies (17–50%). One RLI- or KIAA0036-derived peptide induced tumor-reactive CTLs in PBMCs of HLA-A3+ and -A11+ or HLA-A11+ and -A33+ cancer patients also with various frequencies (22–67%), respectively, whereas the other peptide induced CTL activity in only HLA-A33+ patients. Among the five reference peptides tested, one peptide, TRP2–197, induced CTL activity in both HLA-A11+- and -A33+-restricted manners.Conclusions: We identified new peptide vaccine candidates for HLA-A3, -A11, -A31, and -A33 positive cancer patients. This study may facilitate the development of both basic and clinical studies of peptide-based immunotherapy for cancer patients with other alleles of HLA-A2 and -A24.
Associations between Breast Cancer Susceptibility Gene Polymorphisms and Clinicopathological Features
Authors: Han Wonshik , Kang Daehee , Park In Ae , Kim Seok Won , Bae Ji Yeon , Chung Ki-Wook , Noh Dong-Young 
Published: September 2005

AbstractPurpose: Genetic polymorphisms may affect not only cancer development but also cancer progression, and as a result could influence cancer phenotypes. The aim of this study was to examine the relationship between breast cancer susceptibility gene polymorphisms and clinicopathological features.Experimental Design: We genotyped 664 Korean primary breast cancer patients for 17 single-nucleotide polymorphisms (SNPs) in nine genes, using a high-throughput SNP scoring method.Results: CYP1A1 codon 462 Ile/Val or Val/Val variants and the CYP1B1 codon 432 Leu/Val variant were found more in breast cancer patients ≤35 years of age at onset than the common homozygote [odds ratio (OR), 1.6 and 1.7, respectively]. In combination analysis of these two SNPs, the OR was 1.9 when one of them was heterozygous or a rare homozygous form, and increased to 2.3 when both were variants (P = 0.006). Cases with Ile/Val at CYP1A1 codon 462 were 2.6-fold and those with Val/Val were 5.1-fold more likely to have first-degree relatives with breast cancer than those with Ile/Ile (P = 0.002). In the haplotype study of BRCA1, the 2430C/2731T/3667G/4427C/4956G homozygote showed less estrogen receptor negativity than the most common diplotype (OR, 0.5; 95% confidence interval, 0.26–0.94). TP53 codon 72 Arg/Pro or Pro/Pro variants were associated with negative axillary lymph node status (OR, 0.7; 95% confidence interval, 0.49–0.94).Conclusions: These results indicate that polymorphisms of some selected breast cancer susceptibility genes are associated with the clinicopathological phenotypes of breast cancer.
Heterogeneous Patterns of
FLT3
Asp835 Mutations in Relapsed
de Novo
Acute Myeloid Leukemia
Authors: Shih Lee-Yung , Huang Chein-Fuang , Wu Jin-Hou , Wang Po-Nan , Lin Tung-Liang , Dunn Po , Chou Meng-Chu , Kuo Ming-Chung , Tang Chung-Chih 
Published: September 2005

Abstract
Purpose: We analyzed Asp835 mutations of FLT3 on paired marrow samples at diagnosis and relapse from 120 adult patients with de novo acute myeloid leukemia (AML) to determine the role of FLT3 Asp835 mutation in the relapse of AML.
Experimental Design: Asp835 mutation was analyzed by DNA PCR amplification of exon 20 of FLT3 gene followed by EcoRV digestion. All of the mutations were confirmed by sequence analysis. Mutant to wild-type allelic ratio was determined by Genescan analysis. The Expand Long Template PCR System was used to determine the allelic location of internal tandem duplication of FLT3 (FLT3/ITD) and Asp835 mutations.
Results: Thirteen patients had Asp835 mutations at diagnosis, of them 8 lost the mutations at relapse, and the remaining 5 patients carrying Asp835 mutations at diagnosis relapsed with the identical mutation types. Another 6 patients acquired Asp835 mutations at relapse. Five samples harbored both FLT3/ITD and Asp835 mutations that were found on different alleles by cloning analysis in the 3 patients studied. There were no differences in WBC count, French-American-British subtype, percentage of marrow blasts, or circulating blasts between patients with and without Asp835 mutations, whereas the difference in the prevalence of Asp835 mutations among cytogenetic/molecular subgroups was statistically significant (P = 0.025).
Conclusions: The present study showed that patients with AML had heterogeneous patterns of FLT3 Asp835 mutations, either acquisition or loss of the mutations at relapse. Asp835 mutant clone may develop as a secondary event in a subset of patients with AML.
Phase I and Pharmacokinetic Study of the Cytotoxic Ether Lipid Ilmofosine Administered by Weekly Two-Hour Infusion in Patients with Advanced Solid Tumors
Authors: Giantonio Bruce J. , Derry Christine , McAleer Cecilia , McPhillips Joseph J. , O’Dwyer Peter J. 
Published: September 2005

Abstract
Purpose: A Phase I trial was performed to determine the dose-limiting toxicity and maximum tolerated dose, and to describe the pharmacokinetics of the alkyl-lysophospholipid, ilmofosine, when administered as a weekly 2-h infusion in patients with solid tumors.
Experimental Design: Thirty-nine patients were entered into a trial of ilmofosine administered weekly for 4 weeks followed by a 2-week rest period. Dose escalation occurred in 10 levels from 12 to 650 mg/m2.
Results: Thirty-six patients were evaluable for toxicity. The median number of cycles per patient was 1 (range, 1–4). Dose-limiting gastrointestinal toxicity occurred at 650 mg/m2 with grade 3 nausea in two patients and grade 3 vomiting and diarrhea in one patient. Grade 2 diarrhea was observed in four of six patients treated at 550 mg/m2. In addition, two patients treated at 550 mg/m2 and two patients treated at 650 mg/m2 experienced a decline in performance status of two or more levels that was determined to be due to treatment. There were no tumor responses. Stabilization of disease for at least 8 weeks occurred in six patients. Plasma concentrations of ilmofosine and its sulfoxide metabolite were evaluated by high-pressure liquid chromatography. The elimination of both compounds was biexponential with terminal half-lives of ∼40 h for ilmofosine and 48 h for the sulfoxide. The area under the concentration-time curve was dose-proportional for each compound, and there was no evidence of saturable kinetics.
Conclusions: The dose-limiting toxicity of ilmofosine is gastrointestinal and the recommended dose for Phase II trials is 450 mg/m2 as a 2-h weekly infusion. The relatively long half-life of ilmofosine and its active metabolite support the use of this intermittent schedule.
Comparative Pharmacokinetics of Weekly and Every-Three-Weeks Docetaxel
Authors: Baker Sharyn D. , Zhao Ming , Lee Carlton K. K. , Verweij Jaap , Zabelina Yelena , Brahmer Julie R. , Wolff Antonio C. , Sparreboom Alex , Carducci Michael A. 
Published: September 2005

Abstract
Purpose: Weekly administration of docetaxel has demonstrated comparable efficacy together with a distinct toxicity profile with reduced myelosuppression, although pharmacokinetic data with weekly regimens are lacking. The comparative pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly) administration schedules were evaluated.
Experimental Design: Forty-six patients received weekly docetaxel (35 mg/m2) as a 30-min infusion alone (n = 8) or in combination with irinotecan (n = 12), or in 3-weekly regimens, as a 1-h infusion at 60 mg/m2 with doxorubicin (n = 10), 75 mg/m2 alone (n = 9), or 100 mg/m2 alone (n = 7). Serial blood samples were obtained immediately before and up to 21 days after the infusion. Plasma concentrations were measured by liquid chromatography–mass spectrometry and analyzed by compartmental modeling.
Results: Mean ± SD docetaxel clearance values were similar with weekly and 3-weekly schedules (25.2 ± 7.7 versus 23.7 ± 7.9 liter/h/m2); half-lives were also similar with both schedules of administration (16.5 ± 11.2 versus 17.6 ± 7.4 h). With extended plasma sampling beyond 24 h post-infusion, docetaxel clearance was 18% lower and the terminal half-life was 5-fold longer. At 35 mg/m2, the mean ± SD docetaxel concentration on day 8 was 0.00088 ± 0.00041 μg/ml (1.08 ± 0.51 nm) at 75 mg/m2, concentrations on day 8, 15, and 22 were 0.0014 ± 0.00043 μg/ml (1.79 ± 0.53 nm), 0.00067 ± 0.00025 μg/ml (0.83 ± 0.31 nm), and 0.00047 ± 0.00008 μg/ml (0.58 ± 0.099 nm), respectively.
Conclusion: Docetaxel pharmacokinetics are similar for the weekly and 3-weekly regimens. Prolonged circulation of low nanomolar concentrations of docetaxel may contribute to the mechanism of action of docetaxel through suppression of microtubule dynamics and tumor angiogenesis and enhanced cell radiosensitivity in combined modality therapy.
Prognostic Value of
TP53
Codon 72 Polymorphism in Advanced Gastric Adenocarcinoma
Authors: Zhang Zun-Wu , Laurence Nicola J. , Hollowood Andrew , Newcomb Paul , Moorghen Moganaden , Gupta Jyoti , Feakins Roger , Farthing Michael J. G. , Alderson Derek , Holly Jeff 
Published: September 2005

Abstract
Purpose: A common polymorphism of the tumor suppressor gene TP53 at codon 72 has been associated with human cancer susceptibility. The prognostic role of the polymorphism was assessed in 102 patients with advanced gastric adenocarcinoma.
Experimental Design: We followed up 102 consecutive Caucasian patients with advanced gastric adenocarcinoma for &gt;5 years and determined the status of the TP53 codon 72 polymorphism in DNA samples extracted from archived gastric tissues.
Results: The frequency of the arginine homozygous allele was positively correlated to patient age at baseline (P = 0.002). However, the age-related increase in the percentage of codon 72 arginine p53 was not correlated to the prognosis for gastric cancer patients. Multivariable analysis in patients who had surgery showed that baseline age may be inversely associated with patient survival (odds ratio, 1.1; 95% confidence interval, 1.0–1.2; P = 0.02). Furthermore, alcohol consumption may be associated with reduced survival (P = 0.06).
Conclusions: These findings indicate that codon 72 arginine p53 may not be associated with a prolonged survival in patients with advanced gastric adenocarcinoma, but further study is needed to assess whether this polymorphism is associated with a late onset or slow progress of early gastric adenocarcinoma.
Effect of a Selective Cyclooxygenase-2 Inhibitor, Nimesulide, on the Growth of Lung Tumors and Their Expression of Cyclooxygenase-2 and Peroxisome Proliferator- Activated Receptor-γ
Authors: Shaik Madhu Sudhan , Chatterjee Abhijit , Singh Mandip 
Published: September 2005

Abstract
Purpose: The objectives of this study were to evaluate the effect of a cyclooxygenase (COX)-2 inhibitor, nimesulide, on the growth inhibition of s.c. human lung A549 adenocarcinoma tumors and to assess the effect of nimesulide on the expression of COX-2 and peroxisome proliferator-activated receptor (PPAR)-γ in lung tumors harvested from mice.
Experimental Design: Female nu/nu mice were xenografted with s.c. A549 lung tumors, and 1 day after tumor implantation, the mice were fed with a diet containing nimesulide at 250-1500 ppm doses. Tumor dimensions were monitored twice weekly, and tumor samples isolated from mice were used to determine prostaglandin E2 (PGE2) levels by enzyme immunoassay, expression of COX-2 and PPAR-γ by Western blotting and immunohistochemistry. Furthermore, the induction of apoptosis in tumor specimens was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling staining.
Results: Nimesulide treatment showed a dose-dependent growth-inhibitory effect of A549 tumors with a maximum of 77.7% inhibition at 1500 ppm of nimesulide. Western blotting experiments showed similar expression of COX-2 in both control and nimesulide (250–1500 ppm)-treated mice tumor tissues. PPAR-γ was found to be overexpressed as a result of 1500 ppm nimesulide treatment and was not detected in tumors from control or 250-1000 ppm nimesulide-treated mice. Nimesulide (1500 ppm) significantly reduced intratumor PGE2 levels (P &lt; 0.001) and induced apoptosis in 25% of tumor cells as compared with control tumors.
Conclusions: Nimesulide (1500 ppm) induced growth inhibition of A549 lung tumors is associated with the reduction of intratumor PGE2 levels but without affecting the expression of COX-2. Nimesulide-induced enhancement of the expression of PPAR-γ may also contribute to its antitumor effect, which needs to be further investigated.
Phase I Clinical and Pharmacokinetic Study of BMS-247550, a Novel Derivative of Epothilone B, in Solid Tumors
Authors: Mani Sridhar , McDaid Hayley , Hamilton Anne , Hochster Howard , Cohen Marvin B. , Khabelle Dineo , Griffin Tom , Lebwohl David E. , Liebes Leonard , Muggia Franco , Horwitz Susan Band 
Published: September 2005

Abstract
Purpose: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks.
Experimental Design: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550.
Results: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m2. At 50 mg/m2, 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m2 (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3–4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m2, the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1–2 neuropathy was observed in all patients enrolled and treated at 40 mg/m2. Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naïve breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m2 (recommended Phase II dose) dose level were 21 liters/h/m2, 826 liters/m2, and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar.
Conclusions: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m2, although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study.
Protein Profiling in Brain Tumors Using Mass Spectrometry
Authors: Schwartz Sarah A. , Weil Robert J. , Johnson Mahlon D. , Toms Steven A. , Caprioli Richard M. 
Published: September 2005

Abstract
Purpose: The purpose of this research was to perform a preliminary assessment of protein patterns in primary brain tumors using a direct-tissue mass spectrometric technique to profile and map biomolecules.
Experimental Design: We examined 20 prospectively collected, snap-frozen normal brain and brain tumor specimens using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS), and compared peptide and protein expression in primary brain tumor and nontumor brain tissues.
Results: MS can be used to identify protein expression patterns in human brain tissue and tumor specimens. The mass spectral patterns can reliably identify glial neoplasms of similar histological grade and differentiate them from tumors of different histological grades as well as from nontumor brain tissues. Initial bioinformatics cluster analysis algorithms classified tumor and nontumor tissues into similar groups comparable with their histological grade.
Conclusions: We describe a novel tool for the analysis of protein expression patterns in human glial neoplasms. Initial results demonstrate that MALDI-MS technology can significantly aid in the process of unraveling and understanding the molecular complexities of gliomas. MALDI-MS accurately and reliably identified normal and neoplastic tissues, and could be used to discriminate between tumors of increasing grades.
Prognostic Significance of E-Cadherin Protein Expression in Pathological Stage I-III Endometrial Cancer
Authors: Mell Loren K. , Meyer Jeffrey J. , Tretiakova Maria , Khramtsov Andrey , Gong Can , Yamada S. Diane , Montag Anthony G. , Mundt Arno J. 
Published: September 2005

Abstract
Purpose: Decreased expression of E-cadherin in endometrial cancer cells is associated with adverse prognostic features. This study aimed to evaluate the prognostic significance of decreased E-cadherin expression in patients with endometrial cancer.
Experimental Design: Between 1992 and 1999, 102 endometrial cancer patients with stage I-III disease underwent primary surgery at the University of Chicago. Representative tissue specimens were immunostained with a monoclonal antibody to E-cadherin. A semiquantitative evaluation scale was developed based on the percentage of endometrial cancer cells with membranous E-cadherin staining. Tissue sections were scored as “3” if &gt;75%, “2” if 25–75%, “1” if 5–25%, and “0” if &lt;5% of cells stained. E-Cadherin staining was correlated with overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and extrapelvic progression. Multivariate Cox proportional hazards modeling was used to estimate hazard ratios, controlling for clinicopathological characteristics and adjuvant treatment. Median follow-up for the study group was 58.5 months.
Results: E-Cadherin staining was scored as 0, 1, 2, and 3 in 29.4%, 18.6%, 26.5%, 25.5% of cases, respectively. E-Cadherin expression was positively correlated with myometrial invasion (Kendall τ: 0.30, P &lt; 0.01), and negatively correlated with grade (Kendall τ: −0.13, P = 0.15) and papillary serous or clear cell histology (Kendall τ: −0.14, P = 0.12). Five-year actuarial OS, CSS, PFS, and extrapelvic recurrence rates for negative (score = 0), heterogeneous (score = 1–2), and positive (score = 3) staining were as follows: OS, 69.2 versus 75.7 versus 81.0% (P = 0.64); CSS, 78.8 versus 91.2 versus 95.5% (P = 0.19); PFS, 69.1 versus 88.6 versus 92.2% (P = 0.079), and extrapelvic progression, 20.8 versus 7.3 versus 4.0% (P = 0.17). On multivariate Cox regression, a higher E-cadherin expression score was associated with decreased overall mortality [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.34–1.03; P = 0.066), and statistically significant decreases in endometrial cancer mortality (HR, 0.23; 95% CI, 0.055–0.94; P = 0.040), disease progression (HR, 0.28; 95% CI, 0.10–0.77; P = 0.014), and extrapelvic recurrence (HR, 0.24; 95% CI, 0.062–0.97; P = 0.045).
Conclusions: Decreased E-cadherin expression is an independent prognostic factor for disease progression and mortality in pathological stage I-III endometrial cancer. Evaluation of E-cadherin expression may aid in the selection of patients for more aggressive adjuvant therapy.