bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Requirement of Multimodal Therapy (Vaccine, Local Tumor Radiation, and Reduction of Suppressor Cells) to Eliminate Established Tumors
Authors: Kudo-Saito Chie , Schlom Jeffrey , Camphausen Kevin , Coleman C. Norman , Hodge James W. 
Published: September 2005

AbstractPurpose: Numerous immune-based strategies are currently being evaluated for cancer therapy in preclinical models and clinical trials. Whereas many strategies look promising in preclinical models, they are often evaluated before or shortly following tumor implantation. The elimination of well-established tumors often proves elusive. Here we show that a multimodal immune-based therapy can be successfully employed to eliminate established tumors.Experimental Design: This therapy consists of vaccines directed against a self-tumor-associated antigen, the use of external beam radiation of tumors to up-regulate Fas on tumor cells, and the use of a monoclonal antibody (mAb) to reduce levels of CD4+CD25+ suppressor cells.Results: We show here for the first time that (a) antigen-specific immune responses induced by vaccines were optimally augmented when anti-CD25 mAb was given at the same time as vaccination; (b) anti-CD25 mAb administration in combination with vaccines equally augmented T-cell immune responses specific for a self-antigen as well as those specific for a non–self antigen; (c) whereas the combined use of vaccines and anti-CD25 mAb enhanced antigen-specific immune responses, it was not sufficient to eliminate established tumors; (d) the addition of external beam radiation of tumors to the vaccine/anti-CD25 mAb regimen was required for the elimination of established tumors; and (e) T cells from mice receiving the combination therapy showed significantly higher T-cell responses specific not only for the antigen in the vaccine but also for additional tumor-derived antigens (p53 and gp70).Conclusions: These studies reported here support the rationale for clinical trials employing multimodal immune-based therapies.
Differential Effects of Vascular Endothelial Growth Factor Receptor-2 Inhibitor ZD6474 on Circulating Endothelial Progenitors and Mature Circulating Endothelial Cells: Implications for Use as a Surrogate Marker of Antiangiogenic Activity
Authors: Beaudry Paul , Force Jeremy , Naumov George N. , Wang Andrew , Baker Cheryl H. , Ryan Anderson , Soker Shay , Johnson Bruce E. , Folkman Judah , Heymach John V. 
Published: September 2005

Abstract
Purpose: Circulating endothelial cells (CEC) comprise at least two distinct populations: bone marrow–derived circulating endothelial progenitors (CEP) and mature CECs derived from existing vasculature. We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity.
Experimental Design: The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor (VEGF)–induced mobilization and in mice bearing Lewis lung carcinoma (LLC). Tumor angiogenesis was evaluated in parallel by immunohistochemistry.
Results: In nontumor-bearing mice, VEGF administration increased both mature CECs and CEPs. This increase was inhibited by the VEGF receptor 2 inhibitor ZD6474 as well as the VEGF inhibitor–soluble Flt-1. ZD6474 had no significant effect on CECs in the absence of exogenous VEGF stimulation. In contrast, LLC-bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with ZD6474. The increase in mature CECs was dose-dependent, accompanied by a decrease in tumor microvessel density, and preceded reduction in tumor volume. Treatment of LLC-bearing mice with the vascular targeting agent ZD6126 also increased mature CECs.
Conclusions: VEGF inhibitors can have differential effects on mature CECs and CEPs, and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs. This increase occurs in tumor-bearing but not in nontumor-bearing mice, suggesting that tumor endothelium is a potential source of mature CECs. Therefore, assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity.
Methylation and Messenger RNA Expression of p15INK4b but Not p16INK4a Are Independent Risk Factors for Ovarian Cancer
Authors: Liu Zhensheng , Wang Li-E , Wang Luo , Lu Karen H. , Mills Gordon B. , Bondy Melissa L. , Wei Qingyi 
Published: September 2005

Abstract
Purpose: The purpose of this research was to compare methylation status and mRNA expression of p15INK4b and p16INK4a in serous epithelial ovarian cancer tissues and normal ovarian tissues.
Experimental Design: We analyzed the DNA methylation status and mRNA expression of p15INK4b and p16INK4a in 52 ovarian cancer specimens and 40 normal ovarian specimens by using methylation-specific PCR and real-time reverse transcription-PCR, respectively.
Results: Although the p15INK4b and p16INK4a mRNA expression levels were highly correlated with each other (P &lt; 0.001), the methylation status did not seem to be linked with levels of mRNA expression, as no association between the two events was found for either gene. Promoter hypermethylation of p15INK4b was more common in ovarian cancer (30.8% for the 52 cases) than in normal ovaries (5% for the 40 controls without ovarian cancer; P = 0.005) but not methylation of p16INK4a (25% for cancer versus 37.5% for normal; P = 0.288). The relative mRNA expression levels of p15INK4b were significantly lower in ovarian cancer (12.9%) than in normal ovaries (41.7%; P = 0.008) but not those of p16INK4a (27% for cases versus 32.8% for controls; P = 0.754). Only high methylation rate and low mRNA expression of p15INK4b were independent risk factors for ovarian cancer (adjusted odds ratio, 5.67; 95% confidence interval, 0.85-37.9 for high methylation rate and odds ratio, 8.98; 95% confidence interval, 1.58-50.9 for low mRNA expression, respectively).
Conclusions: Our results suggest that epigenetic alterations in p15INK4b but not p16INK4a have an important role in ovarian carcinogenesis and that mechanisms other than methylation may exist to reduce gene expression of p15INK4b in ovarian cancer.
Dexrazoxane Protects against Myelosuppression from the DNA Cleavage–Enhancing Drugs Etoposide and Daunorubicin but not Doxorubicin
Authors: Hofland Kenneth Francis , Thougaard Annemette Vinding , Sehested Maxwell , Jensen Peter Buhl 
Published: September 2005

Abstract
Purpose: The anthracyclines daunorubicin and doxorubicin and the epipodophyllotoxin etoposide are potent DNA cleavage–enhancing drugs that are widely used in clinical oncology; however, myelosuppression and cardiac toxicity limit their use. Dexrazoxane (ICRF-187) is recommended for protection against anthracycline-induced cardiotoxicity.
Experimental Design: Because of their widespread use, the hematologic toxicity following coadministration of dexrazoxane and these three structurally different DNA cleavage enhancers was investigated: Sensitivity of human and murine blood progenitor cells to etoposide, daunorubicin, and doxorubicin ± dexrazoxane was determined in granulocyte-macrophage colony forming assays. Likewise, in vivo, B6D2F1 mice were treated with etoposide, daunorubicin, and doxorubicin, with or without dexrazoxane over a wide range of doses: posttreatment, a full hematologic evaluation was done.
Results: Nontoxic doses of dexrazoxane reduced myelosuppression and weight loss from daunorubicin and etoposide in mice and antagonized their antiproliferative effects in the colony assay; however, dexrazoxane neither reduced myelosuppression, weight loss, nor the in vitro cytotoxicity from doxorubicin.
Conclusion: Although our findings support the observation that dexrazoxane reduces neither hematologic activity nor antitumor activity from doxorubicin clinically, the potent antagonism of daunorubicin activity raises concern; a possible interference with anticancer efficacy certainly would call for renewed attention. Our data also suggest that significant etoposide dose escalation is perhaps possible by the use of dexrazoxane. Clinical trials in patients with brain metastases combining dexrazoxane and high doses of etoposide is ongoing with the aim of improving efficacy without aggravating hematologic toxicity. If successful, this represents an exciting mechanism for pharmacologic regulation of side effects from cytotoxic chemotherapy.
Microregional Expression of Glucose Transporter-1 and Oxygenation Status: Lack of Correlation in Locally Advanced Cervical Cancers
Authors: Mayer Arnulf , Höckel Michael , Wree Alexander , Vaupel Peter 
Published: September 2005

Abstract
Purpose: Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has been considered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1 may also serve as an indicator for the induction of the transcriptional response to hypoxia, which has been linked to enhanced proliferation, resistance to therapy, and metastatic propagation of cancer cells. Overexpression of GLUT-1 has been shown to correlate with poor prognosis in several tumor entities, among them cancers of the uterine cervix. The validity of these hypotheses is investigated.
Experimental Design: The expression of GLUT-1 was assessed in 80 biopsies of Eppendorf oxygenation measurement tracks from locally advanced cervical cancers in 47 patients using immunohistochemistry.
Results: No correlation was found between the expression of GLUT-1 and oxygenation variables (median pO2, HF 2.5 and HF 5). Expression of GLUT-1 was found greater in larger tumors (P = 0.0001) and to exhibit a linear increase with Fédération Internationale de Gynécologie et d' Obstétrique stage (P = 0.002). Overall survival (P = 0.004) and recurrence-free survival (P = 0.007) were significantly shorter for patients with expression of GLUT-1. In the subgroup of patients treated with surgery, this effect on prognosis was not independent when pT stage or pN stage were included in a multivariate Cox proportional hazards model.
Conclusions: The suitability of GLUT-1 as an endogenous marker of tumor hypoxia seems questionable. The association with prognosis may partially depend on confounding factors.
Reduction of Intracellular pH as a Strategy to Enhance the pH-Dependent Cytotoxic Effects of Melphalan for Human Breast Cancer Cells
Authors: Wong Philip , Lee Carol , Tannock Ian F. 
Published: September 2005

Abstract
The microenvironment within solid tumors is slightly acidic, and manipulation of this extracellular acidity to cause intracellular acidification might be used to increase selective antitumor effects of some anticancer drugs. Potential mechanisms include inhibition of repair of DNA damage and inhibition of repopulation of tumor cells between successive courses of chemotherapy. Here, we evaluate the influence of extracellular pH (pHe) and of two agents that lead to intracellular acidification (cariporide and S3705) on toxicity of melphalan for two human breast cancer cell lines (MDA-MB231 and MCF7). Both the total number and number of colony-forming cells were evaluated during and after three sequential weekly drug treatments. Our results indicate the following: (a) Slow or absent repopulation after the first course of treatment that is influenced minimally by pHe. (b) Rapid repopulation after the second course of treatment that may be inhibited at low pHe. (c) Effects of low pHe following treatment with melphalan to increase cell kill. (d) Small effects of incubation in cariporide and S3705 at low pHe to increase the net cell kill after treatment with melphalan. Although these results add to evidence that manipulation of intracellular pH within the acidic environment of solid tumors can influence the effects of chemotherapy, they are too small and inconsistent to warrant clinical evaluation.
Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor Are Associated with Improved Survival in Gefitinib-Treated Chemorefractory Lung Adenocarcinomas
Authors: Taron Miguel , Ichinose Yukito , Rosell Rafael , Mok Tony , Massuti Bartomeu , Zamora Lurdes , Mate Jose Luis , Manegold Christian , Ono Mayumi , Queralt Cristina , Jahan Thierry , Sanchez Jose Javier , Sanchez-Ronco Maria , Hsue Victor , Jablons David , Sanchez Jose Miguel , Moran Teresa 
Published: September 2005

AbstractPurpose: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR.Experimental Design: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non–small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non–small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers.Results: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P &lt; 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant).Conclusions: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.
Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development
Authors: Kelloff Gary J. , Hoffman John M. , Johnson Bruce , Scher Howard I. , Siegel Barry A. , Cheng Edward Y. , Cheson Bruce D. , O'Shaughnessy Joyce , Guyton Kathryn Z. , Mankoff David A. , Shankar Lalitha , Larson Steven M. , Sigman Caroline C. , Schilsky Richard L. , Sullivan Daniel C. 
Published: September 2005

Abstract2-[18F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non–small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.
Safety and Pharmacokinetics of the Dual Action Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor, BAY 43-9006, in Patients with Advanced, Refractory Solid Tumors
Authors: Clark Jeffrey W. , Eder Joseph P. , Ryan David , Lathia Chetan , Lenz Heinz-Josef 
Published: September 2005

Abstract
Purpose: BAY 43-9006, a novel multikinase inhibitor, prevents tumor growth by combining two antitumor activities: inhibition of both tumor cell proliferation and tumor angiogenesis. This phase I, open-label, nonrandomized, noncontrolled, single-arm, dose escalation study was done to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, effect on biomarkers, and tumor response with BAY 43-9006 in 19 patients with advanced, refractory solid tumors.
Experimental Design: BAY 43-9006 was given orally in repeated cycles of 1-week on/1-week off. The study comprised five dose levels, ranging from 100 mg twice daily (bid) to 800 mg bid. Treatment of each patient continued until unacceptable toxicity, tumor progression, or death.
Results: Rash and hypertension were the dose-limiting toxicities at the 800 mg bid dose requiring study drug discontinuation; therefore, the MTD of BAY 43-9006 in this study was determined to be 600 mg bid. BAY 43-9006 was generally well tolerated, with mild to moderate toxicities. Pharmacokinetic analysis showed early absorption followed by delayed secondary peaks and slow terminal elimination. Stable disease was achieved in five patients: one patient showed reduced tumor activity (positron emission tomography scan) and reduced mitogen-activated protein kinase signaling (lower phospho-ERK); one patient remained on treatment until study end point.
Conclusions: The results confirm the favorable safety profile of BAY 43-9006 and support the development of this compound for the treatment of solid tumors.
Prognostic Factors for Survival of Patients with Stage IV Renal Cell Carcinoma
Authors: Motzer Robert J. , Bacik Jennifer , Mazumdar Madhu 
Published: September 2005

Abstract
Prospective identification of patients with stage IV renal cell carcinoma more likely to benefit from cytokine therapy could be used as a stratification factor in Phase III trials and in risk-directed therapy. The relationship between pretreatment clinical features and survival was evaluated in patients treated in Phase II and III clinical trials for metastatic renal cell carcinoma at the Memorial Sloan-Kettering Cancer Center. The first analysis was performed in 670 patients treated with cytokines or chemotherapy, and a multivariate model was created to predict survival. Studies that followed addressed four topics: (1) the survival of patients given interferon α as first-line therapy, (2) a comparison of survival for patients treated with chemotherapy versus cytokine therapy, (3) survival of patients with nonclear cell histologic features, and (4) survival of patients treated with a second-line therapy. Prognostic models based on pretreatment clinical and laboratory variables can help identify patients more likely to benefit from standard therapies, as well as assist in the interpretation of drug effectiveness in Phase II clinical trials. Investigations into new prognostic factors based on tumor biology are needed and of high priority.
EphB2 is a Prognostic Factor in Colorectal Cancer
Authors: Jubb Adrian M. , Zhong Fiona , Bheddah Sheila , Grabsch Heike I. , Frantz Gretchen D. , Mueller Wolfram , Kavi Vidya , Quirke Phil , Polakis Paul , Koeppen Hartmut 
Published: September 2005

Abstract
A receptor tyrosine kinase for ephrin ligands, EphB2 is expressed in colorectal cancer and has been proposed as a target for immunoconjugate therapy. The aim of this study was to perform a detailed histologic analysis of EphB2 expression in normal and neoplastic colorectal tissues. In addition, we sought to evaluate EphB2 expression as a prognostic factor in colorectal cancer. Expression of EphB2 was examined in normal colon (n = 28), colorectal cell lines (n = 20), colorectal adenomas (n = 148), primary cancers (n = 28), and metastases (n = 39) using immunohistochemistry. In addition, a series of primary cancers and matched normal (n = 342) with outcome data were profiled in tissue microarrays. The intensity of EphB2 expression was assessed in the entire series by immunohistochemistry, and in a subset by in situ hybridization. Overall survival and recurrence-free survival were correlated with EphB2 protein expression in retrospective subset analyses. Epithelial EphB2 expression was shown at all stages of colorectal tumorigenesis, including the base of all normal crypts, 77% of adenomas, 82% of primary cancers, and 64% of metastases. Although homogeneous expression was observed in adenomas, the pattern of staining was focal (mean 25%) in most malignant lesions. Patients whose tumor stained 2+ for EphB2 expression (versus 0/1+) exhibited significantly prolonged overall survival: mean duration of survival, 2,514 versus 1,044 days; hazard ratio, 0.45; 95% confidence interval, 0.18 to 0.95 (P = 0.035). In summary, EphB2 is expressed in normal crypts, colorectal adenomas, primary cancers, and metastases. High levels of EphB2 expression are associated with a longer mean duration of survival in colorectal cancer.
Plasma and Cerebrospinal Fluid Pharmacokinetics of Clofarabine in Nonhuman Primates
Authors: Berg Stacey L. , Bonate Peter L. , Nuchtern Jed G. , Dauser Robert , McGuffey Leticia , Bernacky Bruce , Blaney Susan M. 
Published: September 2005

Abstract
Introduction: Clofarabine (2-chloro-2′fluoro-2′-deoxy-9-β-d-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model.
Methods: A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four animals. Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy.
Results: The median clofarabine clearance was 17 mL/min/kg (range, 15-20), the median plasma area under the concentration-time curve was 452 μmol/L minutes (range, 380-487), and the median terminal half-life was 105 minutes (range, 78-138). Concentrations of clofarabine in CSF could not be modeled reliably because the terminal rate constant was not well defined. The median CSF penetration was 5% (range, 3-26%).
Conclusion: Clofarabine penetrates into the CSF only modestly, but the concentrations obtained may approach those that are cytotoxic in vitro. Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies.