bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer
Authors: Mirchandani Deepu , Hochster Howard , Hamilton Anne , Liebes Leonard , Yee Herman , Curtin John P. , Lee Sang , Sorich Joan , Dellenbaugh Cornelia , Muggia Franco M. 
Published: September 2005

Abstract
Purpose: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors.
Methods: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status &lt;2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan.
Results: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples.
Conclusion: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended.
The Clinical Relevance of Steroid Hormone Receptor Corepressors
Authors: Kumar Rakesh , Gururaj Anupama E. , Vadlamudi Ratna K. , Rayala Suresh K. 
Published: September 2005

AbstractSteroid hormone receptors are ligand-dependent transcription factors that control a variety of essential physiologic and developmental processes in humans. The functional activity of a steroid receptor is regulated not only by hormones but also by an array of regulatory proteins such as coactivators, corepressors, and chromatin modifiers. Contrary to an earlier notion that corepressors and coactivators exist in separate complexes, these molecules, which have apparently opposite functions, are increasingly being found in the same complex, which allows for efficient transcriptional control mechanisms. These control mechanisms are in turn regulated by an array of post-translational modifications under the influence of upstream and local signaling networks. Because the outcome of steroidal hormone receptor transcriptional complexes is measured in terms of the expression of target genes, any dysregulation of coregulator complexes perturbs normal homeostasis and could contribute to the development and maintenance of malignant phenotypes. Increasing evidence implicating steroid hormone receptors and their coregulators in various pathophysiologic conditions has elicited interest in their structure and biology. Further advances in this field of study should open up a unique window for novel targeted therapies for diseases such as cancer. Here we briefly review the clinical relevance of corepressors, with a particular focus on their role in the development of cancerous phenotypes.
Dedifferentiation Precedes Invasion in the Progression from Barrett's Metaplasia to Esophageal Adenocarcinoma
Authors: Helm James , Enkemann Steven A. , Coppola Domenico , Barthel James S. , Kelley Scott T. , Yeatman Timothy J. 
Published: September 2005

Abstract
Purpose: Adenocarcinoma arises in Barrett's esophagus by progression from metaplasia to cancer through grades of dysplasia. Our aim in this exploratory study was to characterize the broad changes in gene expression that underlie this histologic progression to cancer and assess the potential for using these gene expression changes as a marker predictive of malignant progression in Barrett's epithelium.
Experimental Design: Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barrett's epithelia from which three of the cancers had arisen. Pooled samples from the Barrett's epithelia of six patients without cancer or dysplasia served as a reference.
Results: Barrett's epithelia from which cancer had arisen differed from the reference Barrett's epithelia primarily by underexpression of genes, many of which function in governing cell differentiation. These changes in gene expression were found even in those specimens of Barrett's epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barrett's epithelium from which it had arisen primarily by an overexpression of genes, many of which were associated with tissue remodeling and invasiveness. Cancers without identifiable Barrett's epithelium differed from cancers that had arisen from a Barrett's epithelium by having an even greater number of these overexpressed genes.
Conclusions: Histologic progression from Barrett's epithelium to cancer is associated with a gradient of increasing changes in gene expression characterized by an early loss of gene function governing differentiation that begins before histologic change; gain in function of genes related to remodeling and invasiveness follows later. This correlation of histologic progression with increasing changes in gene expression suggests that gene expression changes in biopsies taken from Barrett's epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.
Nuclear Factor-κB Activation Correlates with Better Prognosis and Akt Activation in Human Gastric Cancer
Authors: Lee Byung Lan , Lee Hye Seung , Jung Jieun , Cho Sung Jin , Chung Hee-Yong , Kim Woo Ho , Jin Young-Woo , Kim Chong Soon , Nam Seon Young 
Published: September 2005

AbstractPurpose: Because the biological significance of constitutive nuclear factor-κB (NF-κB) activation in human gastric cancer is unclear, we undertook this study to clarify the regulatory mechanism of NF-κB activation and its clinical significance.Experimental Design: Immunohistochemistry for NF-κB/RelA was done on 290 human gastric carcinoma specimens placed on tissue array slides. The correlations between NF-κB activation and clinicopathologic features, prognosis, Akt activation, tumor suppressor gene expression, or Bcl-2 expression were analyzed. We also did luciferase reporter assay, Western blot analysis, and reverse transcription-PCR using the SNU-216 human gastric cancer cell line transduced with retroviral vectors containing constitutively active Akt or the NF-κB repressor mutant of IκBα.Results: Nuclear expression of RelA was found in 18% of the gastric carcinomas and was higher in early-stage pathologic tumor-node-metastasis (P = 0.019). A negative correlation was observed between NF-κB activation and lymphatic invasion (P = 0.034) and a positive correlation between NF-κB activation and overall survival rate of gastric cancer patients (P = 0.0228). In addition, NF-κB activation was positively correlated with pAkt (P = 0.047), p16 (P = 0.004), adenomatous polyposis coli (P &lt; 0.001), Smad4 (P = 0.002), and kangai 1 (P &lt; 0.001) expression. An in vitro study showed that NF-κB activity in gastric cancer cells is controlled by and controls Akt.Conclusions: NF-κB activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis and Akt activation. These findings suggest that NF-κB activation is a valuable prognostic variable in gastric carcinoma.
Pulsatile Administration of the Epidermal Growth Factor Receptor Inhibitor Gefitinib Is Significantly More Effective than Continuous Dosing for Sensitizing Tumors to Paclitaxel
Authors: Solit David B. , She Yuhong , Lobo Jose , Kris Mark G. , Scher Howard I. , Rosen Neal , Sirotnak Frank M. 
Published: September 2005

Abstract
Purpose: Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Continuous inhibition of EGFR signaling is thought necessary for optimal inhibition of tumor cell proliferation. We hypothesized that continuous gefitinib may antagonize the effects of cytotoxics that inhibit tumor cells in other phases of the cell cycle. Furthermore, we hypothesized that intermittent dosing would allow for dose escalation and greater inhibition of EGFR-dependent antiapoptotic pathways.
Experimental Design: To test these assertions, we compared combinations of paclitaxel and gefitinib using either intermittent or continuous dosing schedules in mice.
Results: We found that when used in combination with paclitaxel, pulsatile gefitinib was significantly superior to continuous dosing. When gefitinib was administered for one or two consecutive days before paclitaxel, much higher doses could be given safely. Two days of gefitinib treatment before paclitaxel was most effective, causing significantly greater mean tumor regression and a higher percentage of complete responses than other schedules.
Conclusions: The results suggest that the dose and schedule of an EGFR inhibitor required to effectively inhibit proliferation may differ from that required to stimulate apoptosis or to induce other effects. The former may require continuous EGFR inhibition to maintain cell cycle arrest, whereas sensitization to apoptosis may be optimally induced by profound but temporary inhibition of survival pathways. Our data suggest that the effects of receptor inhibition vary as a function of dose and schedule and that continuous administration of tyrosine kinase inhibitors may not be the best schedule with which to combine such agents with taxanes.
Proton Beam Therapy for Hepatocellular Carcinoma: A Retrospective Review of 162 Patients
Authors: Chiba Toshiya , Tokuuye Koichi , Matsuzaki Yasushi , Sugahara Shinji , Chuganji Yoshimichi , Kagei Kenji , Shoda Junichi , Hata Masaharu , Abei Masato , Igaki Hiroshi , Tanaka Naomi , Akine Yasuyuki 
Published: September 2005

Abstract
Purpose: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy.
Experimental Design: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days.
Results: The overall survival rate for all of the 162 patients was 23.5% at 5 years. The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients. The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%. The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments.
Conclusions: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases.
Induction of p53 Up-Regulated Modulator of Apoptosis Messenger RNA by Chemotherapeutic Treatment of Locally Advanced Breast Cancer
Authors: Middelburg Rutger , de Haas Richard R. , Dekker Henk , Kerkhoven Ron M. , Pohlmann Paula R. , Fuentes-Alburo Adolfo , Mohar Alejandro , Pinedo Herbert M. , Lankelma Jan 
Published: September 2005

Abstract
Purpose: In biopsies of patients with locally advanced breast cancer, we investigated the in vivo changes of the gene expression pattern induced by chemotherapy to find genes that are potentially responsible for the efficacy of the drug.
Experimental Design: Early cellular responses to chemotherapy-induced damage, both in vivo and in vitro, were investigated by analyzing chemotherapy-induced changes in gene expression profiles. Core biopsies were taken from nine patients with locally advanced breast cancer, before and at 6 hours after initiation of doxorubicin-based chemotherapy. Both samples were cohybridized on the same microarray containing 18,000 cDNA spots.
Results: The analysis revealed marked differences in gene expression profile between treated and untreated samples. The gene which was most frequently found to be differentially expressed was p53 up-regulated modulator of apoptosis (PUMA). This gene was up-regulated in eight of nine patients with an average factor of 1.80 (range, 1.36-2.73). In vitro MCF-7 breast cancer cells exposed to clinically achievable doxorubicin concentrations for 6 hours revealed marked induction of PUMA mRNA, as well.
Conclusions: This is the first report describing PUMA mRNA to be up-regulated as a response to chemotherapy in patients. Because PUMA is a known member of the family of BH3-only proapoptotic proteins, this finding suggests PUMA's potential importance for the response to anticancer drugs.
Prognostic Significance of Fascin Overexpression in Human Esophageal Squamous Cell Carcinoma
Authors: Hashimoto Yosuke , Ito Tetsuo , Inoue Harutaka , Okumura Tomoyuki , Tanaka Eiji , Tsunoda Shigeru , Higashiyama Motoshige , Watanabe Go , Imamura Masayuki , Shimada Yutaka 
Published: September 2005

Abstract
Purpose: Fascin, an actin bundling protein, induces membrane protrusions and increased cell motility in various transformed cells. The expression of fascin in epithelial neoplasms has been described only recently, and the role of fascin in esophageal squamous cell carcinoma (ESCC) is still unknown.
Experimental Design: Paraffin sections of 200 patients with ESCC were immunohistochemically investigated. The expression levels of fascin mRNA in 20 ESCC tissues were compared with that in corresponding normal esophageal epithelium by semiquantitative reverse transcription-PCR. We also examined fascin protein expression in 33 ESCC cell lines. The role of fascin in cell motility and invasiveness in ESCC cells was assessed by the vector-based small interfering RNA.
Results: In immunohistochemical study, the intensity of fascin expression was usually increased in the tumor compared with that in normal epithelium. Fascin overexpression was significantly associated with a poor prognosis (immunoreactive rate, P = 0.033; immunoreactive intensity, P = 0.031). The fascin immunoreactive rate was associated with extent of the tumor (P = 0.002) and lymph node metastasis (P = 0.003). Multivariate analysis showed that fascin expression intensity was an independent prognostic factor, but the immunoreactive rate was not.
In addition, up-regulation of fascin mRNA was found in 60% (12 of 20) of patients. In vitro study revealed that all 33 ESCC cell lines expressed fascin protein at a certain level. KYSE170, one of the fascin-overexpressed cells, decreased its motile and invasive properties after down-regulation of fascin expression.
Conclusion: Our findings suggest that fascin overexpression may play an important role in the progression of ESCC.
Metabolic Signatures Associated with a NAD Synthesis Inhibitor–Induced Tumor Apoptosis Identified by 1H-Decoupled-31P Magnetic Resonance Spectroscopy
Authors: Muruganandham Manickam , Alfieri Alan A. , Matei Cornelia , Chen Yuchun , Sukenick George , Schemainda Isabel , Hasmann Max , Saltz Leonard B. , Koutcher Jason A. 
Published: September 2005

Abstract
Purpose: Attempts to selectively initiate tumor cell death through inducible apoptotic pathways are increasingly being exploited as a potential anticancer strategy. Inhibition of NAD+ synthesis by a novel agent FK866 has been recently reported to induce apoptosis in human leukemia, hepatocarcinoma cells in vitro, and various types of tumor xenografts in vivo. In the present study, we used 1H-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) to examine the metabolic changes associated with FK866 induced tumor cell death in a mouse mammary carcinoma.
Experimental Design: Induction of apoptosis in FK866-treated tumors was confirmed by histology and cytofluorometric analysis. FK866-induced changes in mammary carcinoma tumor metabolism in vivo were investigated using 1H-decoupled 31P MRS. To discern further the changes in metabolic profiles of tumors observed in vivo, high-resolution in vitro 1H-decoupled 31P MRS studies were carried out with perchloric acid extracts of mammary carcinoma tumors excised after similar treatments. In addition, the effects of FK866 on mammary carcinoma tumor growth and radiation sensitivity were studied.
Results: Treatment with FK866 induced a tumor growth delay and enhanced radiation sensitivity in mammary carcinoma tumors that was associated with significant increases in the 31P MR signal in the phosphomonoester region and a decrease in NAD+ levels, pH, and bioenergetic status. The 31P MRS of perchloric acid extracts of treated tumors identified the large unresolved signal in the phosphomonoester region as the resultant of resonances originating from intermediates of tumor glycolysis and guanylate synthesis in addition to alterations in pyridine nucleotide pools and phospholipid metabolism.
Conclusion: The present results suggest that FK866 interferes with multiple biochemical pathways that contribute to the increased cell death (apoptosis) and subsequent radiation sensitivity observed in the mammary carcinoma that could be serially monitored by 31P MRS.
Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer
Authors: Mehta Kshama R. , Nakao Kentaro , Zuraek Marlene B. , Ruan Daniel T. , Bergsland Emily K. , Venook Alan P. , Moore Dan H. , Tokuyasu Taku A. , Jain Ajay N. , Warren Robert S. , Terdiman Jonathan P. , Waldman Frederic M. 
Published: September 2005

Abstract
Purpose: Although liver resection is the primary curative therapy for patients with colorectal hepatic metastases, most patients have a recurrence. Identification of molecular markers that predict patients at highest risk for recurrence may help to target further therapy.
Experimental Design: Array-based comparative genomic hybridization was used to investigate the association of DNA copy number alterations with outcome in patients with colorectal liver metastasis resected with curative intent. DNA from 50 liver metastases was labeled and hybridized onto an array consisting of 2,463 bacterial artificial chromosome clones covering the entire genome. The total fraction of genome altered (FGA) in the metastases and the patient's clinical risk score (CRS) were calculated to identify independent prognostic factors for survival.
Results: An average of 30 ± 14% of the genome was altered in the liver metastases (14% gained and 16% lost). As expected, a lower CRS was an independent predictor of overall survival (P = 0.03). In addition, a high FGA also was an independent predictor of survival (P = 0.01). The median survival time in patients with a low CRS (score 0-2) and a high (≥20%) FGA was 38 months compared with 18 months in patients with a low CRS and a low FGA. Supervised analyses, using Prediction Analysis of Microarrays and Significance Analysis of Microarrays, identified a set of clones, predominantly located on chromosomes 7 and 20, which best predicted survival.
Conclusions: Both FGA and CRS are independent predictors of survival in patients with resected hepatic colorectal cancer metastases. The greater the FGA, the more likely the patient is to survive.
Clinical Significance of Heparin-Binding Epidermal Growth Factor–Like Growth Factor and A Disintegrin and Metalloprotease 17 Expression in Human Ovarian Cancer
Authors: Tanaka Yoshihiro , Miyamoto Shingo , Suzuki Satoshi O. , Oki Eiji , Yagi Hiroshi , Sonoda Kenzo , Yamazaki Ayano , Mizushima Hiroto , Maehara Yoshihiko , Mekada Eisuke , Nakano Hitoo 
Published: September 2005

Abstract
Purpose: Lysophosphatidic acid, which is enriched in the peritoneal fluid of ovarian cancer patients, plays a key role in the progression of ovarian cancer. Lysophosphatidic acid can generate epidermal growth factor receptor (EGFR) signal transactivation involving processing of EGFR ligands by ADAM (a disintegrin and metalloprotease) family metalloproteases. We aimed to investigate the clinical significance of EGFR ligands and ADAM family in the lysophosphatidic acid–induced pathogenesis of ovarian cancer.
Experimental Design: We examined the expression of EGFR ligands and ADAM family members in 108 patients with normal ovaries or ovarian cancer, using real-time PCR, immunohistochemistry, and in situ hybridization, and analyzed the clinical roles of these molecules. Statistical analyses of these data were done using the Mann-Whitney test, Kaplan-Meier method, or Spearman's correlation analysis.
Results: Large differences in expression were found for heparin-binding EGF-like growth factor (HB-EGF) and other EGFR ligands and for ADAM 17 and other ADAM family members. HB-EGF expression was significantly increased in advanced ovarian cancer compared with that in normal ovaries (P &lt; 0.01). HB-EGF expression was significantly associated with the clinical outcome (P &lt; 0.01). ADAM 17 expression was significantly enhanced in both early and advanced ovarian cancer compared with that in normal ovaries (both P &lt; 0.01), although it had no clinical significance in the progression-free survival. HB-EGF expression was significantly correlated with ADAM 17 expression (γ = 0.437, P &lt; 0.01).
Conclusions: Our findings suggest that HB-EGF and ADAM 17 contribute to the progression of ovarian cancer and that HB-EGF plays a pivotal role in the aggressive behavior of a tumor in ovarian cancer.