bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Cdx2 and Hepatocyte Antigen in Gastric Carcinoma: Correlation with Histologic Type and Implications for Prognosis
Authors: Fan Zhaoqing , Li Jiyou , Dong Bin , Huang Xinfu 
Published: September 2005

Abstract
Purpose: This study was designed to (a) analyze the correlation between the expression of Cdx2 and Hep and the clinicopathologic features of patients with gastric carcinoma, and (b) determine the value of combined analysis of Cdx2 and Hep expression in distinguishing histologic types and prognoses of gastric carcinomas.
Experimental Design: The expression of Cdx2 and Hep were studied using immunohistochemistry of paraffin-embedded tumor specimens from 109 patients who underwent D2 resection for gastric adenocarcinoma from 1995 to 1998.
Results: Nuclear Cdx2 and Hep expression was detected in 36.7% (40 of 109) and 54.1% (59 of 109) of gastric carcinoma cases, respectively. Expression of Cdx2 and Hep was significantly higher in intestinal-type carcinomas than in diffuse-type carcinomas (P = 0.027 and P = 0.037, respectively). There was a clear negative correlation between Cdx2 expression and lymph node metastasis (P = 0.029), as well as between Hep expression and depth of wall invasion (P = 0.011). The patients with Cdx2-positive or Hep-positive expression shows higher survival rate than those with Cdx2-negative or Hep-negative expression (P = 0.0008 and P = 0.003, respectively). Multivariate analysis revealed that the expression of Cdx2 and Hep were independent prognostic indicators of gastric carcinoma. The combination of Cdx2 and Hep expression was significantly lower in diffuse-type carcinoma than in intestinal or mixed-type carcinoma. Multivariate analysis revealed that Cdx2 and Hep expression was an independent prognostic indicator of gastric carcinoma (P &lt; 0.001).
Conclusions: These data suggest that combined analysis of Cdx2 and Hep has significant value in distinguishing histologic types and in predicting the prognosis of gastric carcinoma.
Neoadjuvant Docetaxel before Radical Prostatectomy in Patients with High-Risk Localized Prostate Cancer
Authors: Febbo Phillip G. , Richie Jerome P. , George Daniel J. , Loda Massimo , Manola Judith , Shankar Sridhar , Szot Barnes Agnieska , Tempany Clare , Catalona William , Kantoff Philip W. , Oh William K. 
Published: September 2005

Abstract
Purpose: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer.
Experimental Design: Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels &gt;20 ng/mL, and/or clinical stage T3 disease received weekly docetaxel (36 mg/m2) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis.
Results: The 19 patients enrolled received 82% of the planned chemotherapy. Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of &gt;50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46%). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy.
Conclusions: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of &gt;50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.
Enhanced Nectin-1 Expression and Herpes Oncolytic Sensitivity in Highly Migratory and Invasive Carcinoma
Authors: Yu Zhenkun , Chan Mei-Ki , O-charoenrat Pornchai , Eisenberg David P. , Shah Jatin P. , Singh Bhuvanesh , Fong Yuman , Wong Richard J. 
Published: September 2005

Abstract
Purpose: Although a variety of malignant tumors are susceptible to therapy with oncolytic herpes simplex viruses, the determinants of tumor sensitivity to these viruses are poorly understood. Nectin-1 is a cell surface adhesion molecule that is a component of intercellular adherens junctions and also functions as a herpes viral receptor. Because highly invasive cells may have decreased intercellular adhesion, we sought to determine if such cells might also have altered availability of cell surface nectin-1 to act as a herpes receptor.
Experimental Design and Results: A series of squamous cell carcinoma lines of increasing migratory and invasive potential, termed MG1-MG14, were selected by serial passages of murine SCC7 through Matrigel invasion chambers. Available cell surface nectin-1 was enhanced on the MG11 and MG14 cell lines in comparison to SCC7 as measured by cellular ELISA and immunofluorescence microscopy. A replication-competent, oncolytic herpes virus (NV1023) showed an increased ability to enter MG11 and MG14 cells as compared with SCC7 cells. Furthermore, MG11 and MG14 supported increased herpes viral replication and cytotoxicity over SCC7. For all three of the cell lines, viral entry assays revealed that the actively migrating cells were significantly more susceptible to herpes infection than the nonmigrating cells.
Conclusions: These results show that malignant cells with highly migratory and invasive properties may exhibit increased cell surface nectin-1 availability, which may serve as a herpes viral receptor to enhance the efficacy of herpes oncolytic therapy. This finding has implications regarding patient selection for future clinical trials using these promising therapeutic vectors.
Translating Research into Clinical Practice: Deliberations from the American Association for Cancer Research
Authors: Hait William N. 
Published: September 2005

Abstract
Translational research is difficult to define but recognizable to all who engage in it. Academic medical centers struggle to participate effectively, in contrast to the biotechnology or pharmaceutical industry, which are designed for nothing else. The process of translational research can be viewed as a cycle with defined phases and identifiable checkpoints. From the original hypothesis, through early scientific testing, investigators with different skill sets are required to move a fundamental observation through preclinical tests of clinical relevance then ultimately into the clinic. The various investigators must be able to organize effective research teams, whose compositions will differ as one moves closer to treating patients. Each phase, from discovery through application, has a set of barriers that can be summarized as culture, human resources/education, infrastructure, and regulatory. At a retreat of the Clinical Translational Research Committee of the American Association for Cancer Research, many of the issues facing academic centers were discussed and several recommendations are summarized here.
Activity of Suberoylanilide Hydroxamic Acid Against Human Breast Cancer Cells with Amplification of Her-2
Authors: Bali Purva , Pranpat Michael , Swaby Ramona , Fiskus Warren , Yamaguchi Hirohito , Balasis Maria , Rocha Kathy , Wang Hong-Gang , Richon Victoria , Bhalla Kapil 
Published: September 2005

Abstract
Purpose: We determined the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on hsp90 and its client proteins Her-2, AKT, and c-Raf, as well as evaluated the cytotoxic effects of cotreatment of SAHA with trastuzumab or docetaxel in human breast cancer BT-474 and SKBR-3 cells containing amplification of Her-2.
Experimental Design: The cells were treated with SAHA (1.0-5.0 μmol/L) and/or trastuzumab (5-40 μg/mL) or docetaxel (5-20 nmol/L). Following this, apoptosis and the levels of p21WAF1, p27KIP1, AKT, c-Raf, and Her-2, as well as of the key regulators of apoptosis were determined. Synergistic interaction between drugs was evaluated by median dose-effect analysis.
Results: Treatment with SAHA up-regulated p21WAF1 and p27KIP1 levels, increased the percentage of cells in G2-M phase of the cell cycle, as well as induced apoptosis in a dose-dependent manner. This was associated with up-regulation of the pro-death Bak and Bim, as well as with attenuation of the levels of Her-2 and XIAP, survivin, Bcl-2, and Bcl-xL proteins. SAHA treatment induced acetylation of hsp90. This reduced the chaperone association of Her-2 with hsp90, promoting polyubiquitylation and degradation of Her-2. SAHA also attenuated the levels of c-Raf and AKT. Cotreatment with SAHA significantly increased trastuzumab or docetaxel-induced apoptosis of BT-474 and SKBR-3 cells. Additionally, median dose-effect analysis revealed that cotreatment with SAHA and trastuzumab or docetaxel induced synergistic cytotoxic effects against the breast cancer cells.
Conclusions: These preclinical findings support the development of SAHA in combination with docetaxel and/or trastuzumab against Her-2-amplified breast cancer.
CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia
Authors: Lopes de Menezes Daniel E. , Peng Jing , Garrett Evelyn N. , Louie Sharianne G. , Lee Sang H. , Wiesmann Marion , Tang Yan , Shephard Lee , Goldbeck Cheryl , Oei Yoko , Ye Helen , Aukerman Sharon L. , Heise Carla 
Published: September 2005

Abstract
Purpose: Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. Given the relevance of FLT3 mutations in AML, we investigated the activity of CHIR-258, an orally active, multitargeted small molecule, with potent activity against FLT3 kinase and class III, IV, and V RTKs involved in endothelial and tumor cell proliferation in AML models.
Experimental Design: CHIR-258 was tested on two human leukemic cell lines in vitro and in vivo with differing FLT3 mutational status [MV4;11 cells express FLT3 internal tandem duplications (ITD) versus RS4;11 cells with wild-type (WT) FLT3].
Results: Antiproliferative activity of CHIR-258 against MV4;11 was ∼24-fold greater compared with RS4;11, indicating more potent inhibition against cells with constitutively activated FLT3 ITD. Dose-dependent down modulation of receptor phosphorylation and downstream signaling [signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase] in MV4;11 cells with CHIR-258 confirmed the molecular mechanism of action. Target modulation of phospho-FLT3, phospho-STAT5, and phospho-ERK in MV4;11 tumors was achieved at biologically active doses of CHIR-258. Tumor regressions and eradication of AML cells from the bone marrow were shown in s.c. and bone marrow engraftment leukemic xenograft models. Tumor responses were characterized by decreased cellular proliferation and positive immunohistochemical staining for active caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting cell death was mediated in part via apoptosis.
Conclusions: Our data indicate that CHIR-258 may be an effective therapy in FLT3-associated AML and warrants clinical trials.
Hsp90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Prevents Synovial Sarcoma Proliferation via Apoptosis in In vitro Models
Authors: Terry Jefferson , Lubieniecka Joanna M. , Kwan Wanda , Liu Suzanne , Nielsen Torsten O. 
Published: September 2005

Abstract
Synovial sarcoma is a soft tissue malignancy with a poor prognosis; many patients will die from this disease within 10 years of diagnosis, despite treatment. Gene expression profiling and immunohistochemistry studies have identified oncogenes that are highly expressed in synovial sarcoma. Included in this group are receptor tyrosine kinases such as epidermal growth factor receptor, insulin-like growth factor receptor 1, fibroblast growth factor receptor 3, KIT, and HER2. Inhibitors of these growth-promoting receptors are likely to inhibit proliferation of synovial sarcoma; however, the effect of receptor tyrosine kinase inhibitors on synovial sarcoma is largely unknown. We assessed the ability of the following receptor tyrosine kinase inhibitors to halt proliferation and induce apoptosis in synovial sarcoma monolayer and three dimensional spheroid in vitro models: gefitinib (Iressa), NVP-AEW541, imatinib mesylate (Gleevec), SU5402, PRO-001, trastuzumab (Herceptin), and 17-allylamino-17-demethoxygeldanamycin (17-AAG). Gefitinib, NVP-AEW541, and imatinib inhibited proliferation only at relatively high concentrations, which are not clinically applicable. 17-AAG, which destabilizes multiple receptor tyrosine kinases and other oncoproteins through heat shock protein 90 inhibition, prevented proliferation and induced apoptosis in synovial sarcoma monolayer models at concentrations achievable in human serum. 17-AAG treatment was also associated with receptor tyrosine kinase degradation and induction of apoptosis in synovial sarcoma spheroid models. 17-AAG was more effective than doxorubicin, particularly in the spheroid models. Here we provide in vitro evidence that 17-AAG, a clinically applicable drug with known pharmacology and limited toxicity, inhibits synovial sarcoma proliferation by inducing apoptosis, and thus has potential as a systemic therapy for this disease.
Identification of Mammaglobin as a Novel Serum Marker for Breast Cancer
Authors: Bernstein Jonine L. , Godbold James H. , Raptis George , Watson Mark A. , Levinson Brooke , Aaronson Stuart A. , Fleming Timothy P. 
Published: September 2005

Abstract
Purpose: Early detection of breast cancer has implications for the management and treatment of patients with this disease. Currently, there exist no highly sensitive and specific serologic biomarkers for detection of breast cancer. Mammaglobin is predicted to be a secreted protein, and expression of this gene seems to be highly specific in breast cancer. The present studies were undertaken to develop the mammaglobin protein as a serum biomarker for detection of breast cancer.
Experimental Design: We characterized the mammaglobin protein as a secreted, 14- to 21-kDa species, which is likely post-translationally processed based on its predicted 7-kDa size. Immunostaining for mammaglobin was conducted. An ELISA was developed for the detection of the mammaglobin protein in serum, and levels were compared between women with and without breast cancer. A receiver operating characteristic curve was used to show sensitivity and specificity for cut points on the continuous mammaglobin scale.
Results: The protein was detectable by immunostaining in 72% of breast tumors and not in other tumor types. The ELISA was highly sensitive and specific for detection of mammaglobin protein in tissue culture fluids of breast cancer cells and sera of breast cancer patients. The ELISA differentiated healthy women from those with breast cancer with accurate, repeatable results across time and under varying storage conditions.
Conclusion: Our results indicate that mammaglobin, as measured by the ELISA, holds significant promise for breast cancer screening with the realistic potential to impact management of this disease.
Prognostic Significance of Baseline Reverse Transcriptase-PCR for Prostate-Specific Antigen in Men with Hormone-Refractory Prostate Cancer Treated with Chemotherapy
Authors: Ross Robert W. , Manola Judith , Hennessy Kristen , Galsky Matthew , Scher Howard , Small Eric , Kelly W. Kevin , Kantoff Philip W. 
Published: September 2005

Abstract
Purpose: Methods accurately categorizing the diverse biology of prostate cancer are needed. A positive baseline reverse transcriptase-PCR for prostate-specific antigen (RT-PCR PSA) in the androgen-independent setting is an independent prognostic marker of survival. The objectives of the current study were to examine the prognostic implication of baseline RT-PCR PSA positivity during treatment with an active chemotherapeutic agent and explore whether an RT-PCR PSA “response” provides prognostic information.
Materials and Methods: In a combined analysis of a phase I and a randomized phase II trial of BMS-247550 (an epothilone B analogue), 104 patients with hormone-refractory prostate cancer had whole blood samples collected at baseline, then with each cycle of therapy. RT-PCR PSA was assessed and related to time to progression (TTP).
Results: From 100 evaluable patients, 368 samples were received, of which 90.8% were evaluable for RT-PCR PSA status. Baseline RT-PCR PSA status was significantly associated with TTP (hazard ratio, 2.22; 95% confidence interval, 1.40-3.52). Twenty-six of 38 patients positive at first assessment had at least one follow-up RT-PCR PSA that was negative (“response”). In univariate analysis, RT-PCR PSA response was not significantly associated with TTP, but in multivariate analysis, RT-PCR PSA response was of borderline statistical significance in predicting TTP (hazard ratio, 0.41; 95% confidence interval, 0.16-1.01).
Conclusion: These results provide further confirmation that baseline RT-PCR PSA is a statistically significant predictor of TTP in hormone-refractory prostate cancer. Moreover, this is the first report to suggest that RT-PCR PSA response during chemotherapy treatment may predict TTP.
New Paradigm in Dose-Finding Trials: Patient-Specific Dosing and Beyond Phase I
Authors: Rogatko André , Babb James S. , Tighiouart Mourad , Khuri Fadlo R. , Hudes Gary 
Published: September 2005

Abstract
We propose a new paradigm for the clinical evaluation of new cancer therapies. It entails adjusting the search for the optimal dose on the basis of measurable patient characteristics that may be predictive of adverse responses to treatment, and extending this search beyond phase I and into phases II and III. We provide examples of (a) how the fine-tuning of dose may involve utilization of patient-specific attributes to obtain a personalized treatment regimen, and (b) how novel methods for phase I design can be used to update the working dose for the conduct of phase II and III cancer clinical trials. These examples should be interpreted as an enticement for the development of new methods to implement the proposed new paradigm.
Antiangiogenic Treatment with Three Thrombospondin-1 Type 1 Repeats versus Gemcitabine in an Orthotopic Human Pancreatic Cancer Model
Authors: Zhang Xuefeng , Galardi Eric , Duquette Mark , Lawler Jack , Parangi Sareh 
Published: September 2005

Abstract
Purpose: In this study, we investigated the antitumor efficacy of thrombospondin-1 three type 1 repeats (3TSR), the antiangiogenic domain of thrombospondin-1, in comparison and in combination with gemcitabine, in an orthotopic pancreatic cancer model.
Experimental Design: Human pancreatic cancer cells were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR, gemcitabine, 3TSR plus gemcitabine, or vehicle for 3 weeks. Subsequently, the effects of 3TSR and/or gemcitabine on tumor growth, tumor necrosis, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed.
Results: After 3 weeks of treatment, 3TSR reduced tumor volume by 65%, and gemcitabine by 84%. Tumor volume was not statistically different between gemcitabine group and combinatorial treatment group. Extensive necrotic areas were observed in tumors from 3TSR-treated mice, whereas tumors from gemcitabine and combinatorially treated mice were less necrotic than control tumors. 3TSR reduced tumor microvessel density and increased tumor blood vessel endothelial cell apoptosis. In contrast, gemcitabine induced apoptosis and inhibited proliferation of cancer cells.
Conclusion: 3TSR, the antiangiogenic domain of thrombospondin-1, showed comparable antitumor efficacy to gemcitabine in a human pancreatic cancer orthotopic mouse model. No synergistic effect was found when the two drugs were combined and possible reasons are discussed in detail. A delicate balance between normalization and excessive regression of tumor vasculature is important when initiating alternative combinatorial regimens for treatment of patients with pancreatic cancer.
Phase II Study of Gefitinib in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma and Evaluation of Epidermal Growth Factor Receptor Mutations and Immunohistochemical Expression: A Gynecologic Oncology Group Study
Authors: Schilder Russell J. , Sill Michael W. , Chen Xiaowei , Darcy Kathleen M. , Decesare Steven L. , Lewandowski George , Lee Roger B. , Arciero Cletus A. , Wu Hong , Godwin Andrew K. 
Published: September 2005

AbstractPurpose: This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR).Experimental Design: Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib.Results: Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free &gt;6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation.Conclusions: Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.