bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal Use of a Panel of Methylation Markers with GSTP1 Hypermethylation in the Diagnosis of Prostate Adenocarcinoma
Authors: Tokumaru Yutaka , Harden Susan V. , Sun Dong-Il , Yamashita Keishi , Epstein Jonathan I. , Sidransky David 
Published: September 2005

Abstract
Purpose: In this study, we tested the ability of a panel of hypermethylation markers to improve the sensitivity of histologic prostate cancer detection in sextant needle biopsies.
Experimental Design: We obtained fresh-frozen sextant biopsies from 72 excised prostates and directly compared blinded histologic review and quantitative real-time methylation-specific PCR for hypermethylation of four genes, Tazarotene-induced gene 1 (TIG1), adenomatous polyposis coli (APC), retinoic acid receptor β2 (RARβ2), and glutathione S-transferase π (GSTP1) to detect the presence of prostate cancer. Results were compared with the final surgical pathological review of the resected prostates as the gold standard.
Results: Histologic review alone detected carcinoma with a sensitivity of 64% (39 of 61 cases) and 100% specificity. Quantitative real-time methylation-specific PCR for TIG1, APC, RARβ2, and GSTP1 detected carcinoma with a sensitivity of 70%, 79%, 89%, and 75%, respectively, with 100% specificity for all of the genes. Using this panel of methylation markers in combination with histology resulted in the detection of 59 of 61 (97%) cases of prostate with 100% specificity, a 33% improvement over histology alone.
Conclusion: The use of a panel of methylation markers as an adjunct to histologic review may substantially augment prostate cancer diagnosis from needle biopsies.
HER-2 Amplification, HER-1 Expression, and Tamoxifen Response in Estrogen Receptor-Positive Metastatic Breast Cancer
Authors: Arpino Grazia , Green Stephanie J. , Allred D. Craig , Lew Dannika , Martino Silvana , Osborne C. Kent , Elledge Richard M. 
Published: September 2005

Abstract
Purpose: Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen.
Patients and Methods: Three hundred and forty nine patients had estrogen receptor (ER)-positive breast cancer and received daily tamoxifen as initial therapy for advanced disease. HER-2 gene amplification, detected by fluorescence in situ hybridization, and HER-1 expression, evaluated by immunohistochemistry, was determined on 136 and 204 patients, respectively.
Results: HER-2 amplification was correlated with lower ER (P = 0.02), HER-1 positivity (P = 0.004), and HER-2 protein overexpression (P &lt; 0.00001). The response rate was 56% for HER-2 non-amplified versus 47% for HER-2 amplified tumors (P = 0.38), and 58% for HER-1–negative versus 36% for HER-1–positive (P = 0.05). Time to treatment failure (TTF) was 7 months for non-amplified HER-2 tumors and 5 months (P = 0.007) for amplified HER-2 tumors, and there was a trend toward a better overall survival (OS) in patients with non-amplified HER-2 tumors (median 31 versus 25 months, respectively, P = 0.07). For positive versus negative HER-1 tumors, TTF was 4 versus 8 months (P = 0.08) and median survival was 24 versus 31 months (P = 0.41). Combining HER-1 expression and HER-2 gene status, patients with both negative HER-1 expression and non-amplified HER-2 had longer TTF (P = 0.001) and OS (P = 0.03) than if either were positive. In multivariate analysis, HER-2 was not an independent factor for TTF and OS, although HER-1 was significant for TTF only (P ≤ 0.001).
Conclusion: Patients with HER-2 amplification and HER-1 expression had lower ER levels and were modestly less responsive to tamoxifen, suggesting that molecular events in addition to those involving the ErbB receptors are important in determining the endocrine-resistant phenotype.
Her-2/neu Expression in Prostate Cancer
Authors: Carles Joan , Lloreta Josep , Salido Marta , Font Albert , Suarez Marta , Baena Veronica , Nogue Miquel , Domenech Montserrat , Fabregat Xavier 
Published: September 2005

Abstract
The clinical effects of targeting Her-2/neu in prostate carcinoma are not known. This study explores the feasibility of molecular profiling to determine the correlation between Her-2/neu expression and hormonal sensitivity.
Patients with progressive androgen-independent prostate carcinoma were eligible to participate in the study. Her-2/neu expression was assessed on pretreatment tissue specimens and on bone marrow obtained in progressive androgen-independent disease. Her-2/neu expression was evaluated by immunohistochemistry and by fluorescence in situ hybridization in a consecutive series of 26 progressive androgen-independent prostate cancer patients.
Twenty four bone marrow biopsy specimens and 16 prostate biopsies from 26 patients were analyzed. These biopsies were categorized by androgen sensitivity at the time of the biopsy. In total, 90% of specimens from bone marrow were Her-2/neu positive, and 10% of the specimens were Her-2/neu negative. Of the prostate biopsies, all were from patients with androgen-dependent disease. Three of 13 androgen-dependent prostate biopsies (23%) overexpressed Her-2/neu. Of the 10 tumor samples analyzed by fluorescence in situ hybridization, genomic amplification of the Her-2/neu locus was not detected in any of the metastatic prostate tumors.
Her-2/neu expression varies with the clinical state of patients with prostate carcinoma: Accurate Her-2/neu profiling requires sampling metastatic tissue in patients with metastatic disease. Her-2/neu sampling from metastatic prostate carcinoma is not feasible until more reliable and practical methods can be developed.
Increased Expression of the Copper Efflux Transporter ATP7A Mediates Resistance to Cisplatin, Carboplatin, and Oxaliplatin in Ovarian Cancer Cells
Authors: Samimi Goli , Safaei Roohangiz , Katano Kuniyuki , Holzer Alison K. , Rochdi Myriam , Tomioka Mika , Goodman Murray , Howell Stephen B. 
Published: September 2005

Abstract
Purpose: The goal of this study was to determine the effect of small changes in ATP7A expression on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin in human ovarian carcinoma cells.
Experimental Design: Drug sensitivity and cellular pharmacology parameters were determined in human 2008 ovarian carcinoma cells and a subline transfected with an ATP7A-expression vector ATP7A (2008/MNK). Drug sensitivity was determined by clonogenic assay, platinum (Pt) levels were measured by inductively coupled plasma mass spectroscopy, copper (Cu) accumulation was quantified with 64Cu, and the subcellular distribution of ATP7A was assessed by confocal digital microscopy.
Results: The 1.5-fold higher expression of ATP7A in the 2008/MNK cells was sufficient to alter Cu cellular pharmacokinetics but not confer Cu resistance. In contrast, it was sufficient to render the 2008/MNK cells resistant to cisplatin, carboplatin, and oxaliplatin. Resistance was associated with increased rather than decreased whole-cell Pt drug accumulation and increased sequestration of Pt into the vesicular fraction. Cu triggered relocalization of ATP7A away from the perinuclear region, whereas at equitoxic concentrations the Pt drugs did not.
Conclusions: A small increase in ATP7A expression produced resistance to all three of the clinically available Pt drugs. Whereas increased expression of ATP7A reduced Cu accumulation, it did not reduce accumulation of the Pt drugs. Under conditions where Cu triggered ATP7A relocalization, the Pt drugs did not. Thus, although ATP7A is an important determinant of sensitivity to the Pt drugs, there are substantial differences between Cu and the Pt drugs with respect to how they interact with ATP7A and the mechanism by which ATP7A protects the cell.
A Novel Effective and Safe Consolidation for Patients Over 60 Years with Acute Myeloid Leukemia
Authors: Sperr Wolfgang R. , Piribauer Maria , Wimazal Friedrich , Fonatsch Christa , Thalhammer-Scherrer Renate , Schwarzinger Ilse , Geissler Klaus , Knöbl Paul , Jäger Ulrich , Lechner Klaus , Valent Peter 
Published: September 2005

Abstract
Purpose: High-dose intermittent cytarabine is an effective postremission treatment for patients with acute myeloid leukemia (AML). This regimen is a safe approach in patients &lt; 60 years but produced severe neurotoxicity in the elderly.
Experimental Design: We have established a dose-reduced age-adapted consolidation using intermediate dose (IDAC; 2 × 1 g/m2 i.v., days 1, 3, and 5) for AML patients ≥ 60 years. Forty-seven de novo AML patients in complete remission (CR; median age, 70 years) were scheduled to receive four consolidation cycles of IDAC.
Results: In 25 of 47 patients (53%), all four cycles were administered: 9 (19%) received three cycles; 7 (15%) received two cycles; and 6 patients (12%) one cycle. Treatment was well tolerated without neurotoxicity. The median number of days with severe neutropenia (absolute neutrophil count &lt; 500/μl) was 9. Neutropenic fever occurred in 22 of 47 patients (49%) during the first cycle, in 24 of 41 (60%) during the second, in 15 of 34 (44%) during the third, and in 18 of 25 (72%) during the fourth cycle. Only 1 patient died during consolidation (cardiac failure). The median overall survival, disease-free survival, and continuous CR were 10.6, 15.5, and 15.9 months, respectively. The probability of overall survival, disease-free survival, and continuous CR at 5 years were 18, 22, and 30%, respectively.
Conclusions: IDAC is a safe and effective postremission therapy for elderly patients with AML.
Antitumor Activity of Gefitinib in Malignant Rhabdoid Tumor Cells
In vitro
and
In vivo
Authors: Kuwahara Yasumichi , Hosoi Hajime , Osone Shinya , Kita Masakazu , Iehara Tomoko , Kuroda Hiroshi , Sugimoto Tohru 
Published: September 2005

Abstract
Purpose: Malignant rhabdoid tumor (MRT) is a rare and highly aggressive neoplasm of young children. Current treatments have had only limited success. Epidermal growth factor receptor (EGFR) was found recently to be expressed on MRT cell lines. Gefitinib (trade name Iressa) is an oral and selective EGFR-tyrosine kinase inhibitor and has been demonstrated to be effective in inhibiting the proliferation of cancer cells in vivo as well as in clinical trials. This encouraged us to examine the antitumor effects of gefitinib on MRT cells in vitro and in vivo.
Experimental Design: The expression of EGFR in two MRT tumors and two MRT cell lines (MP-MRT-AN and KP-MRT-NS), established from these two tumor tissues, was examined by immunohistochemistry, immunofluorescence, and immunoblot. The effect of gefitinib on EGFR phosphorylation was examined by immunoblot. The effects of gefitinib on cell growth and apoptosis were examined by cell growth assay and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. The in vivo effect of gefitinib was assessed in athymic mice that had been xenografted with MRT cells.
Results: The expression of EGFR was detected in both tumor tissues and cell lines. Gefitinib inhibited EGFR-phosphorylation (IC50 &lt; 0.1 μmol/L) and in vitro cell growth (IC50 = approximately 10–12 μmol/L), and a high concentration of gefitinib (20 μmol/L) induced apoptosis in vitro (MP-MRT-AN, 42.9% and KP-MRT-NS, 47.2%). Furthermore, gefitinib at 150 mg/kg had a cytostatic effect on established MRT xenografts (MP-MRT-AN, P = 0.039 and 0.0014; and KP-MRT-NS, P = 0.048 and 0.0086).
Conclusions: Our results demonstrate that gefitinib has antitumor effects in MRT cells in vitro and in vivo and, thus, has promise as a novel and therapeutic strategy for MRT.
Combinatorial Administration of Molecules That Simultaneously Inhibit Angiogenesis and Invasion Leads to Increased Therapeutic Efficacy in Mouse Models of Malignant Glioma
Authors: Bello Lorenzo , Lucini Valeria , Costa Francesco , Pluderi Mauro , Giussani Carlo , Acerbi Francesco , Carrabba Giorgio , Pannacci Marilou , Caronzolo Dario , Grosso Silvia , Shinkaruk Svetlana , Colleoni Federica , Canron Xavier , Tomei Giustino , Deleris Gerard , Bikfalvi Andreas 
Published: September 2005

Abstract
Purpose: We investigated the ability of the combinatorial administration of different inhibitors with activities on glioma angiogenesis, migration, and proliferation to produce a prolonged inhibition of glioma growth.
Experimental Design: We combined inhibitors affecting solely tumor angiogenesis (PF-4/CTF, cyclo-VEGI) or inhibitors affecting both angiogenesis and invasion together (PEX, PF-4/DLR).
Results: When administered in combination, these drugs produced a prolonged and increased inhibition of glioma growth independently from the type of inhibitor used. The combinatory administration was more effective than the administration of a single inhibitor alone, and a strong therapeutic response was reached with a significantly lower amount of protein. The strongest inhibition was observed when human PEX and PF-4/DLR, which affect both glioma angiogenesis and invasion by separate mechanisms, were combined.
Conclusions: This supports the concept that prolonged glioma growth inhibition can be achieved by simultaneous delivery of molecules that target both tumor and endothelial cells and acting by separate mechanisms.
p53 Expression as a Prognostic Marker in Inflammatory Breast Cancer
Authors: Gonzalez-Angulo Ana M. , Sneige Nour , Buzdar Aman U. , Valero Vicente , Kau Shu-Wan , Broglio Kristine , Yamamura Yuko , Hortobagyi Gabriel N. , Cristofanilli Massimo 
Published: September 2005

Abstract
Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Nuclear expression of p53 protein in breast cancer correlates with more aggressive tumors. We retrospectively analyze the expression of p53 as a prognostic marker to predict pathological complete response and survival in patients with IBC.
Experimental Design: Fifty-nine patients with IBC were treated from January 1994 to April 2000. Forty-eight patients were included. Diagnostic core biopsies were taken before treatment was started. Expression of hormone receptors and p53 was determined by immunohistochemistry. All patients received an anthracycline-based regimen preoperatively; 22 patients (46%) also received paclitaxel. Forty-four patients (92%) achieved an objective clinical response and underwent mastectomies.
Results: Median age at diagnosis was 48 years. Thirty patients (63%) had hormone receptor-negative tumors. Twenty-eight patients (58%) had p53-positive tumors, and 20 patients (42%) had p53-negative tumors. Nine patients (19%) achieved a pathological complete response. At a median follow-up of 77 months, 28 recurrences (58%) and 26 deaths (54%) had occurred. Patients with p53-positive tumors were younger (P = 0.02) and tended to have lower 5-year progression-free survival rates (35% versus 55%; P = 0.3) and overall survival rates (44% versus 54%; P = 0.4).
Conclusions: This retrospective analysis demonstrates that nuclear p53 protein expression may represent an adverse prognostic marker in IBC and may provide a valuable tool for selecting treatment for this aggressive disease.
Imaging Correlates of Molecular Signatures in Oligodendrogliomas
Authors: Megyesi Joseph F. , Kachur Edward , Lee Donald H. , Zlatescu Magdalena C. , Betensky Rebecca A. , Forsyth Peter A. , Okada Yoshifumi , Sasaki Hikaru , Mizoguchi Masahiro , Louis David N. , Cairncross J. Gregory 
Published: September 2005

Abstract
Molecular subsets of oligodendroglioma behave in biologically distinct ways. Their locations in the brain, rates of growth, and responses to therapy differ with their genotypes. Retrospectively, we inquired whether allelic loss of chromosomal arms 1p and 19q, an early molecular event and favorable prognostic marker in oligodendrogliomas, were reflected in their appearance on magnetic resonance imaging. Loss of 1p and 19q was associated with an indistinct border on T1 images and mixed intensity signal on T1 and T2. Loss of 1p and 19q was also associated with paramagnetic susceptibility effect and with calcification, a common histopathological finding in oligodendrogliomas. These data encourage prospective evaluation of molecular alterations and magnetic resonance imaging characteristics of glial neoplasms.
Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer
Authors: Monnerat Christian , Le Chevalier Thierry , Kelly Karen , Obasaju Coleman K. , Brahmer Julie , Novello Silvia , Nakamura Takashi , Liepa Astra M. , Bozec Laurence , Bunn Paul A. , Ettinger David S. 
Published: September 2005

Abstract
Purpose: Cisplatin is one of the most active agents for the treatment of non-small cell lung cancer (NSCLC). It is also known for significant toxicity, which makes it unsuitable for certain patients. Our purpose was to evaluate the efficacy and toxicity of a promising cisplatin-free combination, gemcitabine plus pemetrexed, in NSCLC.
Experimental Design: Chemo-naive patients with inoperable NSCLC were eligible for this study. Gemcitabine (1250 mg/m2) was given intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8. After inclusion of 13 patients, folic acid and vitamin B12 supplementation was added to lower pemetrexed-induced toxicity. Quality of life was assessed with the Lung Cancer Symptom Scale.
Results: Sixty patients enrolled; 58 were evaluable for response. All patients had a World Health Organization performance status of 0 or 1. Eighty-seven percent had stage IV disease. Nine patients had a confirmed partial response [overall response rate, 15.5%; 95% confidence interval (CI), 7.3–27.4%]. Twenty-nine (50.0%) patients had stable disease. Median overall survival was 10.1 months (95% CI, 7.9–13.0 months), with a 1- and 2-year overall survival of 42.6% (95% CI, 30.0–55.3%) and 18.5% (95% CI, 7.9–29.1%). Median progression-free survival was 5.0 months. Median response duration was 3.3 months. There were no deaths attributed to treatment. Common Toxicity Criteria grade 3/4 toxicities were neutropenia (61.7%), febrile neutropenia (16.7%), fatigue (23.3%), and elevations of aspartate aminotransferase (15.0%) and alanine aminotransferase (20.0%).
Conclusions: This combination had good tolerance and achieved promising overall survival with extended 1- and 2-year survival rates. This cisplatin-free regimen warrants further evaluation in randomized trials.
Sp1-Mediated Transcriptional Control of Fibroblast Growth Factor Receptor 4 in Sarcomas of Skeletal Muscle Lineage
Authors: Yu Shun Jiang , Zheng Lei , Ladanyi Marc , Asa Sylvia L. , Ezzat Shereen 
Published: September 2005

Abstract
Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of differentiating and proliferative actions. FGFR4 is expressed mainly in lung, kidney, pancreas, spleen, and developing muscle. FGFR4 was found to be overexpressed in some human malignancies, where it has been implicated in their pathogenesis. Recently, FGFR4 was found to be overexpressed in pediatric rhabdomyosarcomas, based on cDNA microarray analysis. Using Northern blotting, reverse transcription-polymerase chain reaction, and Western blotting, we classified four human rhabdomyosarcoma-derived cell lines based on their relative expression of FGFR4. We defined a 214 bp (−115/+99) promoter that functioned as a minimal promoter and examined cis-DNA elements implicated in the control of expression of the FGFR4 gene in these cells. Overlapping 40- to 50-bp fragments of the minimal promoter were examined by electrophoretic mobility shift assay using nuclear extracts from cell lines with high (HS729-1015) or low (HS729-1016) FGFR4 expression. Fragment C (−65/−26) formed specific complexes with nuclear extracts from both cell lines. Fragment B (−95/−56), however, formed distinct complexes mainly with the high FGFR4-expressing HS729-1015 cells. Both fragments yielded complexes that were competed by an Sp oligonucleotide and supershifted by Sp1 and by Sp3 antibodies. Transfection of Sp1 but not Sp3 efficiently activated FGFR4 promoter activity, an effect that was significantly more pronounced in the HS729-1015 cell line than in the low FGFR4-expressing HS729-1016 cell line. Deletion of each of the two Sp-binding sites in fragments B and C resulted in loss of promoter activity. In particular, deletion of the 5′ Sp-binding site in fragment B was associated with the greatest loss of activity. Sp1 protein expression correlated with FGFR4 expression in cell lines and primary human rhabdomyosarcomas. Furthermore, transfection of Sp1 and methylation inhibition was effective in inducing the endogenous FGFR4 gene in HS729-1015 cells. Our findings point to Sp1 as an important contributor to FGFR4 transcriptional control and elucidate a potential mechanism for the heterogenous expression of FGFR4 in neoplasms derived from the same cell lineage.
The Contribution of Genetic and Epigenetic Changes in Granulosa Cell Tumors of Ovarian Origin
Authors: Dhillon Varinderpal S. , Aslam Mohammad , Husain Syed Akhtar 
Published: September 2005

Abstract
Purpose: Granulosa cell tumors (GCTs) are relatively rare and are subtypes of the sex-cord stromal neoplasms. A better understanding of the molecular genetics underlying various steps in malignant transformation is critical to success in the battle against this disease. Changes in the status of methylation, known as epigenetic alterations, are one of the most common molecular alterations in human cancers, including GCTs. Chromosomal instability and microsatellite instability (MSI) are common in these GCTs. We tested the hypothesis that C→T transition polymorphism in the promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and its altered expression are also associated with hypermethylation of the genes. We also attempted to determine the relationship between MSI of ovarian carcinoma and hMLH1 hypermethylation in these tumors.
Experimental Design: We studied chromosome instability in 25 GCTs by detecting gross chromosome rearrangements in cultured peripheral blood lymphocytes. MSI was assessed using six microsatellite markers (BAT25, BAT26, D2S123, D5S346, D11S1318, and D17S250). Using sensitive methylation-specific PCR, we searched for aberrant promoter hypermethylation in a panel of genes including p16, BRCA1, RASSF1A, ER-α, TMS1, TIMP3, Twist, GSTP1, AR, and hMLH1. Polymorphism in the DNMT3B gene was assessed by the PCR-RFLP method, and DNMT3B expression was studied by reverse transcription-PCR assay.
Results: Chromosome instability was indicated by significantly higher frequencies of chromosome aberrations (6.24%; P &lt; 0.001) compared with controls (2.12%). The most frequently observed changes include trisomy 14 and monosomy 22. MSI has been found in 19 of 25 tumors, and loss of heterozygosity has been found in 9 of 25 tumors. Frequencies of methylation in GCTs were 40% for p16 and ER-α; 36% for BRCA1 and RASSF1A; 28% for hMLH1; 24% for TIMP3, Twist, and GSTP1; and 20% in TMS1 and AR. TT genotype was found only in two cases; the remainder were either CC or CT type. There was no significant alteration in the expression of DNMT3B in these patients.
Conclusions: Coexistence of chromosome instability, MSI, and hypermethylation suggests that both genetic and epigenetic mechanisms may act in concert to inactivate the above-mentioned genes in these GCTs. These mechanisms can be an early event in the pathogenesis of these tumors, and it can be a critical step in the tumorigenic process. All these events might play an important role in early clinical diagnosis and in chemotherapeutic management and treatment of the disease. Larger studies may lend further understanding to the etiology and clinical behavior of these tumors.