bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of p27kip-1 Expression in Colorectal Adenocarcinomas Is Associated with Tumor Stage
Authors: Manne Upender , Jhala Nirag C. , Jones Jennifer , Weiss Heidi L. , Chatla Chakrapani , Meleth Sreelatha , Suarez-Cuervo Catalina , Grizzle William E. 
Published: September 2005

Abstract
Purpose: Although the decreased expression of p27kip-1, a cyclin-dependent kinase inhibitor, has been correlated with advanced tumor stage and short survival of patients with colorectal adenocarcinomas (CRCs), its prognostic value based on the tumor site, tumor stage, and patient ethnicity was not assessed. Therefore, in this study, we investigated whether the prognostic value of p27kip-1 expression varies with the tumor site, tumor stage and patient ethnicity.
Experimental Design: We evaluated 206 (85 African Americans and 121 Caucasians) archival tissue specimens of first primary CRCs for immunohistochemical expression of p27kip-1, and its prognostic significance was analyzed using univariate Kaplan-Meier and multivariate Cox regression survival methods.
Results: Although, similar proportion of CRCs with decreased p27kip-1 expression was observed in all stages (range, 26–36%), the decreased p27kip-1 expression has been shown as a marker of poor prognosis only for patients with stage III tumors both in univariate (log-rank test, P = 0.014) and multivariate (hazard ratio = 3.2, 95% confidence interval = 1.3–7.7; P = 0.01) survival analyses. The decreased expression of p27kip-1 was associated with a high histologic grade (P = 0.016) in stage II CRCs, and with distal tumors (P = 0.001), tumor invasion (P = 0.044), and with local recurrence (P = 0.008) in stage III CRCs.
Conclusions: No prognostic significance was found for p27kip-1 expression in stages I, II, or IV CRCs, and its prognostic value was not associated with either ethnicity or tumor location. These studies suggest that decreased expression of p27kip-1 is an indicator of poor prognosis and aids in identifying a subset of patients with aggressive forms of stage III CRCs.
High Specificity of Quantitative
Excision Repair Cross-Complementing 1
Messenger RNA Expression for Prediction of Minor Histopathological Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer
Authors: Warnecke-Eberz Ute , Metzger Ralf , Miyazono Futoshi , Baldus Stephan E. , Neiss Susanne , Brabender Jan , Schaefer Hartmut , Doerfler Walter , Bollschweiler Elfriede , Dienes Hans P. , Mueller Rolf P. , Danenberg Peter V. , Hoelscher Arnulf H. , Schneider Paul M. 
Published: September 2005

Abstract
Purpose: The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT2–4, Nx, M0).
Experimental Design: Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/β-actin in tumor)/(ERCC1/β-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained &lt;10% of residual vital tumor cells or in case a pathologically complete response was achieved.
Results: Twelve of 36 tumors showed a major histopathological response, and 24 of 36 showed a minor histopathological response. Relative expression levels of ERCC1 of &gt;1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P &lt; 0.001).
Conclusions: Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.
Very High Frequency of Hypermethylated Genes in Breast Cancer Metastasis to the Bone, Brain, and Lung
Authors: Mehrotra Jyoti , Vali Mustafa , McVeigh Megan , Kominsky Scott L. , Fackler Mary Jo , Lahti-Domenici Jaana , Polyak Kornelia , Sacchi Nicoletta , Garrett-Mayer Elizabeth , Argani Pedram , Sukumar Saraswati 
Published: September 2005

Abstract
Purpose: Most often it is not the primary tumor, but metastasis to distant organs that results in the death of breast cancer patients. To characterize molecular alterations in breast cancer metastasis, we investigated the frequency of hypermethylation of five genes (Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) in metastasis to four common sites: lymph node, bone, brain, and lung.
Experimental Design: Methylation-specific PCR for the five genes was performed on DNA extracted from archival paraffin-embedded specimens of paired primary breast cancer and its lymph nodes (LN) metastasis (n = 25 each); in independent samples of metastasis to the bone (n = 12), brain (n = 8), and lung (n = 10); and in normal bone, brain, and lung (n = 22).
Results: No hypermethylation was detected in the five genes in the normal host tissues. In paired samples, LN metastasis had a trend of higher prevalence of methylation compared with the primary breast carcinoma for all five genes with significance for HIN-1 (P = 0.04). Compared with the primary breast carcinomas, all five genes had higher methylation frequencies in the bone, brain, and lung metastasis, with HIN-1 and RAR-β methylation being significantly higher (P &lt; 0.01) in each group. Loss of expression of all five genes correlated, with a few exceptions, to hypermethylation of their promoter sequences in metastatic carcinoma cells microdissected from LNs.
Conclusion: The frequent presence of hypermethylated genes in locoregional and distant metastasis could render them particularly susceptible to therapy targeted toward gene reactivation combining demethylating agents, histone deacetylase inhibitors, and/or differentiating agents.
Analysis of Aberrant DNA Methylation and Human Papillomavirus DNA in Cervicovaginal Specimens to Detect Invasive Cervical Cancer and Its Precursors
Authors: Widschwendter Andreas , Gattringer Conny , Ivarsson Lennart , Fiegl Heidi , Schneitter Alois , Ramoni Angela , Müller Hannes M. , Wiedemair Annemarie , Jerabek Susanne , Müller-Holzner Elisabeth , Goebel Georg , Marth Christian , Widschwendter Martin 
Published: September 2005

Abstract
Purpose: Cancer of the uterine cervix is an important cause of death in women worldwide. Pap smears as a tool for screening decreased the incidence and mortality of cervical cancer dramatically. This proof of principle study aimed to develop a potential tool for cervical screening using a test that can be applied by patients without visiting a physician and to increase the coverage rate, especially of the high-risk population with low socioeconomic status.
Experimental Design: Human papillomavirus (HPV) DNA testing and methylation analysis of DNA obtained from cervicovaginal specimens of 13, 31, and 11 patients with no dysplasia/low-grade squamous intraepithelial lesion (SIL), high-grade SIL, and invasive cervical cancer, respectively, collected on a tampon, was performed using PCR-based methods to detect invasive cervical cancer and study whether these changes are already present in the precursor lesions.
Results: High-risk HPV DNA was present in 68 and 82% of patients with high-grade SIL and invasive cervical cancer. DNA methylation of the 11 genes tested increased with severity of the cervical lesion. Unsupervised hierarchical cluster analysis using solely information on DNA methylation of the 11 genes was able to predict the presence of invasive cervical cancers: one of the two clusters formed contained 9 of 11 invasive cervical cancers, as well as two high-grade SILs.
Conclusions: HPV DNA and DNA methylation analyzed in cervicovaginal specimens are able to predict invasive cervical cancers. To detect all high-grade SILs when applying this test, genes that become methylated earlier throughout cervical carcinogenesis have to be defined.
Serum Macrophage Inhibitory Cytokine 1 as a Marker of Pancreatic and Other Periampullary Cancers
Authors: Koopmann Jens , Buckhaults Phillip , Brown David A. , Zahurak Marianna L. , Sato Norihiro , Fukushima Noriyoshi , Sokoll Lori J. , Chan Daniel W. , Yeo Charles J. , Hruban Ralph H. , Breit Samuel N. , Kinzler Kenneth W. , Vogelstein Bert , Goggins Michael 
Published: September 2005

Abstract
Purpose: Patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis. One effective strategy likely to improve the morbidity and mortality from pancreatic cancer would be the identification of accurate, noninvasive diagnostic markers that would enable earlier diagnosis of symptomatic patients and earlier detection of cancer in asymptomatic individuals at high risk for developing pancreatic cancer. In this study, we evaluated serum macrophage inhibitory cytokine-1 (MIC-1) as a marker of pancreatic cancer.
Experimental Design: MIC-1 expression in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines was determined using the National Center for Biotechnology Information serial analysis of gene expression database, oligonucleotide microarrays analysis, in situ hybridization, and immunohistochemistry. Serum MIC-1 levels were determined by ELISA in 80 patients with pancreatic adenocarcinomas, in 30 patients with ampullary and cholangiocellular carcinomas, in 42 patients with benign pancreatic tumors, in 76 patients with chronic pancreatitis, and in 97 healthy control subjects. The diagnostic performance of serum MIC-1 as a marker of pancreatic cancer was compared with that of serum CA19–9.
Results: Oligonucleotide microarray and serial analysis of gene expression data demonstrated that MIC-1 RNA levels were higher in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines than in nonneoplastic pancreatic ductal epithelium. MIC-1 expression was localized to the malignant epithelium in pancreatic adenocarcinomas by in situ hybridization. MIC-1 protein was expressed in 14 of 16 primary pancreatic adenocarcinomas (88%) by immunohistochemistry and was also expressed in some pancreata affected by pancreatitis but not in normal pancreas. Serum MIC-1 levels were significantly higher in patients with pancreatic ductal adenocarcinoma (mean ± SD, 2428 ± 2324 pg/ml) and in patients with ampullary and cholangiocellular carcinomas (2123 ± 2387 pg/ml) than in those with benign pancreatic neoplasms (940 ± 469 pg/ml), chronic pancreatitis (1364 ± 1236 pg/ml), or in healthy controls (546 ± 262 pg/ml). An elevated serum MIC-1 (defined as 2 SD above the mean for healthy controls) performed as well as CA19–9 (area under the receiver operating characteristic curve, 0.81 and 0.77, respectively), and the combination of MIC-1 and CA19–9 significantly improved diagnostic accuracy (P &lt; 0.05; area under the receiver operating characteristic curve, 0.87; sensitivity, 70%; specificity, 85%).
Conclusion: Serum MIC-1 measurement can aid in the diagnosis of pancreatic adenocarcinoma.
NY-ESO-1 Protein Formulated in ISCOMATRIX Adjuvant Is a Potent Anticancer Vaccine Inducing Both Humoral and CD8+ T-Cell-Mediated Immunity and Protection against NY-ESO-1+ Tumors
Authors: Maraskovsky Eugene , Sjölander Sigrid , Drane Debbie P. , Schnurr Max , Le Thuy T. T. , Mateo Luis , Luft Thomas , Masterman Kelly-Anne , Tai Tsin-Yee , Chen Qiyuan , Green Simon , Sjölander Anders , Pearse Martin J. , Lemonnier Francois A. , Chen Weisan , Cebon Jonathan , Suhrbier Andreas 
Published: September 2005

Abstract
NY-ESO-1 is a 180 amino-acid human tumor antigen expressed by many different tumor types and belongs to the family of “cancer-testis” antigens. In humans, NY-ESO-1 is one of the most immunogenic tumor antigens and NY-ESO-1 peptides have been shown to induce NY-ESO-1-specific CD8+ CTLs capable of altering the natural course of NY-ESO-1-expressing tumors in cancer patients. Here we describe the preclinical immunogenicity and efficacy of NY-ESO-1 protein formulated with the ISCOMATRIX adjuvant (NY-ESO-1 vaccine). In vitro, the NY-ESO-1 vaccine was readily taken up by human monocyte-derived dendritic cells, and on maturation, these human monocyte-derived dendritic cells efficiently cross-presented HLA-A2-restricted epitopes to NY-ESO-1-specific CD8+ T cells. In addition, epitopes of NY-ESO-1 protein were also presented on MHC class II molecules to NY-ESO-1-specific CD4+ T cells. The NY-ESO-1 vaccine induced strong NY-ESO-1-specific IFN-γ and IgG2a responses in C57BL/6 mice. Furthermore, the NY-ESO-1 vaccine induced NY-ESO-1-specific CD8+ CTLs in HLA-A2 transgenic mice that were capable of lysing human HLA-A2+ NY-ESO-1+ tumor cells. Finally, C57BL/6 mice, immunized with the NY-ESO-1 vaccine, were protected against challenge with a B16 melanoma cell line expressing NY-ESO-1. These data illustrate that the NY-ESO-1 vaccine represents a potent therapeutic anticancer vaccine.
The Clinical Application of Targeting Cancer through Histone Acetylation and Hypomethylation
Authors: Gilbert Jill , Gore Steve D. , Herman James G. , Carducci Michael A. 
Published: September 2005

Abstract
Methods of gene inactivation include genetic events such as mutations or deletions. Epigenetic changes, heritable traits that are mediated by changes in DNA other than nucleotide sequences, play an important role in gene expression. Two epigenetic events that have been associated with transcriptional silencing include methylation of CpG islands located in gene promoter regions of cancer cells and changes in chromatin conformation involving histone acetylation. Recent evidence demonstrates that these processes form layers of epigenetic silencing. Reversal of these epigenetic processes and up-regulation of genes important to prevent or reverse the malignant phenotype has therefore become a new therapeutic target in cancer treatment.
Predicting Radiosensitivity Using DNA End-Binding Complex Analysis
Authors: Ismail Sheikh M. , Puppi Monica , Prithivirajsingh Sheela , Munshi Anupama , Raju Uma , Meyn Raymond E. , Buchholz Thomas A. , Story Michael D. , Brock William A. , Milas Luka , Thames Howard D. , Stevens Craig W. 
Published: September 2005

Abstract
Previous reports have suggested that measuring radiosensitivity of normal and tumor cells would have significant clinical relevance for the practice of radiation oncology. We hypothesized that radiosensitivity might be predicted by analyzing DNA end-binding complexes (DNA-EBCs), which form at DNA double-strand breaks, the most important cytotoxic lesion caused by radiation. To test this hypothesis, the DNA-EBC pattern of 21 primary human fibroblast cultures and 15 tumor cell lines were studied. DNA-EBC patterns were determined using a modified electrophoretic mobility shift assay and were correlated with radiosensitivity, as measured by SF2. DNA-EBC analysis identified a rapidly migrating ATM-containing band (identified as “band-A”) of which the density correlated with SF2 (0.02 ≤ SF2 ≤ 0.41) in primary fibroblasts (r2 = 0.77). The DNA-EBC pattern of peripheral blood lymphocytes was identical to that of fibroblasts. In addition, band-A density correlated with SF2 (0.35 ≤ SF2 ≤ 0.80) in 15 human tumor cell lines (r2 = 0.91). Densitometry of other bands, or total DNA-EBC binding, correlated more poorly with SF2 (r2 &lt; 0.45). These data indicate that DNA-EBC analysis may be a practical, clinically relevant predictor of tumor and primary cell radiosensitivity.
Molecular Differences between Sporadic Serrated and Conventional Colorectal Adenomas
Authors: Konishi Kazuo , Yamochi Toshiko , Makino Reiko , Kaneko Kazuhiro , Yamamoto Taikan , Nozawa Hisako , Katagiri Atsushi , Ito Hiroaki , Nakayama Kentarou , Ota Hidekazu , Mitamura Keiji , Imawari Michio 
Published: September 2005

AbstractPurpose: The purpose is to compare the molecular characteristics of serrated adenomas (SAs) with those of conventional adenomas (CADs) and hyperplastic polyps (HPs).Experimental Design: We evaluated the proliferative activity and molecular alterations in 47 SAs (25 pure-type and 22 mixed-type), 71 CADs, and 23 HPs.Results: The proliferative activity of SAs, as evaluated by Ki-67 expression, was intermediate between CADs and HPs. There was no significant difference in the incidence of KRAS or p53 mutations between the three histological groups. In the microsatellite instability (MSI) analysis, 21% of SAs (9 of 43) showed MSI at two or more loci (MSI-H); corresponding values were 5% of CADs (3 of 64) and 8% of HPs (1 of 13; SAs versus CADs, P = 0.0125). MSI-H was more likely to be found in pure-type SAs (36%; 8 of 22) than in mixed-type SAs (5%; 1 of 21; P = 0.0212). Loss of hMLH-1 expression was found in 8 of 9 SAs with MSI-H. The incidence of BRAF or KRAS mutations was 36 and 15% of SAs, respectively; the combined incidence of BRAF and KRAS mutations occurred in 49% of SAs. However, there was no significant difference in the incidence of BRAF or KRAS mutations between SAs with and without MSI-H.Conclusions: Genetic instability is more frequently implicated in the tumorigenesis of SAs, especially pure-type SAs, than in that of CADs. In contrast, activation of the Ras/Raf/MEK/MAP kinase cascade by BRAF or KRAS mutation, independently of the genetic instability, may be associated with the progression of about half of SAs.
Enhanced Chemosensitivity to Irinotecan by RNA Interference-Mediated Down-Regulation of the Nuclear Factor-κB p65 Subunit
Authors: Guo Jun , Verma Udit N. , Gaynor Richard B. , Frenkel Eugene P. , Becerra Carlos R. 
Published: September 2005

Abstract
In preclinical tumor models, inhibition of nuclear factor-κB (NF-κB) has been associated with increased sensitivity to chemotherapeutic agents such as irinotecan (CPT-11). This is based on the fact that a variety of chemotherapy agents such as CPT-11 activate NF-κB to result in the expression of genes such as c-IAP1 and c-IAP2 that might be responsible for the inhibition of chemotherapy-induced apoptosis. In this study, RNA interference [small interfering RNA (siRNA)] was used to down-regulate the NF-κB p65 subunit in the HCT116 colon cancer cell line, and its role, in the presence and absence of CPT-11, was assessed on cell growth and apoptosis. Reduction of endogenous p65 by siRNA treatment significantly impaired CPT-11-mediated NF-κB activation, enhanced apoptosis, and reduced colony formation in soft agar. Furthermore, the in vivo administration of p65 siRNA reduced HCT116 tumor formation in xenograft models in the presence but not the absence of CPT-11 administration. These data indicate that the administration of siRNA directed against the p65 subunit of NF-κB can effectively enhance in vitro and in vivo sensitivity to chemotherapeutic agents.
Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors
Authors: Khuri Fadlo R. , Glisson Bonnie S. , Kim Edward S. , Statkevich Paul , Thall Peter F. , Meyers Michael L. , Herbst Roy S. , Munden Reginald F. , Tendler Craig , Zhu Yali , Bangert Sandra , Thompson Elizabeth , Lu Charles , Wang Xue-Mei , Shin Dong M. , Kies Merrill S. , Papadimitrakopoulou Vali , Fossella Frank V. , Kirschmeier Paul , Bishop W. Robert , Hong Waun Ki 
Published: September 2005

Abstract
Purpose: To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen.
Experimental Design: In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m2 or 175 mg/m2 administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient.
Results: Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m2. Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses.
Conclusions: When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m2 of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.
Skp2
Gene Copy Number Aberrations Are Common in Non-Small Cell Lung Carcinoma, and Its Overexpression in Tumors with
ras
Mutation Is a Poor Prognostic Marker
Authors: Zhu Chang Qi , Blackhall Fiona H. , Pintilie Melania , Iyengar Pratibha , Liu Ni , Ho James , Chomiak Taylor , Lau Davina , Winton Timothy , Shepherd Frances A. , Tsao Ming-Sound 
Published: September 2005

Abstract
Purpose: Skp2 plays a critical role in cell cycle progression, especially at the G1-S transition, putatively through its control of several cell cycle regulator proteins. The Skp2 gene is located on a region of chromosome 5p that is commonly overrepresented in lung cancer. The present study aimed to evaluate Skp2 abnormalities and their prognostic value in non-small cell lung cancer (NSCLC).
Experimental Design: In total 16 NSCLC cell lines and 163 primary tumors were included in studies to measure Skp2 relative gene copy number, mRNA abundance, and protein level. The tumors were also evaluated for p27 protein expression level and ras mutation. These values were correlated with the clinical and pathological features of the patients.
Results: Skp2 relative gene copy number aberrations were found in 88 and 65% of NSCLC cell lines and primary tumors, respectively. Overrepresentation was especially common among squamous cell carcinoma (74%). Both gene copy overrepresentation (13%) and loss (35%) were found in adenocarcinoma. Skp2 relative gene copy number was significantly correlated with mRNA and protein levels, but none of these were correlated with p27 protein levels. Neither high Skp2 protein expression nor ras mutation was prognostically significant. In NSCLCs with ras mutation, however, high Skp2 protein expression was a significant independent poor prognostic marker.
Conclusion: There appears to be a synergistic interaction between high Skp2 protein expression and ras mutation with negative impact on the survival of NSCLC patients.