bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphorylated Pak1 Level in the Cytoplasm Correlates with Shorter Survival Time in Patients with Glioblastoma
Authors: Aoki Hiroshi , Yokoyama Tomohisa , Fujiwara Keishi , Tari Ana M. , Sawaya Raymond , Suki Dima , Hess Kenneth R. , Aldape Kenneth D. , Kondo Seiji , Kumar Rakesh , Kondo Yasuko 
Published: November 2007

Abstract
Purpose: Glioblastoma is the most common primary malignant tumor in the brain. It aggressively invades the surrounding parenchyma, often allowing the tumor to progress after surgery. Accumulating evidence has shown that phosphorylated p21-activated kinase 1 (Pak1), a mediator of small guanosine triphosphatases, plays a role in the proliferation, survival, and invasiveness of cancer cells. Thus, we examined patterns of Pak1 expression in glioblastoma and sought to determine whether the level of phosphorylated Pak1 in glioblastoma cells is associated with patient survival time.
Experimental Design: We carried out immunohistochemical staining for phosphorylated Pak1 in tumor specimens from 136 patients with glioblastoma; the tumors were classified according to Pak1 protein levels in the cytoplasm and nucleus. We compared the patients' overall survival times using Kaplan-Meier analysis and estimated the effects of levels of cytoplasmic or nuclear phosphorylated Pak1. We then down-regulated Pak1 by using small interfering RNA to knock down Pak1 in two glioblastoma cell lines to determine whether Pak1 contributed to cell viability and invasion.
Results: Median overall survival was significantly shorter in patients with tumors showing a moderate or high level of cytoplasmic phosphorylated Pak1 than in patients with tumors showing no cytoplasmic phosphorylated Pak1. The level of nuclear phosphorylated Pak1 was not related to survival time. Knockdown of Pak1 suppressed the invasion, but not the viability, of U87-MG and U373-MG cells.
Conclusions: The presence of phosphorylated Pak1 in the cytoplasm of glioblastoma cells is associated with shorter survival, and Pak1 plays a role in the invasiveness of glioblastoma. These data suggest that Pak1 might be a potential target for the management of glioblastoma.
Relationship ofEGFRMutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines
Authors: Liu Wanqing , Wu Xiaolin , Zhang Wei , Montenegro Raquel C. , Fackenthal Donna Lee , Spitz Jared A. , Huff Lyn Mickley , Innocenti Federico , Das Soma , Cook, Edwin H. , Cox Nancy J. , Bates Susan E. , Ratain Mark J. 
Published: November 2007

AbstractPurpose: The mechanism of sensitivity and resistance to epidermal growth factor receptor (EGFR) inhibitors is incompletely understood, particularly in cancers other than non–small-cell lung cancer (NSCLC). To understand the variable response to this class of drugs, we used the NCI60 cancer cell lines. We aimed to determine if there are interactions between EGFR expression, mutations, polymorphisms, and gene amplification, and whether these factors are associated with variability in response to EGFR inhibitors.Experimental Design: The EGFRVIII and tyrosine kinase (TK) domain mutations were examined in the NCI60 cancer cell lines. Five polymorphisms, −216G/T, −191C/A, intron 1 (CA)n, R497K, and 2607A/G, were genotyped. EGFR amplification was also assessed with high-density single-nucleotide polymorphism chip and real-time PCR, respectively. The results were correlated with cytotoxicity data for erlotinib and other 11 EGFR inhibitors, as well as other publicly available data for these lines.Results: All 12 inhibitors behaved similarly. No EGFRVIII but putative TK mutations in two cell lines were found. Both mutant cell lines were insensitive to all inhibitors. Meanwhile, response did not correlate with EGFR amplification but with EGFR gene expression, especially in the cell lines with relatively normal gene status. In addition, EGFR expression was associated with the −216G/T polymorphism but not with the intron 1 (CA)n polymorphism. A combination of −216G/T and R497K polymorphisms was weakly associated with drug response.Conclusions: These observations suggest that in addition to TK mutations, germ-line variability may also contribute to the pharmacodynamics of EGFR inhibitors, particularly when EGFR is genetically normal.
Matrix Metalloproteinase Single-Nucleotide Polymorphisms and Haplotypes Predict Breast Cancer Progression
Authors: Hughes Simon , Agbaje Olorunsola , Bowen Rebecca L. , Holliday Deborah L. , Shaw Jacqueline A. , Duffy Stephen , Jones J. Louise 
Published: November 2007

AbstractPurpose: Polymorphisms within the promoter region of several matrix metalloproteinase (MMP) genes have been linked to alterations in the level of transcription. We hypothesized that an individual's MMP genotype and haplotype will influence breast tumor progression and help predict prognosis.Experimental Design: This study has evaluated the association between single-nucleotide polymorphisms (SNP) in the promoter regions of MMP-1, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13 and metastatic spread of breast cancer in 128 lymph node–negative and 93 lymph node–positive patients. The study cohort was of mixed ethnicity, with Caucasian patients comprising 65%. Associations between genotype and lymph node status were estimated by logistic regression and with overall survival using the method of Kaplan-Meier and log-rank test. Associations between haplotype and lymph node status were also investigated.Results: The data show a significant and independent association of the C/T genotype for MMP-9 [mixed ethnicities odds ratio 3.6, 95% confidence interval (95% CI) 1.2-11.1; Caucasian odds ratio 9.1, 95% CI 1.7-48.4] and the 2G/2G genotype for MMP-1 (mixed ethnicities odds ratio 3.9, 95% CI 1.7-9.4; Caucasian odds ratio 2.6, 95% CI 1.0-6.9) with lymph node–positive disease. MMP-1 2G/2G was associated with reduced survival (hazard ratio 3.1, 95% CI 1.1-8.7), although this is dependent on lymph node status. Two haplotypes, driven by the MMP-1 2G allele, were significantly associated with lymph node–positive disease and survival.Conclusions: These results suggest that MMP single-nucleotide polymorphisms influence breast cancer behavior and that the MMP-1 2G/2G genotype increases the risk of lymph node metastasis and predicts poor prognosis.
Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate
Authors: McAuliffe John C. , Lazar Alexander J.F. , Yang Dan , Steinert Dejka M. , Qiao Wei , Thall Peter F. , Raymond A. Kevin , Benjamin Robert S. , Trent Jonathan C. 
Published: November 2007

Abstract
Purpose: Imatinib mesylate (imatinib) has revolutionized clinical outcomes of patients with advanced gastrointestinal stromal tumor (GIST). However, the degree of individual benefit varies, and little is known about prognostic factors for these patients. Importantly, selected patients may be treated with an approach to target both Kit and vascular endothelial growth factor receptor (VEGFR) expression.
Experimental Design: Using tissue microarray technology, we analyzed 53 imatinib-naive GISTs for vascular endothelial growth factor (VEGF) expression from patients who then received imatinib. In multivariate analyses, we evaluated overall survival (OS) and progression-free survival (PFS) of these patients based on putative prognostic factors, including VEGF expression. In a separate study, 12 matched pre-imatinib and post-imatinib GIST patient specimens and two human GIST cell lines were assessed for VEGF production in response to imatinib.
Results: Independent of kit genotype, patients with GIST expressing high VEGF had inferior median PFS (7.1 months versus 29 months, P = 0.42) and median OS (20 months versus not reached at &gt;50 months; P = 0.02) compared with weak or nonexpressers of VEGF. Non–exon 11 kit mutation predicted inferior PFS but not OS. High mitotic rate was marginally predictive of improved OS. Imatinib resulted in decreased production of VEGF in only a subset of GIST patients (2 of 12) and both cell lines.
Conclusions: We present a study to address the prognostic factors for patients with GIST in the imatinib era. We present a rationale to consider exploration of a front-line therapy of GIST with a regimen targeting both Kit and VEGFR based on the presence of tumor VEGF levels.
Gene Expression Analysis Proposes Alternative Pathways for the Mechanism by Which Celecoxib Selectively Inhibits the Growth of Transformed but not Normal Enterocytes
Authors: Sagiv Eyal , Rozovski Uri , Kazanov Diana , Liberman Eliezer , Arber Nadir 
Published: November 2007

Abstract
Purpose: Cyclooxygenase-2 inhibitor (celecoxib, Pfizer) is a promising chemopreventive agent, yet its long-term use may be limited due to increased cardiovascular toxicity. This study was aimed to identify genes and pathways involved in colorectal tumorigenesis and affected by celecoxib.
Experimental Design: Normal rat enterocytes (IEC18 cells) and their Ras-transformed derivatives (R1) were exposed for 72 h or over 6 months to celecoxib and analyzed for gene expression pattern using Genechip (RG-U34). Cluster and pathway analyses were done using GeneSpring software and Gene Ontology database. Cyclin D1 was overexpressed in IEC18 cells using stable transfection; cell cycle and prostaglandin synthesis were assessed.
Results: Five hundred thirty-eight genes were differentially expressed after transformation, and 70 and 126 genes, respectively, were affected by short and long treatments with celecoxib. Clusters of expression showed different expression in the transformed cells that revert to normal after treatment; they included Ras/Erk/Ral-B, Jagged2/Notch, calcineurin, lysyl-oxidase, etc. Cyclin D1 is up-regulated under the Ras pathway and is down-regulated by celecoxib. Thus, we showed that cyclin D1–transformed cells are resistant to inhibition by celecoxib. Celecoxib was also shown to work via cyclooxygenase-2 inhibition in transformed cells.
Conclusions: Celecoxib selectively affects transformed and not normal enterocytes by targeting genes and pathways that are involved in the transformation. Thus, an alternative mechanism is proposed for the cancer-preventive role of celecoxib other than the classic mechanism of inhibiting prostaglandin synthesis, stressing mainly the role of cyclin D1. These data may help in the development of safer and more effective preventive drugs.
Optimal Methods for Staging Rectal Cancer
Authors: Muthusamy V. Raman , Chang Kenneth J. 
Published: November 2007

AbstractAt present, several modalities exist for the preoperative staging of rectal lesions, including computed tomography (CT), body coil or endorectal coil magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) done by rigid or flexible probes, and positron emission tomography (PET). Staging accuracy for CT ranges from 53% to 94% for T-stage accuracy and from 54% to 70% for N-stage accuracy. Improved CT accuracy is observed at higher disease stages. Body coil MRI has shown T- and N-stage accuracy ranging from 59% to 95% and 39% to 95%, respectively. Endorectal coil MRI has shown improved T- and N-stage accuracy, with rates of 66% to 91% and 72% to 79%, respectively. The development of phased-array MRI, combining high spatial resolution with a larger field of view, offers promise to improve on these rates. EUS, considered the current gold standard, has shown T-stage accuracy ranging from 75% to 95%, with N-stage accuracy ranging from 65% to 80%. Flexible EUS probes have the advantage of being able to access and sample iliac nodes. Recent studies also suggest that three-dimensional EUS may provide greater accuracy than conventional two-dimensional EUS. Limited studies exist on the use of PET in primary tumor staging. PET may upstage disease in 8% to 24% of patients and has also been used in posttreatment restaging and surveillance. Postradiation edema, necrosis, and fibrosis seem to decrease restaging accuracy in all modalities. This article reviews the current literature about the staging accuracy of the various modalities and suggests a staging algorithm for rectal cancer.
Radiation Therapy in Stage II and III Rectal Cancer
Authors: Willett Christopher G. , Czito Brian G. , Bendell Johanna C. 
Published: November 2007

Abstract
Over the past 25 years, significant advances have been made in the management of patients with rectal cancer. Phase III studies have shown the efficacy of postoperative radiation therapy and chemotherapy in improving local control and survival of patients with resected stage II and III disease. Data from the randomized German CAO/ARO/AIO-94 trial of preoperative versus postoperative chemoradiation have provided a strong rationale and support for the use of preoperative chemoradiation in the treatment of patients with clinical stage II and III rectal cancer. Current phase III studies are evaluating novel combinations of chemotherapy and targeted agents with radiation therapy.
A Promoter Methylation Pattern in the N-Methyl-d-Aspartate Receptor 2B Gene Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma
Authors: Kim Myoung Sook , Yamashita Keishi , Chae Young Kwang , Tokumaru Yutaka , Chang Xiaofei , Zahurak Marianna , Osada Motonobu , Park Hannah Lui , Chuang Alice , Califano Joseph A. , Sidransky David 
Published: November 2007

Abstract
Purpose: To investigate whether the promoter methylation pattern in N-methyl-d-aspartate receptor 2B (NMDAR2B) is correlated with clinical features of human esophageal squamous cell carcinoma (ESCC), the methylation status of the gene was examined at three different sites (P1, P2, and P3) where two CpG islands reside within 1 kb upstream of the transcription start site.
Experimental Design: Three independent modalities for methylation analysis (bisulfite sequencing, combined bisulfite restriction analysis, and TaqMan methylation-specific PCR) were done to analyze total 67 ESCC tissues that included 43 primary tumors with well-characterized clinicopathologic variables including patient outcome.
Results: Using an optimized cutoff value based on quantitative methylation-specific PCR, we found that patients with higher NMDAR2B methylation ratio in the proximal region (P1) showed a worse 5-year disease-specific survival rate than those without NMDAR2B methylation (P &lt; 0.006). A significant correlation was also seen between NMDAR2B promoter methylation and the presence of vascular permeation (P = 0.03).
Conclusion: NMDAR2B promoter methylation could be a clinically applicable marker in ESCC.
Circumferential Margin Involvement Is the Crucial Prognostic Factor after Multimodality Treatment in Patients with Locally Advanced Rectal Carcinoma
Authors: Gosens Marleen J.E.M. , Klaassen René A. , Tan-Go Ivonne , Rutten Harm J.T. , Martijn Hendrik , van den Brule Adriaan J.C. , Nieuwenhuijzen Grard A.P. , van Krieken J. Han J.M. , Nagtegaal Iris D. 
Published: November 2007

Abstract
Purpose: After preoperative (radio)chemotherapy, histologic determinants for prognostification have changed. It is unclear which variables, including assessment of tumor regression, are the best indicators for local recurrence and survival.
Experimental Design: A series of 201 patients with locally advanced rectal cancer (cT3/T4, M0) presenting with an involved or at least threatened circumferential margin (CRM) on preoperative imaging (&lt;2 mm) were evaluated using standard histopathologic variables and four different histologic regression systems. All patients received neoadjuvant radiochemotherapy or radiotherapy. The prognostic value of all factors was tested with univariate survival analysis of time to local recurrence and overall survival.
Results: Local recurrence occurred in only 8% of the patients with a free CRM compared with 43% in case of CRM involvement (P &lt; 0.0001). None of the four regression systems were associated with prognosis, not even when corrected for CRM status. However, we did observe a higher degree of tumor regression after radiochemotherapy compared with radiotherapy (P &lt; 0.001). Absence of tumor regression was associated with increasing invasion depth and a positive CRM (P = 0.02 and 0.03, respectively).
Conclusions: Assessment of CRM involvement is the most important pathologic variable after radiochemotherapy. Although tumor regression increases the chance on a free CRM, in cases with positive resection margins prognosis is poor irrespective of the degree of therapy-induced regression.
Population Pharmacokinetic Analysis of Topotecan in Pediatric Cancer Patients
Authors: Schaiquevich Paula , Panetta John C. , Iacono Lisa C. , Freeman Burgess B. , Santana Victor M. , Gajjar Amar , Stewart Clinton F. 
Published: November 2007

AbstractPurpose: To characterize the population pharmacokinetics of topotecan lactone in children with cancer and identify covariates related to topotecan disposition.Patients and Methods: The study population consisted of 162 children in seven clinical trials receiving single agent topotecan as a 30-min infusion. A population approach via nonlinear mixed effects modeling was used to conduct the analysis.Results: A two-compartment model was fit to topotecan lactone plasma concentrations (n = 1874), and large pharmacokinetic variability was observed among studies, among individuals, and within individuals. We conducted a covariate analysis using demographics, biochemical data, trial effects, and concomitant drugs. The most significant covariate was body surface area, which explained 54% of the interindividual variability for topotecan systemic clearance. Interoccasion variability was considerable in both clearance and volume (20% and 22%, respectively), but was less than interindividual variability in both variables. Other covariates related to clearance were concomitant phenytoin, calculated glomerular filtration rate, and age (&lt;0.5 years). Including them in the model reduced the interindividual variability for topotecan clearance by an additional 48% relative to the body surface area–normalized model. The full covariate model explained 76% and 50% of interindividual variability in topotecan clearance and volume, respectively.Conclusions: We developed a descriptive and robust population pharmacokinetic model which identified patient covariates that account for topotecan disposition in pediatric patients. Additionally, dosing topotecan based on the covariate model led to a more accurate and precise estimation topotecan systemic exposure compared with a fixed dosing approach, and could be a tool to assist clinicians to individualize topotecan dosing.
Optimal Pathologic Staging: Defining Stage II Disease
Authors: Compton Carolyn C. 
Published: November 2007

Abstract
Tumor stage remains the most important determinant of prognosis in colorectal cancer and is the basis of all authoritative patient management guidelines. The pathologic assessment of stage II disease is especially critical because it may help to identify patients at additional risk for whom surgery alone may not be curative. Accurate analysis of regional lymph nodes, extent of tumor penetration, and circumferential resection margins constitute the most crucial issues. For assignment of pN0, adequacy of the surgical resection and thoroughness of the lymph node harvest from the resection specimen are both essential. The minimum number of lymph nodes has been variably determined to be between 12 and 18 for assignment of pN0, but the confidence level increases with increasing numbers of nodes examined. The ability of exhaustive analysis of sentinel lymph nodes using special techniques to substitute for an exhaustive lymph node harvest and standard node examination has not been definitively shown. Although special techniques may facilitate the identification of minute amounts of tumor (i.e., isolated tumor cells) in regional lymph nodes, the prognostic significance of such findings remains unclear. Additional stage-independent pathologic features that have been validated as adverse prognostic factors include involvement by tumor of mural lymphovascular channels, venous vessels, or the surgical resection margin of the operative specimen and high tumor grade. The presence of these features may help to identify patients for whom surgery alone will not be curative and adjuvant therapies may be appropriate.
Prognostic Significance ofp53andX-ray Repair Cross-complementing Group 1Polymorphisms on Prostate-Specific Antigen Recurrence in Prostate Cancer Post–Radical Prostatectomy
Authors: Huang Shu-Pin , Huang Chao-Yuan , Wang Jyh-Seng , Liu Chia-Chu , Pu Yeong-Shiau , Yu Hong-Jeng , Yu Chia-Cheng , Wu Tony T. , Huang Chun-Hsiung , Wu Wen-Jeng , Chou Yii-Her , Wu Ming-Tsang 
Published: November 2007

AbstractPurpose: The tumor suppressor p53 and DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) are thought to play important roles on prostate cancer susceptibility and tumor development. We investigated the potential prognostic roles of p53 (codon 72) and XRCC1 (codons 194, 280, and 399) polymorphisms in clinical localized prostate cancer after radical prostatectomy.Experimental Design: A total of 126 clinical localized prostate cancer patients undergoing curative radical prostatectomy at the Kaohsiung Medical University Hospital and Kaohsiung Veterans General Hospital were included in this study. The p53 codon 72 and XRCC1 codons 194, 280 and 399 polymorphisms were determined by the PCR-RFLP method. Their prognostic significance on prostate-specific antigen (PSA) recurrence were assessed using the Kaplan-Meier analysis and Cox regression model.Results: The p53 codon 72 Arg/Arg genotype was associated with increased PSA recurrence risk compared with the Arg/Pro and Pro/Pro genotypes, although the difference did not reach significance (30.3% versus 20.4%, P = 0.247). Of these three XRCC1 polymorphisms, the codon 399 Arg/Gln + Gln/Gn genotypes were significantly associated with higher risk of PSA recurrence after radical prostatectomy compared with the Arg/Arg genotype (34.0% versus 15.1%, P = 0.013) and poorer PSA-free survival (log-rank test, P = 0.0056). After considering for other covariates in a Cox proportional hazard model, the XRCC1 Arg/Gln and Gln/Gln genotypes (hazard ratio, 4.73; 95% confidence interval, 1.61-13.92; P = 0.005) and high Gleason score (Gleason score, 8-10; hazard ratio, 5.58; 95% confidence interval, 1.58-19.71; P = 0.008) were still independent predictors of poor PSA-free survival after radical prostatectomy. The similar significant results were not found in XRCC1 codons 194 and 280.Conclusions: Our results suggest that the XRCC1 codon 399 polymorphism may be a prognostic factor for PSA recurrence after radical prostatectomy.