bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous Expression of Embryonic Factors and p53 Point Mutations in Aged Mesenchymal Stem Cells: A Model of Age-Related Tumorigenesis In Mice
Authors: Li Hanchen , Fan Xueli , Kovi Ramesh C. , Jo YunJu , Moquin Brian , Konz Richard , Stoicov Calin , Kurt-Jones Evelyn , Grossman Steven R. , Lyle Steven , Rogers Arlin B. , Montrose Marshall , Houghton JeanMarie
Published: November 2007

Aging is the single most common risk factor for cancer. Peripheral and marrow-derived stem cells are long lived and are candidate cells for the cancer-initiating cell. Repeated rounds of replication are likely required for accumulation of the necessary genetic mutations. Based on the facts that mesenchymal stem cells (MSC) transform with higher frequency than other cell types, and tumors in aged C57BL/6 mice are frequently fibrosarcomas, we used a genetically tagged bone marrow (BM) transplant model to show that aged mice develop MSC-derived fibrosarcomas. We further show that, with aging, MSCs spontaneously transform in culture and, when placed into our mouse model, recapitulated the naturally occurring fibrosarcomas of the aged mice with gene expression changes and p53 mutation similar to the in vivo model. Spontaneously transformed MSCs contribute directly to the tumor, tumor vasculature, and tumor adipose tissue, recruit additional host BM-derived cells (BMDC) to the area, and fuse with the host BMDC. Unfused transformed MSCs act as the cancer stem cell and are able to form tumors in successive mice, whereas fusion restores a nonmalignant phenotype. These data suggest that MSCs may play a key role in age-related tumors, and fusion with host cells restores a nonmalignant phenotype, thereby providing a mechanism for regulating tumor cell activity. [Cancer Res 2007;67(22):10889–98]
Distinct Loci Influence Radiation-Induced Alveolitis from Fibrosing Alveolitis in the Mouse
Authors: Haston Christina K. , Begin Michelle , Dorion Genevieve , Cory Sean M.
Published: November 2007

Thoracic radiotherapy may produce the morbidity-associated lung responses of alveolitis or fibrosing alveolitis in treated cancer patients. The genetic factors that influence a patient's likelihood of developing alveolitis and the relationship of this inflammatory response to the development of fibrosis are largely unknown. Herein we use genetic mapping to identify radiation-induced lung response susceptibility loci in reciprocal backcross mice bred from C3H/HeJ (alveolitis response) and C57BL/6J (fibrosing alveolitis/fibrosis response) strains. Mice were treated with 18-Gy whole thorax irradiation and their survival, lung histopathology, and bronchoalveolar lavage cell types were recorded. A genome-wide scan was completed using 139 markers. The C3H/HeJ alveolitis response included mast cell infiltration and increased neutrophil numbers in the lavage compared with the level in the C57BL/6J strain, which developed fibrosis. In backcross mice, posttreatment survival was dictated by the development of an alveolitis response with increased mast cell, bronchoalveolar lavage total cell, and neutrophil numbers. Fibrosis was measured only in a subset of mice developing alveolitis and, in these mice, was associated with neutrophil count. Genotyping revealed coinheritance of C3H alleles (chromosomes 2, 4, 19, and X) and C57BL/6J alleles (chromosomes 1, 7, 9, and 17) to result in higher fibrosis scores in backcross mice. Mice that inherited C57BL/6J alleles at the putative alveolitis susceptibility loci were spared this response and lived to the end of the experiment. In this animal model, independent loci control the development of alveolitis from fibrosis, whereas fibrosing alveolitis occurs with the coinheritance of these factors. [Cancer Res 2007;67(22):10796–803]
Common and Distinct Genomic Events in Sporadic Colorectal Cancer and Diverse Cancer Types
Authors: Martin Eric S. , Tonon Giovanni , Sinha Raktim , Xiao Yonghong , Feng Bin , Kimmelman Alec C. , Protopopov Alexei , Ivanova Elena , Brennan Cameron , Montgomery Kate , Kucherlapati Raju , Bailey Gerald , Redston Mark , Chin Lynda , DePinho Ronald A.
Published: November 2007

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and elucidation of its underlying genetics has advanced diagnostic screening, early detection, and treatment. Because CRC genomes are characterized by numerous non-random chromosomal structural alterations, we sought to delimit regions of recurrent amplifications and deletions in a collection of 42 primary specimens and 37 tumor cell lines derived from chromosomal instability neoplasia and microsatellite instability neoplasia CRC subtypes and to compare the pattern of genomic aberrations in CRC with those in other cancers. Application of oligomer-based array-comparative genome hybridization and custom analytic tools identified 50 minimal common regions (MCRs) of copy number alterations, 28 amplifications, and 22 deletions. Fifteen were highly recurrent and focal (<12 genes) MCRs, five of them harboring known CRC genes including EGFR and MYC with the remaining 10 containing a total of 65 resident genes with established links to cancer. Furthermore, comparisons of these delimited genomic profiles revealed that 22 of the 50 CRC MCRs are also present in lung cancer, glioblastoma, and/or multiple myeloma. Among 22 shared MCRs, nine do not contain genes previously shown genetically altered in cancer, whereas the remaining 13 harbor 35 known cancer genes, of which only 14 have been linked to CRC pathogenesis. Together, these observations point to the existence of many yet-to-be discovered cancer genes driving CRC development, as well as other human cancers, and show the utility of high-resolution copy number analysis in the identification of genetic events common and specific to the development of various tumor types. [Cancer Res 2007;67(22):10736–43]
Deregulated Overexpression of hCdt1 and hCdc6 Promotes Malignant Behavior
Authors: Liontos Michalis , Koutsami Marilena , Sideridou Maria , Evangelou Konstantinos , Kletsas Dimitris , Levy Brynn , Kotsinas Athanassios , Nahum Odelia , Zoumpourlis Vassilis , Kouloukoussa Mirsini , Lygerou Zoi , Taraviras Stavros , Kittas Christos , Bartkova Jirina , Papavassiliou Athanasios G. , Bartek Jiri , Halazonetis Thanos D. , Gorgoulis Vassilis G.
Published: November 2007

The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients. Abnormal accumulation of both proteins occurred early from the stage of dysplasia. A frequent cause of unregulated hCdc6 and hCdt1 expression was gene amplification, suggesting that these components can play a role per se in cancer development. Overexpression of hCdt1 and hCdc6 promoted rereplication and generated a DNA damage response, which activated the antitumor barriers of senescence and apoptosis. Generating an inducible hCdt1 cellular system, we observed that continuous stimulus by deregulated hCdt1 led to abrogation of the antitumor barriers and resulted in the selection of clones with more aggressive properties. In addition, stable expression of hCdc6 and hCdt1 in premalignant papilloma cells led to transformation of the cells that produced tumors upon injection into nude mice depicting the oncogenic potential of their deregulation. [Cancer Res 2007;67(22):10899–909]
Anoikis, Initiated by Mcl-1 Degradation and Bim Induction, Is Deregulated during Oncogenesis
Authors: Woods Nicholas T. , Yamaguchi Hirohito , Lee Francis Y. , Bhalla Kapil N. , Wang Hong-Gang
Published: November 2007

Anoikis, a Bax-dependent apoptosis triggered by detachment from the extracellular matrix, is often dysfunctional in metastatic cancer cells. Using wild-type and c-Src–transformed NIH3T3 cells as a model, we identified Mcl-1 degradation and Bim up-regulation as a critical determinant of anoikis initiation. Detachment rapidly degraded Mcl-1 via a GSK-3β–dependent proteasomal pathway and transcriptionally up-regulated Bim expression. Mcl-1 degradation in the presence of Bim was sufficient to induce anoikis. By analyzing nonmetastatic Saos-2 and metastatic derivative LM7 cells, we confirmed that dysregulation of Mcl-1 degradation and Bim induction during detachment contributes to decreased anoikis sensitivity of metastatic cells. Furthermore, knockdown of Mcl-1 or pharmacologic inhibition of the phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase pathways that suppress Mcl-1 degradation and Bim expression could markedly sensitize metastatic breast cancer cells to anoikis and prevent metastases in vivo. Therefore, Mcl-1 degradation primes the cell for Bax activation and anoikis, which can be blocked by oncogenic signaling in metastatic cells. [Cancer Res 2007;67(22):10744–52]
Trends in the Use and Role of Biomarkers in Phase I Oncology Trials
Authors: Goulart Bernardo H.L. , Clark Jeffrey W. , Pien Homer H. , Roberts Thomas G. , Finkelstein Stan N. , Chabner Bruce A.
Published: November 2007

Purpose: There has been interest in using biomarkers that aid the evaluation of new anticancer agents. We evaluated trends in the use of biomarkers and their contribution to the main goals of phase I trials.

Experimental Design: We did a systematic review of abstracts submitted to the American Society of Clinical Oncology annual meeting from 1991 to 2002 and the publications related to these abstracts. We analyzed the use of biomarkers and their contribution to published phase I trials.

Results: Twenty percent of American Society of Clinical Oncology phase I abstracts (503 of 2458) from 1991 to 2002 included biomarkers. This proportion increased over time (14% in 1991 compared with 26% in 2002; P < 0.02). Independent predictors of the use of biomarkers included National Cancer Institute sponsorship, submission in the time period of 1999 to 2002, adult population, and drug family (biological agents). Biomarkers supported dose selection for phase II studies in 11 of 87 of the trials (13%) emanating from these abstracts. However, the primary determinants of phase II dose and schedule were toxicity and/or efficacy in all but one of these 87 trials (1%). Biomarker studies provided evidence supporting the proposed mechanism of action in 34 of 87 of the published trials (39%).

Conclusions: The use of biomarkers in phase I trials has increased over the period from 1991 to 2002. To date, biomarker utilization has made a limited and primarily supportive contribution to dose selection, the primary end point of phase I studies. Additional studies are needed to determine what type of biomarker information is most valuable to evaluate in phase I trials.
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

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

Purpose: 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

Purpose: 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

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 >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

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

At 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

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

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 < 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

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 (<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 < 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 < 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

Purpose: 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 (<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

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

Purpose: 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.
Preclinical Studies of Celastrol and Acetyl Isogambogic Acid in Melanoma
Authors: Abbas Sabiha , Bhoumik Anindita , Dahl Russell , Vasile Stefan , Krajewski Stan , Cosford Nicholas D.P. , Ronai Ze'ev A.
Published: November 2007

Purpose: Sensitize melanomas to apoptosis and inhibit their growth and metastatic potential by compounds that mimic the activities of activating transcription factor 2 (ATF2)-driven peptides.

Experimental Design: Small-molecule chemical library consisting of 3,280 compounds was screened to identify compounds that elicit properties identified for ATF2 peptide, including (a) sensitization of melanoma cells to apoptosis, (b) inhibition of ATF2 transcriptional activity, (c) activation of c-Jun NH2-terminal kinase (JNK) and c-Jun transcriptional activity, and (d) inhibition of melanoma growth and metastasis in mouse models.

Results: Two compounds, celastrol (CSL) and acetyl isogambogic acid, could, within a low micromolar range, efficiently elicit cell death in melanoma cells. Both compounds efficiently inhibit ATF2 transcriptional activities, activate JNK, and increase c-Jun transcriptional activities. Similar to the ATF2 peptide, both compounds require JNK activity for their ability to inhibit melanoma cell viability. Derivatives of CSL were identified as potent inducers of cell death in mouse and human melanomas. CSL and a derivative (CA19) could also efficiently inhibit growth of human and mouse melanoma tumors and reduce the number of lung metastases in syngeneic and xenograft mouse models.

Conclusions: These studies show for the first time the effect of CSL and acetyl isogambogic acid on melanoma. These compounds elicit activities that resemble the well-characterized ATF2 peptide and may therefore offer new approaches for the treatment of this tumor type.
Immunity against Tumor Angiogenesis Induced by a Fusion Vaccine with Murine β-Defensin 2 and mFlk-1
Authors: Wang Yong-sheng , Wang Guo-qing , Wen Yan-jun , Wang Lian , Chen Xian-cheng , Chen Ping , Kan Bin , Li Jiong , Huang Canhua , Lu You , Zhou Qin , Xu Ning , Li Dan , Fan Ling-yu , Yi Tao , Wu Hong-bo , Wei Yu-quan
Published: November 2007

Purpose: Previous studies indicated that humoral or cellular immunity against murine vascular endothelial growth factor 2 (mFlk-1) was elicited to inhibit tumor growth. Here we describe a genetic fusion vaccine, pMBD2-mFlk-1, based on the targeting of a modified mFlk-1 to antigen-presenting cells by a murine β-defensin 2 (MBD2) protein to induce both humoral and cellular immunity against mFlk-1, with the targeting especially focused on immature dendritic cells.

Experimental Design: The protective and therapeutic antitumor immunity of the fusion vaccine was investigated in mouse models. Antiangiogenesis effect was detected by immunohistochemical staining and alginate-encapsulate tumor cell assay. The mechanisms of the fusion vaccine were primarily explored by detection of autoantibodies and CTL activity and confirmed by the deletion of immune cell subsets.

Results: The fusion vaccine elicited a strong protective and therapeutic antitumor immunity through antiangiogenesis in mouse models, and this worked through stimulation of an antigen-specific CD8+ T-cell response as well as a specific B-cell response against mFlk-1. The findings were confirmed by depletion of immune cell subsets and in knockout mice.

Conclusion: Our study showed that a fusion vaccine based on self immune peptide (MBD2) and self antigen (mFlk-1) induced autoimmunity against endothelial cells, resulting in inhibition of tumor growth, and could be further exploited in clinical applications of cancer immunotherapy.
Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer
Authors: Friedman Jay , Nottingham Liesl , Duggal Praveen , Pernas Francisco G. , Yan Bin , Yang Xin Ping , Chen Zhong , Van Waes Carter
Published: November 2007

Purpose: To determine the nature and potential pharmacologic reversibility of deficient TP53 expression and function in head and neck squamous cell carcinomas (HNSCC) with wild-type TP53, previously associated with decreased sensitivity to cisplatin therapy.

Experimental Design: TP53 genotype, mRNA and protein expression, TP53-induced p21 expression, and TP53 DNA–binding and reporter gene function were determined in a panel of nine previously characterized HNSCC cell lines from the University of Michigan squamous cell carcinoma (UM-SCC) series. The genotoxic drug doxorubicin and the anti-inflammatory and antimalarial drug quinacrine, previously identified as inducers of TP53, were used to examine the nature and potential reversibility of deficient TP53 expression and function. The specific role of inducible TP53 on function and cellular proliferation was confirmed using selective TP53 inhibitor pifithrin-α or short hairpin RNA knockdown. The capability of quinacrine to sensitize HNSCC to the cytotoxic effects of cisplatin was assessed.

Results: UM-SCC cell lines with wild-type TP53 genotype underexpressed TP53 mRNA and protein when compared with normal human keratinocytes or UM-SCC with mutant TP53. Although doxorubicin failed to induce TP53 expression or functional activity, quinacrine induced TP53 mRNA and protein expression, increased TP53 reporter activity and p21 protein expression, and induced growth inhibition in these wild-type TP53 cell lines. Quinacrine-induced TP53 reporter activity and growth suppression were attenuated by pifithrin-α and TP53 short hairpin RNA knockdown. Furthermore, quinacrine sensitized UM-SCC to cisplatin in vitro.

Conclusions: Deficient TP53 mRNA and protein expression underlies decreased function in a subset of HNSCC with wild-type TP53 and can be restored together with cisplatin sensitization by quinacrine.
New Approaches to Assessing and Treating Early-Stage Colon and Rectal Cancer: Summary Statement from 2007 Santa Monica Conference
Authors: Rosen Lee S. , Bilchik Anton J. , Beart Robert W. , Benson Al B. , Chang Kenneth J. , Compton Carolyn C. , Grothey Axel , Haller Daniel G. , Ko Clifford Y. , Lynch Patrick M. , Nelson Heidi , Stamos Michael J. , Turner Roderick R. , Willett Christopher G.
Published: November 2007

The 2007 Santa Monica Conference on Assessing and Treating Early-Stage Colon and Rectal Cancer, a multidisciplinary meeting of leaders in surgery, medical and radiation oncology, and pathology, was convened on January 12 to 13, 2007. The purpose of the meeting was to assess current data and issues in the field and to develop recommendations for advancing patient care and clinical research. Topics included pathologic assessment and staging, transanal versus laparoscopic versus open resection, adjuvant therapy, genetic testing and counseling, cooperative group strategies, and the use of biological therapies and novel agents. A review of the key issues discussed, as well as conclusions and recommendations considered significant to the field, is summarized below and presented at greater length in the individual manuscripts and accompanying discussion that comprise the full conference proceedings. Although the management of early-stage colon and rectal cancers remains a challenge for all of us, the development and use of new technologies and methods of assessment and treatment over the past several decades is yielding encouraging results. A variety of opportunities to further improve outcomes were addressed in this forum, including recommendations that specific protocols be adopted regarding surgical and pathologic dissection and reporting, particularly for stage II disease; the corollary need to increase active multidisciplinary collaboration; and the development of comprehensive consensus guidelines and recommendations to standardize care in early-stage colorectal cancer.
Neural Correlates of Morphological Processes in Hebrew
Authors: Bick Atira , Goelman Gadi , Frost Ram
Published: November 2007

Is morphology a discrete and independent element of lexical structure or does it simply reflect a fine tuning of the system to the statistical correlation that exists among the orthographic and semantic properties of words? Imaging studies in English failed to show unequivocal morphological activation that is distinct from semantic or orthographic activation. Cognitive research in Hebrew has revealed that morphological decomposition is an important component of print processing. In Hebrew, morphological relatedness does not necessarily induce a clear semantic relatedness, thus, Hebrew provides a unique opportunity to investigate the neural substrates of morphological processing. In this functional magnetic resonance imaging study, participants were required to perform judgment tasks of morphological relatedness, semantic relatedness, rhyming, and orthographic similarity. Half of the morphologically related words were semantically related and half were semantically unrelated. This design was chosen to induce explicit morphological processing. We identified two locations involved in morphological processing: the left middle frontal gyrus and the left inferior parietal sulcus. Comparing locations of morphological related activation to the locations of semantic and orthographic related activation, we found that the areas neighbored but only partially overlapped. The similarity in activation between the two morphological conditions eliminates the possibility that morphological activation simply results from the semantic properties of the words. These results demonstrate the important role of morphological processing in reading and suggest that morphological analysis is a distinct process of visual word recognition.
Parallel Response Selection after Callosotomy
Authors: Hazeltine Eliot , Weinstein Andrea , Ivry Richard B.
Published: November 2007

Two studies [Ivry, R. B., Franz, E. A., Kingstone, A., & Johnston, J. C. The psychological refractory period effect following callosotomy: Uncoupling of lateralized response codes. Journal of Experimental Psychology: Human Perception and Performance, 24, 463–480, 1998; Pashler, H., Luck, S., Hillyard, S. A., Mangun, G. R., O'Brien, S., & Gazzaniga, M. S. Sequential operation of disconnected hemispheres in split-brain patients. NeuroReport, 5, 2381–2384, 1994] reported robust dual-task costs in split-brain patients even when the two tasks were associated with separate cerebral hemispheres. Although the patients failed to demonstrate specific forms of interference observed in control participants, the timing of the two responses suggested that performance was constrained such that the responses could not be initiated independently. Alternatively, the split-brain participants may have adopted a strategy in which the second response was withheld until the first was initiated. The present study revisits this phenomenon using a procedure in which the stimuli for both tasks are presented simultaneously and neither is given priority over the other. Under these conditions, neurologically intact participants show robust dual-task costs that are mediated by compatibility effects between the responses of the two hands. In contrast, the split-brain participants show greatly reduced dual-task costs and compatibility effects. The minimal dual-task costs observed in the current study indicate that previous dual-task costs in split-brain patients may be strategic, reflecting experimental instructions to prioritize one task, rather than reflect fundamental constraints of the cognitive architecture.
The Hippocampus is Preferentially Associated with Memory for Spatial Context
Authors: Ross Robert S. , Slotnick Scott D.
Published: November 2007

The existence of a functional-anatomic dissociation for retrieving item versus contextual information within subregions of the medial temporal lobe (MTL) is currently under debate. We used a spatial source memory paradigm during event-related functional magnetic resonance imaging to investigate this issue. At study, abstract shapes were presented to the left or right of fixation. During test, old and new shapes were presented at fixation. Participants responded whether each shape had been previously presented on the “left,” the “right,” or was “new.” Activity associated with contextual memory (i.e., source memory) was isolated by contrasting accurate versus inaccurate memory for spatial location. Item-memory-related activity was isolated by contrasting accurate item recognition without contextual memory with forgotten items. Source memory was associated with activity in the hippocampus and parahippocampal cortex. Although item memory was not associated with unique MTL activity at our original threshold, a region-of-interest (ROI) analysis revealed item-memory-related activity in the perirhinal cortex. Furthermore, a functional-anatomic dissociation within the parietal cortex for retrieving item and contextual information was not found in any of three ROIs. These results support the hypothesis that specific subregions in the MTL are associated with item memory and memory for context.
Going AWOL in the Brain: Mind Wandering Reduces Cortical Analysis of External Events
Authors: Smallwood Jonathan , Beach Emily , Schooler Jonathan W. , Handy Todd C.
Published: November 2007

Converging evidence from neuroscience suggests that our attention to the outside world waxes and wanes over time. We examined whether these periods of “mind wandering” are associated with reduced cortical analysis of the external environment. Participants performed a sustained attention to response task in which they responded to frequent “nontargets” (digits 0–9) and withheld responses for infrequent “targets” (the letter X). Mind wandering was defined both behaviorally, indicated by a failure to withhold a response to a target, and subjectively, via self-report at a thought probe. The P300 event-related potential component for nontargets was reduced prior to both the behavioral and subjective reports of mind wandering, relative to periods of being “on-task.” Regression analysis of P300 amplitude revealed significant common variance between behavioral and subjective markers of mind wandering, suggesting that both markers reflect a common underlying mental state. Finally, control analysis revealed that the effect of mind wandering on the P300 could not be ascribed to changes in motor activity nor was it associated with general arousal. Our data suggest that when trying to engage attention in a sustained manner, the mind will naturally ebb and flow in the depth of cognitive analysis it applies to events in the external environment.