bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysfunctional Transforming Growth Factor-β Receptor II Accelerates Prostate Tumorigenesis in the TRAMP Mouse Model
Authors: Pu Hong , Collazo Joanne , Jones Elisabeth , Gayheart Dustin , Sakamoto Shinichi , Vogt Adam , Mitchell Bonnie , Kyprianou Natasha
Published: September 2009

The contribution of a dysfunctional transforming growth factor-β type II receptor (TGFβRII) to prostate cancer initiation and progression was investigated in an in vivo mouse model. Transgenic mice harboring the dominant-negative mutant TGF-β type II receptor (DNTGFβRII) in mouse epithelial cell were crossed with the TRAMP prostate cancer transgenic mouse to characterize the in vivo consequences of inactivated TGF-β signaling on prostate tumor initiation and progression. Histopathologic diagnosis of prostate specimens from the TRAMP+/DNTGFβRII double transgenic mice revealed the appearance of early malignant changes and subsequently highly aggressive prostate tumors at a younger age, compared with littermates TRAMP+/Wt TGFβRII mice. Immunohistochemical and Western blotting analysis revealed significantly increased proliferative and apoptotic activities, as well as vascularity and macrophage infiltration that correlated with an elevated vascular endothelial growth factor and MCP-1 protein levels in prostates from TRAMP+/DNTGFβRII+ mice. An epithelial-mesenchymal transition (EMT) effect was also detected in prostates of TRAMP+/DNTGFβRII mice, as documented by the loss of epithelial markers (E-cadherin and β-catenin) and up-regulation of mesenchymal markers (N-cadherin) and EMT-transcription factor Snail. A significant increase in the androgen receptor mRNA and protein levels was associated with the early onset of prostate tumorigenesis in TRAMP+/DNTGFβRII mice. Our results indicate that in vivo disruption of TGF-β signaling accelerates the pathologic malignant changes in the prostate by altering the kinetics of prostate growth and inducing EMT. The study also suggests that a dysfunctional TGFβRII augments androgen receptor expression and promotes inflammation in early stage tumor growth, thus conferring a significant contribution by TGF-β to prostate cancer progression. [Cancer Res 2009;69(18):7366–74]
In situStimulation of CD40 and Toll-like Receptor 3 Transforms Ovarian Cancer–Infiltrating Dendritic Cells from Immunosuppressive to Immunostimulatory Cells
Authors: Scarlett Uciane K. , Cubillos-Ruiz Juan R. , Nesbeth Yolanda C. , Martinez Diana G. , Engle Xavier , Gewirtz Andrew T. , Ahonen Cory L. , Conejo-Garcia Jose R.
Published: September 2009

Boosting therapeutically relevant immunity against lethal epithelial tumors may require targeting tumor-induced immunosuppression on an individualized basis. Here, we show that, in the ovarian carcinoma microenvironment, CD11c+MHC-II+ dendritic cells spontaneously engulf tumor materials but, rather than enhancing antitumor immunity, suppress T-cell function. In situ costimulation of CD40 and Toll-like receptor (TLR) 3 on tumor-infiltrating dendritic cells decreased their l-arginase activity, enhanced their production of type I IFN and interleukin-12 (p70), augmented their capacity to process antigens, and up-regulated costimulatory molecules in vivo in mice and in vitro in human dissociated tumors. Synergistic CD40/TLR activation also induced the migration of activated dendritic cells to lymphatic locations and promoted their capacity to present antigens. Correspondingly, without exogenous antigen, combined CD40/TLR agonists boosted measurable T-cell–mediated antitumor immunity and induced the rejection of otherwise lethal i.p. ovarian carcinomas. Our results highlight the potential of transforming tumor-infiltrating dendritic cells (the most abundant leukocyte subset in the solid ovarian carcinoma microenvironment) from an immunosuppressive to an immunostimulatory cell type. Combined administration of synergistic CD40 and TLR3 agonists could enhance their individual therapeutic effects against ovarian and other lethal epithelial cancers. [Cancer Res 2009;69(18):7329–37]
Targeted Disruption of Stat3 Reveals a Major Role for Follicular Stem Cells in Skin Tumor Initiation
Authors: Kim Dae Joon , Kataoka Ken , Rao Dharanija , Kiguchi Kaoru , Cotsarelis George , DiGiovanni John
Published: September 2009

The initiation stage of mouse skin carcinogenesis involves the induction of mutations in keratinocyte stem cells (KSC), which confers a selective growth advantage allowing clonal expansion during tumor promotion. Targeted disruption of signal transducer and activator of transcription 3 (Stat3) in bulge region KSCs was achieved by treating K15.CrePR1 × Stat3fl/fl mice with RU486. Deletion of Stat3 prior to skin tumor initiation with 7,12-dimethylbenz(a)anthracene significantly increased the number of apoptotic KSCs and decreased the frequency of Ha-ras codon 61 A182→T transversion mutations in this cell population compared with wild-type littermates. Targeted disruption of Stat3 in bulge region KSCs at the time of initiation also dramatically reduced the number of skin tumors (by ∼80%) produced following promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. These results show that Stat3 is required for the survival of bulge region KSCs during tumor initiation. Furthermore, these data provide direct evidence that bulge region KSCs are the primary targets for the initiation of skin tumors in this model system. [Cancer Res 2009;69(19):7587–94]
Development and Cancer: At the Crossroads of Nodal and Notch Signaling
Authors: Strizzi Luigi , Hardy Katharine M. , Seftor Elisabeth A. , Costa Fabricio F. , Kirschmann Dawn A. , Seftor Richard E.B. , Postovit Lynne-Marie , Hendrix Mary J.C.
Published: September 2009

Aggressive tumor cells express a plastic, multipotent phenotype similar to embryonic stem cells. However, the absence of major regulatory checkpoints in these tumor cells allows aberrant activation of embryonic signaling pathways, which seems to contribute to their plastic phenotype. Emerging evidence showing the molecular cross-talk between two major stem cell signaling pathways Nodal and Notch suggests a promising therapeutic strategy that could target aggressive tumor cells on the basis of their unique plasticity, and provide new insights into the mechanisms underlying the re-emergence of developmental signaling pathways during tumor progression. [Cancer Res 2009;69(18):7131–4]
Resveratrol Suppresses Growth of Human Ovarian Cancer Cells in Culture and in a Murine Xenograft Model: Eukaryotic Elongation Factor 1A2 as a Potential Target
Authors: Lee Mee-Hyun , Choi Bu Young , Kundu Joydeb Kumar , Shin Young Kee , Na Hye-Kyung , Surh Young-Joon
Published: September 2009

The eukaryotic elongation factor 1A2 (eEF1A2) is known to retain oncogenic potential and is recognized as a novel target for cancer prevention and therapy. Resveratrol (trans-3,4′,5-trihydroxystilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the growth-inhibitory effects of resveratrol in human ovarian cancer PA-1 cells, considering eEF1A2 as a potential molecular target. Pretreatment with resveratrol attenuated proliferation of serum-starved PA-1 cells stimulated with insulin or serum. Resveratrol also activated caspase-9, -7, and -3 and induced apoptosis in PA-1 cells in the presence of insulin or serum. Insulin or serum stimulation of PA-1 cells resulted in the marked induction of eEF1A2, which was suppressed by pretreatment with resveratrol. Moreover, resveratrol inhibited insulin- or serum-induced soft-agar colony formation in eEF1A2-transfected NIH3T3 cells. An antibody array directed to assess the phosphorylation of protein kinases revealed that treatment with insulin or serum induced the phosphorylation of Akt in PA-1 cells. Pharmacologic inhibition of Akt with LY294002 abrogated insulin- or serum-induced eEF1A2 expression and increased the caspase-3 activity. In another experiment, i.p. administration of resveratrol retarded the growth of PA-1 cell xenograft and the expression of eEF1A2 in athymic nude mice in association with decreased bromodeoxyuridine positivity, reduced expression of proliferating cell nuclear antigen, increased the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and caspase-3 staining, and diminished CD31 positivity. Taken together, eEF1A2 may be considered as a potential molecular target for the antiproliferative effects of resveratrol in PA-1 ovarian cancer cells. [Cancer Res 2009;69(18):7449–58]
Tuberous Sclerosis Complex Suppression in Cerebellar Development and Medulloblastoma: Separate Regulation of Mammalian Target of Rapamycin Activity and p27Kip1 Localization
Authors: Bhatia Bobby , Northcott Paul A. , Hambardzumyan Dolores , Govindarajan Baskaran , Brat Daniel J. , Arbiser Jack L. , Holland Eric C. , Taylor Michael D. , Kenney Anna Marie
Published: September 2009

During development, proliferation of cerebellar granule neuron precursors (CGNP), candidate cells-of-origin for the pediatric brain tumor medulloblastoma, requires signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF), the pathways of which are also implicated in medulloblastoma. One of the consequences of IGF signaling is inactivation of the mammalian target of rapamycin (mTOR)–suppressing tuberous sclerosis complex (TSC), comprised of TSC1 and TSC2, leading to increased mRNA translation. We show that mice, in which TSC function is impaired, display increased mTOR pathway activation, enhanced CGNP proliferation, glycogen synthase kinase-3α/β (GSK-3α/β) inactivation, and cytoplasmic localization of the cyclin-dependent kinase inhibitor p27Kip1, which has been proposed to cause its inactivation or gain of oncogenic functions. We observed the same characteristics in wild-type primary cultures of CGNPs in which TSC1 and/or TSC2 were knocked down, and in mouse medulloblastomas induced by ectopic Shh pathway activation. Moreover, Shh-induced mouse medulloblastomas manifested Akt-mediated TSC2 inactivation, and the mutant TSC2 allele synergized with aberrant Shh signaling to increase medulloblastoma incidence in mice. Driving exogenous TSC2 expression in Shh-induced medulloblastoma cells corrected p27Kip1 localization and reduced proliferation. GSK-3α/β inactivation in the tumors in vivo and in primary CGNP cultures was mTOR-dependent, whereas p27Kip1 cytoplasmic localization was regulated upstream of mTOR by TSC2. These results indicate that a balance between Shh mitogenic signaling and TSC function regulating new protein synthesis and cyclin-dependent kinase inhibition is essential for the normal development and prevention of tumor formation or expansion. [Cancer Res 2009;69(18):7224–34]
The Potential Role of Curcumin in Patients with Monoclonal Gammopathy of Undefined Significance—Its Effect on Paraproteinemia and the Urinary N-Telopeptide of Type I Collagen Bone Turnover Marker
Authors: Golombick Terry , Diamond Terrence H. , Badmaev Vladimir , Manoharan Arumugam , Ramakrishna Rajeev
Published: September 2009

Purpose: To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS.

Experimental Design: Twenty-six patients with MGUS were recruited into the study and administered 4 grams/day oral curcumin. Blood and urine samples were collected at specified visits after initiating therapy. Full blood count, B2 microglobulin, serum paraprotein, and immunoglobulin electrophoresis (IEPG and EPG) were determined for all patients at each visit. Serum calcium, 25 hydroxyvitamin D3, and bone-specific alkaline phosphatase were determined at baseline only. Urine, as a morning second-void sample, was collected at each visit for urinary N-telopeptide of type I collagen.

Results: Our results show that oral curcumin is able to decrease paraprotein load in a select group (i.e., those having a paraprotein level of >20 g/L) of patients with MGUS. Fifty percent (5 of 10) of these patients had a 12% to 30% reduction in their paraprotein levels, while on curcumin therapy. In addition, 27% of patients on curcumin had a >25% decrease in urinary N-telopeptide of type I collagen.

Conclusion: Due to the possible progression of MGUS to multiple myeloma, the potential role of curcumin as a therapeutic intervention for MGUS patients warrants further investigation. (Clin Cancer Res 2009;15(18):5917–22)
Circulating Levels of Soluble KIT Serve as a Biomarker for Clinical Outcome in Gastrointestinal Stromal Tumor Patients Receiving Sunitinib following Imatinib Failure
Authors: DePrimo Samuel E. , Huang Xin , Blackstein Martin E. , Garrett Christopher R. , Harmon Charles S. , Schöffski Patrick , Shah Manisha H. , Verweij Jaap , Baum Charles M. , Demetri George D.
Published: September 2009

Purpose: To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study.

Experimental Design: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis.

Results: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40).

Conclusions: The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings. (Clin Cancer Res 2009;15(18):5869–77)
EGFRvIII Deletion Mutations in Pediatric High-Grade Glioma and Response to Targeted Therapy in Pediatric Glioma Cell Lines
Authors: Bax Dorine A. , Gaspar Nathalie , Little Suzanne E. , Marshall Lynley , Perryman Lara , Regairaz Marie , Viana-Pereira Marta , Vuononvirta Raisa , Sharp Swee Y. , Reis-Filho Jorge S. , Stávale João N. , Al-Sarraj Safa , Reis Rui M. , Vassal Gilles , Pearson Andrew D.J. , Hargrave Darren , Ellison David W. , Workman Paul , Jones Chris
Published: September 2009

Purpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG).

Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib.

Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model.

Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children. (Clin Cancer Res 2009;15(18):5753–61)
Cancer-Selective Targeting and Cytotoxicity by Liposomal-Coupled Lysosomal Saposin C Protein
Authors: Qi Xiaoyang , Chu Zhengtao , Mahller Yonatan Y. , Stringer Keith F. , Witte David P. , Cripe Timothy P.
Published: September 2009

Purpose: Saposin C is a multifunctional protein known to activate lysosomal enzymes and induce membrane fusion in an acidic environment. Excessive accumulation of lipid-coupled saposin C in lysosomes is cytotoxic. Because neoplasms generate an acidic microenvironment, caused by leakage of lysosomal enzymes and hypoxia, we hypothesized that saposin C may be an effective anticancer agent. We investigated the antitumor efficacy and systemic biodistribution of nanovesicles comprised of saposin C coupled with dioleoylphosphatidylserine in preclinical cancer models.

Experimental Design: Neuroblastoma, malignant peripheral nerve sheath tumor and, breast cancer cells were treated with saposin C–dioleoylphosphatidylserine nanovesicles and assessed for cell viability, ceramide elevation, caspase activation, and apoptosis. Fluorescently labeled saposin C–dioleoylphosphatidylserine was i.v. injected to determine in vivo tumor-targeting specificity. Antitumor activity and toxicity profile of saposin C–dioleoylphosphatidylserine were evaluated in xenograft models.

Results: Saposin C–dioleoylphosphatidylserine nanovesicles, with a mean diameter of ∼190 nm, showed specific tumor-targeting activity shown through in vivo imaging. Following i.v. administration, saposin C–dioleoylphosphatidylserine nanovesicles preferentially accumulated in tumor vessels and cells in tumor-bearing mice. Saposin C–dioleoylphosphatidylserine induced apoptosis in multiple cancer cell types while sparing normal cells and tissues. The mechanism of saposin C–dioleoylphosphatidylserine induction of apoptosis was determined to be in part through elevation of intracellular ceramides, followed by caspase activation. In in vivo models, saposin C–dioleoylphosphatidylserine nanovesicles significantly inhibited growth of preclinical xenografts of neuroblastoma and malignant peripheral nerve sheath tumor. I.v. dosing of saposin C–dioleoylphosphatidylserine showed no toxic effects in nontumor tissues.

Conclusions: Saposin C–dioleoylphosphatidylserine nanovesicles offer promise as a novel, nontoxic, cancer-targeted, antitumor agent for treating a broad range of cancers. (Clin Cancer Res 2009;15(18):5840–51)
Metabolic Tumor Volume of [18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Predicts Short-Term Outcome to Radiotherapy With or Without Chemotherapy in Pharyngeal Cancer
Authors: Chung Man Ki , Jeong Han-Sin , Park Sang Gyu , Jang Jeon Yeob , Son Young-Ik , Choi Joon Young , Hyun Seung Hyup , Park Keunchil , Ahn Myung-Ju , Ahn Yong Chan , Kim Hyung-Jin , Ko Young-Hyeh , Baek Chung-Hwan
Published: September 2009

Purpose: This study aimed to investigate whether metabolic tumor volume (MTV) measured from [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) predicts short-term outcome to radiotherapy with or without chemotherapy and disease-free survival (DFS) in patients with pharyngeal cancers.

Experimental Design: The MTVs of primary sites with or without neck nodes were measured in 82 patients. Short-term outcome was assessed using the treatment response evaluation by the Response Evaluation Criteria in Solid Tumors and recurrence events during follow-up (complete response/no recurrence or residual disease/recurrence).

Results: A total of 64 patients had complete response/no recurrence as of the last follow-up. A cutoff of 40 mL for the MTV was the best discriminative value for predicting treatment response. By univariate analyses, patients with MTV >40 mL showed a significantly lower number of complete response/no recurrence than did patients with MTV ≤40 mL [68.2% versus 87.8%; hazard ratio (HR), 3.34; 95% confidence interval (95% CI), 1.09-10.08; P = 0.03], as is the same in tumor-node-metastasis stage (87.5% for I-II versus 90% for III versus 63.8% for IV; P = 0.02). However, MTV was only a significant predictor of short-term outcome by multivariate analyses (HR, 4.09; 95% CI, 1.02-16.43; P = 0.04). MTV >40 mL indicated a significantly worse DFS than MTV ≤40 mL (HR, 3.42; 95% CI, 1.04-11.26;P = 0.04). The standardized uptake value for the primary tumor did not show any correlation with treatment outcome or DFS.

Conclusion: MTV has a potential value in predicting short-term outcome and DFS in patients with pharyngeal cancers. (Clin Cancer Res 2009;15(18):5861–8)
MicroRNA Expression Signatures in Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Yang Hushan , Gu Jian , Wang Kenneth K. , Zhang Wei , Xing Jinliang , Chen Zhinan , Ajani Jaffer A. , Wu Xifeng
Published: September 2009

Purpose: Esophageal adenocarcinoma is a highly aggressive malignancy that frequently develops from Barrett's esophagus, a premalignant pathologic change occurring in the lower end of the esophagus. Identifying Barrett's esophagus patients at high risk of malignant transformation is essential to the prevention of esophageal adenocarcinoma. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of esophageal adenocarcinoma have not been extensively evaluated.

Experimental Design: In this study, we analyzed the expression patterns of 470 human miRNAs using Agilent miRNA microarray in 32 disease/normal-paired tissues from 16 patients diagnosed with Barrett's esophagus of either low- or high-grade dysplasia, or esophageal adenocarcinoma.

Results: Using unsupervised hierarchical clustering and class comparison analyses, we found that miRNA expression profiles in tissues of Barrett's esophagus with high-grade dysplasia were significantly different from their corresponding normal tissues. Similar findings were observed for esophageal adenocarcinoma, but not for Barrett's esophagus with low-grade dysplasia. The expression patterns of selected miRNAs were further validated using quantitative reverse transcription real-time PCR in an independent set of 75 pairs of disease/normal tissues. Finally, we identified several miRNAs that were involved in the progressions from low grade-dysplasia Barrett's esophagus to esophageal adenocarcinoma.

Conclusions: We showed that miRNAs were involved in the development and progression of esophageal adenocarcinoma. The identified significant miRNAs that may become potential targets for early detection, chemoprevention, and treatment of esophageal cancer. (Clin Cancer Res 2009;15(18):5744–52)
Molecular Target Modulation, Imaging, and Clinical Evaluation of Gastrointestinal Stromal Tumor Patients Treated with Sunitinib Malate after Imatinib Failure
Authors: Demetri George D. , Heinrich Michael C. , Fletcher Jonathan A. , Fletcher Christopher D.M. , Van den Abbeele Annick D. , Corless Christopher L. , Antonescu Cristina R. , George Suzanne , Morgan Jeffrey A. , Chen Ming Hui , Bello Carlo L. , Huang Xin , Cohen Darrel P. , Baum Charles M. , Maki Robert G.
Published: September 2009

Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.

Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed.

Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity.

Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. (Clin Cancer Res 2009;15(18):5902–9)
Association of Inflammation-Related and microRNA Gene Expression with Cancer-Specific Mortality of Colon Adenocarcinoma
Authors: Schetter Aaron J. , Nguyen Giang Huong , Bowman Elise D. , Mathé Ewy A. , Yuen Siu Tsan , Hawkes Jason E. , Croce Carlo M. , Leung Suet Yi , Harris Curtis C.
Published: September 2009

Purpose: Inflammatory genes and microRNAs have roles in colon carcinogenesis; therefore, they may provide useful biomarkers for colon cancer. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression.

Experimental Design: Quantitative reverse transcriptase-PCR. was used to measure the expression of 23 inflammatory genes in colon adenocarcinomas and adjacent noncancerous tissues from 196 patients. These data were used to develop models for cancer-specific mortality on a training cohort (n = 57), and this model was tested in both a test (n = 56) and a validation (n = 83) cohort. Expression data for miR-21 were available for these patients and were compared and combined with inflammatory gene expression.

Results: PRG1, IL-10, CD68, IL-23a, and IL-12a expression in noncancerous tissue, and PRG1, ANXA1, IL-23a, IL-17a, FOXP3, and HLA-DRA expression in tumor tissues were associated with poor prognosis based on Cox regression (|Z-score| >1.5) and were used to generate the inflammatory risk score (IRS). IRS was associated with cancer-specific mortality in the training, test (P = 0.01), and validation (P = 0.02) cohorts. This association was strong for stage II cases (P = 0.002). Expression of miR-21 was associated with IL-6, IL-8, IL-10, IL-12a, and NOS2a, providing evidence that the function of this microRNA and these inflammatory genes are linked. Both IRS and miR-21 expression were independently associated with cancer-specific mortality, including stage II patients alone.

Conclusion: IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients. (Clin Cancer Res 2009;15(18):5878–87)
Guiding the Optimal Translation of New Cancer Treatments From Canine to Human Cancer Patients
Authors: Khanna Chand , London Cheryl , Vail David , Mazcko Christina , Hirschfeld Steven
Published: September 2009

On June 20, 2008, a meeting entitled “Translation of new cancer treatments from canine to human cancer patients,” sponsored by the National Cancer Institute in Bethesda, Maryland, was convened to discuss the potential value, opportunity, risks, and rewards of an integrated and comparative drug development path for new cancer therapeutics that includes naturally occurring cancers in pet animals. A summary of this meeting and subsequent discussion are provided here to afford clarity on the conduct of these studies so as to optimize the opportunities provided by this novel drug development and modeling strategy. (Clin Cancer Res 2009;15(18):5671–7)
Biomarkers in GIST: Partly Ready for Prime-Time Use
Authors: Blanke Charles D.
Published: September 2009

Gastrointestinal stromal tumors, or GISTs, are now among the most treatable of solid malignancies. Assessing actual tumor response remains challenging; however, in this issue of Clinical Cancer Research, two articles discuss biomarkers potentially helpful in predicting response or other long-term benefits with standard tyrosine kinase therapy use. (Clin Cancer Res 2009;15(18):5603–5)
Adenovirus-mediated down-regulation of X-linked inhibitor of apoptosis protein inhibits colon cancer
Authors: Dai Yun , Qiao Liang , Chan Kwok Wah , Yang Mo , Ye Jieyu , Zhang Rongxin , Ma Juan , Zou Bing , Lam Colin S.C. , Wang Jide , Pang Roberta , Tan Victoria P.Y. , Lan H.Y. , Wong Benjamin C.Y.
Published: September 2009

Our previous studies and those of others have indicated that X-linked inhibitor of apoptosis protein (XIAP) holds promise as a target gene in colon cancer gene therapy. In this study, we constructed an adenoviral vector to deliver small hairpin RNA (shRNA) against XIAP (XIAP-shRNA) into colon cancer cells and tested its therapeutic efficacy in vitro and in vivo. We first confirmed an overexpression of XIAP in colon cancer cells and human cancer tissues. We then designed XIAP-small interfering RNA (siRNA) and confirmed the knockdown effect of these siRNAs in colon cancer cells. The sequences of the effective siRNAs were converted into shRNA and then packed into replication-deficient adenoviral vectors using BLOCK-iT Adenoviral RNAi Expression System to generate Adv-XIAP-shRNA. Infection of HT29 and HCT116 cells with Adv-XIAP-shRNA led to enhanced caspase-3 activity, which was associated with increased apoptosis and reduced cell proliferation. The therapeutic effect of Adv-XIAP-shRNA was then tested in xenograft tumors in nude mice. We showed that treatment of the xenograft tumors derived from HCT116 cells with Adv-XIAP-shRNA resulted in a retardation of tumor growth, which was associated with enhanced apoptosis, increased caspase-3 activity, and reduced expression of proliferating cell nuclear antigen in the tumor tissues. Treatment of xenograft tumors with Adv-XIAP-shRNA did not affect the expressions of inflammatory cytokines in tumor-bearing mice. Thus, Adv-XIAP-shRNA–mediated down-regulation of XIAP exerts a therapeutic effect in colon cancer by promoting apoptosis and inhibiting proliferation of colon cancer cells, and the antitumor effect of Adv-XIAP-shRNA was unlikely to be related to virus-induced immune response. [Mol Cancer Ther 2009;8(9):2762–70]
Exon Array Profiling DetectsEML4-ALKFusion in Breast, Colorectal, and Non–Small Cell Lung Cancers
Authors: Lin Eva , Li Li , Guan Yinghui , Soriano Robert , Rivers Celina Sanchez , Mohan Sankar , Pandita Ajay , Tang Jerry , Modrusan Zora
Published: September 2009

The echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non–small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis. (Mol Cancer Res 2009;7(9):1466–76)
Leukotriene B4 Creates a Favorable Microenvironment for Murine Melanoma Growth
Authors: Bachi André Luis Lacerda , Kim Fabiana Jin Kyung , Nonogaki Suely , Carneiro Célia Regina Whitaker , Lopes José Daniel , Jasiulionis Miriam Galvonas , Correa Mariangela
Published: September 2009

Chronic inflammation has long been associated with neoplastic progression. Our group had recently shown that the addition of a large number of apoptotic tumor cells to the tumor microenvironment induces a potent acute inflammatory reaction capable of promoting melanoma growth; however, primarily necrotizing cells do not cause such a reaction. Here, we show that potent inflammatory agents, such as lipopolysaccharide (LPS) and carrageenan, also promote growth of subtumorigenic doses of melanoma cells, having no effect on melanoma proliferation in vitro. Inhibition of 5-lipoxygenase (5-LOX) seems to have a pivotal role in this model because caffeic acid and MK886, a FLAP (5-LOX–activating protein) inhibitor, partially hindered tumor growth induced by apoptotic cells or LPS. Other enzymes of the arachidonic acid pathway, cyclooxygenase-1 and cyclooxygenase-2, seem to have no participation in this tumor promoter effect, as the inhibitor of both enzymes (indomethacin) did not alter melanoma growth. Leukotriene B4 (LTB4), the main product of the 5-LOX pathway, was able to induce growth of subtumorigenic inocula of melanoma cells, and a LTB4 receptor antagonist inhibited acute inflammation-associated tumor growth. Addition to the tumor inflammatory microenvironment of eicosapentaenoic acid, an ω3-polyunsaturated fatty acid with anti-inflammatory properties, or leukotriene B5, an eicosapentaenoic acid–derived leukotriene, significantly inhibited tumor development. These results give new insights to the mechanisms through which inflammation may contribute to tumor progression and suggest that LOX has an important role in tumor progression associated with an inflammatory state in the presence of apoptosis, which may be a consideration for apoptosis-inducing treatments, such as chemotherapy and radiotherapy. (Mol Cancer Res 2009;7(9):1417–24)
Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells
Authors: Huang Baoying , Deo Dayanand , Xia Mingxuan , Vassilev Lyubomir T.
Published: September 2009

Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies. (Mol Cancer Res 2009;7(9):1497–509)
Medical Comorbidity Affects Antidepressant Treatment Response in Patients with Melancholic Depression
Authors: Pohle K. , Domschke K. , Roehrs T. , Arolt V. , Baune B.T.
Published: September 2009

Background: This study aimed at the impact of medical comorbidity (MC) on response to antidepressant treatment over 6 weeks in diagnostic subtypes of patients with major depressive episode (MDE). Methods: In a clinical sample of 241 admitted patients with MDE, MC was assessed by medical specialists and weekly response to antidepressant treatment was assessed with the Hamilton Depression Scale (HAM-D 21). Results: Over 6 weeks of treatment, patients with melancholic depression and MC had poorer treatment response on the HAM-D scale and a worse functional outcome (GAF) as opposed to their counterparts without MC, which was first detected after 4 weeks of treatment (p = 0.02). More specifically, subjects with melancholic depression and cardiovascular or endocrinological MC showed significantly poorer treatment response over 6 weeks. Interestingly, these effects were not related to various antidepressant treatment regimens. Conclusions: MC has a negative impact on treatment response in patients with melancholic depression.
Is There a Decline in the Vascular Event Rate after Transient Ischemic Attack or Stroke in Antiplatelet Trials?
Authors: Lemmens Robin , Chen Feng , Ni Yicheng , Fieuws Steffen , Thijs Vincent
Published: September 2009

Background: We examined the baseline characteristics and the rates of serious vascular events in randomized clinical trials after cerebral ischemia of presumed arterial origin to identify study features that predict vascular event incidence and to identify whether event rates have declined over time. Methods: We performed a systematic review to identify all published randomized controlled trials of patients with stroke or transient ischemic attack of presumed arterial origin that included an aspirin arm. We performed metaregression to analyze whether baseline features of included patients, design features and the year of study start and publication influenced vascular event rates under aspirin treatment. Results: Included studies comprised 23,247 patients who had 3,615 serious vascular events. Baseline characteristics of patients included in the different trials varied substantially over time. In multivariate metaregression analysis a shorter maximum allowed delay from symptom onset to randomization (p = 0.012) and a double-blind design were associated with higher annual event rates (p = 0.014). Event rates did not significantly decrease over time (p = 0.242). Conclusion: The baseline characteristics of patients included in trials that study antiplatelet agents have changed over time. The strongest predictors for higher event rates are a double-blind design and a short delay between symptom onset and randomization. An important reduction in event rates over time could not be demonstrated.
Evolution of Stroke Diagnosis in the Emergency Room – A Prospective Observational Study
Authors: Rizos T. , Ringleb P.A. , Huttner H.B. , Köhrmann M. , Jüttler E.
Published: September 2009

Background: Access to acute neurological care is limited. Especially in nonurban areas, and owing to uncertainties in diagnosing stroke, non-neurologists often misinterpret stroke symptoms. We evaluated the profile of patients with suspected stroke and the accuracy of the admission diagnosis ‘stroke’ in the setting of a specialized neurological emergency department in a nonurban region. Methods: In this prospective observational study, (1) data from all 4,174 patients with the discharge diagnosis ‘stroke’ and (2) data from 1,800 consecutive patients (3 cohorts per year over 3 years) with the admission diagnosis ‘stroke’ were included over a 3-year period. Results: The positive predictive value of the admission diagnosis ‘stroke’ was 0.34; the negative predictive value was 0.97. The rate of misdiagnosis significantly correlated with age and time from symptom onset to presentation. During the study period, the proportion of patients with the admission diagnosis ‘stroke’ admitted early after symptom onset increased from 19.9 to 27.8% within 3 h and from 26.4 to 32.7% within 4.5 h, respectively. Thrombolysis rates increased (from 9.4 to 15.4%). Conclusion: The uncertainties in interpreting stroke symptoms and the lack of facilities for treating emergency stroke in nonurban areas may be outweighed by offering access to a specialized neurological emergency room, thus rectifying any misinterpretation of stroke symptoms and shortening in-hospital time windows for treatment. Still, the rate of misdiagnosis is high, requiring expensive resources, despite the constant flow of information to the public. Therefore, more prospective data comparing different emergency room settings are needed which focus in particular on patients with the admission diagnosis ‘stroke’.
Recurrent Cancer of the Parotid Gland: How Well Does Salvage Surgery Work for Locoregional Failure?
Authors: Kobayashi Kenya , Nakao Kazunari , Yoshida Masafumi , Ando Mizuo , Ebihara Yasuhiro , Asakage Takahiro , Yamasoba Tatsuya
Published: September 2009

Purpose: Many articles have discussed the clinical features of previously untreated parotid cancer, but the clinical characteristics and treatment of recurrent parotid cancer have not yet been fully described. Materials: We retrospectively reviewed 20 patients with recurrent parotid cancer and analyzed the therapeutic strategies and the prognostic factors. Results: Twelve patients (60%) underwent definitive surgery, including 3 who underwent skull base surgery. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) in the surgery group were 66.7 and 64.1%. In the definitive surgery group, the presence of lymph node metastasis and high-grade malignant histopathology were associated with a poor prognosis (p < 0.01). On the other hand, the presence of facial palsy at presentation, the surgical margin, the time of relapse and the T stage did not affect the DFS in our series. Conclusions: The results suggest that aggressive definitive surgery may be justified for the treatment of recurrent parotid cancer. The presence of lymph node metastasis and the histopathological malignancy grade are poor prognostic factors for OS and DFS.
Retrospective Evaluation of CO2 Laser Conization in Pregnant Women with Carcinoma in situ or Microinvasive Carcinoma
Authors: Tsuritani Mitsuhiro , Watanabe Yoh , Kotani Yasushi , Kataoka Taeko , Ueda Haruhiko , Hoshiai Hiroshi
Published: September 2009

Background: We evaluated the safety and efficacy of CO2 laser conization in pregnant women with cervical intraepithelial neoplasia 3/carcinoma in situ (CIN3/CIS) or microinvasive carcinoma (MIC). Objectives: A total of 49 pregnant women with biopsy-proven CIN3/CIS (30 patients) or MIC (19 patients) were studied.Methods: Retrospective analysis based on clinical records. Results: Median age and median week of gestation were 31 years (range: 22–39) and 17 weeks (range: 7–33), respectively. The median length of cervix resected by conization, median duration of surgery and median blood loss were 14 mm (range: 5–23), 20 min (range: 7–35) and 78 ml (range: 10–797), respectively. One biopsy-proven CIN3/CIS patient was diagnosed with Federation of Gynecology and Obstetrics (FIGO) Ia2 and 3 biopsy-proven MIC patients were diagnosed with FIGO Ib1 based on conization specimens. A total of 35 patients could be followed until delivery, of which 27 (77.1%) patients delivered transvaginally. Although 8 patients (22.9%) had a cesarean section and 6 patients (17.1%) delivered preterm, no conization-related obstetric complications were observed. Conclusion: Since it results in few obstetric complications, CO2 laser conization within 20 mm of length can be considered a safe procedure for pregnant women.
Predictors of Hyperkalemia Risk following Hypertension Control with Aldosterone Blockade
Authors: Khosla Nitin , Kalaitzidis Rigas , Bakris George L.
Published: September 2009

Background: Aldosterone antagonists have proven efficacy for management of resistant hypertension and proteinuria reduction; however, they are not widely used due to risk of hyperkalemia. This study assesses the risk factors for hyperkalemia in patients with chronic kidney disease (CKD) and resistant hypertension whose blood pressure (BP) is reduced to a guideline goal. Methods: This is a two-center study conducted in university-based hypertension clinics directed by clinical hypertension specialists. Forty-six patients with resistant hypertension and stages 2 or 3 CKD (mean estimated glomerular filtration rate (eGFR) 56.5 ± 16.2 ml/min/1.73 m2) were evaluated for safety and efficacy of aldosterone blockade added to preexisting BP-lowering regimens. All patients were on three mechanistically complementary antihypertensive agents including a diuretic and a renin-angiotensin system blocker. Patients were evaluated after a median of 45 treatment days. The primary endpoint was change in systolic BP. Secondary endpoints included change in serum potassium, creatinine, eGFR, diastolic BP and tolerability. Results: The mean age of the patients studied was 64.9 ± 10.7 years, all were obese and 86% had type 2 diabetes, with 82% being African-American. Addition of aldosterone antagonism yielded a further mean reduction in systolic BP of 14.7 ± 5.1 mm Hg (p = 0.001). Females with BMI >30 and those with a baseline systolic BP >160 mm Hg were more likely to have a greater BP reduction to aldosterone antagonism. In total, 39% of the patients had a >30% decrease in eGFR when the BP goal was achieved. The mean increase in serum potassium was 0.4 mEq/l above baseline (p = 0.001), with 17.3% manifesting hyperkalemia, i.e. serum potassium >5.5 mEq/l. Predictors of hyperkalemia included a baseline eGFR of ≤45 ml/min/1.73 m2 in whom serum potassium was >4.5 mEq/l on appropriately dosed diuretics. Contributing risks in this subgroup included a systolic BP reduction of >15 mm Hg associated with an eGFR fall of >30%. Conclusion: Aldosterone antagonism is effective and safe for achieving a BP goal among people with diabetic nephropathy when added to a triple antihypertensive regimen that includes a blocker of the renin-angiotensin system and an appropriately selected and dosed diuretic. Caution is advised when using aldosterone blockade for BP control in people with advanced stage 3 nephropathy with a serum potassium of >4.5 mEq/l for safety reasons.