bluuebunny/crossref_metadata_2025_split huggingface dataset:
p66 Shc Tumor Levels Show a Strong Prognostic Correlation with Disease Outcome in Stage IIA Colon Cancer
Authors: Grossman Steven R. , Lyle Stephen , Resnick Murray B. , Sabo Edmond , Lis Rosina T. , Rosinha Elizabeth , Liu Qin , Hsieh Chung-Cheng , Bhat Gajanan , Frackelton A. Raymond , Hafer Laurie J. 
Published: October 2007

Abstract
Purpose: Most stage IIA colon cancer patients receive no adjuvant therapy despite an estimated 15% risk of disease-related death within 5 years of resection. Prognostication of disease outcome would benefit the clinician by categorizing patients with stage IIA disease by risk. The abundance of the signal transduction proteins p66 Shc and tyrosine-phosphorylated (PY)-Shc in tumor cells is a prognostic indicator of disease outcome in breast cancer, suggesting that Shc analysis may provide prognostic information in stage IIA colon cancer.
Experimental Design: Immunohistochemical staining of p66 Shc and PY-Shc was examined in resection specimens from 240 chemotherapy-naïve patients with stage IIA (T3N0M0) colon cancer from two independent (130 and 110 cases, respectively) retrospective cohorts. Staining was scored on a 0 to 5 scale and correlated with relapse-free survival and disease-specific survival in a multivariate analysis to obtain hazard ratios (HR) for both outcomes.
Results: In a pooled analysis of both cohorts, p66 Shc score was a significant prognostic indicator of relapse-free survival (full-range HR, 13.0; P = 0.012) and disease-specific survival (full-range HR, 36.6; P = 0.004) when analyzed as a continuous variable in a multivariate Cox proportional hazards model stratified by study site and adjusted for age, sex, grade, and lymphovascular involvement. PY-Shc in this multivariate Cox model, however, did not achieve statistical significance for either outcome.
Conclusions: Measuring p66 Shc tumor levels provides a unique and simple tool for stratifying stage IIA colon cancer patients by risk of recurrence and disease-specific death and may assist in determining treatment strategies for these patients.
Genetic Variants in Cell Cycle Control Pathway Confer Susceptibility to Lung Cancer
Authors: Wang Wei , Spitz Margaret R. , Yang Hushan , Lu Charles , Stewart David J. , Wu Xifeng 
Published: October 2007

Abstract
Purpose: To test the hypothesis that common sequence variants of cell cycle control genes may affect lung cancer predisposition.
Experimental Design: We explored lung cancer risk associations of 11 polymorphisms in seven cell cycle genes in a large case-control study including 1,518 Caucasian lung cancer patients and 1,518 controls.
Results: When individuals with variant-containing genotypes were compared with homozygous wild-type carriers, a significantly increased lung cancer risk was identified for polymorphisms in p53 intron 6 [rs1625895; odds ratio (OR), 1.29; 95% confidence interval (95% CI), 1.08-1.55] and in p27 5′ untranslated region (UTR; rs34330; OR, 1.27; 95% CI, 1.01-1.60). Compared with homozygous wild-types, the homozygous variant genotypes of STK15 F31I and CCND1 G870A were associated with a significantly altered lung cancer risk with ORs of 0.58 (95% CI, 0.37-0.90) and 1.26 (95% CI, 1.03-1.53), respectively. To assess the cumulative effects of all the investigated polymorphisms on lung carcinogenesis, we conducted a combined analysis and found that compared with low-risk individuals with few adverse alleles, individuals with more adverse alleles had an increased risk in a significant dose-dependent manner (Ptrend = 0.041). This pattern was more evident in ever smokers (Ptrend = 0.037), heavy smokers (Ptrend = 0.020), and older subjects (Ptrend = 0.011). Higher-order gene-gene interactions were evaluated using the classification and regression tree analysis, which indicated that STK15 F31I and p53 intron 6 polymorphisms might be associated with lung carcinogenesis in never/light-smokers and heavy smokers, respectively.
Conclusions: Our results suggest that cell cycle gene polymorphisms and smoking may function collectively to modulate the risk of lung cancer.
Adjuvant Adenovirus-Mediated Delivery of Herpes Simplex Virus Thymidine Kinase Administration Improves Outcome of Liver Transplantation in Patients with Advanced Hepatocellular Carcinoma
Authors: Li Ning , Zhou Jianfeng , Weng Danhui , Zhang Chenghua , Li Lixin , Wang Beibei , Song Yang , He Qiang , Lin Dongdong , Chen Dazhi , Chen Gang , Gao Qinglei , Wang Shixuan , Xu Gang , Meng Li , Lu YunPing , Ma Ding 
Published: October 2007

Abstract
Purpose: Previous poor results of liver transplantation (LT) have been confirmed in patients with advanced hepatocellular carcinoma (HCC). Adenovirus-mediated delivery of herpes simplex virus thymidine kinase (ADV-TK) therapy is an established adjuvant treatment in cancer, and we evaluated its potential as an adjuvant treatment for HCC patients who underwent LT.
Experimental Design: Forty-five HCC patients with tumors &gt;5 cm in diameter participated in the study over a follow-up period of 50 months. Among these patients, 22 received LT only, and 23 received LT combined with ADV-TK therapy. All HCC patients enrolled in this study had tumors &gt;5 cm in diameter and no metastasis in lungs or bones was detected by computed tomography or magnetic resonance imaging scans.
Results: The recurrence-free survival and the overall survival in the LT plus ADV-TK therapy group were 43.5% and 69.6%, respectively, at 3 years; both values were significantly higher than those in the LT-only group (9.1% and 19.9%, respectively). In the nonvascular invasion subgroup, overall survival was 100% and recurrence-free survival was 83.3% in the patients receiving LT plus ADV-TK, significantly higher than the patients receiving LT only.
Conclusions: HCC patients with no vascular invasion could be selected for LT followed by adjuvant ADV-TK therapy, regardless of intrahepatic huge or diffuse tumor. We propose that the current criteria for LT based on tumor size may be expanded if accompanied by ADV-TK therapy due to improved prognosis.
The Therapeutic Efficacy of Anti–Vascular Endothelial Growth Factor Antibody, Bevacizumab, and Pemetrexed against Orthotopically Implanted Human Pleural Mesothelioma Cells in Severe Combined Immunodeficient Mice
Authors: Li Qi , Yano Seiji , Ogino Hirokazu , Wang Wei , Uehara Hisanori , Nishioka Yasuhiko , Sone Saburo 
Published: October 2007

Abstract
Purpose: Malignant pleural mesothelioma (MPM) is an aggressive malignancy, which has a poor prognosis with a median survival of less than 1 year. The vascular endothelial growth factor (VEGF) has been reported to be an ideal therapeutic target, and a multitargeted antifolate, pemetrexed, has been clinically used for the treatment of MPM.
Experimental Design: We examined the therapeutic efficacy of the antihuman VEGF neutralizing antibody, bevacizumab, in combination with pemetrexed against two different human MPM cells, EHMES-10 and MSTO-211H, orthotopically inoculated into severe combined immunodeficient mice.
Results: Bevacizumab inhibited a VEGF-induced proliferation of the human endothelial cells in a dose-dependent manner, but it had no effect on the proliferation of the two MPM cell lines in vitro. The orthotopically inoculated EHMES-10 cells (VEGF high expressing) produced thoracic tumors and a large volume of bloody pleural effusion, whereas the MSTO-211H cells (VEGF low expressing) produced thoracic tumors and a small volume of bloody effusions. Treatment with bevacizumab effectively inhibited the production of thoracic tumors and dramatically prevented the production of pleural effusion by the EHMES-10 cells but not the MSTO-211H cells. Treatment with bevacizumab reduced the number of enlarged tumor-associated vessels and proliferating tumor cells. Moreover, treatment with bevacizumab in combination with pemetrexed more effectively suppressed the formation of the pleural effusion and prolonged the survival compared with the control and monotherapy in the EHMES-10 cell–bearing severe combined immunodeficient mice.
Conclusions: These results suggest that the combined use of bevacizumab and pemetrexed may therefore be promising for controlling the progression of MPM highly expressing VEGF.
Comparative Analysis of Peritoneum and Tumor Eicosanoids and Pathways in Advanced Ovarian Cancer
Authors: Freedman Ralph S. , Wang Ena , Voiculescu Sonia , Patenia Rebecca , Bassett Roland L. , Deavers Michael , Marincola Francesco M. , Yang Peiying , Newman Robert A. 
Published: October 2007

AbstractPurpose: To describe the eicosanoid profile and differentially expressed eicosanoid and arachidonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC).Experimental Design: We first employed electrospray tandem mass spectrometry to determine tissue-specific concentrations of the eicosanoids prostaglandin E2 (PGE2), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB4), selected for tumor growth potential, and two other bioactive lipids (15-HETE and 13-HODE) with tumor cell proliferation interference potential. The cellular location of eicosanoid activity was identified by immunofluorescence antibody costaining and confocal microscopy. Differential analysis of eicosanoid and arachidonic pathway genes was done using a previously validated cDNA microarray platform. Tissues used included EOC tumor, tumor-free malignant peritoneum (MP), and benign peritoneum (BP) from patients with benign pelvic disease.Results: (a) Eicosanoid products were detected in tumor, MP, and BP specimens. PGE2 levels were significantly elevated in tumors in an overall comparison with MP or BP (P &lt; 0.001). Combined levels of PGE2, 12-HETE, 5-HETE, and LTB4 increased progressively from low to high concentrations in BP, MP, and tumors (P = 0.012). Neither 15-HETE nor 13-HODE showed a significant opposite trend toward levels found in BP. (b) Tissue specimens representing common EOC histotypes showed strong coexpressions of cyclooxygenases (COX-1) and prostaglandin E synthases (PGES-1) on tumor cells, whereas intratumoral or peritumoral MO/MA coexpressed COX-1 and COX-2 and PGES-1 and PGES-2, respectively. (c) cDNA microarray analysis of MP, BP, and tumor showed that a number of eicosanoid and arachidonic acid pathway genes were differentially expressed in MP and BP compared with tumor, except for CYP2J2, which was increased in tumors.Conclusions: Elevated levels of eicosanoid metabolites in tumors and differential expression of eicosanoid and arachidonic acid pathway genes in the peritoneum support the involvement of bioactive lipids in the inflammatory tumor environment of EOC.
Identification of Toll-Like Receptor 3 as a Potential Therapeutic Target in Clear Cell Renal Cell Carcinoma
Authors: Morikawa Teppei , Sugiyama Akira , Kume Haruki , Ota Satoshi , Kashima Takeshi , Tomita Kyoichi , Kitamura Tadaichi , Kodama Tatsuhiko , Fukayama Masashi , Aburatani Hiroyuki 
Published: October 2007

Abstract
Purpose: Renal cell carcinoma (RCC) is one of the most drug-refractory cancers. The aim of this study is to discover a novel therapeutic target molecule for clear cell RCC (CCRCC), which accounts for the majority of RCC.
Experimental Design: Gene expression profiles of 27 CCRCCs and 9 normal kidney tissues as well as 15 various adult normal tissues were examined by Affymetrix U133 Plus 2.0 arrays. Among the 34 genes specifically up-regulated in CCRCC, overexpression of Toll-like receptor 3 (TLR3) mRNA and its protein was validated by quantitative reverse transcription-PCR, immunoblot, and immunohistochemistry. The effects of TLR3 signaling on in vitro cell growth were examined.
Results: TLR3 gene was highly expressed in CCRCC, with only limited expression in a panel of normal tissues. On immunohistochemical analysis using a monoclonal antibody against TLR3, overexpression of TLR3 was observed in 139 of 189 (73.5%) cases of CCRCC as well as in lung metastatic CCRCC (6 of 8), whereas TLR3 expression was entirely absent in chromophobe RCC (0 of 8). Polyinosinic-polycytidilic acid, a TLR3 ligand, exerted a growth-inhibitory effect against RCC cells in a TLR3-dependent manner. Moreover, a combination of polyinosinic-polycytidilic acid and IFNα exerted a synergistic growth-inhibitory effect against Caki-1 RCC cells.
Conclusions: This is the first report that TLR3 is overexpressed in CCRCC. These observations suggest that TLR3 pathway may represent a novel therapeutic target in CCRCC.
Inflammatory Breast Cancer as a Model Disease to Study Tumor Angiogenesis: Results of a Phase IB Trial of Combination SU5416 and Doxorubicin
Authors: Overmoyer Beth , Fu Pingfu , Hoppel Charles , Radivoyevitch Tomas , Shenk Robert , Persons Marjie , Silverman Paula , Robertson Kelly , Ziats Nicholas P. , Wasman Jay K. , Abdul-Karim Fadi W. , Jesberger John A. , Duerk Jeffrey , Hartman Paul , Hanks Shelli , Lewin Jonathan , Dowlati Afshin , McCrae Keith , Ivy Percy , Remick Scot C. 
Published: October 2007

Abstract
Purpose: We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin.
Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy.
Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival.
Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.
Neutralizing B-Cell–Activating Factor Antibody Improves Survival and Inhibits Osteoclastogenesis in a Severe Combined Immunodeficient Human Multiple Myeloma Model
Authors: Neri Paola , Kumar Shaji , Fulciniti Maria Teresa , Vallet Sonia , Chhetri Shweta , Mukherjee Sidhartha , Tai YuTzu , Chauhan Dharminder , Tassone Pierfrancesco , Venuta Salvatore , Munshi Nikhil C. , Hideshima Teru , Anderson Kenneth C. , Raje Noopur 
Published: October 2007

AbstractPurpose: B-cell–activating factor (BAFF) is a tumor necrosis factor superfamily member critical for the maintenance and homeostasis of normal B-cell development. It has been implicated in conferring a survival advantage to B-cell malignancies, including multiple myeloma (MM).Experimental Design: Here, we validate the role of BAFF in the in vivo pathogenesis of MM examining BAFF and its receptors in the context of patient MM cells and show activity of anti-BAFF antibody in a severe combined immunodeficient model of human MM.Results: Gene microarrays and flow cytometry studies showed increased transcripts and the presence of all three receptors for BAFF in CD138+ patient MM cells, as well as an increase in plasma BAFF levels in 51 MM patients. Functional studies show that recombinant BAFF protects MM cells against dexamethasone-induced apoptosis accompanied by an increase in survival proteins belonging to the BCL family. These in vitro studies led to the evaluation of a clinical grade–neutralizing antibody to BAFF in a severe combined immunodeficient human MM model. Anti-BAFF–treated animals showed decreased soluble human interleukin 6 receptor levels, a surrogate marker of viable tumor, suggesting direct anti-MM activity. This translated into a survival advantage of 16 days (P &lt; 0.05), a decrease in tartrate-resistant acid phosphatase–positive osteoclasts, and a reduction in radiologically evident lytic lesions in anti-BAFF–treated animals.Conclusions: Our data show a role for BAFF as a survival factor in MM. Importantly, the in vivo antitumor activity of neutralizing anti-BAFF antibody provide the preclinical rationale for its evaluation in the treatment of MM.
Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors
Authors: Ali Yaqoob , Lin Yong , Gharibo Mecide M. , Gounder Murugesan K. , Stein Mark N. , Lagattuta Theodore F. , Egorin Merrill J. , Rubin Eric H. , Poplin Elizabeth A. 
Published: October 2007

Abstract
Purpose: Preclinical data shows improvements in response for the combination of imatinib mesylate (IM, Gleevec) and gemcitabine (GEM) therapy compared with GEM alone. Our goals were to determine the maximum tolerated dose of GEM and IM in combination, the pharmacokinetics of GEM in the absence and in the presence of IM, and IM pharmacokinetics in this combination.
Patients and Methods: Patients with refractory malignancy, intact intestinal absorption, measurable/evaluable disease, adequate organ function, Eastern Cooperative Oncology Group PS 0-2, and signed informed consent were eligible. Initially, treatment consisted of 600 mg/m2 of GEM (10 mg/m2/min) on days 1, 8, and 15, and 300 mg of IM daily every 28 days. Due to excessive toxicity, the schedule was altered to IM on days 1 to 5 and 8 to 12, and GEM on days 3 and 10 every 21 days. Two final cohorts received IM on days 1 to 5, 8 to 12, and 15 to 19.
Results: Fifty-four patients were treated. IM and GEM given daily at 500 to 600 mg/m2 on days 1, 8, and 15 produced frequent dose-limiting toxicities. With the modified scheduling, GEM given at 1,500 mg/m2/150 min was deliverable, along with 400 mg of IM, without dose-limiting toxicities. Three partial (laryngeal, renal, and mesothelioma) and two minor (renal and pancreatic) responses were noted at GEM doses of 450 to 1,500 mg/m2. Stable disease &gt;24 weeks was seen in 17 patients. CA19-9 in 7 of 10 patients with pancreatic cancer was reduced by ∼90%. IM did not significantly alter GEM pharmacokinetics.
Conclusion: The addition of intermittently dosed IM to GEM at low to full dose was associated with broad antitumor activity and little increase in toxicity.
Molecular Alterations in Prostate Carcinomas that Associate with In vivo Exposure to Chemotherapy: Identification of a Cytoprotective Mechanism Involving Growth Differentiation Factor 15
Authors: Huang Chung-Ying , Beer Tomasz M. , Higano Celestia S. , True Lawrence D. , Vessella Robert , Lange Paul H. , Garzotto Mark , Nelson Peter S. 
Published: October 2007

Abstract
Purpose: To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance.
Experimental Design: Patients with high-risk localized prostate cancer (tumor-node-metastasis ≥ T2b or prostate-specific antigen ≥ 15 ng/mL or Gleason glade ≥ 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done.
Results: Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1β. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone.
Conclusions: Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-κB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.
Phase I Dose Escalation Study of the Anti–Insulin-Like Growth Factor-I Receptor Monoclonal Antibody CP-751,871 in Patients with Refractory Solid Tumors
Authors: Haluska Paul , Shaw Heather M. , Batzel Gretchen N. , Yin Donghua , Molina Julian R. , Molife L. Rhoda , Yap Timothy A. , Roberts M. Luisa , Sharma Amarnath , Gualberto Antonio , Adjei Alex A. , de Bono Johann S. 
Published: October 2007

Abstract
Purpose: This phase I study was undertaken to define the maximum tolerated dose, safety, and pharmacokinetic profile of CP-751,871.
Experimental Design: Using a rapid dose escalation design, patients with advanced nonhematologic malignancies were treated with CP-751,871 in four dose escalation cohorts. CP-751,871 was administered i.v. on day 1 of each 21-day cycle. Pharmacokinetic evaluation was done in all treatment cohorts during cycles 1 and 4.
Results: Twenty-four patients received 110 cycles at four dose levels. The maximum tolerated dose exceeded the maximal feasible dose of 20 mg/kg and, thus, was not identified. Treatment-related toxicities were generally mild. The most common adverse events were hyperglycemia, anorexia, nausea, elevated aspartate aminotransferase, elevated γ-glutamyltransferase, diarrhea, hyperuracemia, and fatigue. At 20 mg/kg, 10 of 15 patients experienced stability of disease. Two of these patients experienced long-term stability. There were no objective responses. Pharmacokinetic analysis revealed a dose-dependent increase in CP-751,871 exposure and ∼2-fold accumulation on repeated dosing in 21-day cycles. Plasma concentrations of CP-751,871 attained were several log-fold greater than the biologically active concentration. Treatment with CP-751,871 increased serum insulin and human growth hormone levels, with modest increases in serum glucose levels.
Conclusions: CP-751,871 has a favorable safety profile and was well tolerated when given in continuous cycles. At the maximal feasible dose of 20 mg/kg, there was a moderate accumulation in plasma exposure, and most of the treated patients experienced stability of disease.