bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matriptase-2 Inhibits Breast Tumor Growth and Invasion and Correlates with Favorable Prognosis for Breast Cancer Patients
Authors: Parr Christian , Sanders Andrew J. , Davies Gaynor , Martin Tracey , Lane Jane , Mason Malcolm D. , Mansel Robert E. , Jiang Wen G. 
Published: June 2007

Abstract
Purpose: The type II transmembrane serine proteases are cell surface proteolytic enzymes that mediate a diverse range of cellular functions, including tumor invasion and metastasis. Matriptase (matriptase-1) and matriptase-2 belong to the type II transmembrane serine protease family. Matriptase-1 is known to play a role in breast cancer progression, and elevated levels of matriptase-1 correlate with poor patient outcome. The role of matriptase-2 and its cellular function in cancer is unknown. This study aimed to provide new insights into the significance of matriptase-2 in cancer.
Experimental Design: Matriptase-2 expression levels were assessed in a cohort of human breast cancer specimens (normal, n = 34; cancer, n = 95), in association with patient clinical variables, using both quantitative and qualitative analysis of the matriptase-2 transcript along with immunohistochemical techniques. Matriptase-2 was also experimentally overexpressed in the MDA-MB-231 human breast cancer cell line. The effects of matriptase-2 overexpression were examined through a series of in vitro and in vivo studies.
Results: Here, we show that reduced matriptase-2 levels in breast cancer tissues correlate with an overall poor prognosis for the breast cancer patient. This study also reveals that matriptase-2 overexpression in breast cancer cells significantly suppressed tumorigenesis in CD1 athymic mice (P = 0.000003). Furthermore, we report that matriptase-2 overexpression dramatically reduced the invasive (P = 0.0001) and migratory properties (P = 0.01) of the breast cancer cells.
Conclusions: Matriptase-2 suppresses breast tumor development in vivo, displays prognostic value for breast cancer patients, inhibits both breast cancer cell invasion and motility in vitro, and may play a contrasting role to matriptase-1 in breast cancer.
A Randomized, Double-Blind, Phase II Study of Two Doses of Pemetrexed as First-Line Chemotherapy for Advanced Breast Cancer
Authors: Llombart-Cussac Antonio , Martin Miguel , Harbeck Nadia , Anghel Rodica M. , Eniu Alexandra E. , Verrill Mark W. , Neven Patrick , De Grève Jacques , Melemed Allen S. , Clark Romnee , Simms Lorinda , Kaiser Christopher J. , Ma Doreen 
Published: June 2007

Abstract
Purpose: Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity.
Experimental Design: Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m2 (P600 arm) or 900 mg/m2 (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B12 supplementation.
Results: The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with ∼50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia &lt;20%, leukopenia &lt;9%, and other toxicities &lt;5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. γ-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low γ-glutamyl hydrolase (P = 0.024).
Conclusion: The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.
Dose-Escalating and Pharmacologic Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer Institute Organ Dysfunction Working Group Study
Authors: Synold Timothy W. , Takimoto Chris H. , Doroshow James H. , Gandara David , Mani Sridhar , Remick Scot C. , Mulkerin Daniel L. , Hamilton Anne , Sharma Sunil , Ramanathan Ramesh K. , Lenz Heinz Josef , Graham Martin , Longmate Jeffrey , Kaufman Bennett M. , Ivy Percy 
Published: June 2007

AbstractPurpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.Experimental Design: Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m2 every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP ≤ upper limit of normal (ULN)], mild dysfunction group B (bilirubin ≤ ULN, ULN &lt; AST ≤ 2.5 × ULN, or ULN &lt; AP ≤ 5 × ULN), moderate dysfunction group C (ULN &lt; bilirubin ≤ 3.0 mg/dL, AST &gt; 2.5 × ULN, or AP &gt; 5 × ULN), severe dysfunction group D (bilirubin &gt; 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.Results: Dose escalation of single-agent oxaliplatin to 130 mg/m2 was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months.Conclusions: Oxaliplatin at 130 mg/m2 every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.
Neutrophils Promote Aerogenous Spread of Lung Adenocarcinoma with Bronchioloalveolar Carcinoma Features
Authors: Wislez Marie , Antoine Martine , Rabbe Nathalie , Gounant Valérie , Poulot Virginie , Lavolé Armelle , Fleury-Feith Jocelyne , Cadranel Jacques 
Published: June 2007

Abstract
Purpose: Adenocarcinoma with bronchioloalveolar carcinoma (BAC) features is a subtype of non–small cell lung cancers characterized by an intense inflammatory reaction composed of macrophages and neutrophils and by a distinct natural history with intrapulmonary spread leading to death due to respiratory failure. We hypothesized that neutrophils could promote aerogenous spread of lung adenocarcinoma with BAC features.
Experimental Design: We examined the effect of neutrophils on A549 cell line detachment in vitro and we quantified desquamation of tumor cells on tumor tissue (n = 25) and on matched bronchioloalveolar lavage (n = 17) in vivo in a series of patients with adenocarcinoma with BAC features.
Results: Neutrophils induced A549 detachment mediated by signals through cell-to-cell contact. Detached A549 cells were still viable and able to proliferate in vitro. Neutralization studies identified several membrane-bound molecules involved in detachment (i.e., intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, tumor necrosis factor α/tumor necrosis factor α receptor inhibitor, interleukin-1α /interleukin-1α receptor, and neutrophil elastase). In tumor tissue, shedding was detected in all samples, with a median shedding score of 42% (range, 4-95%). Micropapillary clusters were detected in 23 of the 25 tumor tissue samples, with a median micropapillary score of 1.40 (range, 0-2.1), and tumor cells were detected in 7 of 17 lavages. The micropapillary score was associated with a high neutrophil count in bronchioloalveolar lavage (P = 0.051). The shedding cell percentage was a significant factor in shorter survival (P = 0.034, univariate Cox analysis).
Conclusions: Tumor shedding is induced by neutrophils. It is a significant factor of shorter survival and may be an important event in adenocarcinoma progression.
Inhibition of the T790M Gatekeeper Mutant of the Epidermal Growth Factor Receptor by EXEL-7647
Authors: Gendreau Steven B. , Ventura Richard , Keast Paul , Laird A. Douglas , Yakes F. Michael , Zhang Wentao , Bentzien Frauke , Cancilla Belinda , Lutman Jeffery , Chu Felix , Jackman Lisa , Shi Yongchang , Yu Peiwen , Wang Jing , Aftab Dana T. , Jaeger Christopher T. , Meyer Stephanie M. , De Costa Anushka , Engell Kelly , Chen Jason , Martini Jean-Francois , Joly Alison H. 
Published: June 2007

AbstractPurpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non–small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.Experimental Design: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.
Bcl-2 and Bax Expression Predict Prostate Cancer Outcome in Men Treated with Androgen Deprivation and Radiotherapy on Radiation Therapy Oncology Group Protocol 92-02
Authors: Khor Li Yan , Moughan Jennifer , Al-Saleem Tahseen , Hammond Elizabeth H. , Venkatesan Varagur , Rosenthal Seth A. , Ritter Mark A. , Sandler Howard M. , Hanks Gerald E. , Shipley William U. , Pollack Alan 
Published: June 2007

Abstract
Purpose: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another Radiation Therapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT).
Experimental Design: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure.
Results: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT.
Conclusions: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.
Early Response Assessment Using 3′-Deoxy-3′-[18F]Fluorothymidine-Positron Emission Tomography in High-Grade Non-Hodgkin's Lymphoma
Authors: Herrmann Ken , Wieder Hinrich A. , Buck Andreas K. , Schöffel Marion , Krause Bernd-Joachim , Fend Falko , Schuster Tibor , Meyer zum Büschenfelde Christian , Wester Hans-Jürgen , Duyster Justus , Peschel Christian , Schwaiger Markus , Dechow Tobias 
Published: June 2007

Abstract
Purpose: To evaluate 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography (FLT-PET) for early monitoring response of high-grade non-Hodgkin's lymphoma to treatment with cyclophosphamide-adriamycin-vincristine-prednisone chemotherapy with or without rituximab immunotherapy (R-CHOP/CHOP).
Experimental Design: Twenty-two patients with histologically proven high-grade non-Hodgkin's lymphoma scheduled to undergo first line treatment with R-CHOP/CHOP were included. All patients received baseline imaging before therapy with FLT-PET. For noninvasive assessment of treatment response, FLT-PET was repeated at following time points: group 1 (n = 6), 1 and 6 weeks after R-CHOP/CHOP; group 2 (n = 16), 2 days after rituximab and 2 days after CHOP application. Emission images were acquired 45 min after injection of 300 to 370 MBq of FLT. FLT uptake was quantified by region-of-interest technique on a lesion basis. Maximum standardized uptake values (SUV) for FLT were calculated using circular region of interest (diameter, 1.5 cm).
Results: In all patients, morphologically proven lesions showed initially high FLT uptake (mean SUV, 8.1 ± 3.9). In group 1, mean FLT SUV decreased 7 days after R-CHOP/CHOP by 77% (P &lt; 0.001), the reduction in FLT SUV from baseline was 85% after 40 days (P = 0.003). In group 2, FLT uptake in patients without dexamethasone pretreatment revealed no significant reduction after rituximab (P = 0.3) but significantly decreased 2 days after CHOP to 32% compared with the baseline value (P = 0.004).
Conclusions: Administration of R-CHOP/CHOP is associated with an early decrease in lymphoma FLT uptake. Interestingly, there was no reduction of FLT uptake after rituximab alone, indicating no early antiproliferative effect of immunotherapy. FLT-PET seems to be promising for early evaluation of drug effects in lymphoma.
αv Integrin-Targeted Immunoconjugates Regress Established Human Tumors in Xenograft Models
Authors: Chen Qiming , Millar Hillary J. , McCabe Francis L. , Manning Carol D. , Steeves Rita , Lai Kate , Kellogg Brenda , Lutz Robert J. , Trikha Mohit , Nakada Marian T. , Anderson G. Mark 
Published: June 2007

Abstract
Purpose: Targeted delivery of cytotoxic agents to solid tumors through cell surface antigens can potentially reduce systemic toxicity and increase the efficacy of the targeted compounds. The purpose of this study was to show the feasibility of treating solid tumors by targeting αv integrins with antibody-maytansinoid conjugates and to test the relative in vivo activities of several linker-maytansinoid chemistries.
Experimental Design: CNTO 364, CNTO 365, and CNTO 366 are targeted cytotoxic agents created by conjugating the CNTO 95 anti-αv integrin antibody with three distinct maytansinoid-linker structures. These structures were designed to have varying degrees of chemical substitution surrounding the disulfide bond linking the cytotoxic agent to the antibody. A model conjugate was shown to be specifically cytotoxic in vitro and highly active against established human tumor xenografts in immunocompromised rats. The in vivo antitumor activities of CNTO 364, CNTO 365, and CNTO 366 were compared in rat xenograft models.
Results: CNTO 365, with a linker chemistry of expected intermediate stability, was shown to be substantially more active than the other two conjugates with lesser or greater substitution around the disulfide linkage.
Conclusion: CNTO 95–maytansinoid immunoconjugates are potent antitumor agents against αv integrin–expressing human carcinomas. These studies show for the first time the feasibility of targeting αv integrins on solid tumors with tumor-activated prodrugs. The DM4 linker-maytansinoid configuration of CNTO 365 was substantially more active in the models tested here when compared with alternative configurations with greater or lesser chemical substitution surrounding the linker.
Ex vivoNicotine Stimulation Augments the Efficacy of Therapeutic Bone Marrow–Derived Dendritic Cell Vaccination
Authors: Gao Feng Guang , Wan Da Fang , Gu Jian Ren 
Published: June 2007

AbstractPurpose: To explore the preventive and therapeutic antitumor effects of nicotine-treated immature dendritic cells (imDC).Experimental Design: First, bone marrow–derived imDCs were stimulated with nicotine in vitro, and nicotinic acetylcholine receptor, costimulator molecules, chemokine receptor, and endocytosis ability of imDCs were detected by flow cytometry. Second, the DC-dependent antigen-specific T-cell proliferation, CTL priming, and interleukin-12 secretion were determined by flow cytometry, enzyme-linked immunospot assay, and ELISA, respectively. Finally, preventive and therapeutic antitumor effects of such imDCs were determined by i.p. transfer against tumor challenge or implantation in mice.Results: Nicotine could up-regulate expression of nicotinic acetylcholine receptor, costimulatory molecules, such as CD80, CD86, and CD40, adhesion molecule CD11b, and chemokine receptor CCR7 and enhance endocytosis ability of imDCs. In addition, nicotine could promote imDC-dependent CTL priming and interleukin-12 secretion in vitro. Most importantly, systemic transfer of ex vivo nicotine-stimulated imDCs could reveal preventive and therapeutic effect on tumor development.Conclusions: Ex vivo nicotine stimulation can significantly improve the efficacy of imDCs for adaptive therapy of cancer and nicotine-treated imDCs may be considered as a potential candidate for preventive and therapeutic tumor vaccination.
A Parallel Dose-Escalation Study of Weekly and Twice-Weekly Bortezomib in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced Solid Tumors
Authors: Voortman Jens , Smit Egbert F. , Honeywell Richard , Kuenen Bart C. , Peters Godefridus J. , van de Velde Helgi , Giaccone Giuseppe 
Published: June 2007

Abstract
Purpose: To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors.
Experimental Design: Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m2 days 1 and 8 and cisplatin 70 mg/m2 day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD.
Results: Thirty-four patients were enrolled of whom 27 had non–small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m2 in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m2 as well. Most common ≥grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade ≥3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule.
Conclusions: Weekly bortezomib 1.0 mg/m2 plus gemcitabine 1,000 mg/m2 and cisplatin 70 mg/m2 is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.
Tumor-Specific Positron Emission Tomography Imaging in Patients: [18F] Fluorodeoxyglucose and Beyond
Authors: Mankoff David A. , Eary Janet F. , Link Jeanne M. , Muzi Mark , Rajendran Joseph G. , Spence Alexander M. , Krohn Kenneth A. 
Published: June 2007

AbstractBiochemical and molecular imaging of cancer using positron emission tomography (PET) plays an increasing role in the care of cancer patients. Most clinical work to date uses the glucose analogue [18F]fluorodeoxyglucose (FDG) to detect accelerated and aberrant glycolysis present in most tumors. Although clinical FDG PET has been used largely to detect and localize cancer, more detailed studies have yielded biological insights and showed the utility of FDG as a prognostic marker and as a tool for therapeutic response evaluation. As cancer therapy becomes more targeted and individualized, it is likely that PET radiopharmaceuticals other than FDG, aimed at more specific aspects of cancer biology, will also play a role in guiding cancer therapy. Clinical trials designed to test and validate new PET agents will need to incorporate rigorous quantitative image analysis and adapt to the evolving use of imaging as a biomarker and will need to incorporate cancer outcomes, such as survival into study design.
Spatio-Temporal Control of Gene Expression and Cancer Treatment Using Magnetic Resonance Imaging–Guided Focused Ultrasound
Authors: Moonen Chrit T.W. 
Published: June 2007

Abstract
Local temperature elevation may be used for tumor ablation, gene expression, drug activation, and gene and/or drug delivery. High-intensity focused ultrasound (HIFU) is the only clinically viable technology that can be used to achieve a local temperature increase deep inside the human body in a noninvasive way. Magnetic resonance imaging (MRI) guidance of the procedure allows in situ target definition and identification of nearby healthy tissue to be spared. In addition, MRI can be used to provide continuous temperature mapping during HIFU for spatial and temporal control of the heating procedure and prediction of the final lesion based on the received thermal dose. The primary purpose of the development of MRI-guided HIFU was to achieve safe noninvasive tissue ablation. The technique has been tested extensively in preclinical studies and is now accepted in the clinic for ablation of uterine fibroids. MRI-guided HIFU for ablation shows conceptual similarities with radiation therapy. However, thermal damage generally shows threshold-like behavior, with necrosis above the critical thermal dose and full recovery below. MRI-guided HIFU is being clinically evaluated in the cancer field. The technology also shows great promise for a variety of advanced therapeutic methods, such as gene therapy. MR-guided HIFU, together with the use of a temperature-sensitive promoter, provides local, physical, and spatio-temporal control of transgene expression. Specially designed contrast agents, together with the combined use of MRI and ultrasound, may be used for local gene and drug delivery.