bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of Protracted Daily Temozolomide for Low-Grade Gliomas in Adults
Authors: Kesari Santosh , Schiff David , Drappatz Jan , LaFrankie Debra , Doherty Lisa , Macklin Eric A. , Muzikansky Alona , Santagata Sandro , Ligon Keith L. , Norden Andrew D. , Ciampa Abigail , Bradshaw Joanna , Levy Brenda , Radakovic Gospova , Ramakrishna Naren , Black Peter M. , Wen Patrick Y. 
Published: December 2008

AbstractPurpose: Resistance to temozolomide chemotherapy is partly mediated by O6-methylguanine-DNA methlytransferase (MGMT). Protracted treatment with temozolomide potentially overcomes MGMT resistance and improves outcome. We conducted a phase II study of protracted daily temozolomide in adults with low-grade gliomas.Experimental Design: Patients with newly diagnosed oligodendroglioma or oligoastrocytoma with a MIB-1 index of &gt;5% or recurrent low-grade gliomas received temozolomide (75 mg/m2/day in 11-week cycles of 7 weeks on/4 weeks off). Treatment continued for a total of six cycles or until tumor progression or unacceptable toxicity. Primary end point was best overall response rate; secondary end points were progression-free survival, overall survival, and toxicity. We correlated response with MGMT promoter methylation and chromosome 1p/19q deletion status.Results: Forty-four patients were treated (14 female, 30 male) with a median follow-up of 39.4 months. Median age was 43 years (range, 20-68 years) and median Karnofsky performance status was 90 (range, 70-100). The regimen was well tolerated. No patients had a complete response (0%), 9 had partial response (20%), 33 had stable disease (75%), and 2 had progressive disease (5%). A total of 21 patients eventually progressed with an overall median progression-free survival of 38 months. Patients with methylated MGMT promoter had a longer overall survival (P = 0.008). Deletion of either 1p or 19q chromosomes also predicted longer overall survival (hazard ratio, 0.17; 95% confidence interval, 0.03-0.93; log-rank P = 0.02).Conclusions: A protracted course of daily temozolomide is a well-tolerated regimen and seems to produce effective tumor control. This compares favorably with historical data on the standard 5-day temozolomide regimen.
Advancing Bioluminescence Imaging Technology for the Evaluation of Anticancer Agents in the MDA-MB-435-HAL-Luc Mammary Fat Pad and Subrenal Capsule Tumor Models
Authors: Zhang Cathy , Yan Zhengming , Arango Maria E. , Painter Cory L. , Anderes Kenna 
Published: December 2008

AbstractPurpose: Tumors grafted s.c. or under the mammary fat pad (MFP) rarely develop efficient metastasis. By applying bioluminescence imaging (BLI) technology, the MDA-MB-435-HAL-Luc subrenal capsule (SRC) model was compared with the MFP model for disease progression, metastatic potential, and response to therapy.Experimental Design: The luciferase-expressing MDA-MB-435-HAL-Luc cell line was used in both MFP and SRC models. BLI technology allowed longitudinal assessment of disease progression and the therapeutic response to PD-0332991, Avastin, and docetaxel. Immunohistochemical analysis of Ki67 and CD31 staining in the primary tumors was compared in these models. Caliper measurement was used in the MFP model to validate the BLI quantification of primary tumors.Results: The primary tumors in MDA-MB-435-HAL-Luc MFP and SRC models displayed comparable growth rates and vascularity. However, tumor-bearing mice in the SRC model developed lung metastases much earlier (4 weeks) than in the MFP model (&gt;7 weeks), and the metastatic progression contributed significantly to the survival time. In the MFP model, BLI and caliper measurements were comparable for quantifying palpable tumors, but BLI offered an advantage for detecting the primary tumors that fell below a palpable threshold and for visualizing metastases. In the SRC model, BLI allowed longitudinal assessment of the antitumor and antimetastatic effects of PD-0332991, Avastin, and docetaxel, and the results correlated with the survival benefits of these agents.Conclusions: The MDA-MB-435-HAL-Luc SRC model and the MFP model displayed differences in disease progression. BLI is an innovative approach for developing animal models and creates opportunities for improving preclinical evaluations of anticancer agents.
Phase I and Pharmacokinetic Study of Gimatecan Given Orally Once a Week for 3 of 4 Weeks in Patients with Advanced Solid Tumors
Authors: Zhu Andrew X. , Ready Neal , Clark Jeffrey W. , Safran Howard , Amato Antonino , Salem Nadia , Pace Silvia , He Xiaoying , Zvereva Nela , Lynch Thomas J. , Ryan David P. , Supko Jeffrey G. 
Published: December 2008

Abstract
Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks.
Experimental Design: Adult patients with advanced solid tumors with good performance status and adequate hematologic, hepatic, and renal function were eligible for the study. The plasma pharmacokinetics of the drug was characterized during the initial 28-day cycle.
Results: A total of 33 patients were evaluated at 7 dose levels ranging from 0.27 to 3.20 mg/m2/wk. Anemia, fatigue, neutropenia, nausea, and vomiting were the principal toxicities. DLTs experienced by 3 of 7 patients in dose level 7 (3.20 mg/m2) were grade 2 hyperbilirubinemia and grade 3 to 4 fatigue. DLT (anorexia and nausea) occurred in only 1 of 11 patients evaluated at the MTD of 2.40 mg/m2. There were no objective responses, although disease stabilization was observed in 4 patients. Gimatecan has a very long apparent biological half-life (mean ± SD, 77 ± 37 h) and exists in plasma almost entirely as the pharmacologically active intact lactone form. At the MTD, mean peak concentrations of the drug in plasma ranged from 67 to 82 ng/mL for the 3 weekly doses and the mean concentration 7 days after dosing was 15 ± 18 ng/mL.
Conclusions: Administration of gimatecan orally once a week at doses that are well tolerated provides continuous exposure to potentially effective plasma concentrations of the biologically active form of the drug. This regimen deserves further evaluation to define its antitumor activity in specific tumor types either alone or in combination with other agents.
Tissue Specific Cytotoxicity of Colon Cancer Cells Mediated by Nanoparticle-delivered Suicide Gene In vitro and In vivo
Authors: Zhang Guiying , Liu Ting , Chen Yong-Heng , Chen Yuxiang , Xu Meihua , Peng Jie , Yu Shuyi , Yuan Jianwei , Zhang Xiuwu 
Published: December 2008

Abstract
Purpose: This study aimed to develop an efficient and safe strategy to introduce suicide genes into colon cancer cells.
Experimental Design: In this study, we fused an enhanced carcinoembryonic antigen promoter (CEA) to a suicide gene, cytosine deaminase (CD). This construct was delivered into colon cancer cells using calcium phosphate nanoparticles (CPNP). The cells were then treated with the prodrug 5-FC. The therapeutic effect was evaluated in vitro and in vivo.
Results: Our study showed that the CEA promoter–driven, CPNP-delivered suicide gene was only expressed in CEA-positive colon cancer cells, and resulted in significant cytotoxicity after administration of the prodrug 5-FC in vitro. Moreover, our in vivo study showed that CPNP-mediated CEA-CD delivery, together with 5-FC treatment, resulted in significant tumor growth delay in xenograft human colon carcinoma.
Conclusions: Our study indicates that the combination of CPNP and CEA-CD gene expression represents a novel approach for CEA-positive tumor gene therapy.
Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study
Authors: Cortes Javier , Di Cosimo Serena , Climent Miguel A. , Cortés-Funes Hernán , Lluch Ana , Gascón Pere , Mayordomo José I. , Gil Miguel , Benavides Manuel , Cirera Lluís , Ojeda Belén , Rodríguez César A. , Trigo José M. , Vazquez Josep , Regueiro Pilar , Dorado Juan F. , Baselga José ,   on behalf of the Spanish Breast Cancer Cooperative Group SOLTI
Published: December 2008

Abstract
Purpose: To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC).
Experimental Design: Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) &gt;50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter.
Results: Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC). The recommended doses of TLC-D99 and paclitaxel were 50 mg/m2 every 3 weeks and 80 mg/m2/wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to ≥50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1 months (95% confidence interval, 16.4-46.3) in MBC patients.
Conclusions: Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.
Niche-Dependent Tumorigenic Capacity of Malignant Ovarian Ascites-Derived Cancer Cell Subpopulations
Authors: Katz Ehood , Skorecki Karl , Tzukerman Maty 
Published: December 2008

Abstract
Purpose: In previous studies, we have used human embryonic stem cells (hESC) to generate a tissue microenvironment in immunocompromised mice as an experimental approach for studying human tumorigenesis. We now examine the attributes of such a cellular microenvironment in supporting the growth of human cancer cells freshly harvested from malignant ovarian ascites and to determine whether there are differences among subsets of ascites-derived cancer cells in terms of tumorigenic capacity in the conventional murine xenograft model and in the hESC-derived microenvironment.
Experimental Design: Freshly harvested malignant ovarian ascites-derived cancer cells and six derivative ovarian cancer cell subpopulations (CCSP) were characterized for ovarian cancer–associated biomarker expression both in vitro and in vivo and for their capacity to generate tumors in the two models.
Results: Ovarian cancer–associated biomarkers were detected in the ascites-derived cancer cells and in the six newly established CCSPs. Nevertheless, certain CCSPs that did not develop into tumors in a conventional murine xenograft model did generate tumors in the hESC-derived cellular microenvironment, indicating variable niche dependency for the tumorigenic capacity of the different CCSPs. The hESC-derived microenvironment provided an improved niche for supporting growth of certain tumor cell subpopulations.
Conclusions: The results highlight the experimental utility of the hESC-derived cellular microenvironment to enable functional distinction of CCSPs, including the identification of cells that do not grow into a tumor in the conventional direct tumor xenograft platform, thereby rendering such cells accessible to characterization and testing of anticancer therapies.
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6-Methylguanine DNA Methyltransferase Deficiency and Response to Temozolomide-Based Therapy in Patients with Neuroendocrine Tumors
Authors: Kulke Matthew H. , Hornick Jason L. , Frauenhoffer Christine , Hooshmand Susanne , Ryan David P. , Enzinger Peter C. , Meyerhardt Jeffrey A. , Clark Jeffrey W. , Stuart Keith , Fuchs Charles S. , Redston Mark S. 
Published: December 2008

Abstract
Purpose: Recent studies suggest that temozolomide has activity in neuroendocrine tumors. Low levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), are associated with sensitivity to temozolomide in other tumor types. We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens.
Experimental Design: The prevalence of MGMT deficiency, measured by immunohistochemistry, was assessed in 97 archival neuroendocrine tumor specimens. Rates of treatment response and survival were next evaluated in a cohort of 101 consecutive neuroendocrine tumor patients who had received treatment with a temozolomide-based regimen at one of three institutions. MGMT expression was directly correlated with treatment response in 21 patients who had available tumor tissue and response data.
Results: In archival specimens, MGMT deficiency was observed in 19 of 37 (51%) pancreatic neuroendocrine tumors and 0 of 60 (0%) carcinoid tumors (P &lt; 0.0001). In the clinical cohort, 18 of 53 (34%) patients with pancreatic neuroendocrine tumors but only 1 of 44 (2%) patients with carcinoid tumors (P &lt; 0.001) experienced a partial or complete response to temozolomide-based therapy. Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide, 4 of 5 patients with MGMT-deficient tumors (all pancreatic neuroendocrine tumors) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment (P = 0.001).
Conclusions: MGMT deficiency, measured by immunohistochemistry, is more common in pancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide-based therapy. Absence of MGMT may explain the sensitivity of some pancreatic neuroendocrine tumors to treatment.
HLA Class I–Associated Immunodominance Affects CTL Responsiveness to an ESO Recombinant Protein Tumor Antigen Vaccine
Authors: Bioley Gilles , Guillaume Philippe , Luescher Immanuel , Yeh Alice , Dupont Bo , Bhardwaj Nina , Mears Gregory , Old Lloyd J. , Valmori Danila , Ayyoub Maha 
Published: December 2008

Abstract
Purpose: Vaccination with full-length human tumor antigens aims at inducing or increasing antitumor immune responses, including CD8 CTL in cancer patients across the HLA barrier. We have recently reported that vaccination with a recombinant tumor-specific NY-ESO-1 (ESO) protein, administered with Montanide and CpG resulted in the induction of specific integrated antibody and CD4 T cell responses in all vaccinated patients examined, and significant CTL responses in half of them. Vaccine-induced CTL mostly recognized a single immunodominant region (ESO 81-110). The purpose of the present study was to identify genetic factor(s) distinguishing CTL responders from nonresponders.
Experimental Design: We determined the HLA class I alleles expressed by CTL responders and nonresponders using high-resolution molecular typing. Using short overlapping peptides spanning the ESO immunodominant CTL region and HLA class I/ESO peptide tetramers, we determined the epitopes recognized by the majority of vaccine-induced CTL.
Results: CTL induced by vaccination with ESO protein mostly recognized distinct but closely overlapping epitopes restricted by a few frequently expressed HLA-B35 and HLA-Cw3 alleles. All CTL responders expressed at least one of the identified alleles, whereas none of the nonresponders expressed them.
Conclusions: Expression of HLA-B35 and HLA-Cw3 is associated with the induction of immunodominant CTL responses following vaccination with recombinant ESO protein. Because recombinant tumor-specific proteins are presently among the most promising candidate anticancer vaccines, our findings indicate that the monitoring of cancer vaccine trials should systematically include the assessment of HLA association with responsiveness.
Polymeric Tubulysin-Peptide Nanoparticles with Potent Antitumor Activity
Authors: Schluep Thomas , Gunawan Paula , Ma Ling , Jensen Gregory S. , Duringer Julienne , Hinton Steven , Richter Wolfgang , Hwang Jungyeong 
Published: December 2008

AbstractPurpose: Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines. However, they are also highly toxic in animal models. In order to improve the therapeutic index of this class of compounds, a nanoparticle prodrug of tubulysin A (TubA) was synthesized and evaluated in vitro and in vivo.Experimental Design: A thiol derivative of TubA was covalently attached to a linear, β-cyclodextrin based polymer through a disulfide linker (CDP-TubA). The polymer conjugate assembled into stable nanoparticles. Inhibition of tubulin polymerization and antiproliferative activity of the polymer conjugate were evaluated in vitro. The preclinical efficacy of CDP-TubA administered i.v. was evaluated in nude mice bearing s.c. implanted human HT29 colorectal and H460 non–small cell lung carcinoma tumors.Results: The IC50 of CDP-TubA (in Tub A equivalents) was 24, 5, and 10 nmol/L versus 3, 1, and 2 nmol/L for Tub A in NCI-H1299 (lung), HT-29 (colon), and A2780 (ovarian) cell lines, respectively. Tub A and the active thiol derivative were potent inhibitors of tubulin polymerization, whereas CDP-TubA showed minimal inhibition, indicating that target inhibition requires release of the peptide drug from the nanoparticles. The maximum tolerated dose of CDP-TubA was 6 mg/kg (in TubA equivalents) versus 0.05 mg/kg for TubA in nude mice. In vivo, a single treatment cycle of three weekly doses of CDP-TubA showed a potent antitumor effect and significantly prolonged survival compared with TubA alone.Conclusions: Cyclodextrin polymerized nanoparticles are an enabling technology for the safe and effective delivery of tubulysins for the treatment of cancer.
Clinical Implications of CYP2D6 Genotyping in Tamoxifen Treatment for Breast Cancer
Authors: Dezentjé Vincent O. , Guchelaar Henk-Jan , Nortier Johan W.R. , van de Velde Cornelis J.H. , Gelderblom Hans 
Published: December 2008

Abstract
In October 2006 the Food and Drug Administration recommended an update in the tamoxifen label to reflect the increased risk of recurrence in breast cancer patients who are cytochrome P450 2D6 (CYP2D6) poor metabolizers. This recommendation was based on only a few studies at that time. More clinical studies addressing the relation between the CYP2D6 genotype and tamoxifen efficacy have been published since, mostly describing Caucasian populations in the adjuvant treatment setting. An updated analysis of the literature is presented. Furthermore, the possibility to implement CYP2D6 genotyping in clinical practice is evaluated by analyzing the results of six studies on mainly Caucasian patients using adjuvant tamoxifen. Three studies were consistent with the FDA advice, but the three other studies showed contradictory results. Although some of the published criticism on the negative studies is justified, this does not imply that these results should be discarded. The reviewed literature is put in perspective acknowledging the limiting effect of Mendelian randomization on confounding and the limitations of the various study designs. The current accumulation of data showing worse clinical outcome in patients with decreased CYP2D6 metabolism in other types of populations still indicates that the CYP2D6 genotype may well become a clinically relevant predictive marker. The CYP2D6 genotype might be one of the first predictors of therapeutic response in cancer care based on germline DNA creating the possibility to analyze blood instead of tumor.
Overexpression of the KIT/SCF in Uveal Melanoma Does Not Translate into Clinical Efficacy of Imatinib Mesylate
Authors: Hofmann Uta B. , Kauczok-Vetter Claudia S. , Houben Roland , Becker Jürgen C. 
Published: December 2008

Abstract
Purpose: Recently, gene amplification and overexpression of KIT as well as activating mutations in the KIT gene have been described to occur in certain subsets of melanoma. These findings suggest KIT as a potential target for therapy with imatinib mesylate in these melanomas. To date, data on the KIT status in uveal melanoma (UM) is limited.
Experimental Design: We analyzed the expression of the KIT protein (CD117, c-kit) and its ligand, stem cell factor (SCF), in primary and metastatic UM.
Results: By immunohistochemistry, SCF-positive tumor cells (&gt;90%) were detectable in 43% of primary UM and in 58% of UM metastases. Strong expression of KIT (&gt;90%) in tumor cells was present in 55% of primary UM and in 76% of UM metastases. This overexpression of both KIT and SCF suggests the clinical application of imatinib mesylate in metastatic UM. This notion was tested in a clinical study using Simon's two-stage design. Patients received imatinib (600 mg p.o. daily) until progress or unacceptable toxicities. The trial did not enter stage II as no objective response was observed in the first group. This observation prompted further molecular analysis, which revealed no mutations in the genomic sequence of KIT in exons 11, 13, 17, and 18. Moreover, the mitogen-activated protein kinase pathway was not activated in any of the tumors as measured by ERK phosphorylation.
Conclusions: These results show the lack of clinical effectiveness of imatinib in UM, which was originally anticipated based on the high levels of KIT and SCF expression.
Numerical Simulations of Wind Wave Growth under a Coastal Wind Jet through the Kanmon Strait
Authors: Shimada Teruhisa , Isoguchi Osamu , Kawamura Hiroshi 
Published: December 2008

Abstract
The development of a coastal wind jet flowing through the Kanmon Strait and the associated wind wave growth are investigated from a case study on 24–26 July 1999. This study presents a realistic example of fetch-limited wave growth under a developing wind jet outflowing from a terrestrial gap of a coast. A series of numerical simulations are used by one-way coupling between a mesoscale meteorological model and a shallow-water wave model with high spatiotemporal resolutions of 2 km and 1 h. The simulated fields of wind and wave are compared with satellite and in situ observations and it is confirmed that they coincide with observations. A complete picture of the wind jet is obtained from the wind simulations, and wave simulations demonstrate the areal extent of higher waves growing with the development of the wind jet. The wind maximum region is localized and extends downwind. The maximum wave height region is highly localized but located more downwind of the wind speed maximum. The high wave region completely reaches the southern coast of the Korean Peninsula before the strong wind. In the lee of the islands, waves are blocked. The conventional fetch growth of waves holds in waves at the more upwind locations than the highest wave region. The forecasting of localized waves under a coastal wind jet is a case in which adequately high spatiotemporal resolution is required for both the wave simulation and wind input.