bluuebunny/crossref_metadata_2025_split huggingface dataset:
Species Differences in Troxacitabine Pharmacokinetics and Pharmacodynamics
Authors: Gourdeau Henriette , Leblond Lorraine , Hamelin Bettina , Dong Kelly , Ouellet France , Boudreau Chantal , Custeau Dominique , Richard Annie , Gilbert Marie-Josée , Jolivet Jacques 
Published: September 2005

Abstract
Purpose: Troxacitabine is the first unnatural l-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models.
Experimental Design: Clonal and thymidine incorporation assays were used to investigate the in vitro antiproliferative activity of troxacitabine on a selected panel of mouse and human tumor cell lines and normal hemapoietic cells. Analysis of the intracellular metabolites of [14C]troxacitabine was determined in mouse and human T-lymphocytes obtained from peripheral blood. The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model. We also determined plasma concentrations of troxacitabine using the different administration schedules.
Results: Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines. Furthermore, the sensitivity of cells of both species to troxacitabine was strongly time dependent, requiring &gt;24 hours exposure for maximum activity. Analysis of the intracellular metabolites of [14C]troxacitabine in T-lymphocytes obtained from peripheral blood revealed subsequently higher levels of mono-, di-, and triphosphates in human compared with mouse. Antitumor efficacy studies revealed that prolonged exposure schedules (up to 6 days) showed equivalent efficacy to repeated high-dose bolus administrations. Five-day continuous infusion of 20 mg/mL troxacitabine via subcutaneous implanted mini-osmotic pump maintained systemic concentrations of 262 ng/mL (1.2 μmol/L) for the duration of administration, which are clinically achievable plasma concentrations, and led to significant antitumor activity [treated versus control (T/C) of 27% and tumor regression during treatment].
Conclusions: These studies support the hypothesis that troxacitabine infusions might be the administration regimen with the greatest likelihood of fully exploiting clinically the potent preclinical antitumor activity of troxacitabine.
Recurrent Ovarian Cancer
Authors: Herzog Thomas J. 
Published: September 2005

Abstract
Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non–cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients’ quality of life, and evidence addressing the potential benefits of longer-term treatment.
Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer
Authors: Schiff Bradley A. , McMurphy Andrea B. , Jasser Samar A. , Younes Maher N. , Doan Dao , Yigitbasi Orhan G. , Kim Seungwon , Zhou Ge , Mandal Mahitosh , Bekele Benjamin N. , Holsinger F. Christopher , Sherman Steven I. , Yeung Sai-Ching , El-Naggar Adel K. , Myers Jeffrey N. 
Published: September 2005

Abstract
Purpose: No effective treatment options currently are available to patients with anaplastic thyroid cancer (ATC), resulting in high mortality rates. Epidermal growth factor (EGF) has been shown to play a role in the pathogenesis of many types of cancer, and its receptor (EGFR) provides an attractive target for molecular therapy.
Experimental Design: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. We assessed the potential of the EGFR inhibitor gefitinib (“Iressa,” ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis, and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel.
Results: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. Activation of EGFR by EGF was blocked by the addition of gefitinib. In vitro studies showed that gefitinib greatly inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of thyroid carcinoma cells injected subcutaneously.
Conclusions: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro. Our in vivo results show that gefitinib has significant antitumor activity against ATC in a subcutaneous nude mouse tumor model and therefore is a potential candidate for human clinical trials.
X-Tile
Authors: Camp Robert L. , Dolled-Filhart Marisa , Rimm David L. 
Published: September 2005

Abstract
The ability to parse tumors into subsets based on biomarker expression has many clinical applications; however, there is no global way to visualize the best cut-points for creating such divisions. We have developed a graphical method, the X-tile plot that illustrates the presence of substantial tumor subpopulations and shows the robustness of the relationship between a biomarker and outcome by construction of a two dimensional projection of every possible subpopulation. We validate X-tile plots by examining the expression of several established prognostic markers (human epidermal growth factor receptor-2, estrogen receptor, p53 expression, patient age, tumor size, and node number) in cohorts of breast cancer patients and show how X-tile plots of each marker predict population subsets rooted in the known biology of their expression.
Autoantibody Profiles and Neurological Correlations of Thymoma
Authors: Vernino Steven , Lennon Vanda A. 
Published: September 2005

Abstract
Purpose: Determine muscle and neuronal autoantibody frequencies in patients with thymoma, with and without paraneoplastic neurological accompaniments.
Experimental Design: Analysis of IgG autoantibodies in stored serum collected between 1985 and 2003 from 201 patients with histologically diagnosed thymoma (including six with thymic carcinoma). Contemporary assays quantitated antibodies reactive with muscle and neuronal cation channels, muscle sarcomeric proteins and neuronal cytoplasmic, and nuclear proteins.
Results: Neurological diagnoses included myasthenia gravis (MG), myositis, encephalitis, neuromuscular hyperexcitability, autonomic neuropathy, and subacute hearing loss, a previously unrecognized accompaniment of thymoma. Muscle acetylcholine receptor (AChR) binding antibodies were found in all patients with a diagnosis of MG. Muscle autoantibodies (AChR-binding, AChR-modulating, or striational) were also found in 59% of patients without any neurological disorder. One or more neuronal autoantibodies were found in 41% of patients without any neurological disorder, 43% of patients with MG only, and 78% of patients with other neurological disorders. Neuronal autoantibody specificities were, in descending order of frequency, as follows: glutamic acid decarboxylase, voltage-gated potassium channel, collapsin response-mediator protein-5, ganglionic AChR, and antineuronal nuclear antibody-type 1 (ANNA-1).
Conclusions: Neuronal autoantibodies complement skeletal muscle autoantibodies as serological markers of thymoma in patients with and without clinical evidence of a neurological disorder. The high prevalence of glutamic acid decarboxylase autoantibody, not previously considered a paraneoplastic marker, justifies its consideration as a marker of thymoma-related neurological autoimmunity. Serological evaluation of a patient’s profile of neuronal and muscle autoantibodies may aid in preoperative identification of an indeterminate mediastinal mass.
Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration
Authors: Steege Jessica C. A. Bouma-ter , Baeten Coen I. M. , Thijssen Victor L. J. L. , Satijn Sietske A. , Verhoeven Inge C. L. , Hillen Harry F. P. , Wagstaff John , Griffioen Arjan W. 
Published: September 2005

Abstract
To study the relationship between the angiogenic profile and leukocyte infiltration of tumors, single cell suspensions of archival frozen medullary and ductal breast cancer tissues were analyzed by flow cytometry. The amount of leukocytes and endothelial cells was measured, as well as the expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell fraction. A significantly higher number (3.2-fold) of infiltrating leukocytes was observed in medullary carcinoma. The composition of this infiltrate was similar to that seen in ductal carcinomas. The more intense infiltrate was explained by the ∼3-fold enhanced endothelial ICAM-1 expression in medullary carcinoma. The angiogenic profile of all tumors was assessed by quantitative real-time reverse transcription-PCR analysis. Vascular endothelial growth factor (VEGF)-C and VEGF-D, but not VEGF-A, basic fibroblast growth factor, placental growth factor, and angiopoietins 1, 2, and 3 showed a relatively higher level of expression in ductal carcinoma than in medullary carcinoma. In vitro, both VEGF-C and VEGF-D were found to decrease endothelial ICAM-1 expression in the presence of basic fibroblast growth factor. These data suggest that in vivo angiogenic stimuli prevent the formation of an effective leukocyte infiltrate in tumors by suppressing endothelial ICAM-1 expression.
Impact of Human Neutralizing Antibodies on Antitumor Efficacy of an Oncolytic Adenovirus in a Murine Model
Authors: Tsai Van , Johnson Duane E. , Rahman Amena , Wen Shu Fen , LaFace Drake , Philopena Jennifer , Nery Jonathan , Zepeda Monica , Maneval Daniel C. , Demers G. William , Ralston Robert 
Published: September 2005

AbstractPurpose: The purpose of this study was to assess the impact of anti-adenovirus neutralizing antibodies (AdNAbs) on the distribution, tolerability, and efficacy of intravenously administered oncolytic adenovirus. A translational model was developed to evaluate the impact of humoral immunity on intravenous administration of oncolytic adenovirus in humans.Experimental Design: Initially, severe combined immunodeficient (SCID)/beige mice were passively immunized with various amounts of human sera to establish a condition of preexisting humoral immunity similar to humans. A replication-deficient adenovirus encoding β-galactosidase (rAd-βgal) was injected intravenously into these mice. An AdNAb titer that mitigated galactosidase transgene expression was determined. A xenograft tumor-bearing nude mouse model was developed to assess how a similar in vivo titer would impact the activity of 01/PEME, an oncolytic adenovirus, after intravenous administration.Results: In SCID/beige mice, there was a dose dependence between AdNAbs and galactosidase transgene expression; 90% of transgene expression was inhibited when the titer was 80. A similar titer reconstituted in the nude mice with human serum, as was done in the SCID/beige mice, did not abrogate the antitumor efficacy of the replicating adenovirus after intravenous administration. Viral DNA increased in tumors over time.Conclusions: In intravenous administration, preexisting AdNAb titer of 80 significantly attenuated the activity of a 2.5 × 1012 particles per kilogram dose of nonreplicating adenovirus; the same titer had no affect on the activity of an equivalent dose of replicating adenovirus. Our results suggest that a majority of patients with preexisting adenovirus immunity would be candidates for intravenous administration of oncolytic adenovirus.
Mouse Mammary Tumor Virus-like RNA Transcripts and DNA Are Found in Affected Cells of Human Breast Cancer
Authors: Ford Caroline E. , Faedo Margaret , Rawlinson William D. 
Published: September 2005

Abstract
Identifiable risk factors for the development of breast cancer include age, diet, family history, and lifetime estrogen exposure. An infectious agent (mouse mammary tumor virus; MMTV) is known to cause murine breast tumors and may be involved in the pathogenesis of human disease. Multiple studies have detected MMTV-like sequences in 30 to 60% of breast cancer samples and up to 1.8% of samples from normal breast. Using in situ PCR of MMTV-like sequences of formalin-fixed, paraffin-embedded breast tissue, viral sequences have been located in cancerous epithelial cells in breast acini of male and female breast tumors, but not in adjacent nonmalignant cells. MMTV-like sequences were also located in the epithelial cells of male gynecomastia samples. Using reverse transcriptase in situ PCR, RNA transcripts from the env gene were also detected within cancerous epithelial cells of 78% of DNA-positive tumors, 80% of gynecomastia samples, and 0% of normal tissues screened. This suggests the virus may be replicating in these cells. The epidemiologic and histopathological data are consistent with the association of an MMTV-like virus with breast cancers in men and women. The association with gynecomastia, a benign, possibly premalignant condition suggests hormonal influences, rather than cancer per se, may be the dominant factor in determining viral presence and replication.
Functionalization of Tumor Necrosis Factor-α Using Phage Display Technique and PEGylation Improves Its Antitumor Therapeutic Window
Authors: Shibata Hiroko , Yoshioka Yasuo , Ikemizu Shinji , Kobayashi Kyoko , Yamamoto Yoko , Mukai Yohei , Okamoto Takayuki , Taniai Madoka , Kawamura Maki , Abe Yasuhiro , Nakagawa Shinsaku , Hayakawa Takao , Nagata Satoshi , Yamagata Yuriko , Mayumi Tadanori , Kamada Haruhiko , Tsutsumi Yasuo 
Published: September 2005

Abstract
Purpose: In this study, the optimization of antitumor therapy with tumor necrosis factor-α (TNF-α) was attempted.
Experimental Design: Using the phage display technique, we created a lysine-deficient mutant TNF-α (mTNF-K90R). This mutant had higher affinities to both TNF receptors, despite reports that certain lysine residues play important roles in trimer formation and receptor binding.
Results: The mTNF-K90R showed an in vivo therapeutic window that was 13-fold higher than that of the wild-type TNF-α (wTNF-α). This was due to the synergistic effect of its 6-fold stronger in vitro bioactivity and its 2-fold longer plasma half-life derived from its surface negative potential. The reason why the mTNF-K90R showed a higher bioactivity was understood by a molecular modeling analysis of the complex between the wTNF-α and TNF receptor-I. The mTNF-K90R, which was site-specifically mono-PEGylated at the NH2 terminus (sp-PEG-mTNF-K90R), had a higher in vitro bioactivity and considerably longer plasma half-life than the wTNF-α, whereas the randomly mono-PEGylated wTNF-α had 6% of the bioactivity of the wTNF-α. With regard to effectiveness and safety, the in vivo antitumor therapeutic window of the sp-PEG-mTNF-K90R was 60-fold wider than that of the wTNF-α.
Conclusions: These results indicated that this functionalized TNF-α may be useful not only as an antitumor agent but also as a selective enhancer of vascular permeability in tumors for improving antitumor chemotherapy.
Breast Cancer Resistance Protein and P-Glycoprotein in 149 Adult Acute Myeloid Leukemias
Authors: Benderra Zineb , Faussat Anne-Marie , Sayada Lydia , Perrot Jean-Yves , Chaoui Driss , Marie Jean-Pierre , Legrand Ollivier 
Published: September 2005

Abstract
Purpose: Recently, a new ABC protein, breast cancer resistance protein (BCRP), was described. But its prognosis is not known in acute myeloid leukemia (AML). In addition, the prognosis of P-glycoprotein (Pgp) and BCRP in patients treated homogeneously by the same anthracycline (daunorubicin, idarubicin, or mitoxantrone) during all of the treatment with aracytine is not known. Therefore, we have evaluated the relationship between drug resistance phenotype, in vitro anthracene sensitivity, and the relation to treatment outcome.
Experimental Design: We have analyzed 149 AML treated according to protocol of the European Organization for Research and Treatment of Cancer group. The prognostic value of BCRP and Pgp were analyzed in the whole population and according to intercalating agent.
Results: BCRP was a prognostic factor, for achievement of complete remission (43% in positive patients and 69% in negative patients, P = 0.005), the 4-year disease-free survival (12% versus 33%, P = 0.03), and the 4-year overall survival (19% versus 38%, P = 0.003). When BCRP expression and Pgp function were categorized in three groups, +/+, +/− or −/+, and −/−, the achievement of complete remission was 45%, 66%, and 90% (P = 0.0003), the 4-year disease-free survival was 8%, 26%, and 40% (P = 0.01), and the 4-year overall survival was 16%, 37%, and 48% (P = 0.001), respectively. Pgp function was a prognostic factor in patients treated by daunorubicin and idarubicin but not by mitoxantrone. In contrast, BCRP expression was a prognostic factor in patients treated by daunorubicin and mitoxantrone but not by idarubicin.
Conclusions: BCRP would be implicated in the resistance to chemotherapies in AML. But these are the patients expressing both BCRP and Pgp who have the poorest prognosis.
Monoclonal Immunoglobulin Production Is a Frequent Event in Patients with Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Wöhrer Stefan , Streubel Berthold , Bartsch Rupert , Chott Andreas , Raderer Markus 
Published: September 2005

Abstract
Purpose: Mucosa-associated lymphoid tissue (MALT) lymphoma comprises 7% of all newly diagnosed non-Hodgkin’s lymphomas and is therefore among the most common lymphoma entities. Monoclonal gammopathy due to production of a monoclonal immunoglobulin by lymphoma cells is a well-known phenomenon associated with various types of B-cell non-Hodgkin’s lymphomas. The objective of the present study was to evaluate the incidence and clinical relevance of paraprotein (PP) production in patients with MALT lymphoma.
Experimental Design: Fifty two patients were prospectively evaluated with regard to differentiation of the MALT lymphoma cells, t(11;18) translocation, monoclonal immunoglobulin production, Helicobacter pylori (HP) status, stage, treatment, and clinical outcome.
Results: Nineteen of 52 MALT lymphoma patients (36%) had PP (8 IgMκ, 6 IgGκ, 4 IgMλ, and 1 IgAκ). The histologic feature of plasmacytic differentiation correlated significantly with the production of PP (P = 0.001). No correlation was found between PP and clinical stage, HP status, and t(11;18) status. PP was, however, negatively associated with response to eradication of HP in gastric MALT lymphoma, and PP levels declined significantly in patients responding to chemotherapy or radiation. Importantly, both immunofixation and serum electrophoresis have to be performed to detect low PP levels.
Conclusions: In conclusion, PP levels may probably be used as a potential prognostic tool for response to HP eradication, and serial measurements may also allow for noninvasive assessment of response to radiation or chemotherapy in patients with MALT lymphoma.
Dominant Papillary Subtype Is a Significant Predictor of the Response to Gefitinib in Adenocarcinoma of the Lung
Authors: Kim Young Hak , Ishii Genichiro , Goto Koichi , Nagai Kanji , Tsuta Koji , Shiono Satoshi , Nitadori Junichi , Kodama Testuro , Nishiwaki Yutaka , Ochiai Atsushi 
Published: September 2005

Abstract
Purpose: Gefitinib (IRESSA; AstraZeneca, Osaka, Japan) shows excellent antitumor activity against advanced non–small-cell lung cancer, especially for the treatment of adenocarcinoma. However, the predictive factors for the response to gefitinib are still controversial. The aim of this study was to identify the clinicopathological and immunohistochemical features that are favorable to the use of gefitinib in adenocarcinoma patients.
Experimental Design: Between June 2002 and October 2003, 36 adenocarcinoma patients who experienced a relapse after surgical resection were treated with gefitinib at our hospital. The histologic patterns of the tumors were divided into four distinctive subtypes according to the revised World Health Organization histologic classification, and the dominant histologic subtype for the maximum cut surface of each resected specimen was documented. Association between the response to gefitinib and the clinicopathological features or immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, or c-erbB-2 were then investigated.
Results: A significant association between the response to gefitinib and dominant papillary subtype findings was observed (P = 0.0021); the survival time of papillary subtype patients was also significantly prolonged compared with that of non-papillary subtype patients (P = 0.03). No other clinicopathological features or the expression of EGFR, phosphorylated EGFR, or c-erbB-2 were associated with the response to gefitinib.
Conclusions: The results of the present study indicate that dominant papillary subtype findings of lung adenocarcinomas can be an important predictor of the response to gefitinib. Thus, this type of adenocarcinoma might be susceptible to postoperative adjuvant treatment with gefitinib.