bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Significance of Micrometastatic Cells Detected by E48 (Ly-6D) Reverse Transcription-Polymerase Chain Reaction in Bone Marrow of Head and Neck Cancer Patients
Authors: Colnot David R. , Nieuwenhuis Eline J. C. , Kuik Dirk J. , Leemans C. René , Dijkstra Janny , Snow Gordon B. , van Dongen Guus A. M. S. , Brakenhoff Ruud H. 
Published: September 2005

AbstractPurpose: Despite improvements in locoregional treatment of head and neck squamous cell carcinoma (HNSCC), local and distant failure rates remain high. The strongest prognostic indicator of HNSCC is the presence of lymph node metastases in the neck, but the value of this indicator has limitations when using for the individual patient. The presence of micrometastatic cells in bone marrow has been shown to be a putative prognostic indicator in HNSCC and other epithelial malignancies, which might allow more accurate staging and selection of patients for whom adjuvant or experimental therapy is recommended. The gene encoding the E48 antigen is selectively expressed by HNSCC, and the detection of E48 transcripts in bone marrow by reverse transcription-polymerase chain reaction (RT-PCR) presumably represents the presence of micrometastatic cells. The purpose of this study was to determine the association between the presence of micrometastatic cells in bone marrow of HNSCC patients and clinical outcome.Experimental Design: A total of 162 patients treated surgically for primary HNSCC underwent a single bone marrow aspiration from the upper iliac crest for detection of micrometastatic cells using E48 RT-PCR. In total, 139 patients were evaluable. The primary statistical endpoints were disease-free survival and distant metastasis-free survival. In addition, bone marrow samples of 30 noncancer controls were evaluated.Results: E48 RT-PCR indicated the presence of micrometastatic cells in the bone marrow in 56 of 139 (40%) of the HNSCC patients and 0 of 30 of the noncancer controls (P &lt; 0.0001). The presence of micrometastatic cells had no significant influence on disease-free survival or distant metastasis-free survival for the whole group of HNSCC patients (P = 0.1460 and P = 0.2912, respectively). For patients with ≥2 lymph node metastases, however, the presence of micrometastatic cells was associated with a poor distant metastasis-free survival (P = 0.0210).Conclusions: The presence of micrometastatic cells in bone marrow of HNSCC patients with ≥2 lymph node metastases is correlated with a poor distant metastasis-free survival. In this subgroup of HNSCC patients, E48 RT-PCR seems to be a valuable tool to identify patients who are at increased risk for development of distant metastases and therefore might benefit from experimental adjuvant systemic therapy.
Circulating Tumor Cells in Patients with Breast Cancer Dormancy
Authors: Meng Songdong , Tripathy Debasish , Frenkel Eugene P. , Shete Sanjay , Naftalis Elizabeth Z. , Huth James F. , Beitsch Peter D. , Leitch Marilyn , Hoover Susan , Euhus David , Haley Barbara , Morrison Larry , Fleming Timothy P. , Herlyn Dorothee , Terstappen Leon W. M. M. , Fehm Tanja , Tucker Thomas F. , Lane Nancy , Wang Jianqiang , Uhr Jonathan W. 
Published: September 2005

AbstractPurpose: The purpose of this study was to test the hypothesis that circulating tumor cells (CTCs) are present in patients many years after mastectomy without evidence of disease and that these CTCs are shed from persisting tumor in patients with breast cancer dormancy.Experimental Design: We searched for CTCs in 36 dormancy candidate patients and 26 age-matched controls using stringent criteria for cytomorphology, immunophenotype, and aneusomy.Results: Thirteen of 36 dormancy candidates, 7 to 22 years after mastectomy and without evidence of clinical disease, had CTCs, usually on more than one occasion. Only 1 of 26 controls had a possible CTC (no aneusomy). The statistical difference of these two distributions was significant (exact P = 0.0043). The CTCs in patients whose primary breast cancer was just removed had a half-life measured in 1 to 2.4 hours.Conclusions: The CTCs that are dying must be replenished every few hours by replicating tumor cells somewhere in the tissues. Hence, there appears to be a balance between tumor replication and cell death for as long as 22 years in dormancy candidates. We conclude that this is one mechanism underlying tumor dormancy.
Low Levels of Estrogen Receptor β Protein Predict Resistance to Tamoxifen Therapy in Breast Cancer
Authors: Hopp Torsten A. , Weiss Heidi L. , Parra Irma S. , Cui Yukun , Osborne C. Kent , Fuqua Suzanne A. W. 
Published: September 2005

Abstract
Purpose: Breast cancer is a hormone-dependent cancer, and the presence of estrogen receptor α (ER-α) in tumors is used clinically to predict the likelihood of response to hormonal therapies. The clinical value of the second recently identified ER isoform, called ER-β, is less clear, and there is currently conflicting data concerning its potential role as a prognostic or predictive factor.
Experimental Design: To assess whether ER-β expression is associated with clinical outcome, protein levels were measured by immunoblot analysis of a retrospective bank of tumor cell lysates from 305 axillary node-positive patients. A total of 119 received no adjuvant therapy, and 186 were treated with tamoxifen only. The median follow-up time was 65 months. Univariate and multivariate Cox regression modeling was done to assess the prognostic and predictive significance of ER-β expression.
Results: Expression of ER-β protein did not correlate significantly with any other clinical variables, including ER and progesterone levels (as measured ligand binding assay), tumor size, age, or axillary nodal status. In the untreated population, those patients whose tumors who expressed both receptor isoforms exhibited the most favorable outcome as compared with those patients who had lost ER-α expression. However, there was no association between ER-β levels alone and either disease-free or overall survival in the untreated patient population. In contrast, in both univariate and multivariate analyses, high levels of ER-β predicted an improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy.
Conclusions: These findings provide evidence that ER-β may be an independent predictor of response to tamoxifen in breast cancer. Furthermore, these results suggest that ER-β may influence tumor progression in ways different from those mediated by the ER-α isoform.
Dietary Flaxseed Enhances the Inhibitory Effect of Tamoxifen on the Growth of Estrogen-Dependent Human Breast Cancer (MCF-7) in Nude Mice
Authors: Chen Jianmin , Hui Evon , Ip Terence , Thompson Lilian U. 
Published: September 2005

Abstract
Purpose: This study determined the effect of 10% dietary flaxseed (FS) and tamoxifen (TAM), alone and in combination, on the growth of estrogen-dependent human breast cancer (MCF-7) in athymic mice with or without 17β-estradiol (E2) supplementation.
Experimental Design: Ovariectomized mice received injection with MCF-7 cells, were implanted with an E2 pellet (1.7 mg), and fed the basal diet (BD). When tumor reached ∼40 mm2, the E2 implant was removed, and mice were randomized to the following groups and maintained at either low (E2 pellet removed) or high E2 level (new E2 pellet implanted) for 6 weeks: (a) positive control with new E2 pellet, fed BD, (b) negative control with no E2 implant, fed BD, (c) TAM group with TAM pellet (5 mg) implant, fed BD, (d) FS group fed 10% FS, (e) FS+TAM group with TAM implant, fed 10% FS. Tumor growth was monitored weekly.
Results: At low E2 level, FS regressed the pretreatment tumor size by 74%. TAM regressed tumor initially but later induced an increase so that the tumor size was finally similar to the pretreatment size. A tumor regression &gt;53% was induced by FS+TAM than by TAM alone. At high E2 level, FS, TAM, and FS+TAM inhibited the tumor growth by 22, 41, and 50%, respectively, compared with the positive control. Decreased tumor size was attributable to reduced tumor cell proliferation and increased apoptosis.
Conclusions: FS inhibited the growth of human estrogen-dependent breast cancer and strengthened the tumor-inhibitory effect of TAM at both low and high E2 levels.
Apurinic Endonuclease Activity in Adult Gliomas and Time to Tumor Progression after Alkylating Agent-Based Chemotherapy and after Radiotherapy
Authors: Bobola Michael S. , Emond Mary J. , Blank A. , Meade Elizabeth H. , Kolstoe Douglas D. , Berger Mitchel S. , Rostomily Robert C. , Silbergeld Daniel L. , Spence Alexander M. , Silber John R. 
Published: September 2005

Abstract
Purpose: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that cleaves DNA at cytotoxic abasic sites caused by alkylating agents and radiation. We have observed that human glioma cells deficient in Ap endo activity are hypersensitive to clinically used alkylators (Silber et al., Clin Cancer Res 2002;8:3008.). Here we examine the association of glioma Ap endo activity with clinical response after alkylating agent-based chemotherapy or after radiotherapy.
Experimental Design: Cox proportional hazards regression models were used to analyze the relationship of Ap endo activity with time to tumor progression (TTP).
Results: In a univariate model with Ap endo activity entered as a continuous variable, the hazard ratio (HR) for progression after alkylator therapy in 30 grade III gliomas increased by a factor of 1.061 for every 0.01 increase in activity (P = 0.013). Adjusting for age, gender, extent of resection, and prior treatment strengthened slightly the association (HR = 1.094; P = 0.003). Similarly, the HR for progression after radiotherapy in 44 grade II and III tumors increased by a factor of 1.069 (P = 0.008). Adjusting for the aforementioned variables had little effect on the association. In contrast, we observed no association between activity and TTP in grade IV gliomas after either alkylator therapy in 34 tumors or radiotherapy in 26 tumors.
Conclusions: Our data suggest that Ap endo activity mediates resistance to alkylating agents and radiation and may be a useful predictor of progression after adjuvant therapy in a subset of gliomas.
Sensitization of Tumor-Associated Endothelial Cell Apoptosis by the Novel Vascular-Targeting Agent ZD6126 in Combination with Cisplatin
Authors: Goto Hisatsugu , Yano Seiji , Matsumori Yuka , Ogawa Hirohisa , Blakey David C. , Sone Saburo 
Published: September 2005

Abstract
Purpose: ZD6126 is a novel vascular-targeting agent that selectively disrupts the tubulin cytoskeleton of endothelial cells. In the immature vessels characteristic of tumor vasculature, this leads to endothelial cell contraction, blood vessel congestion, and, consequently, tumor cell death. ZD6126 has been shown to delay tumor growth in a range of xenograft models. The antitumor effect of ZD6126 can be increased in combination with cisplatin or radiation therapy, although the precise mechanism of this enhancement has not been demonstrated. ZD6126 treatment has also been shown to inhibit lung metastasis, and the present study has explored the potential to increase the antimetastatic effect of ZD6126 by combining with cisplatin, and the underlining mechanism has been investigated.
Experimental Design: Human lung adenocarcinoma PC14PE6 cells were injected into the tail vein of nude mice. Five weeks after injection animals were treated with ZD6126 (200 mg/kg i.p.), cisplatin (6 mg/kg i.v.), or a combination of the two agents. The animals were sacrificed 24 hours later, and the extent of lung metastases and the presence of apoptotic cells were assessed.
Results: Histologic analysis revealed that the ZD6126/cisplatin combination resulted in a 2 to 4-fold increase in the total number of tumor-associated apoptotic cells compared with either treatment alone. ZD6126 alone induced apoptosis of tumor-associated endothelial cells in tumors, and the extent of apoptosis was increased 2-fold in combination with cisplatin. The lung weight was significantly reduced, and the number of metastatic nodules significantly was lower in the combined treatment group than in the control group.
Conclusions: These data suggest that the antimetastatic effect of the vascular-targeting agent ZD6126 can be increased by use in combination with cisplatin, which increases the incidence of endothelial cell apoptosis.
Application of a Macromolecular Contrast Agent for Detection of Alterations of Tumor Vessel Permeability Induced by Radiation
Authors: Kobayashi Hisataka , Reijnders Koen , English Sean , Yordanov Alexander T. , Milenic Diane E. , Sowers Anastasia L. , Citrin Deborah , Krishna Murali C. , Waldmann Thomas A. , Mitchell James B. , Brechbiel Martin W. 
Published: September 2005

Abstract
Permeability of tumor vasculature can be a major barrier to successful drug delivery, particularly for high molecular weight agents such as monoclonal antibodies and their diagnostic or therapeutic conjugates. In this study, changes in permeability of SCCVII tumor vessels after radiation treatment were evaluated by dynamic magnetic resonance imaging as a function of time after irradiation using a generation-8 polyamidoamine dendrimer (G8-Gd-D)-based magnetic resonance imaging contrast agent shown previously to be confined to tumor blood vessels. Tumor irradiation consisted of either single doses (2–15 Gy) or various daily fractionated doses (5 days). A single radiation dose of 15 Gy resulted in significant transient image enhancement of the tumor tissue with a maximum occurring between 7 and 24 hours after radiation treatment. No observable enhancement was recorded for fractionated radiation doses. Use of dynamic magnetic resonance imaging coupled with G8-Gd-D provides an exquisite methodology capable of defining the timing of enhanced permeability of macromolecules in tumors after irradiation. Such information might be applied to optimize the efficacy of subsequent or concurrent therapies including radiolabeled antibodies or other anticancer agents in combination with external beam therapies.
S-1 Plus Cisplatin Combination Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Ichinose Yukito , Yoshimori Kozo , Sakai Hiroshi , Nakai Yushi , Sugiura Takahiko , Kawahara Masaaki , Niitani Hisanobu 
Published: September 2005

Abstract
Purpose: To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent, S-1 that consisted of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, for non–small-cell lung cancer (NSCLC) patients.
Experimental Design: In this phase II trial, patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m2 twice a day for 21 consecutive days while cisplatin (60 mg/m2) was administered intravenously on day 8. This schedule was repeated every 5 weeks.
Results: Of 56 patients enrolled in the study, 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range, 1–12 cycles). Among these 55 patients, one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval, 34–61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%). No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%), vomiting (7%), or diarrhea (7%).
Conclusions: S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC.
Lack of Impact of the Loss of Constitutive Folate Receptor α Expression, Achieved by RNA Interference, on the Activity of the New Generation Antifolate Pemetrexed in HeLa Cells
Authors: Chattopadhyay Shrikanta , Wang Yanhua , Zhao Rongbao , Goldman I. David 
Published: September 2005

Abstract
Pemetrexed [PMX (Alimta)] is a new generation antifolate with activity in a variety of solid tumors. It is an excellent substrate for most folate transporters, notably the reduced folate carrier (RFC) and folate receptor (FR)-α. The role of FR-α in PMX pharmacological activity is uncertain. Whereas high-level expression may enhance the activity of this agent, it is not clear what role constitutive levels of this transporter contribute to PMX activity. In this study, constitutive levels of FR-α expression were abolished by small interfering RNA-induced silencing in HeLa cells and RFC-null HeLa R5 cells as confirmed by Northern blotting, immunohistochemistry, and cell surface binding. PMX growth inhibition was unchanged in HeLa and R5 cells in the absence of FR-α expression. Loss of FR-α expression did not decrease net accumulation of PMX in either wild-type or RFC-null HeLa cells. Likewise, folate pools in wild-type HeLa cells were not decreased by FR-α gene silencing and were negligibly affected in the RFC-null R5 subline grown with 5-formyltetrahydrofolate. FR-α surface binding in HeLa cells was shown to be greater than that in a variety of other human solid tumor cell lines. Hence, constitutively expressed FR-α in HeLa cells does not contribute to PMX activity in the presence or absence of RFC function. This is likely the case in many human solid tumor cell lines.
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis Is Inhibited by Bcl-2 but Restored by the Small Molecule Bcl-2 Inhibitor, HA 14-1, in Human Colon Cancer Cells
Authors: Sinicrope Frank A. , Penington Robert C. , Tang Xi Ming 
Published: September 2005

Abstract
Purpose: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that induces apoptosis in multiple tumor cell types while sparing most normal cells. We determined the effect of ectopic Bcl-2 expression on TRAIL-induced apoptosis and whether the small molecule Bcl-2 inhibitor, HA14-1, could increase TRAIL sensitivity.
Experimental Design: SW480 human colon cancer cells were stably transfected with the PC3-Bcl-2 plasmid or vector alone. Cells were incubated with recombinant human TRAIL ± HA14-1 or caspase-9 inhibitor (Z-LEHD-FMK). Apoptosis was analyzed by Annexin V-fluorescein isothiocyanate labeling and DNA fragmentation factor 45 (DFF45) cleavage. Clonigenic survival was also studied. Caspase activation was determined by immunoblotting or colorimetric assay. The cytosolic expression of Bid, Bax, and XIAP and release of cytochrome c and Smac/DIABLO were determined by immunoblotting.
Results: Bcl-2 overexpression partially protected SW480 cells from a dose-dependent induction of apoptosis by TRAIL, as did a caspase-9 inhibitor, and increased their clonogenic survival. Bcl-2 overexpression attenuated TRAIL-induced cleavage of caspase-8, indicating its activation upstream and downstream of mitochondria, as well as cleavage of Bid and caspase-3. Bcl-2 inhibited TRAIL-induced Bax translocation, cytosolic release of cytochrome c and Smac/DIABLO, and the downstream cleavage of XIAP and DFF45. Coadministration of HA14-1 and TRAIL increased apoptosis in SW480/Bcl-2 cells by restoring Bax redistribution and cytochrome c release.
Conclusions: Bcl-2 confers apoptosis resistance to TRAIL by inhibiting a mitochondrial amplification step and by inactivating downstream XIAP in SW480 cells. HA14-1 reversed Bcl-2–mediated TRAIL resistance, suggesting a novel strategy for increasing TRAIL sensitivity in Bcl-2–overexpressing colon cancers.
Lack of Microvessels in Well-Differentiated Regions of Human Head and Neck Squamous Cell Carcinoma A253 Associated with Functional Magnetic Resonance Imaging Detectable Hypoxia, Limited Drug Delivery, and Resistance to Irinotecan Therapy
Authors: Bhattacharya Arup , Tóth Károly , Mazurchuk Richard , Spernyak Joseph A. , Slocum Harry K. , Pendyala Lakshmi , Azrak Rami , Cao Shousong , Durrani Farukh A. , Rustum Youcef M. 
Published: September 2005

Abstract
Purpose: Combination chemotherapy with irinotecan (CPT-11; 50 mg/kg/week × 4 intravenously), followed 24 hour later by 5-fluorouracil (50 mg/kg/week × 4 intravenously), results in 10 and 100% cure rates of animals bearing human head and neck squamous cell carcinoma xenografts A253 and FaDu, respectively. A253 consists of 30% well-differentiated and avascular and 70% poorly differentiated regions with low microvessel density (10/×400), whereas FaDu is uniformly poorly differentiated with higher microvessel density (19/×400). Studies were carried out for determining the role of well-differentiated and avascular regions in drug resistance in A253 and detection of such regions with noninvasive functional magnetic resonance (fMR) imaging.
Experimental Design: Tumors were harvested for histopathologic evaluation and immunohistochemistry (CD31, CD34; differentiation marker: involucrin; hypoxia markers: carbonic anhydrase IX, pimonidazole; vascular endothelial factor (VEGF) and Ki67) immediately after fMR imaging following the 3rd dose of chemotherapy. High-performance liquid chromatography determination of intratumoral drug concentration of 7-ethyl-10-hydroxyl-camptothecin and autoradiography with 14C-labeled CPT-11 was done 2 hours after CPT-11 administration.
Results: Although A253 xenografts showed three times higher concentration of 7-ethyl-10-hydroxyl-camptothecin, FaDu was more responsive to therapy. After therapy, A253 tumor consisted mostly (∼80%) of well-differentiated regions (positive for involucrin) lacking microvessels with a hypoxic rim (positive for carbonic anhydrase IX and pimonidazole) containing few proliferating (Ki67 positive) poorly differentiated cells. Autoradiography revealed that well-differentiated A253 tumor regions showed 5-fold lower 14C-labeled CPT-11 concentrations compared with poorly differentiated areas (P &lt; 0.001). Blood oxygen level dependant fMR imaging was able to noninvasively distinguish the hypoxic and well-vascularized regions within the tumors.
Conclusion: Avascular-differentiated regions in squamous cell carcinoma offer sanctuary to some hypoxic but viable tumor cells (carbonic anhydrase IX and Ki67 positive) that escape therapy because of limited drug delivery. This study provides direct evidence that because of a specific histologic structure, avascular, well-differentiated hypoxic regions in tumors exhibit low drug uptake and represent a unique form of drug resistance.