bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiangiogenic Therapy of Cerebral Melanoma Metastases Results in Sustained Tumor Progression via Vessel Co-Option
Authors: Leenders William P. J. , Küsters Benno , Verrijp Kiek , Maass Cathy , Wesseling Pieter , Heerschap Arend , Ruiter Dirk , Ryan Andy , de Waal Robert 
Published: September 2005

Abstract
Purpose: In the brain, tumors may grow without inducing angiogenesis, via co-option of the dense pre-existent capillary bed. The purpose of this study was to investigate how this phenomenon influences the outcome of antiangiogenic therapy.
Experimental Design: Mice carrying brain metastases of the human, highly angiogenic melanoma cell line Mel57-VEGF-A were either or not treated with different dosages of ZD6474, a vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor. Effect of treatment was evaluated using contrast-enhanced magnetic resonance imaging (CE- MRI) and (immuno)morphologic analysis.
Results: Placebo-treated Mel57-VEGF-A brain metastases evoked an angiogenic response and were highlighted in CE-MRI. After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens. However, (immuno)histologic analysis revealed the presence of numerous, small, nonangiogenic lesions. Treatment with 25 mg/kg ZD6474 also resulted in efficient blockade of vessel formation, but it did not fully inhibit vascular leakage, thereby still allowing visualization in CE-MRI scans.
Conclusions: Our data show that, although angiogenesis can be effectively blocked by ZD6474, in vessel-dense organs this may result in sustained tumor progression via co-option, rather than in tumor dormancy. Importantly, blocking VEGF-A may result in undetectability of tumors in CE-MRI scans, leading to erroneous conclusions about therapeutic efficacy during magnetic resonance imaging follow-up. The maintenance of VEGF-A-induced vessel leakage in the absence of neovascularization at lower ZD6474 doses may be exploited to improve delivery of chemotherapeutic agents in combined treatment regimens of antiangiogenic and chemotherapeutic compounds.
Characterization of the Hollow Fiber Assay for the Determination of Microtubule DisruptionIn vivo
Authors: Suggitt Marie , Swaine David J. , Pettit George R. , Bibby Michael C. 
Published: September 2005

AbstractPurpose: The hollow fiber assay is used successfully as a routine in vivo screening model to quantitatively define anticancer activity by the National Cancer Institute. This study investigates whether the hollow fiber assay can be used as a short-term in vivo model to demonstrate specific pharmacodynamic end points, namely microtubule and cell cycle disruption.Experimental Design: The growth of A549 cells was characterized within hollow fibers over 5 days in vivo at both subcutaneous (s.c.) and intraperitoneal (i.p.) sites. Drugs were administered on day 4 (i.p.).Results: At 24 hours, cells were retrieved from fibers at both i.p. and s.c. sites of paclitaxel-treated (20 mg/kg) and combretastatin A1 phosphate–treated (150 mg/kg) mice. Cell cycle analysis after paclitaxel treatment revealed a mean G2-M phase population of 48.04% (i.p.) and 25.76% (s.c.) compared with vehicle group mice (6.78 and 5.56%, respectively; P = &lt;0.001 and 0.005, respectively). Tumor cells retrieved from combretastatin A1 phosphate–treated mice had a mean G2-M phase population of 36.3% (i.p.) and 29.36% (s.c.) compared with cells retrieved from vehicle group mice (5.58 and 5.49%, respectively; P = &lt;0.001). Using fluorescence and laser-confocal microscopy, paclitaxel was revealed to induce the formation of spindle asters and tubulin polymerization. Combretastatin A1 phosphate was shown to hold cells in mitosis. Changes in nuclear morphology were also observed.Conclusion: These data demonstrate that the hollow fiber assay can be used as a short-term in vivo model for studying the pharmacodynamic effects of both standard and novel compounds on microtubules. Evidence has also been provided to support the routine use of the in vivo hollow fiber assay for demonstrating the mechanism of action of a drug.
Galectin-9 as a Prognostic Factor with Antimetastatic Potential in Breast Cancer
Authors: Irie Akemi , Yamauchi Akira , Kontani Keiichi , Kihara Minoru , Liu Dage , Shirato Yukako , Seki Masako , Nishi Nozomu , Nakamura Takanori , Yokomise Hiroyasu , Hirashima Mitsuomi 
Published: September 2005

Abstract
Purpose: Galectin-9, a member of the β-galactoside–binding galectin family, induces aggregation of certain cell types. We assessed the contribution of galectin-9 to the aggregation of breast cancer cells as well as the relation between galectin-9 expression in tumor tissue and distant metastasis in patients with breast cancer.
Experimental Design: Subclones of MCF-7 breast cancer cells with high or low levels of galectin-9 expression were established and either cultured on plastic dishes or transplanted into nude mice. The tumors of 84 patients with breast cancer were tested for galectin-9 expression by immunohistochemistry. The patients were followed up for 14 years.
Results: MCF-7 subclones with a high level of galectin-9 expression formed tight clusters during proliferation in vitro, whereas a subclone (K10) with the lowest level of galectin-9 expression did not. However, K10 cells stably transfected with a galectin-9 expression vector aggregated in culture and in nude mice. Ectopic expression of galectin-9 also reduced MCF-7 cell adhesion to extracellular matrix proteins. Tumors of 42 of the 84 patients were galectin-9 positive, and those of 19 of the 21 patients with distant metastasis were galectin-9 negative. None of the 13 patients with galectin-9–positive tumors and lymph node metastasis up to level II manifested distant metastasis. The cumulative disease-free survival ratio for galectin-9–positive patients was more favorable than that for the galectin-9–negative group (P &lt; 0.0001). Multivariate analysis revealed that galectin-9 status influenced distant metastasis independently of and to a greater extent than lymph node metastasis.
Conclusions: Galectin-9 is a possible prognostic factor with antimetastatic potential in breast cancer.
Characterization of Active Mitogen-Activated Protein Kinase in Ovarian Serous Carcinomas
Authors: Hsu Chih-Yi , Bristow Robert , Cha Moon Seok , Wang Brant G. , Ho Chung-Liang , Kurman Robert J. , Wang Tian-Li , Shih Ie-Ming 
Published: September 2005

Abstract
Purpose: Mitogen-activated protein kinase (MAPK) plays a pivotal role in signal transduction. Activation of MAPK is regulated by upstream kinases including KRAS and BRAF, which are frequently mutated in low-grade ovarian serous carcinoma. This study evaluates the expression of active MAPK in ovarian serous carcinomas, with response to treatment and survival.
Experimental Design: Expression of active MAPK was assessed by immunohistochemistry in 207 cases of ovarian serous tumors. Immunoreactivity was correlated with tumor grade, mutational status of KRAS and BRAF, in vitro drug resistance, and clinical outcome.
Result: There was a lower frequency of expression of active MAPK in high-grade ovarian serous carcinomas as compared with low-grade serous tumors, including borderline tumors and low-grade serous carcinoma (P &lt; 0.001). Active MAPK was present in all of the 19 low-grade tumors with either KRAS or BRAF mutations as well as in 14 (41%) of 34 tumors with wild-type KRAS and BRAF in both low- and high-grade carcinomas. Expression of active MAPK alone served as a good survival indicator in the 2-year follow-up (P = 0.037) but not in the 5-year follow-up (P = 0.145). However, a combination of expression of active MAPK and in vitro sensitivity of paclitaxel significantly correlated with a better prognosis in 5-year survival rate (P = 0.048) in patients with advanced-stage high-grade serous carcinoma.
Conclusions: Active MAPK is more frequently expressed in low-grade than in high-grade ovarian serous carcinoma. Active MAPK serves as a good prognostic marker in patients with high-grade serous carcinomas.
A Phase II Trial of Neoadjuvant Docetaxel and Capecitabine for Locally Advanced Breast Cancer
Authors: Lebowitz Peter F. , Eng-Wong Jennifer , Swain Sandra M. , Berman Arlene , Merino Maria J. , Chow Catherine K. , Venzon David , Zia Farah , Danforth David , Liu Edison , Zujewski JoAnne 
Published: September 2005

Abstract
Purpose: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer.
Experimental Design: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m2 i.v. day 1) and capecitabine (1000 mg/m2 orally twice daily days 2–15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m2 i.v. day 1) and capecitabine (937.5 mg/m2 orally twice daily days 2–15).
Results: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m2 at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m2/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine.
Conclusions: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m2 docetaxel and 1600 mg/m2/day days 2–15 is recommended.
Immediate Gene Expression Changes After the First Course of Neoadjuvant Chemotherapy in Patients with Primary Breast Cancer Disease
Authors: Modlich Olga , Prisack Hans-Bernd , Munnes Marc , Audretsch Werner , Bojar Hans 
Published: September 2005

Abstract
Purpose: Our goal was to identify genes undergoing expressional changes shortly after the beginning of neoadjuvant chemotherapy for primary breast cancer.
Experimental Design: The biopsies were taken from patients with primary breast cancer prior to any treatment and 24 hours after the beginning of the neoadjuvant chemotherapy. Expression analyses from matched pair samples representing 25 patients were carried out with Clontech filter arrays. A subcohort of those 25 paired samples were additionally analyzed with the Affymetrix GeneChip platform. All of the transcripts from both platforms were queried for expressional changes.
Results: Performing hierarchical cluster analysis, we clustered pre- and posttreatment samples from individual patients more closely to each other than the samples taken from different patients. This reflects the rather low number of transcripts responding directly to the drugs used. Although transcriptional drug response occurring during therapy differed between individual patients, two genes (p21WAF1/CIP1 and MIC-1) were up-regulated in posttreatment samples. This could be validated by semiquantitative and real-time reverse transcription-PCR. Partial least- discriminant analysis based on approximately 25 genes independently identified by either Clontech or Affymetrix platforms could clearly discriminate pre- and posttreatment samples. However, correlation of certain gene expression levels as well as of differential patterns and clusters as determined by a different platform was not always satisfying.
Conclusions: This study has demonstrated the potential of monitoring posttreatment changes in gene expression as a measure of the pharmacodynamics of drugs. As a clinical laboratory model, it can be useful to identify patients with sensitive and reactive tumors and to help for optimized choice for sequential therapy and obviously improve relapse- free and overall survival.
Prospective Evaluation of Body Surface Area as a Determinant of Paclitaxel Pharmacokinetics and Pharmacodynamics in Women with Solid Tumors
Authors: Miller Antonius A. , Rosner Gary L. , Egorin Merrill J. , Hollis Donna , Lichtman Stuart M. , Ratain Mark J. ,   for the Cancer and Leukemia Group B
Published: September 2005

Abstract
Purpose: To study a fixed dose (360 mg) of paclitaxel given i.v. over 3 hours to female patients, and to evaluate prospectively the relationships between the following: body surface area and toxicity; body surface area and pharmacokinetics; and pharmacokinetics and toxicity.
Experimental Design: The eligibility criteria included the following: female sex; solid tumors; no more than one prior chemotherapy regimen; no prior paclitaxel; performance status of 0 to 2; and normal organ function. Paclitaxel plasma concentrations were quantified by high-performance liquid chromatography. The area under the curve, total body clearance, and hours above 0.05 μmol/L (T &gt; 0.05) were calculated.
Results: Thirty-two patients were enrolled, and 29 patients received the correct dose and regimen. For statistical analyses, 26 patients had complete follow-up blood counts, 23 patients had complete data to correlate blood counts and area under the curve, and 25 patients had data to correlate blood counts and T &gt; 0.05. The main toxicity was neutropenia of grade 3 and 4 severity in 21% and 25% of patients, respectively, in cycle 1. The worst grade of any toxicity, nadir WBC and absolute neutrophil count, and survival fractions were assessed; no significant relationship was found between body surface area and any measure of toxicity. Body surface area correlated inversely with area under the curve (r = −0.67; P &lt; 0.001) and correlated with total body clearance (r = 0.69; P &lt; 0.001), but body surface area did not correlate with T &gt; 0.05. Neither area under the curve nor total body clearance were correlated with nadir absolute neutrophil count or survival fractions, but a significant correlation was found between T &gt; 0.05 and log(nadir absolute neutrophil count; r = −0.41; P = 0.04).
Conclusions: These results suggest that fixed dosing of paclitaxel is feasible in women, which would simplify the administration of this drug.
Epigenetic Modulation of Retinoic Acid Receptor β2 by the Histone Deacetylase Inhibitor MS-275 in Human Renal Cell Carcinoma
Authors: Wang Xiao-fei , Qian David Z. , Ren Mingqiang , Kato Yukihiko , Wei Yongfeng , Zhang Lu , Fansler Zoya , Clark Doug , Nakanishi Osamu , Pili Roberto 
Published: September 2005

AbstractPurpose: Histone deacetylase (HDAC) inhibitors have been shown to reverse epigenetic repression of certain genes, including retinoic acid receptor β2 (RARβ2). In this study, we examined whether RARβ2 expression is repressed in human renal cell carcinoma (RCC) and whether the HDAC inhibitor MS-275 may revert its epigenetic repression.Experimental Design: Six human tumor RCC cell lines were analyzed for RARβ2 gene expression and for methylation and acetylation status at the promoter level. Modulation of RARβ2 expression and correlation with antitumor activity by combination of MS-275 with 13-cis-retinoic acid (CRA) was assessed in a RARβ2-negative RCC cell line.Results: RARβ2 expression was either strongly present, weakly expressed, or absent in the RCC cell lines analyzed. Methylation-specific PCR indicated that the RARβ2 promoter was partially methylated in three of the cell lines. CRA treatment did not inhibit clonogenic growth in the RARβ2-negative cell line RCC1.18, whereas MS-275 induced a dose-dependent inhibitory effect. A greater inhibitory effect was observed with combination treatment (MS-275 + CRA). Treatment with MS-275 was associated with histone acetylation at the promoter level and synergistic gene reexpression of RARβ2 in combination with CRA. RARβ2 reexpression was associated with synergistic induction of the retinoid-responsive gene HOXA5. In vivo, single-agent CRA treatment showed no significant effect, whereas MS-275 and the combination induced a regression of RCC1.18 tumor xenografts. Discontinuation of treatment produced tumor recurrence in MS-275-treated mice, whereas animals treated with the combination remained tumor free.Conclusion: The HDAC inhibitor MS-275 seems to revert retinoid resistance due to epigenetic silencing of RARβ2 in a human RCC model and has greater antitumor activity in combination with CRA compared with single agents. Thus, the combination of HDAC inhibitors and retinoids may represent a novel therapeutic approach in patients with RCC.
Nucleotide Excision Repair Gene Polymorphisms and Recurrence after Treatment for Superficial Bladder Cancer
Authors: Gu Jian , Zhao Hua , Dinney Colin P. , Zhu Yong , Leibovici Dan , Bermejo Carlos E. , Barton Grossman H. , Wu Xifeng 
Published: September 2005

Abstract
Purpose: Interindividual differences in DNA repair capacity not only modify individual susceptibility to carcinogenesis, but also affect individual response to cancer treatment. Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells involved in the removal of a wide variety of DNA lesions. Polymorphisms in NER genes may influence DNA repair capacity and affect clinical outcome of bladder cancer treatment.
Experimental Design: To test the influence of NER gene polymorphisms on superficial bladder cancer outcome (recurrence and progression), we conducted a follow-up study of 288 patients with superficial bladder cancer. Median follow-up among patients who were recurrence-free at the end of observation was 21.7 months from diagnosis. The specific polymorphic loci examined include XPA [A/G at 5′ untranslated region (UTR)], XPC (poly AT, Ala499Val, Lys939Gln), XPD (Asp312Asn, Lys751Gln), XPG (His1104Asp), ERCC 1 (G/T at 3′ UTR), and ERCC6 (Met1097Val, Arg1230Pro).
Results: The ERCC6 (Met1097Val) polymorphism had a significant impact on recurrence: carriers of at least one variant allele (Val) had a significantly higher recurrence risk than carriers of the wild-type allele (Met/Met; hazard ratio, 1.54; 95% confidence interval, 1.02-2.33). There were no overall statistically significant differences in the distributions of the other polymorphisms between patients with and without recurrence. However, when we combined these variant genotypes, there was a significant trend for an increased recurrence risk with an increasing number of putative high-risk alleles. Using individuals with five or fewer putative high-risk alleles as the reference group, individuals with six to seven risk alleles and individuals with eight or more risk alleles had higher recurrence risks, with hazard ratios of 0.92 (0.54-1.57) and 2.53 (1.48-4.30), respectively (P for trend &lt; 0.001). There was also a significant trend for shorter recurrence-free survival time with increasing number of variant alleles (log rank test, P = 0.0007). When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively). There were no significant individual or joint associations between these polymorphisms and progression.
Conclusions: These data suggest that interindividual differences in DNA repair capacity may have an important impact on superficial bladder cancer recurrence. A pathway-based approach is preferred to study the effects of individual polymorphism on clinical outcomes.
Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model
Authors: Touma Sue Ellen , Goldberg Jonathan S. , Moench Paul , Guo Xiaojia , Tickoo Satish K. , Gudas Lorraine J. , Nanus David M. 
Published: September 2005

Abstract
Purpose: Therapy for advanced renal cell carcinoma (RCC) is ineffective in the majority of patients. We have previously reported that retinoid-induced up-regulation of retinoic acid receptor β (RARβ) correlated with antitumor effects in RCCs. Recent studies show that there is a reduction in the level of RARβ2 expression in cancer cells due in part to histone hypoacetylation. Therefore, we tested whether combining histone deacetylase inhibitors with retinoic acid (RA) would restore RARβ2 receptor expression, leading to increased growth inhibition in RCC cells.
Experimental Design: Cell proliferation, Western blot, and reverse transcription-PCR analyses of two RA-resistant RCC cell lines, SK-RC-39 and SK-RC-45, were assessed in the presence of all-trans retinoic acid (ATRA), trichostatin A (TSA), or the combination of ATRA and TSA. Analysis of apoptosis was also done on SK-RC-39 cells treated with these combinations. Additionally, a xenograft tumor model (SK-RC-39) was used in this study to investigate the efficacy of a liposome-encapsulated, i.v. form of ATRA (ATRA-IV) plus TSA combination therapy.
Results: Enhanced inhibition of the proliferation of RCC cell lines and of tumor growth in a xenograft model was observed with the combination of ATRA plus TSA. Reactivation of RARβ2 mRNA expression was observed in SK-RC-39 and SK-RC-45 cells treated with TSA alone or TSA in combination with ATRA. A partial G0-G1 arrest and increased apoptosis were observed with SK-RC-39 cells on treatment with ATRA and TSA.
Conclusions: The combination of ATRA and the histone deacetylase inhibitor TSA elicits an additive inhibition of cell proliferation in RCC cell lines. These results indicate that ATRA and histone deacetylase inhibitor therapies should be explored for the treatment of advanced RCC.
Pathologic Assessment of Melanoma Sentinel Nodes: A Role for Molecular Analysis Using Quantitative Real-Time Reverse Transcription-PCR for MART-1 and Tyrosinase Messenger RNA
Authors: Abrahamsen Helene Nortvig , Sandahl Sorensen Boe , Nexo Ebba , Hamilton-Dutoit Stephen J. , Larsen Jørn , Steiniche Torben 
Published: September 2005

Abstract
Purpose: Molecular analysis of melanoma sentinel nodes (SN) is sensitive, but poorly specific because metastases cannot be distinguished from benign nevus inclusions (BNI). We investigated whether quantitative reverse transcription-PCR (RT-PCR) detection of MART-1 and tyrosinase mRNAs could improve this specificity and contribute to SN assessment.
Experimental Design: Two hundred twenty SNs from 95 melanoma patients analyzed by extensive immunohistopathology and real-time quantitative RT-PCR.
Results: Using histopathology, SNs and patients were allotted to three diagnostic groups: (a) metastasis positive, (b) BNI positive, and (c) melanocyte-free. Median MART-1 and tyrosinase mRNA levels in SNs were significantly different in patients with metastasis compared with patients with BNIs (P &lt; 0.05) and patients without melanocytic lesions (P &lt; 0.001). However, a “gray-zone” was observed where distinction, based on mRNA levels, could not be made between the three groups. For both genes, the highest mRNA level recorded in each RT-PCR-positive patient was positively correlated with Breslow's tumor thickness. For SNs with metastases, tumor burden was significantly correlated to the mRNA level. Using the presence of a MART-1 RT-PCR signal to detect patients with metastases, a sensitivity of 100% and a negative predictive value of 100% were achieved when extensive immunohistology was used as reference.
Conclusions: Quantitative RT-PCR MART-1 and tyrosinase mRNA analysis cannot be used alone for SN diagnosis because of its poor specificity for melanoma metastasis. However, in approximately one third of cases without RT-PCR evidence of MART-1 expression, extensive histopathologic SN investigation is not necessary, thus substantially reducing the cost of SN analysis. The level of melanocyte-associated mRNA is associated with both tumor thickness and tumor burden as measured histopathologically, suggesting that this may be of prognostic value.