bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma
Authors: Zangari Maurizio , Anaissie Elias , Stopeck Alison , Morimoto Alyssa , Tan Nguyen , Lancet Jeffrey , Cooper Maureen , Hannah Alison , Garcia-Manero Guillermo , Faderl Stephan , Kantarjian Hagop , Cherrington Julie , Albitar Maher , Giles Francis J. 
Published: September 2005

Abstract
Purpose: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with multiple myeloma (MM). VEGF, a soluble circulating angiogenic molecule, acts via receptor tyrosine kinases, including VEGF receptor 2. SU5416 is a small molecule VEGF receptor 2 inhibitor.
Experimental Design: Adult patients with advanced MM were entered on a multicenter phase II study.
Results: Twenty-seven patients (median age 69, range 39–79), median 4 (0–10) lines of prior therapy, 14 with prior thalidomide therapy, received SU5416 at 145 mg/m2 twice weekly i.v. for a median of two 4-week cycles (range 0.2–9). Grade 3/4 toxicities were rarely observed; the most frequent was thrombocytopenia (12%). Mild-to-moderate toxicities included nausea (63%), headache (56%), diarrhea, vomiting (both 37%), and fatigue (33%). There were three thromboembolic episodes and five cases of new onset hypertension. Two (7%) patients did not complete the first 4-week cycle of therapy because of adverse events (pneumonia and headache). There were no objective responses. Four patients had disease stabilization for ≥4 months. A decrease in median VEGF plasma levels was observed in patients with stable disease (n = 7) compared with patients with progressive disease (n = 5). Overall median survival was 42 weeks (range 3–92+).
Conclusions: Although SU5416 had minimal clinical activity, signs of biological activity (decrease in plasma VEGF levels) suggest that angiogenic modulation may be of value in patients with MM.
Detection and Grading of Soft Tissue Sarcomas of the Extremities with 18F-3′-Fluoro-3′-Deoxy-l-Thymidine
Authors: Cobben David C. P. , Elsinga Philip H. , Suurmeijer Albert J. H. , Vaalburg Wim , Maas Bram , Jager Piet L. , Hoekstra Harald J. 
Published: September 2005

Abstract
Purpose: The aim of the study was to investigate the feasibility of 18F-3′-fluoro-3′-deoxy-l-thymidine positron emission tomography (FLT-PET) for the detection and grading of soft tissue sarcoma (STS).
Experimental Design: Nineteen patients with 20 STSs of the extremities were scanned, using attenuation corrected whole-body FLT-PET. Standardized uptake values (SUVs) and tumor:nontumor ratios (TNTs) were compared with histopathological parameters using French and Japanese grading systems.
Results: Mean SUV, maximal SUV, and TNT could differentiate between low-grade (grade 1; n = 6) STS and high-grade (grade 2 and 3; n = 14) STS according to the French grading system (P = 0.001). Mean SUV, max SUV, and TNT correlated with mitotic score, MIB-1 score, the French and Japanese grading system (• = 0.550–0.747).
Conclusions: FLT-PET is able to visualize STS and differentiate between low-grade and high-grade STS. The uptake of FLT correlates with the proliferation of STS.
Predicting Early Failure after Adjuvant Chemotherapy in High-Risk Breast Cancer Patients with Extensive Lymph Node Involvement
Authors: Faneyte Ian F. , Peterse Johannes L. , van Tinteren Harm , Pronk Corina , de Vries Elisabeth G. E. , Rodenhuis Sjoerd , van de Vijver Marc J. 
Published: September 2005

Abstract
Purpose: There is limited knowledge of risk factors for breast cancer recurrence within 2 years. This study aimed to predict early failure and identify high-risk patients for prognostic and therapeutic purposes.
Experimental Design: We studied 739 patients from a randomized trial who were &lt;56 years of age and had ≥4 or more positive lymph nodes, no distant metastases, and no previous other malignancies. After complete surgical treatment, patients received conventional-dose anthracycline-based chemotherapy or a high-dose scheme of anthracycline-based plus alkylating chemotherapy. We assessed clinical and (immuno)histological parameters to predict recurrence within 2 years.
Results: Early failure occurred in 19% (n = 137). Median survival after early failure was limited to 0.7 year. Estrogen and progesterone receptor negativity and visceral relapse predicted poor prognosis. Early failure was associated with young age, large tumors, high histological grade, angio-invasion, apical node metastasis, and ≥10 involved nodes. Estrogen receptor, progesterone receptor, and p27 negativity; HER2 overexpression; and p53 positivity also predicted early failure. The surgical or chemotherapy regimen and histological type did not. The same parameters except tumor size were associated with early death. Grade III, ≥10 involved nodes, and estrogen receptor negativity were independently associated with early failure and together identified a subset of patients (7%) with 3-fold increased early failure and 5-fold increased early death.
Conclusions: Early failure is associated with poor survival. The combination of three commonly determined parameters constitutes a strong predictive model for early failure and death.
Generation of Kidney Cancer-Specific Antitumor Immune Responses Using Peripheral Blood Monocytes Transduced With a Recombinant Adenovirus Encoding Carbonic Anhydrase 9
Authors: Mukouyama Hideki , Janzen Nicolette K. , Hernandez Jose M. , Lam John S. , Caliliw Randy , Wang Allen Y. , Figlin Robert A. , Belldegrun Arie S. , Zeng Gang 
Published: September 2005

AbstractPurpose: Carbonic anhydrase 9 (CA9) is the most promising molecular marker described for renal cell carcinoma (RCC) to date. We investigated whether transduction of monocytes from peripheral blood with adenovirus encoding the CA9 gene (AdV-CA9) could stimulate a T-cell mediated immune response against cancer cells expressing CA9. The ability to consistently generate a T-cell response is an important step toward the development of a CA9-specific RCC vaccine.Experimental Design: AdV-CA9 was generated using the AdEasy system. AdV-CA9-transduced peripheral blood mononuclear cell (PBMC)-derived monocytes were used to raise CTLs from autologous peripheral blood lymphocytes (PBLs). The ability of CTLs to lyse targets expressing CA9 was assessed by 51Cr-release.Results: Monocytes were efficiently transduced with AdV-CA9. In five of six experiments, AdV-CA9-transduced monocytes were able to induce a population of CTLs from bulk PBLs. CTLs were capable of lysing autologous, but not allogeneic monocytes expressing CA9. Furthermore, CTLs were able to lyse autologous RCC tumor cells expressing CA9. The ability of CTLs to lyse relevant targets was blocked by anti-CD3, anti-CD8, and anti-MHC class I antibodies demonstrating a MHC class I restricted response.Conclusions: These results suggest that PBMC-derived monocytes transduced with AdV-CA9 can generate RCC-specific MHC class I restricted CTLs capable of lysing CA9-expressing cancer cells. Transduction of PBMC-derived monocytes with adenovirus provides a simple and effective alternative to the use of dendritic cells for the induction of antigen-specific CTL.
Somatostatin Receptor Subtype 2 Is Expressed by Supratentorial Primitive Neuroectodermal Tumors of Childhood and Can Be Targeted for Somatostatin Receptor Imaging
Authors: Frühwald Michael C. , Rickert Christian H. , O’Dorisio M. Sue , Madsen Mark , Warmuth-Metz Monika , Khanna Geetika , Paulus Werner , Kühl Joachim , Jürgens Heribert , Schneider Peter , Müller Hermann L. 
Published: September 2005

Abstract
Purpose: Although gliomas predominate among central nervous system (CNS) neoplasms in adulthood, embryonal tumors are the most common malignant brain tumors in children. Despite novel treatment approaches, including improved radiotherapy and high-dose chemotherapy, survival rates remain unsatisfactory. The timely diagnosis of residual or recurrent embryonal CNS tumors and thus the earliest possible time point for intervention is often hampered by inaccuracies of conventional imaging techniques. Novel and refined imaging methodologies are urgently needed.
Experimental Design: We have previously demonstrated the use of somatostatin receptor imaging (SRI) in the diagnosis of recurrent and residual medulloblastomas. Here, we evaluated somatostatin receptor type 2 (sst2) expression using an antibody in an array of CNS tumors of childhood. Eight high-grade gliomas, 4 atypical teratoid/rhabdoid tumors, 7 supratentorial primitive neuroectodermal tumors (stPNET), 1 medulloepithelioma (ME), and 8 ependymomas were screened. Tumors positive in vitro were additionally analyzed in vivo using SRI.
Results: Abundant expression of somatostatin receptor type 2 in stPNET, a ME, and ependymomas warranted in vivo imaging of 7 stPNET, 1 rhabdomyosarcoma, 3 ependymomas, 1 ME, and 1 glioblastoma. Although SRI was positive in 6/7 stPNET, 1 rhabdomyosarcoma, and 1 ME, none of the ependymomas nor the glioblastoma could be imaged using SRI. In selected cases SRI was more sensitive in the detection of relapse than conventional imaging by magnetic resonance imaging and computed tomography.
Conclusions: SRI should be considered in the evaluation of residual or recurrent embryonal CNS tumors, especially stPNET. The strengths of SRI lie in the differentiation of reactive tissue changes versus residual or recurrent tumor, the detection of small lesions, and possibly in the distinction of stPNET from gliomas.
Alterations of the Tumor Suppressor Gene
Parkin
in Non-Small Cell Lung Cancer
Authors: Picchio Maria Cristina , Martin Eric Santos , Cesari Rossano , Calin George Adrian , Yendamuri Sai , Kuroki Tamotsu , Pentimalli Francesca , Sarti Manuela , Yoder Kristine , Kaiser Larry R. , Fishel Richard , Croce Carlo Maria 
Published: September 2005

Abstract
Purpose: Parkin, a gene mutated in autosomal recessive juvenile Parkinsonism and mapped to the common fragile site FRA6E on human chromosome 6q25-q27, is associated with a frequent loss of heterozygosity and altered expression in breast and ovarian carcinomas. In addition, homozygous deletions of exon 2 creating deleterious truncations of the Parkin transcript were observed in the lung adenocarcinoma cell lines Calu-3 and H-1573, suggesting that the loss of this locus and the resulting changes in its expression are involved in the development of these tumors.
Experimental Design: We examined 20 paired normal and non-small cell lung cancer samples for the presence of Parkin alterations in the coding sequence and changes in gene expression. We also restored gene expression in the Parkin-deficient lung carcinoma cell line H460 by use of a recombinant lentivirus containing the wild-type Parkin cDNA.
Results: Loss of heterozygosity analysis identified a common region of loss in the Parkin/FRA6E locus with the highest frequency for the intragenic marker D6S1599 (45%), and semi-quantitative reverse transcription-PCR revealed reduced expression in 3 of 9 (33%) lung tumors. Although we did not observe any in vitro changes in cell proliferation or cell cycle, ectopic Parkin expression had the ability to reduce in vivo tumorigenicity in nude mice.
Conclusion: These data suggest that Parkin is a tumor suppressor gene whose inactivation may play an important role in non-small cell lung cancer tumorigenesis.
Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia
Authors: Al-Aynati Maamoun M. , Radulovich Nikolina , Riddell Robert H. , Tsao Ming-Sound 
Published: September 2005

Abstract
Purpose: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (E-cadherin) and β-catenin expression changes during multistage, pancreatic ductal carcinogenesis.
Experimental Design: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, β-catenin, and the phosphorylated glycogen synthase kinase-3β of the Wnt/β-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions.
Results: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P &lt; 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P &lt; 0.0001) and normal ducts (P = 0.05). The β-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P &lt; 0.0001). However, there was a lack of correlation between phosphoSer9-glycogen synthase kinase-3β cytoplasmic expression and β-catenin aberrant nuclear expression (P = 0.07).
Conclusions: Aberration in the expression of E-cadherin and its associated β-catenin is evident in pre-invasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to β-catenin stabilization during pancreatic duct cell carcinogenesis.
Inhibition of Orthotopic Human Bladder Tumor Growth by Lentiviral Gene Transfer of Endostatin
Authors: Kikuchi Eiji , Menendez Silvia , Ohori Makoto , Cordon-Cardo Carlos , Kasahara Noriyuki , Bochner Bernard H. 
Published: September 2005

Abstract
Purpose: Inhibitors of endothelial cell proliferation, such as endostatin, result in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory effects depending on the type of tumor treated. The purpose of this study was to investigate whether local overexpression of endostatin could serve to diminish tumor growth of bladder cancer in vivo.
Experimental Design: We examined the capability of lentiviral-mediated gene transfer in vitro and therapeutic effects of lentivirus-based vectors expressing endostatin on tumor growth using an orthotopic human bladder tumor model.
Results: We found that self-inactivating lentivirus vectors containing green fluorescent protein, alone or in combination with endostatin, were capable of efficient and stable gene transfer to a variety of human bladder tumor cell lines. The production and secretion of endostatin from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by Western blot and competitive enzyme immunoassay. Intravesical instillation of untransduced, green fluorescent protein control lentivirus-transduced, and endostatin-transduced KU-7 cells was performed in murine models to establish orthotopic tumors. Sustained long-term expression of endostatin was achieved in lentivirus-transduced orthotopic bladder tumors, and it was associated with decreased vascularization and inhibition of tumor growth. Lentivirus vector-mediated overexpression of endostatin did not affect the intrinsic production of basic fibroblast growth factor and vascular endothelial growth factor.
Conclusions: These findings suggest that lentivirus-mediated gene transfer might represent an effective strategy for expression of angioinhibitory peptides to achieve inhibition of human bladder cancer proliferation and tumor progression.
Histone Deacetylase Inhibitors Have a Profound Antigrowth Activity in Endometrial Cancer Cells
Authors: Takai Noriyuki , Desmond Julian C. , Kumagai Takashi , Gui Dorina , Said Jonathan W. , Whittaker Sadie , Miyakawa Isao , Koeffler H. Phillip 
Published: September 2005

Abstract
Purpose: HDAC inhibitors (HDACIs) have been shown to inhibit cancer cell proliferation, stimulate apoptosis, and induce cell cycle arrest. Our purpose was to investigate the antiproliferative effects of the HDACIs [suberoyl anilide bishydroxamine, valproic acid (VPA), trichostatin A, and sodium butyrate] against six endometrial cancer cell lines.
Experimental Design: Endometrial cancer cells were treated with a variety of HDACIs, and the effect on cell growth, cell cycle, and apoptosis was measured. The ability of VPA to inhibit the growth of endometrial tumors growing in immunodeficient mice was also assessed.
Results: Clonogenic assays showed that all cancer cell lines were sensitive to the growth inhibitory effect of HDACIs. Cell cycle analysis indicated that treatment with HDACIs decreased the proportion of cells in S phase and increased the proportion of cells in the G0-G1 and/or G2-M phases of the cell cycle. Terminal deoxynucleotidyl transferase-mediated nick end labeling assays showed that HDACIs induced apoptosis. This was concomitant with altered expression of genes related to malignant phenotype, including an increase in p21Waf1, p27Kip7, and E-cadherin and a decrease in Bcl-2 and cyclin-D1 and -D2. Chromatin immunoprecipitation analysis revealed a remarkable increase in levels of acetylated histones associated with the p21 promoter after suberoyl anilide bishydroxamine treatment. In nude mice experiments, VPA inhibited significantly human uterine tumor growth without toxic side effects.
Conclusions: These results suggest that HDACIs are effective in inhibiting growth of endometrial cancer cells in vitro and in nude mice, without toxic side effects. The findings raise the possibility that HDACIs may prove particularly effective in treatment of endometrial cancers.
p73 Expression Is Associated with the Cellular Radiosensitivity in Cervical Cancer after Radiotherapy
Authors: Liu Stephanie Si , Leung Rebecca Ching-Yu , Chan Kelvin Yuen-Kwong , Chiu Pui-Man , Cheung Annie Nga-Yin , Tam Kar-Fai , Ng Tong-Yow , Wong Ling-Chui , Ngan Hextan Yuen-Sheung 
Published: September 2005

Abstract
Apoptosis is one of the causes of cell death in cervical cancer following radiotherapy (S. S. Liu et al., Eur. J. Cancer, 37: 1104–1110, 2001). By studying the gene expression profile with cDNA apoptotic array, the p73 gene was found overexpressed in radiosensitive cervical cancers when compared with radioresistant ones. To investigate the role of the p73 gene in relation to clinical assessment of radiosensitivity in cervical cancer based on the findings of residual tumor cells in cervical biopsies after completion of radiotherapy, we studied the protein expression of p73 in 59 cervical cancers after radiotherapy and 68 normal cervices using immunohistochemistry. The expression of p73 was found to be significantly increased in cancer samples and, more importantly, in those samples sensitive to radiotherapy (P &lt; 0.001). The overexpression of p73 actually predicted a better prognosis in cervical cancer patients (P &lt; 0.001). To investigate the possible involvement of p73 downstream genes, the protein expressions of p21 and Bax were studied. The expression of p21, but not Bax, was found to be positively correlated with the expression of p73 (P = 0.001). Furthermore, the epigenetic regulation of p73 expression via DNA methylation was also investigated in 103 cervical cancers and 124 normals. Hypermethylation of p73 gene was observed in 38.8% of cervical cancers, and it was significantly associated with reduced or absent p73 expression (P &lt; 0.001). Reactivation of p73 expression in two cervical cancer cell lines by demethylation treatment supported the role of methylation in the regulation of p73 expression. Our findings suggested that p73 expression was related to the radiosensitivity of cervical cancer cells and may play an important role in the regulation of cellular radiosensitivity.
A Novel Conditionally Replicative Adenovirus Vector Targeting Telomerase-Positive Tumor Cells
Authors: Huang Qian , Zhang Xiuwu , Wang He , Yan Bin , Kirkpatrick John , Dewhrist Mark W. , Li Chuan-Yuan 
Published: September 2005

Abstract
Purpose: To develop a novel conditionally replicative adenovirus vector that targets telomerase-positive cancer cells.
Experimental Design: A telomerase gene-derived promoter was used to control the expression of the E1a gene so that the E1a gene is only expressed in telomerase-positive tumor cells. In addition, a reporter gene was also engineered into the vector so that its infection and replication can be monitored easily.
Results: A novel recombinant adenovirus vector that could selectively replicate in telomerase-positive cancer cells was made successfully. This vector showed active replication in a panel of cancer cells and minimal replication in normal human fibroblast or epithelial cells. The recombinant vector could effectively lyse various cultured tumor cells even at very low multiplicity of infection. The replication efficiency in tumor cells is over 103-fold more than normal fibroblast and epithelial cells. In s.c. tumor models, the newly developed telomerase-selective adenovirus vectors exhibited significantly more virus replication and reporter gene expression.
Conclusions: The telomerase-targeted adenovirus vector has significant potential as an oncolytic virus as well as a tumor-specific therapeutic gene delivery vehicle.
Antisense Oligonucleotide Targeting of Raf-1
Authors: Mullen Peter , McPhillips Fiona , MacLeod Kenneth , Monia Brett , Smyth John F. , Langdon Simon P. 
Published: September 2005

Abstract
Purpose: We sought to identify determinants of growth response to the Raf-1-targeted antisense oligonucleotide (ASO; ISIS 5132) using a large panel of ovarian cancer cell lines.
Experimental Design: First-(ISIS 5132) and second-generation (ISIS 13650) anti-Raf 1 ASOs were compared with control oligonucleotides. Growth was assessed by cell counts; apoptosis was assessed by poly(ADP-ribose) polymerase cleavage; and cell cycle analysis was assessed by flow cytometry. Protein expression was detected by Western blot analysis, and mRNA expression was detected by quantitative reverse transcription-PCR. Raf-1 kinase activity was detected by anti-Raf-1 immunoprecipitation, followed by myelin basic protein phosphorylation.
Results: A panel of 15 ovarian cancer cell lines was used to model a range of growth responses to ASOs targeting Raf-1 mRNA. Growth inhibition varied from 10% to &gt;90% inhibition. Growth inhibition was associated with increased apoptosis and accumulation of cells in the G2-M and S phases of the cell cycle. Growth response was not related to level of Raf-1 protein expression, Raf-1 kinase activity, intracellular ASO uptake, or degree of Raf-1 protein inhibition. However, ASO growth response was associated with a high proportion of Raf-1 mRNA [relative to total (i.e., Raf-1 + A-Raf + B-Raf) Raf mRNA] and significantly higher Raf-1 kinase activity induction following growth factor (transforming growth factor α) stimulation in the cell lines consistent with dependency of these cell lines on Raf-1.
Conclusions: These data indicate that ovarian cancers demonstrate differential sensitivity to ASOs targeted against Raf-1, and target expression levels and degree of utilization of Raf-1 signaling are implicated. Clinically sensitive tumors could feasibly be identified.