bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor in Patients with Refractory Solid Tumors
Authors: Beutel Gernot , Glen Hilary , Schöffski Patrick , Chick Jon , Gill Stan , Cassidy James , Twelves Chris 
Published: September 2005

Abstract
Purpose: OSI-7904L is a liposomal formulation of a potent noncompetitive thymidylate synthase inhibitor (TSI) that does not require polyglutamation for activity. This phase I study was done to establish the safety, tolerability, maximum tolerated dose, recommended dose, and pharmacokinetics of OSI-7904L in patients with advanced solid tumors refractory to standard therapy.
Design: OSI-7904L was given as a 30-minute i.v. infusion every 21 days to 31 patients at eight dose levels from 0.4 to 15.0 mg/m2, using three patients per dose level, up to 10 patients at the recommended dose. Baseline plasma homocysteine and 2′-deoxyuridine and genotype polymorphism were measured as potential predictors of biological activity.
Results: Minimal toxicity was reported up to 9.6 mg/m2, but dose-limiting toxicity was seen in both patients at 15 mg/m2 including stomatitis, fatigue, tachyarrhythmia, rash and hand-foot syndrome, diarrhea, and fatal neutropenic sepsis. Other toxicity such as nausea and vomiting was mild or moderate. This resulted in the investigation of an intermediate dose level of 12 mg/m2, identified as the recommended dose for phase II studies. Prolonged disease stabilization was reported in 11 of 31 heavily pretreated patients. Pharmacokinetic data indicate that this liposomal formulation alters the disposition properties of the parent drug resulting in a prolonged plasma residence time.
Conclusions: OSI-7904L given as a 30-minute i.v. infusion every 21 days is feasible and well tolerated at the recommended phase II dose of 12 mg/m2. The main toxicities are rash, pruritis, lethargy, stomatitis, and myelosuppression. Observed toxicities were predictable and characteristic for TSIs.
Clinical Evaluation of Dendritic Cell Vaccination for Patients with Recurrent Glioma: Results of a Clinical Phase I/II Trial
Authors: Yamanaka Ryuya , Homma Junpei , Yajima Naoki , Tsuchiya Naoto , Sano Masakazu , Kobayashi Tsutomu , Yoshida Seiichi , Abe Takashi , Narita Miwako , Takahashi Masuhiro , Tanaka Ryuichi 
Published: September 2005

AbstractPurpose: To investigate the safety and the immunologic and clinical responses of dendritic cell therapy for patients with recurrent malignant glioma.Experimental Design: Twenty-four patients with recurrent malignant glioma (6 grade 3 and 18 grade 4 patients) were evaluated in a phase I/II clinical study of dendritic cell therapy. All patients were resistant to the standard maximum therapy. The patient's peripheral blood dendritic cells were generated with granulocyte macrophage colony-stimulating factor, plus interleukin 4 with or without OK-432, and pulsed with an autologous tumor lysate. Dendritic cells were injected intradermally, or both intratumorally and intradermally every 3 weeks.Results: The protocols were well tolerated with only local redness and swelling at the injection site in several cases. Clinical responses were as follows: 1 patient with partial response, 3 patients with minor response, 10 patients with stable disease, and 10 patients with progressive disease. The patients whose dendritic cells were matured with OK-432 had longer survival times than the dendritic cells from patients without OK-432 maturation. The patients with both intratumoral and intradermal administrations had a longer survival time than the patients with intradermal administration only. Increased ELISPOT and delayed-type hypersensitivity responses after vaccination could provide good laboratory markers to predict the clinical outcome of patients receiving dendritic cell vaccination. The overall survival of patients with grade 4 glioma was 480 days, which was significantly better than that in the control group.Conclusions: This study showed the safety and clinical response of autologous tumor lysate-pulsed dendritic cell therapy for patients with malignant glioma. Dendritic cell therapy is recommended for further clinical studies in malignant glioma patients.
FGFR3 and Tp53 Mutations in T1G3 Transitional Bladder Carcinomas: Independent Distribution and Lack of Association with Prognosis
Authors: Hernández Silvia , López-Knowles Elena , Lloreta Josep , Kogevinas Manolis , Jaramillo Roberto , Amorós Alex , Tardón Adonina , García-Closas Reina , Serra Consol , Carrato Alfredo , Malats Núria , Real Francisco X. 
Published: September 2005

Abstract
FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.
Down-Regulation of Signal Transducer and Activator of Transcription 3 Expression Using Vector-Based Small Interfering RNAs Suppresses Growth of Human Prostate Tumor In vivo
Authors: Gao Lifang , Zhang Ling , Hu Jiadi , Li Feng , Shao Yueting , Zhao Dan , Kalvakolanu Dhananjaya V. , Kopecko Dennis J. , Zhao Xuejian , Xu De-Qi 
Published: September 2005

Abstract
Purpose: Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a variety of cancers and it is a common feature of prostate cancer. Thus, Stat3 represents a promising molecular target for tumor therapy. We applied a DNA vector–based Stat3-specific RNA interference approach to block Stat3 signaling and to evaluate the biological consequences of Stat3 down-modulation on tumor growth using a mouse model.
Experimental Design: To investigate the therapeutic potential of blocking Stat3 in cancer cells, three small interfering RNAs (siRNA; Stat3-1, Stat3-2, and Stat3-3) specific for different target sites on Stat3 mRNA were designed and used with a DNA vector–based RNA interference approach expressing short hairpin RNAs to knockdown Stat3 expression in human prostate cancer cells in vitro as well as in vivo.
Results: Of the three equivalently expressed siRNAs, only Stat3-3 and Stat3-2, which target the region coding for the SH2 domain and the coiled-coil domain, respectively, strongly suppressed the expression of Stat3 in PC3 and LNCaP cells. The Stat3-1 siRNA, which targeted the DNA-binding domain, exerted no effect on Stat3 expression, indicating that the gene silencing efficiency of siRNA may be dependent on the local structure of Stat3 mRNA. The Stat3 siRNAs down-regulated the expression of Bcl-2 (an antiapoptotic protein), and cyclin D1 and c-Myc (cell growth activators) in prostate cancer cells. Inhibition of Stat3 and its related genes was accompanied by growth suppression and induction of apoptosis in cancer cells in vitro and in tumors implanted in nude mice.
Conclusions: These data indicate that Stat3 signaling is a promising molecular target for prostate cancer therapy and that vector-based Stat3 siRNA may be useful as a therapeutic agent for treatment of prostate cancer.
Phosphorylation of the 6-Phosphofructo-2-Kinase/Fructose 2,6-Bisphosphatase/PFKFB3 Family of Glycolytic Regulators in Human Cancer
Authors: Bando Hidenori , Atsumi Toshiya , Nishio Taro , Niwa Hirokatsu , Mishima Shinya , Shimizu Chikara , Yoshioka Narihito , Bucala Richard , Koike Takao 
Published: September 2005

Abstract
Purpose: Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of phosphofructokinase, which is a rate-limiting enzyme of glycolysis. The concentration of F2,6BP depends on the activity of the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase). Four genes encoding PFK-2/FBPase have been identified and termed PFKFB1 to PFKFB4. PFKFB3 protein is expressed in high levels in human tumors in situ. The purpose of this study was to determine the role of functional interactions between the phosphorylation of PFKFB3 and activated glycolysis in human cancer cells.
Experimental Design: cDNA from several human tumor cell lines and human colon carcinoma were analyzed by reverse transcription-PCR to identify different splicing variants of PFKFB3. The effect of phosphorylation of Ser461 was studied by recombinantly replacing this residue with glutamate (PFKFB3S461E). The phosphorylation of PFKFB3 protein in human cancer was determined by immunostaining using an anti-phospho-PFK-2(PFKFB3) antibody.
Results: Two splicing variants of PFKFB3 are expressed in human cancer cell lines: PFKFB3-ACG and PFKFB3-AG. Quantitative, real-time PCR analysis confirmed the overexpression of PFKFB3 mRNA in colon carcinoma, with the dominant variant being the PFKFB3-ACG isoform that contains a phosphorylation site at Ser461. Forced expression of PFKFB3-ACG in COS-7 cells resulted in enhanced glycolysis. Introduction of PFKFB3-ACGS461E into COS-7 cells led to increased the lactate production and cell proliferation. Highly phosphorylated PFKFB3 protein was found in human tumor cells, vascular endothelial cells, and smooth muscle cells, as determined by immunostaining with an anti-phospho-PFK-2(PFKFB3) antibody.
Conclusions: These findings support a potential role for the phosphorylation of PFKFB3 protein in the progression of cancer and angiogenesis.
Evaluating the Expression and Prognostic Value of TRAIL-R1 and TRAIL-R2 in Breast Cancer
Authors: McCarthy Mary M. , Sznol Mario , DiVito Kyle A. , Camp Robert L. , Rimm David L. , Kluger Harriet M. 
Published: September 2005

Abstract
Purpose: The cell surface receptors tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2 transmit apoptotic signals, and agents that activate these receptors are in clinical development. We sought to determine the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in early-stage breast cancer.
Experimental Design: Tissue microarrays containing specimens from 655 breast cancer patients with 20-year follow-up were employed and evaluated with our automated quantitative analysis (AQUA) system. The system uses cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and measures intensity of TRAIL receptor expression using Cy5 conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathologic variables. TRAIL-R1 and TRAIL-R2 expression were similarly studied on 95 unmatched normal breast specimens.
Results: TRAIL-R1 expression was not associated with survival. High TRAIL-R2 expression strongly correlated with decreased survival (P = 0.0005). On multivariate analysis, high TRAIL-R2 expression remained an independent prognostic marker, as did nodal status and tumor size. High TRAIL-R2 expression correlated strongly with lymph node involvement (P = 0.0003). TRAIL-R2 expression was stronger in malignant specimens than in normal breast epithelium (P &lt; 0.0001).
Conclusions: High TRAIL-R2 expression was independently associated with decreased survival in breast cancer. The biological basis and the sensitivity of high TRAIL-R2 expressing cells to TRAIL agonists and/or chemotherapy are subject to further investigation. Evaluation of TRAIL-R2 expression in early-stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted adjuvant treatment. Clinical trials involving TRAIL-R2 agonists should stratify patients based on TRAIL-R2 expression.
Malignant B-Lymphoid Cells with Bone Lesions Express Receptor Activator of Nuclear Factor-κB Ligand and Vascular Endothelial Growth Factor to Enhance Osteoclastogenesis
Authors: Shibata Hironobu , Abe Masahiro , Hiura Kenji , Wilde Javier , Moriyama Keiji , Sano Toshiaki , Kitazoe Ken-ichi , Hashimoto Toshihiro , Ozaki Shuji , Wakatsuki Shingo , Kido Shinsuke , Inoue Daisuke , Matsumoto Toshio 
Published: September 2005

Abstract
Purpose: Receptor activator of nuclear factor-κB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms.
Experimental Design and Results: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell–derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells.
Conclusions: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.
Glucocorticoids Inhibit Cell Death in Ovarian Cancer and Up-regulate Caspase Inhibitor cIAP2
Authors: Runnebaum Ingo B. , Brüning Ansgar 
Published: September 2005

Abstract
Purpose: Almost all patients with epithelial ovarian cancer receive chemotherapy and, concurrently, the synthetic steroid hormone dexamethasone to alleviate the side effects. This study aims to test the impact of steroid hormones on the apoptosis of epithelial ovarian cancer cells and to identify its mediators.
Experimental Design: Tumor cell lines from 19 patients with advanced epithelial ovarian cancer were analyzed for glucocorticoid receptor, estrogen receptor, progesterone receptor, and androgen receptor expression. Cells were incubated with corresponding steroid hormones at serum-equivalent doses in hormone-depleted medium. Apoptosis was induced by application of tumor necrosis factor–related apoptosis-inducing ligand or staurosporine and determined by poly(ADP-ribose)polymerase cleavage and cell survival. Microarray with 8K cDNA chips including apoptosis-relevant genes was used to study genes regulated by glucocorticoids.
Results: In cell culture, tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis in OV-MZ-30 and OV-MZ-31 cells was reduced after treatment with dexamethasone or cortisol, but not with estradiol, progesterone, or androstenedione. Microarray analysis revealed a 7-fold up-regulation of the caspase inhibitor cIAP2 by dexamethasone in OV-MZ-30 and OV-MZ-31 cells. cIAP2 up-regulation by glucocorticoids was confirmed by RT-PCR and Western blot analysis in OV-MZ-30, OV-MZ-31, OV-CAR3, and SK-OV-3 cells. Down-regulation of cIAP2 expression by small interfering RNA sensitized SK-OV-3 cells to apoptosis inducer staurosporine. Under clinical conditions, treatment with dexamethasone was associated with significant up-regulation of cIAP2 in the ascites cells.
Conclusions: Activation of the glucocorticoid receptor in epithelial ovarian cancer cells caused an antiapoptotic effect associated with the enhanced cellular expression level of cIAP2. Dexamethasone pretreatment of epithelial ovarian cancer patients receiving apoptosis-inducing chemotherapy raises questions about a negative effect on antitumor efficacy.
Can Molecular Markers Predict When to Implement Treatment with Aromatase Inhibitors in Invasive Breast Cancer?
Authors: Tovey Sian , Dunne Barbara , Witton Caroline J. , Forsyth Amanda , Cooke Timothy G. , Bartlett John M.S. 
Published: September 2005

Abstract
Purpose: Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)–negative patients. We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)–positive tamoxifen-treated breast cancer patients.
Experimental Design: Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer–related relapse on tamoxifen) was done.
Results: HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P= 0.017). HER1-3-positive and/or PR-negative patients combined as a “high-risk” group were significantly more likely to relapse on tamoxifen in univariate (P &lt; 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status.
Conclusions: We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.
High-Dose Radioimmunotherapy Combined with Fixed, Low-Dose Paclitaxel in Metastatic Prostate and Breast Cancer by Using a MUC-1 Monoclonal Antibody, m170, Linked to Indium-111/Yttrium-90 via a Cathepsin Cleavable Linker with Cyclosporine to Prevent Human Anti-mouse Antibody
Authors: Richman Carol M. , DeNardo Sally J. , O'Donnell Robert T. , Yuan Aina , Shen Sui , Goldstein Desiree S. , Tuscano Joseph M. , Wun Ted , Chew Helen K. , Lara Primo N. , Kukis David L. , Natarajan Arutselvan , Meares Claude F. , Lamborn Kathleen R. , DeNardo Gerald L. 
Published: September 2005

Abstract
Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer.
Experimental Design: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody.
Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine.
Conclusions: 111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, “fractionated” therapy that could enhance clinical response.