bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors
Authors: Berkenblit Anna , Eder Joseph P. , Ryan David P. , Seiden Michael V. , Tatsuta Noriaki , Sherman Matthew L. , Dahl Thomas A. , Dezube Bruce J. , Supko Jeffrey G. 
Published: January 2007

Abstract
Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel.
Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m2, respectively. After increasing paclitaxel to 175 mg/m2, the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle.
Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m2 paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m2, and 438 mg/m2 was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 ± 0.24 h) and a low steady-state apparent volume of distribution (25.1 ± 8.1 L/m2). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose.
Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.
A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer
Authors: Seiwert Tanguy Y. , Connell Philip P. , Mauer Ann M. , Hoffman Philip C. , George Christopher M. , Szeto Livia , Salgia Ravi , Posther Katherine E. , Nguyen Binh , Haraf Daniel J. , Vokes Everett E. 
Published: January 2007

AbstractPurpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy.Experimental Design: Patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower).Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6).Conclusions: The combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.
Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Weekly Paclitaxel in Patients with Solid Tumors
Authors: Ready Neal E. , Lipton Alan , Zhu Yali , Statkevich Paul , Frank Emily , Curtis Dolores , Bukowski Ronald M. 
Published: January 2007

Abstract
Purpose: To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib (Sarasar, Schering-Plough Corp., Kenilworth, NJ) in combination with weekly paclitaxel in patients with solid tumors. Tolerability, pharmacokinetics, safety, and dose-limiting toxicity were characterized.
Experimental Design: Patients were enrolled from January 2000 to May 2001. Lonafarnib was administered continuously orally twice daily at doses of 100, 125, and 150 mg in combination with paclitaxel at doses of 40, 60, or 80 mg/m2 i.v. over 1 h weekly in 28-day cycles in a phase I design. Plasma samples for determinations of lonafarnib and paclitaxel concentrations were collected at selected time points.
Results: Twenty-seven patients were enrolled. The maximum tolerated dose (the dose level below where dose-limiting toxicity occurred and the recommended phase II dose) was lonafarnib 125 mg/m2 twice daily and paclitaxel 80 mg/m2 weekly. Dose-limiting toxicity was neutropenia with or without fever, which occurred in two of three patients treated at the lonafarnib 150 mg twice daily dose level. Diarrhea was a common side effect of lonafarnib but usually was mild to moderate in severity and could be controlled with standard medication without lonafarnib dose adjustment. Other reported adverse events included nausea, vomiting, fatigue, and taste changes. These adverse events were neither more frequent nor more severe than would be expected with paclitaxel alone. There were no apparent pharmacokinetic interactions between weekly paclitaxel and continuous twice-daily lonafarnib.
Conclusions: The recommended dose of lonafarnib for phase II trials is 125 mg orally twice daily when combined with weekly paclitaxel 80 mg/m2. The dose-limiting toxicity was neutropenia.
Regulation of Hepatocyte Growth Factor Activator Inhibitor 2 by Hypoxia in Breast Cancer
Authors: Generali Daniele , Fox Stephen B. , Berruti Alfredo , Moore John W. , Brizzi Maria Pia , Patel Nilay , Allevi Giovanni , Bonardi Simone , Aguggini Sergio , Bersiga Alessandra , Campo Leticia , Dogliotti Luigi , Bottini Alberto , Harris Adrian L. 
Published: January 2007

Abstract
Purpose: To examine the in vitro regulation of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in breast cancer cells and the in vivo predictive role for the efficacy of chemoendocrine primary therapy in patients with breast cancer.
Materials and Methods: HAI-2 regulation was studied in a panel of breast cancer cell lines comparing normoxia to hypoxia. The effect of HIF-1α RNAi on HAI-2 expression was evaluated in these cells. HAI-2 was examined in breast cancer using in situ hybridization and immunohistochemistry. The HAI-2 predictive role was assessed in T2-4 N0-1 breast cancers (n = 177) enrolled in a neoadjuvant randomized trial comparing epirubicin versus epirubicin + tamoxifen.
Results: HAI-2 mRNA and protein were regulated by hypoxia in the c-erbB2–positive cell lines, SKBR3 and BT474, and controlled by HIF-1α in these cells. Immunohistochemistry confirmed this profile with high expression of HAI-2 in c-erbB2–positive breast cancer. HAI-2 was correlated with T status (P &lt; 0.004), node involvement (P = 0.01), and c-erbB2 expression (P = 0.05). HAI-2 also correlated with hypoxia markers such as carbonic anhydrase IX expression (P = 0.01) and HIF-1α. Additionally, high levels of HAI-2 were a significant predictor for poor clinical complete response to preoperative epirubicin in univariate (P = 0.01) and multivariate analyses (P = 0.016). No correlation with disease-free survival and survival was observed.
Conclusion: HAI-2 expression in breast cancer correlated with tumor aggressiveness in vivo. It is a HIF target in c-erbB2–positive cells and it is an independent negative predictive factor of efficacy of anthracycline therapy. The interaction of HAI-2 with the hepatocyte growth factor activation pathway may be a useful site for therapeutic intervention.
Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Predicts Tumor Differentiation, P-glycoprotein Expression, and Outcome after Resection in Hepatocellular Carcinoma
Authors: Seo Satoru , Hatano Etsuro , Higashi Tatsuya , Hara Tadashi , Tada Masaharu , Tamaki Nobuyuki , Iwaisako Keiko , Ikai Iwao , Uemoto Shinji 
Published: January 2007

Abstract
Purpose: To investigate the diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for prediction of tumor differentiation, P-glycoprotein (P-gp) expression, and outcome in hepatocellular carcinoma (HCC) patients.
Experimental Design: Seventy HCC patients who underwent curative resection were prospectively enrolled in the study. FDG-PET was done 2 weeks preoperatively, and the standardized uptake value (SUV) and the tumor to nontumor SUV ratio (TNR) were calculated from FDG uptake. Tumor differentiation and P-gp expression were examined with H&E and immunohistochemical staining, respectively.
Results: SUV and TNR were significantly higher in poorly differentiated HCCs than in well-differentiated (P = 0.001 and 0.002) and moderately differentiated HCCs (P &lt; 0.0001 and P &lt; 0.0001). The percentage P-gp–positive area was significantly higher in well-differentiated HCCs than in poorly differentiated (P &lt; 0.0001) and moderately differentiated HCCs (P = 0.0001). Inverse correlations were found between SUV and P-gp expression (r = −0.44; P &lt; 0.0001) and between TNR and P-gp expression (r = −0.47; P = 0.01). Forty-three (61.4%) patients had postoperative recurrence. The overall and disease-free survival rates in the high TNR (≥2.0) group were significantly lower than in the low TNR (&lt;2.0) group (P = 0.0001 and 0.0002). In multivariate analysis, a high α-fetoprotein level (risk ratio, 5.46; P = 0.003; risk ratio, 8.78; P = 0.006) and high TNR (risk ratio, 1.3; P = 0.03; risk ratio, 1.6; P = 0.02) were independent predictors of postoperative recurrence and overall survival.
Conclusions: The results suggest that preoperative FDG-PET reflects tumor differentiation and P-gp expression and may be a good predictor of outcome in HCC.
Cyclin A Immunocytology as a Risk Stratification Tool for Barrett's Esophagus Surveillance
Authors: Lao-Sirieix Pierre , Lovat Laurence , Fitzgerald Rebecca C. 
Published: January 2007

Abstract
Purpose: Endoscopic surveillance of Barrett's esophagus (BE) by histopathologic biopsy assessment is suboptimal. A proliferation marker, minichromosome maintenance protein 2, has potential as a biomarker but lacks specificity. We hypothesized that cyclin A, which detects a proportion of proliferating cells, would be more specific. Because cytologic sampling has clinical advantages, we also evaluated the efficacy of cyclin A in endoscopic brushing samples.
Experimental Design: A cross-sectional cyclin A immunostaining study was done in 77 patients attending for BE surveillance and 17 patients undergoing evaluation of esophageal adenocarcinoma. The control tissues were as follows: 30 squamous esophagus, 20 gastric antrum, and 13 duodenum. A nested case-control study was done within the same surveillance cohort (16 progressors compared with 32 matched controls) to determine the relative risk for progression. Immunocytology was done for endoscopic brushings collected prospectively from 75 BE ± dysplasia and 33 esophageal adenocarcinomas.
Results: Surface expression of cyclin A in BE samples correlated with the degree of dysplasia (P = 0.016). In the case-control cohort, patients with biopsies expressing cyclin A at the surface were more likely to progress to adenocarcinoma than those who did not (odds ratio, 7.5; 95% confidence interval, 1.8-30.7). The sensitivity and specificity of cyclin A expression in brushings for the detection of high-grade dysplasia and cancer patients were 97.8% and 58.7%, respectively. The associated negative predictive value was 97.4%.
Conclusions: Cyclin A immunopositivity correlates with cancer risk. Application of this marker to endoscopic brushings could be used as a first step to identify BE patients with the highest risk of progression.
CHIR-124, a Novel Potent Inhibitor of Chk1, Potentiates the Cytotoxicity of Topoisomerase I PoisonsIn vitroandIn vivo
Authors: Tse Archie N. , Rendahl Katherine G. , Sheikh Tahir , Cheema Haider , Aardalen Kim , Embry Millicent , Ma Sylvia , Moler Edward J. , Ni Zhi Jie , Lopes de Menezes Daniel E. , Hibner Barbara , Gesner Thomas G. , Schwartz Gary K. 
Published: January 2007

AbstractPurpose: Chk1 kinase is a critical regulator of both S and G2-M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor effects of a novel Chk1 inhibitor, CHIR124.Experimental Design: CHIR-124 was evaluated for its ability to abrogate cell cycle checkpoints, to potentiate cytotoxicity, and to inhibit Chk1-mediated signaling induced by topoisomerase I poisons in human tumor cell line and xenograft models.Results: CHIR-124 is a quinolone-based small molecule that is structurally unrelated to other known inhibitors of Chk1. It potently and selectively inhibits Chk1 in vitro (IC50 = 0.0003 μmol/L). CHIR-124 interacts synergistically with topoisomerase poisons (e.g., camptothecin or SN-38) in causing growth inhibition in several p53-mutant solid tumor cell lines as determined by isobologram or response surface analysis. CHIR-124 abrogates the SN-38–induced S and G2-M checkpoints and potentiates apoptosis in MDA-MD-435 breast cancer cells. The abrogation of the G2-M checkpoint and induction of apoptosis by CHIR-124 are enhanced by the loss of p53. We have also shown that CHIR-124 treatment can restore the level of cdc25A protein, which is normally targeted by Chk1 for degradation following DNA damage, indicating that Chk1 signaling is suppressed in the presence of CHIR-124. Finally, in an orthotopic breast cancer xenograft model, CHIR-124 potentiates the growth inhibitory effects of irinotecan by abrogating the G2-M checkpoint and increasing tumor apoptosis.Conclusions: CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase I poisons.
Copper-67 Radioimmunotherapy and Growth Inhibition by Anti–L1-Cell Adhesion Molecule Monoclonal Antibodies in a Therapy Model of Ovarian Cancer Metastasis
Authors: Knogler Karin , Grünberg Jürgen , Zimmermann Kurt , Cohrs Susan , Honer Michael , Ametamey Simon , Altevogt Peter , Fogel Mina , Schubiger P. August , Novak-Hofer Ilse 
Published: January 2007

AbstractPurpose: We examined the tumor-targeting and therapeutic effects of 67Cu-labeled single amino acid mutant forms of anti-L1 monoclonal antibody chCE7 in nude mice with orthotopically implanted SKOV3ip human ovarian carcinoma cells.Experimental Design: For radioimmunotherapy, chCE7 antibodies with a mutation of histidine 310 to alanine (chCE7H310A) and a mutation of asparagine 297 to glutamine (chCE7agl) were generated to achieve more rapid blood clearance. Biodistributions of 67Cu-4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid tetrachloride (CPTA)–labeled mutant antibodies were measured in nude mice bearing SKOV3ip human ovarian cancer metastases. The effects of single i.v. injections of 67Cu-chCE7agl alone on tumor reduction and survival were investigated. In addition, a combination of low-dose 67Cu-radioimmunotherapy with unlabeled anti-L1 antibody L1-11A on survival was investigated.Results: 67Cu-CPTA-chCE7agl showed high (up to 49% ID/g) and persistent (up to 168 h) uptake in SKOV3ip metastases, with low levels in normal tissues. 67Cu-CPTA-chCE7H310A revealed a shorter half-life in the blood and a lower tumor uptake and retention. A single low dose of 4 MBq of 67Cu-chCE7agl reduced tumor growth but did not prolong survival significantly, whereas a single 10.5 MBq dose of 67Cu-chCE7agl reduced tumor growth and prolonged survival significantly. The combination of unlabeled monoclonal antibody L1-11A with a subtherapeutic dose of 67Cu-radioimmunotherapy also prolonged survival significantly.Conclusion: The results show improved pharmacokinetics and biodistributions as well as the therapeutic effect of the 67Cu-labeled single amino acid mutant chCE7agl. Therapeutic data indicate, for the first time, the feasibility of combining anti–L1-directed growth inhibition and 67Cu-radioimmunotherapy, thereby increasing the efficiency of antibody treatment of metastatic ovarian carcinoma.
Centromere Protein H Is a Novel Prognostic Marker for Nasopharyngeal Carcinoma Progression and Overall Patient Survival
Authors: Liao Wen-Ting , Song Li-Bing , Zhang Hui-Zhong , Zhang Xing , Zhang Ling , Liu Wan-Li , Feng Yan , Guo Bao-Hong , Mai Hai-Qiang , Cao Su-Mei , Li Man-Zhi , Qin Hai-De , Zeng Yi-Xin , Zeng Mu-Sheng 
Published: January 2007

Abstract
Purpose: The aim of the present study was to analyze the expression of Centromere protein H (CENP-H), one of the fundamental components of the human active kinetochore, in nasopharyngeal carcinoma (NPC) and to correlate it with clinicopathologic data, including patient survival.
Experimental Design: Using reverse transcription-PCR and Western blot, we detected the expression of CENP-H in normal nasopharyngeal epithelial cells, immortalized nasopharyngeal epithelial cell lines, and NPC cell lines. Using immunohistochemistry, we analyzed CENP-H protein expression in 160 clinicopathologically characterized NPC cases. Statistical analyses were applied to test for prognostic and diagnostic associations.
Results: Reverse transcription-PCR and Western blot showed that the expression level of CENP-H was higher in NPC cell lines and in immortalized nasopharyngeal epithelial cells than in the normal nasopharyngeal epithelial cell line at both transcriptional and translational levels. By immunohistochemical analysis, we found that 76 of 160 (47.5%) paraffin-embedded archival NPC biopsies showed high expression of CENP-H. Statistical analysis showed that there was a significant difference of CENP-H expression in patients categorized according to clinical stage (P = 0.024) and T classification (P = 0.027). Patients with higher CENP-H expression had shorter overall survival time, whereas patients with lower CENP-H expression had better survival. A prognostic value of CENP-H was also found of the subgroup of N0-N1 tumor classification. Multivariate analysis showed that CENP-H expression was an independent prognostic indicator for patient's survival.
Conclusions: Our results suggest that CENP-H protein is a valuable marker of NPC progression. High CENP-H expression is associated with poor overall survival in NPC patients.
The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan
Authors: Trudel Suzanne , Stewart A. Keith , Li Zhihua , Shu Yanjun , Liang Sheng-Ben , Trieu Young , Reece Donna , Paterson Josh , Wang Dingyan , Wen Xiao-Yan 
Published: January 2007

Abstract
Purpose: The aim of this study is to investigate the antimyeloma activity of a novel Bcl-2 family inhibitor, ABT-737, in preclinical treatment of multiple myeloma.
Experimental Design: The antimyeloma activity of ABT-737 was evaluated in cultured myeloma cell lines and patient myeloma samples, and in a xenograft mouse myeloma model. Drug combination therapy using ABT-737 with other commonly used myeloma drugs was also investigated.
Results: MY5 and JJN3 cell lines exhibited the most sensitivity to ABT-737 with an EC50 of 0.2 and 0.5 μmol/L, respectively, with increased cell apoptosis and elevated activated caspase-3. We identified two distinct groups of myeloma patient samples that were either sensitive or resistant to the drug. Four of 15 patient bone marrow samples (27%) were highly sensitive to ABT-737 at doses of 0.25 and 0.5 μmol/L, which eliminated 80% to 90% of myeloma cells as a result of cellular apoptosis 3 days after drug treatment. ABT-737 showed a synergistic effect when combined with dexamethasone or melphalan in inducing myeloma cell death. Furthermore, the dexamethasone-resistant MM1(Dex)R myeloma cell line was highly sensitive to 0.2 μmol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 μmol/L ABT-737. ABT-737 dose dependently suppressed tumor growth in a xenograft MY5 mouse model.
Conclusions: These studies show substantial antimyeloma activity of ABT-737 as a single agent or in combination with dexamethasone or melphalan and suggest a rationale for future clinical trials.
A Phase I and Pharmacokinetic Study of Pemetrexed Plus Irinotecan in Patients with Advanced Solid Malignancies
Authors: Rowinsky Eric K. , Beeram Muralidhar , Hammond Lisa A. , Schwartz Garry , De Bono Johann , Forouzesh Baharam , Chu Quincy , Latz Jane E. , Hong Shengyan , John William , Nguyen Binh 
Published: January 2007

Abstract
Purpose: The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies.
Experimental Design: Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation.
Results: Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m2; further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m2, which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses.
Conclusions: The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m2 every 3 weeks with vitamin supplementation.