bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma
Authors: Rajkumar S. Vincent , Richardson Paul G. , Lacy Martha Q. , Dispenzieri Angela , Greipp Philip R. , Witzig Thomas E. , Schlossman Robert , Sidor Carolyn F. , Anderson Kenneth C. , Gertz Morie A. 
Published: October 2007

Abstract
Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties. We report on the first phase II trial of 2ME2 in multiple myeloma.
Experimental Design: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31 men and 29 women) were treated. After 39 patients were accrued, the dose was increased to 800 mg twice daily for the remaining patients.
Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade 1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients.
Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2 was inadequate. A new formulation with better bioavailability will be tested soon in multiple myeloma.
Pharmacogenomic Predictor Discovery in Phase II Clinical Trials for Breast Cancer
Authors: Pusztai Lajos , Anderson Keith , Hess Kenneth R. 
Published: October 2007

Abstract
Purpose: We examined if supervised analysis of gene expression data from phase II studies could identify HER-2 overexpression as a predictor of response to trastuzumab.
Experimental Design: Gene expression data from 132 newly diagnosed breast cancers were used to simulate 50,000 single-agent phase II trastuzumab studies. True HER-2 amplification was assessed by fluorescence in situ hybridization.
Results: Only 3.67% of the simulated studies yielded HER-2 as the top predictor, &gt;96% of the individual “studies” picked a different gene as the most predictive of trastuzumab response. HER-2 was included in the top 10 gene list 9.73% of the time. When HER-2 was a priori defined as a potential predictor, 99.6% of the simulated studies confirmed overexpression among responders. Candidate marker testing may be more efficient than de novo predictor discovery in phase II trials. We describe a tandem, two-step phase II trial design for rapid marker assessment that combines two optimal two-stage phase II trials into a single study. In the first stage, unselected patients are treated, and if insufficient responses are seen, the trial remains open for marker-positive patients only and a second two-stage trial commences.
Conclusions: The probability of successful discovery of drug-specific pharmacogenomic response markers in a typical phase II study is small. The evaluation of predefined predictors using tandem two-step phase II design has the advantages of estimating response rates in both unselected and marker-selected patient populations and allows for simultaneous screening of multiple different predictors for the same drug and several distinct predictor-drug pairs in a single, parallel multiarm trial.
Phase 1 and Pharmacokinetic Study of Lexatumumab in Patients with Advanced Cancers
Authors: Plummer Ruth , Attard Gerhardt , Pacey Simon , Li Louise , Razak Albiruni , Perrett Rebecca , Barrett Mary , Judson Ian , Kaye Stan , Fox Norma Lynn , Halpern Wendy , Corey Alfred , Calvert Hilary , de Bono Johann 
Published: October 2007

Abstract
Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies.
Experimental Design: In this phase 1, open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v. over 30 to 120 min every 21 days. A cohort of four patients, which could be expanded to six patients, was studied at each dose level. The dose-limiting toxicity (DLT) dose was defined as the dose at which the incidence of DLT in the first two cycles was ≥33%. The maximum tolerated dose was defined as the highest dose at which &lt;33% of subjects experienced DLT. The pharmacokinetics and immunogenicity of lexatumumab were also characterized. Tumor specimens from historical or current biopsies, when available, were stained for TRAIL-R2 using immunohistochemistry techniques.
Results: Thirty-seven patients received 120 cycles of lexatumumab at doses ranging from 0.1 to 20 mg/kg every 21 days as of May 2006. The 20 mg/kg dose was identified as the DLT dose based on DLTs in three of seven patients treated with this dose; DLTs included asymptomatic elevations of serum amylase, transaminases, and bilirubin. The 10 mg/kg dose cohort was expanded to 12 patients and the 10 mg/kg dose was identified as the maximum tolerated dose. The mean (±SD) clearance and apparent terminal half-life values at the 10 mg/kg dose averaged 6.0 (2.9) mL/d/kg and 16.4 (10.9) days, respectively. Twelve patients had durable stable disease that lasted a median of 4.5 months, including three patients with sarcoma having prolonged stable disease (≥6.7 months). Immunohistochemistry for TRAIL-R2 showed specific staining in &gt;10% of tumor cells for 16 of the 20 evaluable specimens submitted (80%).
Conclusions: Lexatumumab was safe and well tolerated at doses up to and including 10 mg/kg every 21 days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokinetics were linear over the dose range studied, and consistent with a two-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warranted and ongoing.
High Promoter Methylation Levels of APC Predict Poor Prognosis in Sextant Biopsies from Prostate Cancer Patients
Authors: Henrique Rui , Ribeiro Franclim R. , Fonseca Daniel , Hoque Mohammad O. , Carvalho André L. , Costa Vera L. , Pinto Mafalda , Oliveira Jorge , Teixeira Manuel R. , Sidransky David , Jerónimo Carmen 
Published: October 2007

Abstract
Purpose: Prostate cancer is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality. Owing to the limitations of current clinical, serologic, and pathologic parameters in predicting disease progression, we sought to investigate the prognostic value of promoter methylation of a small panel of genes by quantitative methylation-specific PCR (QMSP) in prostate biopsies.
Experimental Design: Promoter methylation levels of APC, CCND2, GSTP1, RARB2, and RASSF1A were determined by QMSP in a prospective series of 83 prostate cancer patients submitted to sextant biopsy. Clinicopathologic data [age, serum prostate-specific antigen (PSA), stage, and Gleason score] and time to progression and/or death from prostate cancer were correlated with methylation findings. Log-rank test and Cox regression model were used to identify which epigenetic markers were independent predictors of prognosis.
Results: At a median follow-up time of 45 months, 15 (18%) patients died from prostate cancer, and 37 (45%) patients had recurrent disease. In univariate analysis, stage and hypermethylation of APC were significantly associated with worse disease–specific survival, whereas stage, Gleason score, high diagnostic serum PSA levels, and hypermethylation of APC, GSTP1, and RASSF1A were significantly associated with poor disease-free survival. However, in the final multivariate analysis, only clinical stage and high methylation of APC were significantly and independently associated with unfavorable prognosis, i.e., decreased disease-free and disease-specific survival.
Conclusions: High-level APC promoter methylation is an independent predictor of poor prognosis in prostate biopsy samples and might provide relevant prognostic information for patient management.
A Half-Log Increase in BCR-ABL RNA Predicts a Higher Risk of Relapse in Patients with Chronic Myeloid Leukemia with an Imatinib-Induced Complete Cytogenetic Response
Authors: Press Richard D. , Galderisi Chad , Yang Rui , Rempfer Carole , Willis Stephanie G. , Mauro Michael J. , Druker Brian J. , Deininger Michael W.N. 
Published: October 2007

Abstract
Purpose: Imatinib induces a complete cytogenetic response (CCR) in most chronic myeloid leukemia patients in chronic phase. Although CCR is usually durable, a minority of patients relapse. Biomarkers capable of predicting those CCR patients with a higher risk of relapse would improve therapeutic management.
Experimental Design: To assess whether changes in BCR-ABL RNA levels are a prognostic biomarker predictive of relapse, we regularly monitored transcript levels [every 3 months (median)] in 90 patients with CCR during 49 months (median) of imatinib therapy.
Results: Throughout follow-up, the 20 patients with eventual relapse had higher transcript levels than the durable responders. Major molecular response (MMR; &gt;3-log reduction of BCR-ABL RNA) was attained by 76 patients (12 with subsequent relapse) and was a significant predictor of prolonged relapse-free survival (P = 0.0008). A minimal 0.5-log increase in transcripts (before relapse; experienced by 42 patients, 16 with subsequent relapse) conveyed a significantly shorter relapse-free survival (P = 0.0017). Loss of MMR (transcript increase to &lt;2.5-log reduction, before relapse; experienced by 33 patients, 11 with subsequent relapse) was also predictive of shortened relapse-free survival (P = 0.0003). A complete molecular response (undetectable transcripts by nested PCR) was attained by 28 MMR patients (one with subsequent relapse) and conveyed a significantly prolonged relapse-free survival (P = 0.0052).
Conclusions: In chronic myeloid leukemia patients with an imatinib-induced CCR, a minimal half-log increase in BCR-ABL RNA (including loss of MMR) is a significant risk factor for future relapse. The achievement of a complete molecular response imparts longer progression-free survival than the achievement of an MMR.
Wwox and Ap2γ Expression Levels Predict Tamoxifen Response
Authors: Guler Gulnur , Iliopoulos Dimitrios , Guler Nilufer , Himmetoglu Cigdem , Hayran Mutlu , Huebner Kay 
Published: October 2007

Abstract
Purpose: Assessment of expression levels of Wwox, Wwox-interacting proteins Ap2α, Ap2γ, and ErbB4, the Ap2γ transcriptional target protein Her2, and the possible Ap2α transcriptional target PrkaRIα, in breast cancers, to determine their roles in tamoxifen resistance. The hypothesis was that sequestration of Wwox interactors in the cytoplasm might control tamoxifen response.
Experimental Design: Tissue sections from 51 tamoxifen-sensitive and 38 tamoxifen-resistant, estrogen receptor α–positive breast cancers were stained for the above proteins, as well as progesterone receptor (PR). The relation of tamoxifen resistance and other clinical features, with level of expression of these proteins, and pairwise correlations among various immunohistochemical markers were determined.
Results: Menopausal status, tumor, node, and stage, loss of PR, lost or reduced expression of Wwox, and high level of expression of PrkaRIα, Ap2γ, and Her2 were significantly correlated with tamoxifen resistance. In multivariate analysis, Wwox, PrkaRIα, Ap2γ, and ErbB4 were found to be independent markers of tamoxifen resistance. Reduced Wwox expression was better than PR in prediction of resistance, especially in high-risk patients, and nuclear Ap2γ expression was better than Her2, especially in low-risk patients.
Conclusion: The results illustrate the complex relationships among the marker proteins assessed in this in vivo study and suggest new markers for prediction of response to tamoxifen treatment as well as possible new targets for treatment of breast cancer. Wwox and Ap2γ emerge as new biomarkers that may be superior to PR and Her2 in predicting tamoxifen response.
High Levels of B-Cell Activating Factor in Patients with Active Chronic Graft-Versus-Host Disease
Authors: Sarantopoulos Stefanie , Stevenson Kristen E. , Kim Haesook T. , Bhuiya Nazmim S. , Cutler Corey S. , Soiffer Robert J. , Antin Joseph H. , Ritz Jerome 
Published: October 2007

Abstract
Purpose: Recent studies suggest that donor B cells as well as T cells contribute to immune pathology in patients with chronic graft-versus-host disease (GVHD). B-cell activating factor (BAFF) promotes survival and differentiation of activated B cells. Thus, we tested whether BAFF correlated with chronic GVHD disease activity and time of onset after allogeneic hematopoietic stem cell transplantation (HSCT).
Experimental Design: Patients who had undergone allogeneic HSCT between 1994 and 2005 for hematologic malignancies were studied. ELISA was used to measure plasma BAFF levels and flow cytometry was used to assess BAFF receptor expression on B cells in patients with or without chronic GVHD.
Results: In 104 patients, BAFF levels were significantly higher in patients with active chronic GVHD compared with those without disease (P = 0.02 and 0.0004, respectively). Treatment with high-dose prednisone (≥30 mg/d) was associated with reduced BAFF levels in patients with active chronic GVHD (P = 0.0005). Serial studies in 24 patients showed that BAFF levels were high in the first 3 months after HSCT but subsequently decreased in 13 patients who never developed chronic GVHD. In contrast, BAFF levels remained elevated in 11 patients who developed chronic GVHD. Six-month BAFF levels ≥10 ng/mL were strongly associated with subsequent development of chronic GVHD (P &lt; 0.0001). Following transplant, plasma BAFF levels correlated inversely with BAFF receptor expression on B cells (P = 0.01), suggesting that soluble BAFF affected B cells through this receptor.
Conclusion: These results suggest that elevated BAFF levels contribute to B-cell activation in patients with active chronic GVHD.
A New Rexinoid, NRX194204, Prevents Carcinogenesis in Both the Lung and Mammary Gland
Authors: Liby Karen , Royce Darlene B. , Risingsong Renee , Williams Charlotte R. , Wood Matthew D. , Chandraratna Roshantha A. , Sporn Michael B. 
Published: October 2007

Abstract
Purpose: We evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid NRX194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (ER)–negative breast cancer in vivo.
Experimental Design: In cell culture studies, we measured the ability of 4204 to block the effects of lipopolysaccharide and induce apoptosis. For the lung cancer prevention studies, A/J mice were injected with the carcinogen vinyl carbamate and then fed 4204 (30-60 mg/kg diet) for 15 weeks, beginning 1 week after the administration of the carcinogen. For breast cancer prevention studies, mouse mammary tumor virus-neu mice were fed control diet or 4204 (20 mg/kg diet) for 50 weeks; for treatment, tumors at least 32 mm3 in size were allowed to form, and then mice were fed control diet or 4204 (60 mg/kg diet) for 4 weeks.
Results: Low nanomolar concentrations of 4204 blocked the ability of lipopolysaccharide and tumor necrosis factor-α to induce the release of nitric oxide and interleukin 6 and the degradation of IKBα in RAW264.7 macrophage-like cells. In the A/J mouse model of lung cancer, 4204 significantly (P &lt; 0.05) reduced the number and size of tumors on the surface of the lungs and reduced the total tumor volume per slide by 64% to 81% compared with the control group. In mouse mammary tumor virus-neu mice, 4204 not only delayed the development of ER-negative mammary tumors in the prevention studies but also caused marked tumor regression (92%) or growth arrest (8%) in all of the mammary tumors when used therapeutically.
Conclusions: The combined anti-inflammatory and anticarcinogenic actions of 4204 suggest that it is a promising new rexinoid that should be considered for future clinical trials.
p53 Mutations in Deep Tissues Are More Strongly Associated with Recurrence than Mutation-Positive Mucosal Margins
Authors: Huang Xiaohong , Pateromichelakis Stelios , Hills Allison , Sherriff Martyn , Lyons Andrew , Langdon John , Odell Edward , Morgan Peter , Harrison John , Partridge Max 
Published: October 2007

Abstract
Purpose: Application of ultrasensitive diagnostics has shown that small numbers of p53 mutation-positive cells may signify the presence of residual tumor in histologically normal tissues after resection of squamous cell carcinomas arising in the head and neck area. To date, most studies in this area have focused on analysis of tissues at the mucosal aspect of the resection and highlighted the importance of molecular changes in the field with respect to the risk of recurrence.
Experimental Design: In the present investigation, we analyzed normal tissues from mucosal and deep surgical margins, referred to as “molecular margins,” for the presence of the signature p53 mutation identified for each tumor.
Results: The p53 mutation status of these carcinomas did not correlate with clinical or histopathologic variables, but these mutations provided an excellent target for ultrasensitive analysis of margin status. We found that 11 of 16 (68%) of cases with histologically tumor-free (including 9 without dysplasia), but with p53 mutation-positive molecular margins, developed recurrence. The probability of developing local recurrence was significantly higher for the group with p53 mutation-positive margins when compared with the group with clear margins (P = 0.048) and more strongly associated with p53 mutation-positive deep molecular margins than mutation-positive mucosal molecular margins or positivity at both sites (P = 0.009).
Conclusions: This shows that although persistent mucosal fields may contribute to recurrence, clonal p53 mutations in deep tissues are an important cause of treatment failure, and molecular margins from both sites should be analyzed in future prospective series.
Adenovirally Delivered Tumor Necrosis Factor-α Improves the Antiglioma Efficacy of Concomitant Radiation and Temozolomide Therapy
Authors: Yamini Bakhtiar , Yu Xiaohong , Pytel Peter , Galanopoulos Nicholas , Rawlani Vinay , Veerapong Jula , Bickenbach Kai , Weichselbaum Ralph R. 
Published: October 2007

Abstract
Purpose: Treatment of malignant glioma involves concomitant temozolomide and ionizing radiation (IR). Nevertheless, overall patient survival remains poor. This study was designed to evaluate if addition of Ad.Egr–tumor necrosis factor (TNF), a replication defective adenovector encoding a cDNA for TNF-α, to temozolomide and IR can improve overall antiglioma effect.
Experimental Design: The efficacy of combination treatment with Ad.Egr-TNF, IR, and temozolomide was assessed in two glioma xenograft models. Animal toxicity and brain histopathology after treatment were also examined. In addition, in an attempt to explain the antitumor interaction between these treatments, the activation status of the transcription factor nuclear factor-κB was examined.
Results: Triple therapy (Ad.Egr-TNF, IR, and temozolomide) leads to significantly increased survival in mice bearing glioma xenografts compared with dual treatment. Fifty percent of animals treated with the triple regimen survive for &gt;130 days. Pathologic examination shows that triple therapy leads to a complete response with formation of a collagenous scar. No significant change in myelination pattern is noted after triple therapy, compared with any double treatment. Treatment of intracranial glioma bearing mice with Ad.Egr-TNF and IR leads to cachexia and poor feeding that does not improve, whereas triple therapy results in less toxicity, which improves over 21 days. Both Ad.Egr-TNF and IR activate nuclear factor-κB, and temozolomide inhibits this activity in an inhibitor of κBα (IκBα)–independent manner.
Conclusion: This work shows that the addition of adenoviral TNF-α gene delivery to temozolomide and IR significantly improves antiglioma efficacy and illustrates a potential new treatment regimen for use in patients with malignant glioma.
Normalization of the Ovarian Cancer Microenvironment by SPARC
Authors: Said Neveen , Socha Matthew J. , Olearczyk Jeffrey J. , Elmarakby Ahmed A. , Imig John D. , Motamed Kouros 
Published: October 2007

Abstract
Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP−/− mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid–enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of αv and β1 integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP+/+, SP−/− ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP−/− ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F2α) that were positively correlated with extensive infiltration of SP−/− ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation. (Mol Cancer Res 2007;5(10):1015–30)