bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of Recombinant Human Interleukin-7 Administration in Subjects with Refractory Malignancy
Authors: Sportès Claude , Babb Rebecca R. , Krumlauf Michael C. , Hakim Frances T. , Steinberg Seth M. , Chow Catherine K. , Brown Margaret R. , Fleisher Thomas A. , Noel Pierre , Maric Irina , Stetler-Stevenson Maryalice , Engel Julie , Buffet Renaud , Morre Michel , Amato Robert J. , Pecora Andrew , Mackall Crystal L. , Gress Ronald E. 
Published: January 2010

AbstractPurpose: Interleukin-7 (IL-7) has critical and nonredundant roles in T-cell development, hematopoiesis, and postdevelopmental immune functions as a prototypic homeostatic cytokine. Based on a large body of preclinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immunosenescence), pathologic (HIV), or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant), and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans.Design: Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for 2 weeks in a phase I interpatient dose escalation study (3, 10, 30, and 60 μg/kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses, and characterization of biological and, possibly, antitumor effects.Results: Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement, and marked increase in peripheral CD3+, CD4+, and CD8+ lymphocytes were seen in a dose-dependent and age-independent manner in all subjects receiving ≥10 μg/kg/dose, resulting in a rejuvenated circulating T-cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre-B cells showing a spectrum of maturation as well as an increase in circulating transitional B cells.Conclusion: This study shows the potent biological activity of rhIL-7 in humans over a well-tolerated dose range and allows further exploration of its possible therapeutic applications. Clin Cancer Res; 16(2); 727–35
Activities of SYK and PLCγ2 Predict Apoptotic Response of CLL Cells to SRC Tyrosine Kinase Inhibitor Dasatinib
Authors: Song Zibo , Lu Pin , Furman Richard R. , Leonard John P. , Martin Peter , Tyrell Lauren , Lee Francis Y. , Knowles Daniel M. , Coleman Morton , Wang Y. Lynn 
Published: January 2010

Abstract
Purpose: B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL.
Experimental Design: Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors.
Results: Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cγ2, correlate well with the apoptotic response of CLL cells to dasatinib.
Conclusions: Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cγ2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment. Clin Cancer Res; 16(2); 587–99
A CYP3A4 Phenotype–Based Dosing Algorithm for Individualized Treatment of Irinotecan
Authors: van der Bol Jessica M. , Mathijssen Ron H.J. , Creemers Geert-Jan M. , Planting André S.Th. , Loos Walter J. , Wiemer Erik A.C. , Friberg Lena E. , Verweij Jaap , Sparreboom Alex , de Jong Floris A. 
Published: January 2010

Abstract
Purpose: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test.
Experimental Design: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m2 (group A) or doses based on an equation consisting of midazolam clearance, γ-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course.
Results: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P &gt; 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P &gt; 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was &gt;4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%).
Conclusions: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment. Clin Cancer Res; 16(2); 736–42
ERBB2 Induces an Antiapoptotic Expression Pattern of Bcl-2 Family Members in Node-Negative Breast Cancer
Authors: Petry Ilka Brigitte , Fieber Esther , Schmidt Marcus , Gehrmann Mathias , Gebhard Susanne , Hermes Matthias , Schormann Wiebke , Selinski Silvia , Freis Evgenia , Schwender Holger , Brulport Marc , Ickstadt Katja , Rahnenführer Jörg , Maccoux Lindsey , West Jonathan , Kölbl Heinz , Schuler Martin , Hengstler Jan Georg 
Published: January 2010

AbstractPurpose: Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members.Experimental Design: ERBB2-regulated Bcl-2 family members were identified by inducible expression of ERBB2 in MCF-7 breast cancer cells and by correlation analysis with ERBB2 expression in breast carcinomas. The prognostic relevance of ERBB2-regulated and all additional Bcl-2 family members was determined in 782 patients with untreated node-negative breast cancer. The biological relevance of ERBB2-induced inhibition of apoptosis was validated in a murine tumor model allowing conditional ERBB2 expression.Results: ERBB2 caused an antiapoptotic phenotype by upregulation of MCL-1, TEGT, BAG1, BNIP1, and BECN1 as well as downregulation of BAX, BMF, BNIPL, CLU, and BCL2L13. Upregulation of the antiapoptotic MCL-1 [P = 0.001, hazard ratio (HR) 1.5] and BNIP3 (P = 0.024; HR, 1.4) was associated with worse prognosis considering metastasis-free interval, whereas clusterin (P = 0.008; HR, 0.88) and the proapoptotic BCL2L13 (P = 0.019; HR, 0.45) were associated with better prognosis. This indicates that ERBB2 alters the expression of Bcl-2 family members in a way that leads to adverse prognosis. Analysis of apoptosis and tumor remission in a murine tumor model confirmed that the prototypic Bcl-2 family member Bcl-xL could partially substitute for ERBB2 to antagonize tumor remission.Conclusions: Our results support the concept that ERBB2 influences the expression of Bcl-2 family members to induce an antiapoptotic phenotype. Antagonization of antiapoptotic Bcl-2 family members might improve breast cancer therapy, whereby MCL-1 and BNIP3 represent promising targets. Clin Cancer Res; 16(2); 451–60
DNA Microarrays Are Predictive of Cancer Prognosis: A Re-evaluation
Authors: Fan Xiaohui , Shi Leming , Fang Hong , Cheng Yiyu , Perkins Roger , Tong Weida 
Published: January 2010

Abstract
Purpose: The reliability of microarray-based cancer prognosis is questioned by Michiels et al. They reanalyzed seven studies published in the prominent journals as successful stories of microarray-based cancer prognosis and concluded that the originally reported assessments are overoptimistic. We set to investigate the reality of microarrays for predicting cancer prognosis by using the same data sets with commonly accepted data analysis approaches.
Experiment Design: Michiels et al.'s analysis protocol used a correlation-based feature selection method, split sample validation, and a nearest-centroid rule classifier. We examined their results through systematically replacing their analysis approaches with other commonly used methods as a parameter study. In addition, we applied a widely accepted permutation test in conjunction with 5-fold cross-validation to verify Michiels et al.'s findings.
Results: The stability of signature genes is likely obtained when a fold change–based feature selection method is applied. When cross-validation procedures are used to replace Michiels et al.'s split sample validation, only one of the seven studies yielded uninformative classifiers. The permutation test reveals that the confidence interval based on the split sample used in the Michiels et al.'s review is not a rigorous and robust approach to assess the validity of a classifier.
Conclusions: We concluded that the use of DNA microarrays for cancer prognosis can be demonstrated. We also stressed that caution should be exercised when a general conclusion is withdrawn based on a single statistical practice without alternative validation, which can leave a false impression and pessimistic perspective for emerging biomarker methodologies to advance cancer research. Clin Cancer Res; 16(2); 629–36
Phase II Trial of Ixabepilone Administered Daily for Five Days in Children and Young Adults with Refractory Solid Tumors: A Report from the Children's Oncology Group
Authors: Jacobs Shana , Fox Elizabeth , Krailo Mark , Hartley Gwen , Navid Fariba , Wexler Leonard , Blaney Susan M. , Goodwin Anne , Goodspeed Wendy , Balis Frank M. , Adamson Peter C. , Widemann Brigitte C. 
Published: January 2010

Abstract
Purpose: Ixabepilone is a microtubule-stabilizing agent with activity in adult solid tumors and in pediatric tumor xenograft models that are resistant to paclitaxel. The maximum tolerated dose on the daily-for-5-days i.v. schedule was 6 mg/m2/dose in adults and 8 mg/m2/dose in children, and the primary dose-limiting toxicity (DLT) was neutropenia. This study aimed to determine the response rate to ixabepilone in six solid tumor strata in children and young adults.
Experimental Design: We conducted a phase II trial of ixabepilone (8 mg/m2/dose for 5 days every 21 days) using a two-stage design in taxane-naïve children and young adults with treatment-refractory, measurable rhabdomyosarcoma, Ewing sarcoma family tumors, osteosarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor, neuroblastoma, and Wilms tumor.
Results: Sixty-one eligible patients (36 male) were enrolled. Median (range) age was 13 years (range, 3-36). Fifty-nine patients were fully evaluable for toxicity and response. DLTs, most commonly myelosuppression, occurred in 11 patients (15% incidence in 3-18 years old and 33% in 19-36 years old; P = 0.2) during cycle 1. The median (range) number of cycles was 2 (range, 1-38). No partial or complete responses (response evaluation criteria in solid tumors) were observed. Seven patients received ≥3 cycles, and two had prolonged stable disease (Wilms' tumor, 38 cycles; synovial sarcoma, 8 cycles).
Conclusions: Ixabepilone at 8 mg/m2/dose daily for 5 days was tolerable in children and adolescents, but did not show evidence of clinical activity in the childhood solid tumors studied. Clin Cancer Res; 16(2); 750–4
Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors
Authors: Detjen Katharina M. , Rieke Svenja , Deters Antje , Schulz Petra , Rexin Annett , Vollmer Sonja , Hauff Peter , Wiedenmann Bertram , Pavel Marianne , Scholz Arne 
Published: January 2010

Abstract
Purpose: Inhibition of angiogenesis represents a promising therapeutic strategy in neuroendocrine tumors. Angiopoietin-2 (Ang-2), a ligand of the endothelial tyrosine kinase Tie-2, is emerging as a key regulator of vascular remodeling during tumorangiogenesis. We therefore addressed the expression and biological significance of Ang-2 in human neuroendocrine tumors.
Experimental Design: Surgical specimens and serum from neuroendocrine tumor patients were used to determine Ang-2 expression by in situ hybridization or ELISA (circulating Ang-2). Ang-2 biological effects were evaluated following stable transfection into BON human pancreatic neuroendocrine tumor cells. BON clones were grown as orthotopic xenografts in nude mice to determine tumor growth and abdominal metastatic spread. Further analyses included microvessel density, lymphatic vessel density, and nodal invasion.
Results: Specimens from pancreatic neuroendocrine tumors and nontransformed pancreatic tissue revealed uniform expression of Ang-2 mRNA in endothelial cells. In contrast, epithelial expression of Ang-2 mRNA occurred exclusively in neuroendocrine tumors. Overexpression of Ang-2 in BON orthotopic xenografts did not affect primary tumor growth, although successful Ang-2 induction was confirmed from elevated serum levels. However, increased microvessel density and enhanced lymphatic metastasis were evident in Ang-2–expressing tumors, indicating a functional role of Ang-2 in experimental neuroendocrine tumors. Consistent with this notion, circulating Ang-2 was significantly elevated in neuroendocrine tumor patients compared with healthy controls. Circulating Ang-2 furthermore correlated with metastatic versus localized disease. The highest Ang-2 concentrations occurred in patients with liver metastasis, and concentrations ≥75th percentile predicted shorter survival (P = 0.0003).
Conclusion: Induction of Ang-2 in neuroendocrine tumors represents a clinically relevant pathomechanism of disease progression and constitutes an adverse prognostic marker. Clin Cancer Res; 16(2); 420–9.
Improved Potency and Selectivity of an Oncolytic E1ACR2 and E1B19K Deleted Adenoviral Mutant in Prostate and Pancreatic Cancers
Authors: Öberg Daniel , Yanover Eva , Adam Virginie , Sweeney Katrina , Costas Celina , Lemoine Nick R. , Halldén Gunnel 
Published: January 2010

Abstract
Purpose: Replication-selective oncolytic adenoviruses are a promising class of tumor-targeting agents with proven safety in hundreds of patients. However, clinical responses have been limited and viral mutants with higher potency are needed. Here, we report on the generation of a novel set of mutants with improved efficacy in prostate and pancreatic carcinoma models. Currently, no curative treatments are available for late-stage metastatic prostate or rapidly progressing pancreatic cancers.
Experimental Design: Adenovirus type 5 mutants were created with deletions in the E1ACR2 region for tumor selectivity and/or the E1B19K gene for attenuated replication in vivo; all constructs retain the E3 genes intact. Cell-killing efficacy, replication, and cytotoxicity in combination with chemotherapeutics were investigated in normal cells (PrEC and NHBE), seven carcinoma cell lines, and human (PC3 and DU145) and murine (TRAMPC, CMT-64, and CMT-93) tumor models in vivo.
Results: The double-deleted AdΔΔ (ΔE1ACR2 and ΔE1B19K) mutant had high cell-killing activity in prostate, pancreatic, and lung carcinomas. Replication was similar to wild-type in all tumor cells and was attenuated in normal cells to levels less than the single-deleted AdΔCR2 mutant. AdΔΔ combined with the chemotherapeutics docetaxel and mitoxantrone resulted in synergistically enhanced cell killing and greatly improved antitumor efficacy in prostate xenografts in vivo. In murine immunocompetent in vivo models efficacy was greater for mutants with the E3B genes intact even in the absence of viral replication, indicating attenuated macrophage-dependent clearance.
Conclusions: These data suggest that the novel oncolytic mutant AdΔΔ is a promising candidate for targeting of solid tumors specifically in combination with chemotherapeutics. Clin Cancer Res; 16(2); 541–53
Secretory Leukocyte Protease Inhibitor Antagonizes Paclitaxel in Ovarian Cancer Cells
Authors: Rasool Nabila , LaRochelle William , Zhong Haihong , Ara Gulshan , Cohen Joshua , Kohn Elise C. 
Published: January 2010

Abstract
Purpose: Ovarian cancer recurrence with the development of paclitaxel resistance is an obstacle to long-term survival. We showed that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer. We hypothesize that SLPI may antagonize paclitaxel injury.
Experimental Design: Differential SLPI induction in response to paclitaxel and in response to stable forced expression of SLPI was shown in A2780-1A9 cells and their paclitaxel-resistant sublines, PTX10 and PTX22, and confirmed with HEY-A8 cells. SLPI-mediated survival was reduced by the MAP/extracellular signal-regulated kinase (ERK) kinase inhibitor, U0126, and a humanized neutralizing monoclonal anti-SLPI antibody, CR012. OVCAR3 xenographs tested the role of CR012 in vivo.
Results: SLPI expression was lower in A2780-1A9 ovarian cancer cells than in PTX10 and PTX22, and SLPI was induced by paclitaxel exposure. Stable SLPI expression yielded a proliferation advantage (P = 0.01); expression of and response to SLPI in OVCAR3 cells were abrogated by exposure to CR012. SLPI reduced the paclitaxel susceptibility of 1A9 and HEY-A8 cells (P ≤ 0.05), and SLPI expression did not increase the resistance of PTX10 and PTX22 cells. Both paclitaxel and SLPI overexpression induced ERK activation. Inhibition of MAP/ERK kinase with U0126 increased paclitaxel injury and overcame SLPI-mediated cell protection. It did not reinstate PTX10 sensitivity to paclitaxel, which was associated with AKT activation. Significant inhibition of OVCAR3 xenograft growth was observed with CR012 and paclitaxel, over single agents (P ≤ 0.001).
Conclusions: A two-pronged approach confirmed that SLPI overcomes paclitaxel in part through activation of ERK1/2. These results credential SLPI as a molecular target for ovarian cancer and suggest CR012 as a tool for proof of concept. Clin Cancer Res; 16(2); 600–9
Reduced DNA Repair Capacity for Removing Tobacco Carcinogen–Induced DNA Adducts Contributes to Risk of Head and Neck Cancer but not Tumor Characteristics
Authors: Wang Li-E , Hu Zhibin , Sturgis Erich M. , Spitz Margaret R. , Strom Sara S. , Amos Christopher I. , Guo Zhaozheng , Qiao Yawei , Gillenwater Ann Marie , Myers Jeffrey N. , Clayman Gary L. , Weber Randal S. , El-Naggar Adel K. , Mao Li , Lippman Scott M. , Hong Waun Ki , Wei Qingyi 
Published: January 2010

Abstract
Purpose: Although cigarette smoking and alcohol use are known risk factors for squamous cell carcinoma of head and neck (SCCHN), only a few exposed individuals develop this disease, suggesting an individual susceptibility. In this study, we investigated the associations between genetically determined DNA repair capacity (DRC) for removing tobacco-induced DNA adducts and risk of SCCHN and tumor characteristics.
Experimental Design: We measured DRC in cultured T lymphocytes using the host-cell reactivation assay in a hospital-based case-control study of 744 SCCHN patients and 753 age-, sex-, and ethnicity-matched cancer-free controls recruited from The University of Texas M.D. Anderson Cancer Center.
Results: Patients with SCCHN had significantly lower mean DRC (8.84% ± 2.68%) than controls (9.97% ± 2.61%; P &lt; 0.0001), and the difference accounted for ∼2-fold increased risk of SCCHN [adjusted odds ratio (OR), 1.91; 95% confidence interval (CI), 1.52-2.40] after adjustment for other covariates. Compared with the highest DRC quartile of controls, this increased risk was dose dependent (second highest quartile: OR, 1.40; 95% CI, 0.99-1.98; third quartile: OR, 1.87; 95% CI, 1.34-2.62; and fourth quartile: OR, 2.76; 95% CI, 1.98-3.84, respectively; Ptrend &lt; 0.0001). We also assessed the performance of DRC in risk prediction models by calculating the area of under the receiver operating characteristic curve. The addition of DRC to the model significantly improved the sensitivity of the expanded model. However, we did not find the association between DRC and tumor sites and stages.
Conclusion: DRC is an independent susceptibility biomarker for SCCHN risk but not a tumor marker. Clin Cancer Res; 16(2); 764–74
A Phase I Study of 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin in Adult Patients with Refractory or Metastatic Solid Malignancies
Authors: Arnold Susanne M. , Rinehart John J. , Tsakalozou Eleftheria , Eckardt John R. , Fields Scott Z. , Shelton Brent J. , DeSimone Philip A. , Kee Bryan K. , Moscow Jeffrey A. , Leggas Markos 
Published: January 2010

Abstract
Purpose: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors.
Experimental Design and Methods: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters.
Results: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m2/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m2/d. The lactone form was the predominant species in plasma (&gt;87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P &lt; 0.001). A prolonged partial response was observed in one subject with non–small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non–small cell lung cancer, and duodenal cancer.
Conclusions: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m2/d five times every 21 days. Clin Cancer Res; 16(2); 673–80