bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium
Authors: Trippett Tanya M. , Herzog Cynthia , Whitlock James A. , Wolff Johannes , Kuttesch John , Bagatell Rochelle , Hunger Stephen P. , Boklan Jessica , Smith Amy A. , Arceci Robert J. , Katzenstein Howard M. , Harbison Christopher , Zhou Xiaofei , Lu Haolan , Langer Christiane , Weber Martin , Gore Lia 
Published: September 2009

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.
IKZF1(Ikaros) Deletions inBCR-ABL1–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report
Authors: Martinelli Giovanni , Iacobucci Ilaria , Storlazzi Clelia Tiziana , Vignetti Marco , Paoloni Francesca , Cilloni Daniela , Soverini Simona , Vitale Antonella , Chiaretti Sabina , Cimino Giuseppe , Papayannidis Cristina , Paolini Stefania , Elia Loredana , Fazi Paola , Meloni Giovanna , Amadori Sergio , Saglio Giuseppe , Pane Fabrizio , Baccarani Michele , Foà Robin 
Published: September 2009

PurposeThe causes of the aggressive nature of BCR-ABL1–positive adult acute lymphoblastic leukemia (ALL) are unknown. To identify, at the submicroscopic level, oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed an investigation of genomic copy number alterations using single nucleotide polymorphism array, genomic polymerase chain reaction, and sequencing of candidate genes.Patients and MethodsEighty-three patients with de novo adult Philadelphia chromosome (Ph) –positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy.ResultsA 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04).ConclusionWe conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors
Authors: Steeghs Neeltje , Eskens Ferry A.L.M. , Gelderblom Hans , Verweij Jaap , Nortier Johan W.R. , Ouwerkerk Jan , van Noort Conny , Mariani Mariangela , Spinelli Riccardo , Carpinelli Patrizia , Laffranchi Bernard , de Jonge Maja J.A. 
Published: September 2009

Purpose Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments. Patients and Methods Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m2 in the 6-hour IVS, and from 250 mg/m2 in the 3-hour IVS, were studied. Results Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m2 for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m2 or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients. Conclusion Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m2 infused over 6 hours on days 1, 8, and 15 every 28 days.
Phase II Study of Yttrium-90–Ibritumomab Tiuxetan in Patients With Relapsed or Refractory Mantle Cell Lymphoma
Authors: Wang Michael , Oki Yasuhiro , Pro Barbara , Romaguera Jorge Enrique , Rodriguez Maria Alma , Samaniego Felipe , McLaughlin Peter , Hagemeister Frederick , Neelapu Sattva , Copeland Amanda , Samuels Barry I. , Loyer Evelyne M. , Ji Yuan , Younes Anas 
Published: September 2009

Purpose This phase II trial evaluated the safety and efficacy of yttrium-90 (90Y)–ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL). Patients and Methods Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells ≥ 5,000/μL, or history of stem-cell transplant were ineligible. Patients with a platelet count ≥ 150,000/μL received a dose of 0.4 mCi/kg of 90Y–ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/μL received a dose of 0.3 mCi/kg. Results Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured ≥ 5 cm (P = .015). Conclusion The single-agent activity of 90Y–ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.
Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer
Authors: Lee Siow Ming , Rudd Robin , Woll Penella J. , Ottensmeier Christian , Gilligan David , Price Allan , Spiro Stephen , Gower Nicole , Jitlal Mark , Hackshaw Allan 
Published: September 2009

Purpose Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL). Results The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001). Conclusion In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.
New Lesions Detected by Single Nucleotide Polymorphism Array–Based Chromosomal Analysis Have Important Clinical Impact in Acute Myeloid Leukemia
Authors: Tiu Ramon V. , Gondek Lukasz P. , O'Keefe Christine L. , Huh Jungwon , Sekeres Mikkael A. , Elson Paul , McDevitt Michael A. , Wang Xiao Fei , Levis Mark J. , Karp Judith E. , Advani Anjali S. , Maciejewski Jaroslaw P. 
Published: September 2009

PurposeCytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC.Patients and MethodsWe performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.ResultsSNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).ConclusionSNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.
Serum 25-Hydroxyvitamin D3 Levels Are Associated With Breslow Thickness at Presentation and Survival From Melanoma
Authors: Newton-Bishop Julia A. , Beswick Samantha , Randerson-Moor Juliette , Chang Yu-Mei , Affleck Paul , Elliott Faye , Chan May , Leake Susan , Karpavicius Birute , Haynes Sue , Kukalizch Kairen , Whitaker Linda , Jackson Sharon , Gerry Edwina , Nolan Clarissa , Bertram Chandra , Marsden Jerry , Elder David E. , Barrett Jennifer H. , Bishop D. Timothy 
Published: September 2009

Purpose A cohort study was carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. Methods A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years). Results In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio = 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had higher mean 25-hydroxyvitamin D3 levels than relapsers (49 v 46 nmol/L; P = .3; not statistically significant). In the cohort (prospective) study, higher 25-hydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-free survival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) for a 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-hydroxyvitamin D3 levels on RFS. Conclusion Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis, providing evidence that higher 25-hydroxyvitamin D3 levels, at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma.
Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803
Authors: Arndt Carola A.S. , Stoner Julie A. , Hawkins Douglas S. , Rodeberg David A. , Hayes-Jordan Andrea A. , Paidas Charles N. , Parham David M. , Teot Lisa A. , Wharam Moody D. , Breneman John C. , Donaldson Sarah S. , Anderson James R. , Meyer William H. 
Published: September 2009

PurposeThe purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC).Patients and MethodsPatients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC.ResultsA total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups.ConclusionFor intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.
Primary Testicular Diffuse Large B-Cell Lymphoma: A Population-Based Study on the Incidence, Natural History, and Survival Comparison With Primary Nodal Counterpart Before and After the Introduction of Rituximab
Authors: Gundrum Jacob D. , Mathiason Michelle A. , Moore Derek B. , Go Ronald S. 
Published: September 2009

Purpose We performed a population-based study of primary testicular diffuse large B-cell lymphoma (DLBCL) in the United States to determine its incidence and survival trends, prognostic factors, and clinical outcome compared with males with nodal DLBCL. Patients and Methods The Surveillance, Epidemiology, and End Results database was reviewed to identify patients diagnosed between 1980 and 2005. To study the potential impact of the introduction of rituximab on survival, we used the year 2000 as cutoff point. Results We identified 769 patients with testicular DLBCL. The median age at diagnosis was 68.0 years. The incidence of DLBCL increased over time, with the highest rate among whites (twice that of blacks). The median overall survival (OS) for the whole group was 4.6 years, whereas the disease-specific survival (DSS) rates at 3, 5, and 15 years were 71.5%, 62.4%, and 43.0%, respectively. Independent predictors of worse DSS were older age, diagnosis before 1986, advanced stage, left testicular involvement, and not having surgery and radiation. The use of radiation did not change significantly over time. When testicular and nodal DLBCL patients were analyzed together, testicular primary was an independent predictor of better OS and DSS. Unlike nodal DLBCL, DSS did not improve in the patients with testicular DLBCL diagnosed after the year 2000. Conclusion The incidence of testicular DLBCL is increasing. Compared with nodal DLBCL, testicular DLBCL patients have a better overall prognosis but are at higher risk of late disease-related deaths. The introduction of rituximab in clinical practice does not seem to improve their early outcome.
Novel Computer-Controlled Saturation of Dynamic Centrifuge Models Using High Viscosity Fluids
Authors: Stringer M. E. , Madabhushi S. P. G. 
Published: September 2009

Abstract
The practice of saturating centrifuge models with a highly viscous pore fluid is widely used. As the fluid saturates the model, care must be taken to ensure that the hydraulic gradients are not too high to cause excessive disturbance to the model. A new computer-controlled saturation system (CAM-Sat) has been developed and implemented at the University of Cambridge to aid the saturation of soil models with a high viscosity pore fluid. Models are saturated under vacuum and pore fluid enters through ports in the model’s base. The system controls the ingress of pore fluid into the model by monitoring the fluid mass flux and then altering the pressure drop between a reservoir of pore fluid and the model. The system was found to be stable across a wide range of fluid viscosities and sand types. A further test showed that the system was able to respond to changes in mass flux demanded by the researcher.
Distributions of Hydrogen Bond Lifetimes in Instantaneous and Inherent Structures of Water
Authors: Naberukhin Yu. I. , Voloshin V. P 
Published: September 2009

Abstract
Various distribution functions of hydrogen bond lifetimes, used to describe the dynamics of breakage and formation of these bonds are calculated for a molecular dynamics model of water of 3456 molecules at 310 K. Quenched (inherent) structures are derived from instantaneous MD structures. Comparing the distribution functions from I and Q structures allows interpreting their characteristic features. The sharp peak at ~15 fs, which prevails in the most frequently used distributions, is ascribed to short-lived “false” H bonds which results from violations of hydrogen bonding criteria induced by dynamic intermolecular vibrations of molecules. A special type of distribution, proposed earlier [34], contains information not only on dynamics, but on true, or random, breaking of hydrogen bonds. The distributions reveal four different types of characteristic times which reflect different sides of H bond dynamics.
Correlation of Static and Dynamic Heterogeneities in Supercooled Water by Means of Molecular Dynamics Simulations
Authors: Holzmann J. , Appelhagen A. , Ludwig Ralf 
Published: September 2009

Abstract
The unusual increase of diffusivity of supercooled water upon compression seems to be related to the existence of at least two major distinct local structural forms: a "low-density" structure, exhibiting an almost perfect tetrahedral hydrogen bonding network, and a "high-density" structure, characterized by defects in this network. The structural changes can be measured by the "tetrahedricity parameter", describing the deviation from the ideal tetrahedron. In this paper we show that the anomalous diffusion behavior upon compression cannot only be related to the structural heterogeneities but also to dynamical heterogeneities occuring in supercooled liquid water. This is shown for translational heterogeneities which decrease with temperature and pressure. Both, static and dynamic heterogeneities can be correlated. They are substantial at low temperatures and moderate pressures and diminish with increasing temperature and pressure, respectively. Our results are based on molecular dynamics simulations of the TIP4P-Ew water model [1].
The Effects of Temperature and H/D Isotopic Dilution on the Transmission and Attenuated Total Reflection FTIR Spectra of Water
Authors: Riemenschneider Julian , Wulf Alexander , Ludwig Ralf 
Published: September 2009

Abstract
Using a set of IR spectroscopy methods the OH- and OD-stretch region of H2O, D2O and HDO were investigated. With a combination of attenuated total reflection infrared (ATR-IR) and transmission infrared Fourier Transform spectroscopy, temperature dependent experiments were carried out. HDO experiments were done with varying isotopic concentrations. We focused on contributions at higher wavenumbers within the OH/OD-stretch region to discuss coupling effects. We also compared results from ATR and transmission spectroscopy in order to check the comparability of these techniques. In addition we tried to investigate how the overtone of the bending vibration may be included into the analysis of the OH-stretch region of pure water.