bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer
Authors: Gamelin Erick , Delva Remy , Jacob Jacques , Merrouche Yacine , Raoul Jean Luc , Pezet Denis , Dorval Etienne , Piot Gilles , Morel Alain , Boisdron-Celle Michele 
Published: April 2008

Purpose A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival. Patients and Methods Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m2 FU plus 200 mg/m2 folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg·h·L−1) previously established in other studies was reached. Results An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m2/wk in arm A and 1,790 ± 386 mg/m2/wk (range, 900 to 3,300 mg/m2/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003). Conclusion Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.
Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Rubnitz Jeffrey E. , Wichlan David , Devidas Meenakshi , Shuster Jonathan , Linda Stephen B. , Kurtzberg Joanne , Bell Beverly , Hunger Stephen P. , Chauvenet Allen , Pui Ching-Hon , Camitta Bruce , Pullen Jeanette 
Published: April 2008

Purpose To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL). Patients and Methods TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years. Results Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (± SE) for patients with TEL rearrangements was 86% ± 2%, compared with 72% ± 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002). Conclusion We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.
MGMT Promoter Methylation Status Can Predict the Incidence and Outcome of Pseudoprogression After Concomitant Radiochemotherapy in Newly Diagnosed Glioblastoma Patients
Authors: Brandes Alba A. , Franceschi Enrico , Tosoni Alicia , Blatt Valeria , Pession Annalisa , Tallini Giovanni , Bertorelle Roberta , Bartolini Stefania , Calbucci Fabio , Andreoli Alvaro , Frezza Giampiero , Leonardi Marco , Spagnolli Federica , Ermani Mario 
Published: April 2008

Purpose Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression. Methods Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m2/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m2 for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy. Results In 103 patients (mean age, 52 years [range 20 to 73 years]), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival. Conclusion PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment.
Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines
Authors: Haller Daniel G. , Cassidy Jim , Clarke Stephen J. , Cunningham David , Van Cutsem Eric , Hoff Paulo M. , Rothenberg Mace L. , Saltz Leonard B. , Schmoll Hans-Joachim , Allegra Carmen , Bertino Joseph R. , Douillard Jean-Yves , Gustavsson Bengt G. , Milano Gerard , O'Connell Michael , Rustum Youcef , Tabernero Josep , Gilberg Frank , Sirzén Florin , Twelves Chris 
Published: April 2008

Purpose We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. Methods Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study). Results In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. Conclusion Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
Treatment With the Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate: Toxicity, Efficacy, and Survival
Authors: Kwekkeboom Dik J. , de Herder Wouter W. , Kam Boen L. , van Eijck Casper H. , van Essen Martijn , Kooij Peter P. , Feelders Richard A. , van Aken Maarten O. , Krenning Eric P. 
Published: April 2008

Purpose Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. Patients and Methods Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. Results Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. Conclusion Treatment with [177Lu-DOTA0,Tyr3]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.
Leukocytosis and Risk Stratification Assessment in Essential Thrombocythemia
Authors: Carobbio Alessandra , Antonioli Elisabetta , Guglielmelli Paola , Vannucchi Alessandro M. , Delaini Federica , Guerini Vittoria , Finazzi Guido , Rambaldi Alessandro , Barbui Tiziano 
Published: April 2008

Purpose Established risk factors for thrombosis in essential thrombocythemia (ET) include age and previous vascular events. We aimed to refine this risk stratification by adding baseline leukocytosis. Patients and Methods We enrolled 657 patients with ET followed for a median of 4.5 years who developed 72 major thrombosis. Cox proportional hazard model was performed to analyze the thrombotic risk and to discriminate ET patients with or without thrombosis, multivariable C statistic index was used. We searched for leukocytes cutoff with the best sensitivity and specificity by a receiver operating characteristic curve. Results Results confirmed that age and prior events are independent risk factors for thrombosis and showed a gradient between baseline leukocytosis and thrombosis. On the contrary, no significant association was found either for JAK2V617F allele burden and for other laboratory parameters, including platelet number. In the model with conventional risk factors alone, C statistic ratio for total thrombosis was 0.63 and when leukocytosis was added, the change was small (C = 0.67). In contrast, in younger and asymptomatic patients (low-risk category), C statistic value indicated an high risk for thrombosis in patients with leukocytosis, similar to that calculated in conventionally defined high-risk group (C = 0.65). The best leukocyte cutoff values for predicting the events was found to be 9.4 (× 109/L). Conclusion We suggest to include baseline leukocytosis in the risk stratification of ET patients enrolled in clinical trials.
Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy
Authors: Mateo Gema , Montalbán M. Angeles , Vidriales Maria-Belén , Lahuerta Juan J. , Mateos Maria V. , Gutiérrez Norma , Rosiñol Laura , Montejano Laura , Bladé Joan , Martínez Rafael , de la Rubia Javier , Diaz-Mediavilla Joaquín , Sureda Anna , Ribera José M. , Ojanguren José M. , de Arriba Felipe , Palomera Luis , Terol Maria J. , Orfao Alberto , San Miguel Jesús F. 
Published: April 2008

Purpose To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM). Patients and Methods We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol. Results Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001). Conclusion To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.
The impact of numeracy on reactions to different graphic risk presentation formats: An experimental analogue study
Authors: Wright Alison J. , Whitwell Sophia C. L. , Takeichi Chika , Hankins Matthew , Marteau Theresa M. 
Published: April 2008

Objectives. Numeracy, the ability to process basic mathematical concepts, may affect responses to graphical displays of health risk information. Displays of probabilistic risk information using grouped dots are easier to understand than displays using dispersed dots. However, dispersed dots may better convey the randomness with which health threats occur, so increasing perceived susceptibility. We hypothesized that low numeracy participants would better understand risks presented using grouped dot displays, while high numeracy participants would have good understanding, regardless of display type. Moreover, we predicted that dispersed dot displays, in contrast to grouped dot displays, would increase risk perceptions and worry only for highly numerate individuals.Design and method. One hundred and forty smokers read vignettes asking them to imagine being at risk of Crohn's disease, in a 2(display type: dispersed/grouped dots)×3(risk magnitude: 3%/6%/50%)×2(numeracy: high/low) design. They completed measures of risk comprehension, perceived susceptibility and worry.Results. More numerate participants had better objective risk comprehension, but this effect was not moderated by display type. There was marginally significant support for the predicted numeracy × display type interaction for worry about Crohn's disease, but not for perceived susceptibility to the condition.Conclusions. Dispersed dot displays somewhat increase worry in highly numerate individuals, but only numeracy influenced objective risk comprehension. The most effective display type for communicating risk information will depend on the numeracy of the population and the goal(s) of the communication.
A qualitative investigation of women's experiences of the self and others in relation to their menstrual cycle
Authors: Slade Pauline , Haywood Annette , King Helen 
Published: April 2008

Objectives. This study aimed to compare and contrast detailed accounts of a community sample of women, with prospectively defined low or high premenstrual symptoms, highlighting differences/similarities.Methods. Semi‐structured interviews were conducted with 16 women (9 with ‘low’ and 7 with ‘high’ symptom levels) and analysed using template analysis.Results. ‘Low symptom’ women perceived themselves as generally laid back but demonstrated a need for organization and control in the family environment. They accepted less than perfect relationships, compared themselves favourably to others and perceived themselves as having strong support networks. There was a negative perception of the introduction to menarche but this was coupled with strong maternal support. ‘High symptom’ women showed patterns of perfectionism, an emphasis on self‐sacrifice and unfavourable comparison of self with others. They reported feeling alone, overwhelmed by tasks and experienced relationships as characterized by unresolved tensions. Menarche was viewed as a positive experience but accompanied by low maternal support. Both groups viewed their symptoms as irrational and controllable outside the home, but vented on partner, close family and children. There was acknowledgement of difference from ‘normal’ (‘low’) with an emphasis on the all‐encompassing nature of symptoms (‘high’).Conclusions. Women with high and low menstrual cycle symptoms viewed aspects of themselves and their relationships with others in both similar and different ways. A major issue for high symptom women was that they struggled to tolerate imperfections, both in their own performance or in their relationships with others, potentially emphasizing the role of cognitive appraisals in interventions.
An Apparatus for Direct Shear, Pullout, and Uniaxial Testing of Geogrids
Authors: Abdelrahman Ahmed H. , Ashmawy Alaa K. , Abdelmoniem Mohamed 
Published: April 2008

Abstract
In this paper, design and calibration procedures for a new large-scale testing apparatus for testing geosynthetic-soil systems are described. The multiple functionalities of the apparatus are implemented through the use of a single loading frame, driving mechanism, instrumentation, and data acquisition system for three distinct modes of loading: pullout, direct shear, and uniaxial loading. The design is similar to a conventional pullout device, but also includes key modifications and additional modules to adapt it for additional types of experiments. For example, in the uniaxial tension configuration, extension rods are used to transfer the load from the driving mechanism to the mounted specimen. In the direct shear configuration, the bottom half of the shear box is allowed to slide horizontally on low friction roller bearings while connected to the driving mechanism, whereas the top half of the box is fixed. Hydraulic jacks and a steel plate are used to apply the normal pressure in the pullout and direct shear configuration. A series of pullout experiments were performed to validate the functionality of the apparatus and to examine the relationship between the geometry of the geogrid opening and its pullout resistance.
Phonemes in Use: Multiple Activities for a Critical Process
Authors: Manyak Patrick C. 
Published: April 2008

Several decades of research have established the critical role of phonemic awareness in the development of beginning reading. In particular, phonemic awareness makes early phonics instruction useful for children and facilitates their ability to blend letter sounds while decoding words, to learn sight words reliably, and to spell phonetically.A key finding in phonemic awareness research is that instruction involving segmenting and blending phonemes combined with a focus on the letters that represent those phonemes contributes greatly to success in beginning reading and spelling. The author found that students benefit greatly from a variety of activities combining phoneme segmenting and blending with letter—sound instruction. This variety allows children to develop a robust ability to apply phonemic awareness to tasks of reading and writing and supports students who may struggle with this critical process. In this article, the author describes five “phonemes‐in‐use” activities and practical ideas for implementing them in the classroom.
More than inorganic copper is bioavailable to aquatic mosses at environmentally relevant concentrations
Authors: Ferreira Daniel , Tousset Nicolas , Ridame Céline , Tusseau-Vuillemin Marie-Hélène 
Published: April 2008

Abstract
The present study investigates how dissolved organic matter (DOM) alters copper bioavailability at environmentally relevant concentrations (1–5 μg/L of dissolved copper, 1–4 mg/L of dissolved organic copper). A methodology combining two biological endpoints (short-term and steady-state bioaccumulation of copper by the aquatic moss Fontinalis antipyretica) and a sampling of labile copper with diffusion gradient in thin films (DGT) is proposed for batch experiments conducted with mineral water and various DOM, ethylenediaminetetra-acetic acid (EDTA), humic acid, and natural Seine River (France) extracts (hydrophobic and transphilic fractions). All types of DOM reduce the bioavailability of copper to aquatic mosses, and this reduction was more pronounced for the short-term biological endpoint, which was taken as being representative for environmental exposure. Labile copper sampled with DGT made it possible to estimate short-term bioaccumulation in the case of EDTA and natural Seine River extracts. With humic acid solutions, however, labile copper was lower than bioavailable copper. This result suggests that at realistic metal concentrations and with certain types of natural DOM, bioavailable copper might comprise not only inorganic copper but also some weak organic complexes. Hence, labile copper, in situ sampled with DGT, might not systematically overestimate bioavailable copper, as suggested previously on the basis of in vitro toxicity studies.
Differential metallothionein induction patterns in fed and starved carp (Cyprinus carpio) during waterborne copper exposure
Authors: Hashemi Shodja , Kunwar Prabesh S , Blust Ronny , De Boeck Gudrun 
Published: April 2008

Abstract
Starved and fed carp (Cyprinus carpio) were exposed to sublethal waterborne copper exposure (1 μM) for 28 d in softened Antwerp, Belgium, city tap water. Copper accumulation in liver and gill tissues was determined, and changes in branchial Na+/K+–adenosine 5′-triphosphatase (ATPase) activity and metallothionein (MT) induction in gill and liver tissues were investigated following 28-d copper exposure. Gill Na+/K+-ATPase activity in exposed fish, both starved and fed, was at its lowest values after 3 d of exposure, after which it slowly recovered to preexposure values. No significant differences in branchial Na+/K+-ATPase activity were found between starved and fed fish. Copper accumulation in the liver and gills of the exposed starved carp was significantly higher than that in the exposed fed carp. The highest MT induction was found in liver tissues. Different patterns of MT induction were observed in the starved and fed carp during copper exposure. Before exposure, MT concentrations in the livers of the starved fish were significantly higher than those in the fed ones. Copper exposure significantly increased MT concentration in the liver of the fed fish, but no changes occurred in the starved fish. In contrast, copper exposure increased MT concentrations in the gills of the starved fish during the first week of exposure, whereas only a slight increase in MT concentration in the gills of the fed fish was observed. When taking into account the role of feeding status in MT induction, hepatic MT was a more relevant indicator for long-term monitoring of copper pollution in carp, but gill MT provided useful information regarding short-term copper toxicity.