bluuebunny/crossref_metadata_2025 huggingface dataset:
Appointing Senior Managers in Education
Authors: Grummell Bernie , Devine Dympna , Lynch Kathleen
Published: April 2009

While there is extensive research on educational leadership and management, the selection of leaders has received comparatively little attention. This article examines how educational leadership is constructed through the selection process in the context of a qualitative study of Irish education. It highlights the tensions that can exist for selection board assessors as they try to balance increasing performativity and new managerialist demands with the traditional ethical and moral dimensions of educational leadership. Key concepts of `local logics' and `homosociability' frame the analysis as it is shown how assessors often select `safe' candidates according to familiar qualities. This normalization is problematic when educational leadership is faced with intense organizational and socio-cultural change. It is also problematic in gender terms, especially in higher education, where the prevailing leadership model is a masculine one. Differences between education sectors are evident, with the primary and second levels translating criteria to the local logics of the institution and emphasizing the personal qualities of candidates. The higher education sectors were more formalized in their application process, highlighting their own local logics of strategic and professional management criteria.
Gender Balance in Leadership?
Authors: McTavish Duncan , Miller Karen
Published: April 2009

The further education (FE) sector employs a high proportion of women yet relatively few women progress into leadership positions. The article seeks to provide explanations for this gender imbalance and argues that despite change and modernization initiatives, the further education sector remains gendered in many aspects of leadership, governance and managerial practices. The article concludes that while change has increased opportunities for women, masculinized managerial practices have led in many instances to the re-gendering of organizational practices with unequal gender impacts.
What Policymakers Can Do to Make Education Inclusive
Authors: Pijl Sip Jan , Frissen Paul H.A.
Published: April 2009

Inclusive education challenges all schools to cater for a wider range of students. This implies that schools and teachers have to change. This literature study analyses how, if at all, policymakers can bring about changes in schools. Specific steering concepts of policymakers, whose interventions seem to address schools as `machine' bureaucracies, while in fact they are professional ones, force schools to create the illusion they have adapted to include students with special needs. Schools and teachers themselves must be the driving forces of change.
Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity
Authors: Woll Petter S. , Grzywacz Bartosz , Tian Xinghui , Marcus Rebecca K. , Knorr David A. , Verneris Michael R. , Kaufman Dan S.
Published: April 2009

Natural killer (NK) cells serve as important effectors for antitumor immunity, and CD56+CD45+ NK cells can be routinely derived from human embryonic stem cells (hESCs). However, little is know about the ability of hESC-derived NK cells to mediate an effective in vivo antitumor response. Using bioluminescent imaging, we now demonstrate that H9 line hESC-derived NK cells mediate effective clearance of human tumor cells in vivo. In addition to increased in vitro killing of diverse tumor targets, the in vivo tumor clearance by H9 hESC-derived NK cells was more effective compared with NK cells derived from umbilical cord blood (UCB). Phenotypic analysis demonstrates the hESC-derived NK cells are uniformly CD94+CD117low/−, an NK-cell population characterized by potent cytolytic activity and thus more competent to mediate tumor clearance. These studies demonstrate that hESCs provide an important model to study human lymphocyte development and may serve as a novel source for antitumor immunotherapy.
Amelioration of murine β-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both γ-globin and the MGMT drug-resistance gene
Authors: Zhao Huifen , Pestina Tamara I. , Nasimuzzaman Md , Mehta Perdeep , Hargrove Phillip W. , Persons Derek A.
Published: April 2009

Correction of murine models of β-thalassemia has been achieved through high-level globin lentiviral vector gene transfer into mouse hematopoietic stem cells (HSCs). However, transduction of human HSCs is less robust and may be inadequate to achieve therapeutic levels of genetically modified erythroid cells. We therefore developed a double gene lentiviral vector encoding both human γ-globin under the transcriptional control of erythroid regulatory elements and methylguanine methyltransferase (MGMT), driven by a constitutive cellular promoter. MGMT expression provides cellular resistance to alkylator drugs, which can be administered to kill residual untransduced, diseased HSCs, whereas transduced cells are protected. Mice transplanted with β-thalassemic HSCs transduced with a γ-globin/MGMT vector initially had subtherapeutic levels of red cells expressing γ-globin. To enrich γ-globin–expressing cells, transplanted mice were treated with the alkylator agent 1,3-bis-chloroethyl-1-nitrosourea. This resulted in significant increases in the number of γ-globin–expressing red cells and the amount of fetal hemoglobin, leading to resolution of anemia. Selection of transduced HSCs was also obtained when cells were drug-treated before transplantation. Mice that received these cells demonstrated reconstitution with therapeutic levels of γ-globin–expressing cells. These data suggest that MGMT-based drug selection holds promise as a modality to improve gene therapy for β-thalassemia.
IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells
Authors: Brockman Mark A. , Kwon Douglas S. , Tighe Daniel P. , Pavlik David F. , Rosato Pamela C. , Sela Jennifer , Porichis Filippos , Le Gall Sylvie , Waring Michael T. , Moss Kristin , Jessen Heiko , Pereyra Florencia , Kavanagh Daniel G. , Walker Bruce D. , Kaufmann Daniel E.
Published: April 2009

Murine models indicate that interleukin-10 (IL-10) can suppress viral clearance, and interventional blockade of IL-10 activity has been proposed to enhance immunity in chronic viral infections. Increased IL-10 levels have been observed during HIV infection and IL-10 blockade has been shown to enhance T-cell function in some HIV-infected subjects. However, the categories of individuals in whom the IL-10 pathway is up-regulated are poorly defined, and the cellular sources of IL-10 in these subjects remain to be determined. Here we report that blockade of the IL-10 pathway augmented in vitro proliferative capacity of HIV-specific CD4 and CD8 T cells in individuals with ongoing viral replication. IL-10 blockade also increased cytokine secretion by HIV-specific CD4 T cells. Spontaneous IL-10 expression, measured as either plasma IL-10 protein or IL-10 mRNA in peripheral blood mononuclear cells (PBMCs), correlated positively with viral load and diminished after successful antiretroviral therapy. IL-10 mRNA levels were up-regulated in multiple PBMC subsets in HIV-infected subjects compared with HIV-negative controls, particularly in T, B, and natural killer (NK) cells, whereas monocytes were a major source of IL-10 mRNA in HIV-infected and -uninfected individuals. These data indicate that multiple cell types contribute to IL-10–mediated immune suppression in the presence of uncontrolled HIV viremia.
Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations
Authors: Bos Mettine H. A. , Boltz Michael , St. Pierre Liam , Masci Paul P. , de Jersey John , Lavin Martin F. , Camire Rodney M.
Published: April 2009

Venomous snakes produce an array of toxic compounds, including procoagulants to defend themselves and incapacitate prey. The Australian snake Pseudonaja textilis has a venom-derived prothrombin activator homologous to coagulation factors V (FV) and Xa (FXa). Here we show that the FV component (pt-FV) has unique biologic properties that subvert the normal regulatory restraints intended to restrict an unregulated procoagulant response. Unlike human FV, recombinant pt-FV is constitutively active and does not require proteolytic processing to function. Sequence comparisons show that it has shed a large portion of the central B-domain, including residues that stabilize the inactive procofactor state. Remarkably, pt-FV functions in the absence of anionic membranes as it binds snake-FXa with high affinity in solution. Furthermore, despite cleavage in the heavy chain, pt-FV is functionally resistant to activated protein C, an anticoagulant. We speculate this stability is the result of noncovalent interactions and/or a unique disulfide bond in pt-FV linking the heavy and light chains. Taken together, these findings provide a biochemical rationale for the strong procoagulant nature of venom prothrombinase. Furthermore, they illustrate how regulatory mechanisms designed to limit the hemostatic response can be uncoupled to provide a sustained, disseminated procoagulant stimulus for use as a biologic toxin.
Gene expression profiling to characterize sediment toxicity – a pilot study using Caenorhabditis elegans whole genome microarrays
Authors: Menzel Ralph , Swain Suresh C , Hoess Sebastian , Claus Evelyn , Menzel Stefanie , Steinberg Christian EW , Reifferscheid Georg , Stürzenbaum Stephen R
Published: April 2009

Background

Traditionally, toxicity of river sediments is assessed using whole sediment tests with benthic organisms. The challenge, however, is the differentiation between multiple effects caused by complex contaminant mixtures and the unspecific toxicity endpoints such as survival, growth or reproduction. The use of gene expression profiling facilitates the identification of transcriptional changes at the molecular level that are specific to the bio-available fraction of pollutants.

Results

In this pilot study, we exposed the nematodeCaenorhabditis elegansto three sediments of German rivers with varying (low, medium and high) levels of heavy metal and organic contamination. Beside chemical analysis, three standard bioassays were performed: reproduction ofC. elegans, genotoxicity (Comet assay) and endocrine disruption (YES test). Gene expression was profiled using a whole genome DNA-microarray approach to identify overrepresented functional gene categories and derived cellular processes. Disaccharide and glycogen metabolism were found to be affected, whereas further functional pathways, such as oxidative phosphorylation, ribosome biogenesis, metabolism of xenobiotics, aging and several developmental processes were found to be differentially regulated only in response to the most contaminated sediment.

Conclusion

This study demonstrates how ecotoxicogenomics can identify transcriptional responses in complex mixture scenarios to distinguish different samples of river sediments.
Rapid assessment of the effect of ciprofloxacin on chromosomal DNA from Escherichia coli using an in situ DNA fragmentation assay
Authors: Tamayo María , Santiso Rebeca , Gosalvez Jaime , Bou Germán , Fernández José Luis
Published: April 2009

Background

Fluoroquinolones are extensively used antibiotics that induce DNA double-strand breaks (DSBs) by trapping DNA gyrase and topoisomerase IV on DNA. This effect is usually evaluated using biochemical or molecular procedures, but these are not effective at the single-cell level. We assessed ciprofloxacin (CIP)-induced chromosomal DNA breakage in single-cell Escherichia coli by direct visualization of the DNA fragments that diffused from the nucleoid obtained after bacterial lysis in an agarose microgel on a slide.

Results

Exposing the E. coli strain TG1 to CIP starting at a minimum inhibitory concentration (MIC) of 0.012 μg/ml and at increasing doses for 40 min increased the DNA fragmentation progressively. DNA damage started to be detectable at the MIC dose. At a dose of 1 μg/ml of CIP, DNA damage was visualized clearly immediately after processing, and the DNA fragmentation increased progressively with the antibiotic incubation time. The level of DNA damage was much higher when the bacteria were taken from liquid LB broth than from solid LB agar. CIP treatment produced a progressively slower rate of DNA damage in bacteria in the stationary phase than in the exponentially growing phase. Removing the antibiotic after the 40 min incubation resulted in progressive DSB repair activity with time. The magnitude of DNA repair was inversely related to CIP dose and was noticeable after incubation with CIP at 0.1 μg/ml but scarce after 10 μg/ml. The repair activity was not strictly related to viability. Four E. coli strains with identified mechanisms of reduced sensitivity to CIP were assessed using this procedure and produced DNA fragmentation levels that were inversely related to MIC dose, except those with very high MIC dose.

Conclusion

This procedure for determining DNA fragmentation is a simple and rapid test for studying and evaluating the effect of quinolones.
Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiellaspecies: A retrospective matched case-control study
Authors: Song Kyoung-Ho , Jeon Jae Hyun , Park Wan Beom , Park Sang-Won , Kim Hong Bin , Oh Myoung-don , Lee Hyo-Suk , Kim Nam Joong , Choe Kang Won
Published: April 2009

Background

Clinical outcomes of spontaneous bacterial peritonitis (SBP) due to extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella species (ESBL-EK) have not been adequately investigated.

Methods

We conducted a retrospective matched case-control study to evaluate the outcomes of SBP due to ESBL-EK compared with those due to non-ESBL-EK. Cases were defined as patients with liver cirrhosis and SBP due to ESBL-EK isolated from ascites. Control patients with liver cirrhosis and SBP due to non-ESBL-EK were matched in a 3:1 ratio to cases according to the following five variables: age (± 5 years); gender; species of infecting organism; Child-Pugh score (± 2); Acute Physiological and Chronic Health Evaluation II score (± 2). 'Effective initial therapy' was defined as less than 72 hours elapsing between the time of obtaining a sample for culture and the start of treatment with an antimicrobial agent to which the EK was susceptible. Cephalosporin use for ESBL-EK was considered 'ineffective', irrespective of the minimum inhibitory concentration. ESBL production was determined according to the Clinical and Laboratory Standards Institute guidelines on stored isolates.

Results

Of 1026 episodes of SBP in 958 patients from Jan 2000 through Dec 2006, 368 (35.9%) episodes in 346 patients were caused by SBP due to EK, isolated from ascites. Of these 346 patients, twenty-six (7.5%) patients with SBP due to ESBL-EK were compared with 78 matched controls. Treatment failure, evaluated at 72 hours after initial antimicrobial therapy, was greater among the cases (15/26, 58% vs. 10/78, 13%, P = .006); 30-day mortality rate was also higher than in the controls (12/26, 46% vs. 11/78, 15%, P = .001). When the case were classified according to the effectiveness of the initial therapy, 'ineffective initial therapy' was associated with higher 30-day mortality rate (11/18, 61% vs. 1/8, 13%, P = .036).

Conclusion

SBP due to ESBL-EK had poorer outcomes than SBP due to non-ESBL-EK. Ineffective initial therapy seems to be responsible for the higher rate of treatment failure and mortality in SBP due to ESBL-EK.
Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study
Authors: Raoul Jean-Luc , Van Laethem Jean-Luc , Peeters Marc , Brezault Catherine , Husseini Fares , Cals Laurent , Nippgen Johannes , Loos Anja-Helena , Rougier Philippe
Published: April 2009

Background

This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer.

Methods

The 5-FU dose was selected on the basis of dose-limiting toxicities (DLTs) during part I of the study. Patients received cetuximab (400 mg/m2 initial dose and 250 mg/m2/week thereafter) and every 2 weeks irinotecan (180 mg/m2), FA (400 mg/m2) and 5-FU (either low dose [LD], 300 mg/m2 bolus plus 2,000 mg/m2 46-hour infusion, n = 7; or, high-dose [HD], 400 mg/m2 bolus plus 2,400 mg/m2; n = 45).

Results

Only two DLTs occurred in the HD group, and HD 5-FU was selected for use in part II. Apart from rash, commonly observed grade 3/4 adverse events such as leucopenia, diarrhoea, vomiting and asthenia occurred within the expected range for FOLFIRI. Among 52 patients, the overall response rate was 48%. Median progression-free survival (PFS) was 8.6 months (counting all reported progressions) and the median overall survival was 22.4 months. Treatment facilitated the resection of initially unresectable metastases in fourteen patients (27%): of these, 10 patients (71%) had no residual tumour after surgery, and these resections hindered the estimation of PFS.

Conclusion

The combination of cetuximab and FOLFIRI was active and well tolerated in this setting. Initially unresectable metastases became resectable in one-quarter of patients, with a high number of complete resections, and these promising results formed the basis for the investigation of FOLFIRI with and without cetuximab in the phase III CRYSTAL trial.
Foot and ankle injuries during the Athens 2004 Olympic Games
Authors: Badekas Thanos , Papadakis Stamatios A , Vergados Nikolaos , Galanakos Spyros P , Siapkara Angeliki , Forgrave Mike , Romansky Nick , Mirones Steven , Trnka Hans‐Jeorg , Delmi Marino
Published: April 2009

Background

Major, rare and complex incidents can occur at any mass‐gathering sporting event and team medical staff should be appropriately prepared for these. One such event, the Athens Olympic Games in 2004, presented a significant sporting and medical challenge. This study concerns an epidemiological analysis of foot and ankle injuries during the Games.

Methods

An observational, epidemiological survey was used to analyse injuries in all sport tournaments (men's and women's) over the period of the Games.

Results

A total of 624 injuries (525 soft tissue injuries and 99 bony injuries) were reported. The most frequent diagnoses were contusions, sprains, fractures, dislocations and lacerations. Significantly more injuries in male (58%) versus female athletes (42%) were recorded. The incidence, diagnosis and cause of injuries differed substantially between the team sports.

Conclusion

Our experience from the Athens Olympic Games will inform the development of public health surveillance systems for future Olympic Games, as well as other similar mass events.
Phase II Trial of Consolidation Docetaxel and Samarium-153 in Patients With Bone Metastases From Castration-Resistant Prostate Cancer
Authors: Fizazi Karim , Beuzeboc Philippe , Lumbroso Jean , Haddad Vincent , Massard Christophe , Gross-Goupil Marine , Di Palma Mario , Escudier Bernard , Theodore Christine , Loriot Yohann , Tournay Elodie , Bouzy Jeannine , Laplanche Agnes
Published: April 2009

Purpose

To assess docetaxel combined with samarium-153–ethylene diamine tetramethylene phosphonic acid (EDTMP), a radiopharmaceutical with a high affinity for bone, in patients with castration-resistant prostate cancer (CRPC).

Patients and Methods

Patients with bone metastases from CRPC who achieved a response or stabilization after four cycles of docetaxel and estramustine were given consolidation docetaxel 20 mg/m2/wk for 6 weeks and samarium-153-EDTMP (37 MBq/kg) during week 1. Prostate-specific antigen (PSA) response was assessed by using consensus criteria, and pain was assessed by using a visual analog scale (VAS). This study used a Simon two-step design with PSA–progression-free survival (PFS) as the primary end point.

Results

Forty-three patients were included in the trial. A PSA response was obtained in 77% (95% CI, 61% to 82%). The pain response rate was 69% (95% CI, 49% to 85%). At least five of the six planned weekly injections of docetaxel were administered to 34 patients (81%). The consolidation docetaxel–samarium-153–EDTMP regimen was well tolerated; there was no febrile neutropenia, and only two episodes (5%) of rapidly reversible grade 3 thrombocytopenia occurred. Although a serum PSA relapse eventually occurred in all patient cases, this regimen resulted in pain control in the long-term. The median PSA-PFS was 6.4 months (95% CI, 6 to 7 months). The median survival was 29 months (95% CI, 22 to 31); the 1-year survival rate was 77% (62% to 87%); and the 2-year survival rate was 56% (41% to 70%).

Conclusion

Combining docetaxel and samarium-153–EDTMP in patients with bone metastases from CRPC is well tolerated, and it yields major pain relief that persists long after treatment. Overall survival compares favorably with that expected in this population of patients, most of whom exhibit symptoms.
Serum Vascular Endothelial Growth Factor and Fibronectin Predict Clinical Response to High-Dose Interleukin-2 Therapy
Authors: Sabatino Marianna , Kim-Schulze Seunghee , Panelli Monica C. , Stroncek David , Wang Ena , Taback Bret , Kim Dae Won , DeRaffele Gail , Pos Zoltan , Marincola Francesco M. , Kaufman Howard L.
Published: April 2009

Purpose

High-dose interleukin-2 (IL-2) induces durable therapeutic responses in a small subset of patients with metastatic melanoma and renal cell carcinoma, but simple pretreatment predictors of response have not been identified.

Patients and Methods

To identify predictive biomarkers of clinical response, sera from patients treated with high-dose IL-2 were collected for analysis using a customized, multiplex antibody-targeted protein array platform that surveyed expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests.

Results

A training set from 10 patients identified 68 potentially relevant soluble factors that were then tested in an independent validation set of 49 patients. Class comparison revealed a cluster of 11 biomarkers that were associated with therapeutic outcome. Vascular endothelial growth factor (VEGF) and fibronectin were identified as independent predictors of response. In particular, high levels of these proteins were correlated with lack of clinical response and decreased overall survival.

Conclusion

Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy.
Comparison of Sentinel Lymph Node Biopsy Alone and Completion Axillary Lymph Node Dissection for Node-Positive Breast Cancer
Authors: Bilimoria Karl Y. , Bentrem David J. , Hansen Nora M. , Bethke Kevin P. , Rademaker Alfred W. , Ko Clifford Y. , Winchester David P. , Winchester David J.
Published: April 2009

Purpose

For women with breast cancer, the role of completion axillary lymph node dissection (ALND) after identification of nodal metastases by sentinel lymph node biopsy (SLNB) has been questioned. Our objectives were to assess national nodal evaluation practice patterns and to examine differences in recurrence and survival for SLNB alone versus SLNB with completion ALND.

Patients and Methods

From the National Cancer Data Base (1998 to 2005), women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases were identified. Practice patterns and outcomes were examined for patients who underwent SLNB alone versus SLNB with completion ALND (median follow-up, 63 months).

Results

Of 97,314 patients, 20.8% underwent SLNB alone, and 79.2% underwent SLNB with completion ALND. In 2004 to 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non–National Cancer Institute–designated cancer centers. In patients with macroscopic nodal metastases (n = 20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND (v SLNB alone) after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95% CI, 0.32 to 1.06) and overall survival (HR, 0.89; 95% CI, 0.76 to 1.04). In patients with microscopic nodal metastases (n = 2,203 during 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND.

Conclusion

Compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases; however, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease.
Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies
Authors: Kummar Shivaani , Kinders Robert , Gutierrez Martin E. , Rubinstein Larry , Parchment Ralph E. , Phillips Lawrence R. , Ji Jiuping , Monks Anne , Low Jennifer A. , Chen Alice , Murgo Anthony J. , Collins Jerry , Steinberg Seth M. , Eliopoulos Helen , Giranda Vincent L. , Gordon Gary , Helman Lee , Wiltrout Robert , Tomaszewski Joseph E. , Doroshow James H.
Published: April 2009

Purpose

We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.

Patients and Methods

ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.

Results

Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.

Conclusion

Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.
Fertility of Female Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Green Daniel M. , Kawashima Toana , Stovall Marilyn , Leisenring Wendy , Sklar Charles A. , Mertens Ann C. , Donaldson Sarah S. , Byrne Julianne , Robison Leslie L.
Published: April 2009

Purpose

This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility.

Patients and Methods

We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy.

Results

There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose ≥ 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant.

Conclusion

This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.
Reticulin Accumulation in Essential Thrombocythemia: Prognostic Significance and Relationship to Therapy
Authors: Campbell Peter J. , Bareford David , Erber Wendy N. , Wilkins Bridget S. , Wright Penny , Buck Georgina , Wheatley Keith , Harrison Claire N. , Green Anthony R.
Published: April 2009

Purpose

Essential thrombocythemia (ET) manifests substantial interpatient heterogeneity in rates of thrombosis, hemorrhage, and disease transformation. Bone marrow histology reflects underlying disease activity in ET but many morphological features show poor reproducibility.

Patients and Methods

We evaluated the clinical significance of bone marrow reticulin, a measure previously shown to have relatively high interobserver reliability, in a large, prospectively-studied cohort of ET patients.

Results

Reticulin grade positively correlated with white blood cell (P = .05) and platelet counts (P = .0001) at diagnosis. Elevated reticulin levels at presentation predicted higher rates of arterial thrombosis (hazard ratio [HR], 1.8; 95% CI, 1.1 to 2.9; P = .01), major hemorrhage (HR, 2.0; 95% CI, 1.0 to 3.9; P = .05), and myelofibrotic transformation (HR, 5.5; 95% CI, 1.7 to 18.4; P = .0007) independently of known risk factors. Higher reticulin levels at diagnosis were associated with greater subsequent falls in hemoglobin levels in patients treated with anagrelide (P < .0001), but not in those receiving hydroxyurea (P = .9). Moreover, serial trephine specimens in patients randomly assigned to anagrelide showed significantly greater increases in reticulin grade compared with those allocated to hydroxyurea (P = .0003), and four patients who developed increased bone marrow reticulin on anagrelide showed regression of fibrosis when switched to hydroxyurea. These data suggest that patients receiving anagrelide therapy should undergo surveillance bone marrow biopsy every 2 to 3 years and that those who show substantially increasing reticulin levels are at risk of myelofibrotic transformation and may benefit from changing therapy before adverse clinical features develop.

Conclusion

Our results demonstrate that bone marrow reticulin grade at diagnosis represents an independent prognostic marker in ET, reflecting activity and/or duration of disease, with implications for the monitoring of patients receiving anagrelide.
Phase I Study of Samarium-153 Lexidronam With Docetaxel in Castration-Resistant Metastatic Prostate Cancer
Authors: Morris Michael J. , Pandit-Taskar Neeta , Carrasquillo Jorge , Divgi Chaitanya R. , Slovin Susan , Kelly William K. , Rathkopf Dana , Gignac Gretchen A. , Solit David , Schwartz Lawrence , Stephenson Ryan D. , Hong Christina , Delacruz Anthony , Curley Tracy , Heller Glenn , Jia Xiaoyu , O'Donoghue Joseph , Larson Steven , Scher Howard I.
Published: April 2009

Purpose

Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 (153Sm) lexidronam.

Patients and Methods

Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m2 and 153Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and 153Sm-EDTMP was administered on day −1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression.

Results

Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of 153Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 153Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption.

Conclusion

Docetaxel and 153Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.
Pediatric Cancer Survivorship Research: Experience of the Childhood Cancer Survivor Study
Authors: Leisenring Wendy M. , Mertens Ann C. , Armstrong Gregory T. , Stovall Marilyn A. , Neglia Joseph P. , Lanctot Jennifer Q. , Boice John D. , Whitton John A. , Yasui Yutaka
Published: April 2009

The Childhood Cancer Survivor Study (CCSS) is a comprehensive multicenter study designed to quantify and better understand the effects of pediatric cancer and its treatment on later health, including behavioral and sociodemographic outcomes. The CCSS investigators have published more than 100 articles in the scientific literature related to the study. As with any large cohort study, high standards for methodologic approaches are imperative for valid and generalizable results. In this article we describe methodological issues of study design, exposure assessment, outcome validation, and statistical analysis. Methods for handling missing data, intrafamily correlation, and competing risks analysis are addressed; each with particular relevance to pediatric cancer survivorship research. Our goal in this article is to provide a resource and reference for other researchers working in the area of long-term cancer survivorship.
The Childhood Cancer Survivor Study: A National Cancer Institute–Supported Resource for Outcome and Intervention Research
Authors: Robison Leslie L. , Armstrong Gregory T. , Boice John D. , Chow Eric J. , Davies Stella M. , Donaldson Sarah S. , Green Daniel M. , Hammond Sue , Meadows Anna T. , Mertens Ann C. , Mulvihill John J. , Nathan Paul C. , Neglia Joseph P. , Packer Roger J. , Rajaraman Preetha , Sklar Charles A. , Stovall Marilyn , Strong Louise C. , Yasui Yutaka , Zeltzer Lonnie K.
Published: April 2009

Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.
Commentary—Relevancy Is Robust Prediction, Not Alleged Realism
Authors: Shugan Steven M.
Published: April 2009

Remember James Boswell, ninth Laird of Auchinleck, author of the famous maxim that the road to hell is paved with good intentions? Trying to build realistic theories differs dramatically from having correct explanatory theories tested on objective criteria, e.g., verifiable prediction. Evaluating theories on whether assumptions are realistic is potentially subjective, biased, and arbitrary. A theory's domain determines whether its assumptions are sufficiently realistic and when assumptions must hold and to what degree, so testing assumptions in isolation puts an unnecessary burden on the assumptions (i.e., they must hold everywhere). For theories explaining cooperation and information exchange, predictions reveal that the prisoner's dilemma assumptions (only two prisoners, four possible outcomes, two possible actions, etc.) are sufficiently realistic. For theories explaining prisoner sentencing guidelines and probation policy, predictions might suggest otherwise. Scientific methods allow the evaluation of theories on criteria such predictive accuracy, reliability, validity, and robustness—not based on realism. When multiple explanatory theories survive initial testing, one derives conflicting predictions. For example, a theory that people are broccoli produces correct predictions (people are mortal) and incorrect predictions (people are biennial). Tragic consequences can occur when theory adoption depends on whether assumptions are disliked, unpopular, or exclude a favorite variable. Denounce journals that reject models with insightful new implications because the assumptions are too simple or merely disliked. The term “unrealistic” sometimes means personally disliked.
Factors Associated With Living in Developmental Centers in California
Authors: Harrington Charlene , Kang Taewoon , Chang Jamie
Published: April 2009

This study examined need, predisposing, market, and regional factors that predicted the likelihood of individuals with developmental disabilities living in state developmental centers (DCs) compared with living at home, in community care, or in intermediate care (ICFs) and other facilities. Secondary data analysis using logistic regression models was conducted for all individuals ages 21 years or older who had moderate, severe, or profound intellectual disability. Client needs were the most important factors associated with living arrangements, with those in DCs having more complex needs. Men had higher odds of living in DCs than in other settings, whereas older individuals had lower odds of living in DCs than in ICFs for persons with developmental disabilities and other facilities. Asians/Pacific Islanders, African Americans, and Hispanics were less likely to live in DCs than to live at home. The supply of residential care beds for the elderly reduced the likelihood of living in DCs, and the odds of living in a DC varied widely across regions. Controlling for need, many other factors predicted living arrangements. Policymakers need to ensure adequate resources and provider supply to reduce the need by individuals with intellectual disability to live in DCs and to transition individuals from DCs into other living arrangements.
Satisfaction and Sense of Well Being Among Medicaid ICF/MR and HCBS Recipients in Six States
Authors: Stancliffe Roger J. , Lakin K. Charlie , Taub Sarah , Chiri Giuseppina , Byun Soo-yong
Published: April 2009

Self-reported satisfaction and sense of well-being were assessed in a sample of 1,885 adults with intellectual and developmental disabilities receiving Medicaid Home and Community Based Services (HCBS) and Intermediate Care Facility (ICF/MR) services in 6 states. Questions dealt with such topics as loneliness, feeling afraid at home and in one's neighborhood, feeling happy, feeling that staff are nice and polite, and liking one's home and work/day program. Loneliness was the most widespread problem, and there were also small percentages of people who reported negative views in other areas. Few differences were evident by HCBS and ICF/MR status. The findings document consistent benefits of residential support provided in very small settings—with choices of where and with whom to live—and to individuals living with family.
Social Inclusion of Children With Intellectual Disabilities in a Recreational Setting
Authors: Siperstein Gary N. , Glick Gary C. , Parker Robin C.
Published: April 2009

The social acceptance of children with and without intellectual disabilities was examined in an inclusive, summer recreational program. Participants were 67 children entering Grades 3 through 6, of which 29 were identified as having a mild intellectual disability. Children were recruited from economically and racially diverse urban school districts. Results showed that children with and without intellectual disabilities were equally accepted by their peers. Specifically, 95% of children without intellectual disabilities indicated that they liked to “hang out with” at least 1 child with an intellectual disability. Results also indicated that the majority of children without intellectual disabilities made at least 1 new friend with another child with an intellectual disability. The features of recreational programming that promote social inclusion are discussed.
Ketohexokinase: Expression and Localization of the Principal Fructose-metabolizing Enzyme
Authors: Diggle Christine P. , Shires Michael , Leitch Derek , Brooke David , Carr Ian M. , Markham Alex F. , Hayward Bruce E. , Asipu Aruna , Bonthron David T.
Published: April 2009

Ketohexokinase (KHK, also known as fructokinase) initiates the pathway through which most dietary fructose is metabolized. Very little is known about the cellular localization of this enzyme. Alternatively spliced KHK-C and KHK-A mRNAs are known, but the existence of the KHK-A protein isoform has not been demonstrated in vivo. Using antibodies to KHK for immunohistochemistry and Western blotting of rodent tissues, including those from mouse knockouts, coupled with RT-PCR assays, we determined the distribution of the splice variants. The highly expressed KHK-C isoform localized to hepatocytes in the liver and to the straight segment of the proximal renal tubule. In both tissues, cytoplasmic and nuclear staining was observed. The KHK-A mRNA isoform was observed exclusively in a range of other tissues, and by Western blotting, the presence of endogenous immunoreactive KHK-A protein was shown for the first time, proving that the KHK-A mRNA is translated into KHK-A protein in vivo, and supporting the suggestion that this evolutionarily conserved isoform is physiologically functional. However, the low levels of KHK-A expression prevented its immunohistochemical localization within these tissues. Our results highlight that the use of in vivo biological controls (tissues from knockout animals) is required to distinguish genuine KHK immunoreactivity from experimental artifact.
Endocrine Cell Clustering During Human Pancreas Development
Authors: Jeon Jongmin , Correa-Medina Mayrin , Ricordi Camillo , Edlund Helena , Diez Juan A.
Published: April 2009

The development of efficient, reproducible protocols for directed in vitro differentiation of human embryonic stem (hES) cells into insulin-producing β cells will benefit greatly from increased knowledge regarding the spatiotemporal expression profile of key instructive factors involved in human endocrine cell generation. Human fetal pancreases 7 to 21 weeks of gestational age, were collected following consent immediately after pregnancy termination and processed for immunostaining, in situ hybridization, and real-time RT-PCR expression analyses. Islet-like structures appear from approximately week 12 and, unlike the mixed architecture observed in adult islets, fetal islets are initially formed predominantly by aggregated insulin- or glucagon-expressing cells. The period studied (7–22 weeks) coincides with a decrease in the proliferation and an increase in the differentiation of the progenitor cells, the initiation of NGN3 expression, and the appearance of differentiated endocrine cells. The present study provides a detailed characterization of islet formation and expression profiles of key intrinsic and extrinsic factors during human pancreas development. This information is beneficial for the development of efficient protocols that will allow guided in vitro differentiation of hES cells into insulin-producing cells.
Apoptosis and Desquamation of Urothelial Cells in Tissue Remodeling During Rat Postnatal Development
Authors: Erman Andreja , Zupančič Daša , Jezernik Kristijan
Published: April 2009

Postnatal rat urothelium was studied from day 0 to day 14, when intense cell loss as part of tissue remodeling was expected. The morphological and biochemical characteristics of urothelial cells in the tissue and released cells were investigated by light and electron microscopy, by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) assay, by annexin V/propidium iodide assay, and by immunofluorescent detection of active caspases and tight-junction protein occludin. Intense apoptosis and massive desquamation were detected between postnatal days 7 and 10. During this period, active caspases and TUNEL-positive cells were found in the urothelium. Disassembled cell–cell junctions were detected between cells. The majority of desquamated cells expressed no apoptotic cell morphology, but were active caspase positive and TUNEL positive. Ann+/PI- apoptotic bodies and desquamated Ann+/PI+ cells were detected in the lumen. These results indicate that apoptosis and desquamation participate in urothelial cell loss in the rat early postnatal period, indispensable for fast urothelial remodeling during development.
Simple: A Sequential Immunoperoxidase Labeling and Erasing Method
Authors: Glass George , Papin Jason A. , Mandell James W.
Published: April 2009

The ability to simultaneously visualize expression of multiple antigens in cells and tissues can provide powerful insights into cellular and organismal biology. However, standard methods are limited to the use of just two or three simultaneous probes and have not been widely adopted for routine use in paraffin-embedded tissue. We have developed a novel approach called sequential immunoperoxidase labeling and erasing (SIMPLE) that enables the simultaneous visualization of at least five markers within a single tissue section. Utilizing the alcohol-soluble peroxidase substrate 3-amino-9-ethylcarbazole, combined with a rapid non-destructive method for antibody-antigen dissociation, we demonstrate the ability to erase the results of a single immunohistochemical stain while preserving tissue antigenicity for repeated rounds of labeling. SIMPLE is greatly facilitated by the use of a whole-slide scanner, which can capture the results of each sequential stain without any information loss.