bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of residential wood heating in a context of climate change: a population survey in Québec (Canada)
Authors: Bélanger Diane , Gosselin Pierre , Valois Pierre , Abdous Belkacem
Published: May 2008

Background

Wood heating is recommended in several countries as a climate change (CC) adaptation measure, mainly to increase the autonomy of households during power outages due to extreme climatic events. The aim of this study was to examine various perceptions and individual characteristics associated with wood heating through a survey about CC adaptations.

Methods

A telephone survey (n = 2,545) of adults living in the southern part of the province of Québec (Canada) was conducted in the early fall season of 2005. The questionnaire used closed questions and measured the respondents' beliefs and current adaptations about CC. Calibration weighting was used to adjust the data analysis for the respondent's age and language under stratified sampling based on health regions.

Results

More than three out of four respondents had access to a single source of energy at home, which was mainly electricity; 22.2% combined two sources or more; 18.5% heated with wood occasionally or daily during the winter. The prevalence of wood heating was higher in the peripheral regions than in the more urban regions, where there was a higher proportion of respondents living in apartments. The prevalence was also higher with participants completely disagreeing (38.5%) with the eventual prohibition of wood heating when there is smog in winter, compared to respondents somewhat disagreeing (24.2%) or agreeing (somewhat: 17.5%; completely: 10.4%) with the adoption of this strategy. It appears that the perception of living in a region susceptible to winter smog, smog warnings in the media, or the belief in the human contribution to CC, did not influence significantly wood heating practices.

Conclusion

Increased residential wood heating could very well become a maladaptation to climate change, given its known consequences on winter smog and respiratory health. It would thus be appropriate to implement a long-term national program on improved and controlled residential wood heating. This would constitute a "no-regrets" adaptation to climate change, while reducing air pollution and its associated health impacts.
Evaluation of cell types for assessment of cytogenetic damage in arsenic exposed population
Authors: Ghosh Pritha , Basu Arindam , Singh Keshav K , Giri Ashok K
Published: May 2008

Background

Cytogenetic biomarkers are essential for assessing environmental exposure, and reflect adverse human health effects such as cellular damage. Arsenic is a potential clastogen and aneugen. In general, the majority of the studies on clastogenic effects of arsenic are based on frequency of micronuclei (MN) study in peripheral lymphocytes, urothelial and oral epithelial cells. To find out the most suitable cell type, here, we compared cytogenetic damage through MN assay in (a) various populations exposed to arsenic through drinking water retrieved from literature review, as also (b) arsenic-induced Bowen's patients from our own survey.

Results

For literature review, we have searched the Pubmed database for English language journal articles using the following keywords: "arsenic", "micronuclei", "drinking water", and "human" in various combinations. We have selected 13 studies consistent with our inclusion criteria that measured micronuclei in either one or more of the above-mentioned three cell types, in human samples. Compared to urothelial and buccal mucosa cells, the median effect sizes measured by the difference between people with exposed and unexposed, lymphocyte based MN counts were found to be stronger. This general pattern pooled from 10 studies was consistent with our own set of three earlier studies. MN counts were also found to be stronger for lymphocytes even in arsenic-induced Bowen's patients (cases) compared to control individuals having arsenic-induced non-cancerous skin lesions.

Conclusion

Overall, it can be concluded that MN in lymphocytes may be superior to other epithelial cells for studying arsenic-induced cytogenetic damage.
The value of D-dimer in the detection of early deep-vein thrombosis after total knee arthroplasty in Asian patients: a cohort study
Authors: Chen Chung-Jen , Wang Ching-Jen , Huang Chung-Cheng
Published: May 2008

Background and purpose

The relationship of D-dimer and deep-vein thrombosis (DVT) after total knee arthroplasty (TKA) remains controversial. The purpose of this study was to assess the value of D-dimer in the detection of early DVT after TKA.

Methods

The measurements of plasma D-dimer level were obtained preoperatively and at day 7 postoperatively in 78 patients undergoing TKA. Ascending venography was performed in 7 to 10 days after surgery. The plasma D-dimer levels were correlated statistically with the venographic DVT.

Results

Venographic DVT was identified in 40% of patients. High plasma D-dimer level >2.0 μg/ml was found in 68% of patients with DVT and 45% without DVT (P < 0.05). Therefore, high D-dimer level greater than 2.0 μg/ml showed 68% sensitivity, 55% specificity, 60% accuracy, 50% positive predictive rate and 72% negative predictive rate in the detection of early DVT after TKA.

Conclusion

High plasma D-dimer level is a moderately sensitive, but less specific marker in the detection of early of DVT after TKA. Measurement of serum D-dimer alone is not accurate enough to detect DVT after TKA. Venography is recommended in patients with elevated D-dimer and clinically suspected but asymptomatic DVT after TKA.
Closing two doors of viral entry: Intramolecular combination of a coreceptor- and fusion inhibitor of HIV-1
Authors: Kopetzki Erhard , Jekle Andreas , Ji Changhua , Rao Eileen , Zhang Jun , Fischer Stephan , Cammack Nick , Sankuratri Surya , Heilek Gabrielle
Published: May 2008

We describe a novel strategy in which two inhibitors of HIV viral entry were incorporated into a single molecule. This bifunctional fusion inhibitor consists of an antibody blocking the binding of HIV to its co-receptor CCR5, and a covalently linked peptide which blocks envelope mediated virus-cell fusion. This novel bifunctional molecule is highly active on CCR5- and X4-tropic viruses in a single cycle assay and a reporter cell line with IC50 values of 0.03–0.05 nM. We demonstrated that both inhibitors contribute to the antiviral activity. In the natural host peripheral blood mononuclear cells (PBMC) the inhibition of CXCR4-tropic viruses is dependant on the co-expression of CCR5 and CXCR4 receptors. This bifunctional inhibitor may offer potential for improved pharmacokinetic parameters for a fusion inhibitor in humans and the combination of two active antiviral agents in one molecule may provide better durability in controlling the emergence of resistant viruses.
Trends in prevalence of substance use among Icelandic adolescents, 1995–2006
Authors: Sigfusdottir Inga D , Kristjansson Alfgeir L , Thorlindsson Thorolfur , Allegrante John P
Published: May 2008

Background

Adolescent substance use continues to be of great global public health concern in many countries with advanced economies. Previous research has shown that substance use among 15–16 year-old-youth has increased in many European countries in recent years. The aim of this study was to examine trends in prevalence of daily smoking, alcohol intoxication, and illicit substance use among Icelandic adolescents.

Methods

Repeated-measures, population-based cross-sectional surveys of between 3,100 and 3,900 10th-grade students who participated in the annual Youth of Iceland studies were analyzed, with response rates of between 80% and 90%.

Results

The prevalence of daily smoking, alcohol intoxication, and illicit substance use was at a peak in 1998, with almost 23% having reported daily smoking, 42% having reported becoming intoxicated at least once during the last 30 days, and over 17% having used hashish once or more often in their lifetime. By 2006, daily smoking had declined to 12%, having become intoxicated once or more often during the last 30 days to 25%, and having ever used hashish declined to 9%.

Conclusion

The prevalence of substance use among Icelandic 10th graders declined substantially from 1995 to 2006. Proportions of adolescents who smoke cigarettes, had become intoxicated during the last 30 days, as well as those admitting to hashish use all decreased to a great deal during the period under study. The decline in prevalence of adolescent substance use in Iceland is plausibly the result of local community collaboration where researchers, policy makers and practitioners who work with young people have combined their efforts.
Regulation of survival in adult hippocampal and glioblastoma stem cell lineages by the homeodomain-only protein HOP
Authors: De Toni Arianna , Zbinden Marie , Epstein Jonathan A , Altaba Ariel Ruiz i , Prochiantz Alain , Caillé Isabelle
Published: May 2008

Background

Homeodomain proteins play critical roles in shaping the development of the embryonic central nervous system in mammals. After birth, neurogenic activities are relegated to stem cell niches, which include the subgranular layer of the dentate gyrus of the hippocampus. Here, we have analyzed the function of HOP (Homeodomain only protein) in this stem cell niche and in human glioblastomas.

Results

We find that HOP is strongly expressed by radial astrocytes of the dentate gyrus in mice, which are stem cells that give rise to hippocampal granular neurons throughout adulthood. Deletion or down-regulation of HOP results in a decrease of apoptosis of these stem cells without changes in proliferation, and in an increase in the number of newly formed granule neurons. We also find that human glioblastomas largely lack HOP expression and that reintroduction of HOP function in glioma cells cultured as gliomaspheres leads to enhanced apoptosis in a subset of cases. In these cells, HOP function decreases clonogenicity.

Conclusion

These data suggest that HOP participates in the regulation of the adult mouse hippocampal stem cell niche by negatively affecting cell survival. In addition, HOP may work as a tumor suppressor in a subset of glioblastomas. HOP function thus appears to be critical in the adult brain in a region of continued plasticity, and its deregulation may contribute to disease.
Whole genome identification of Mycobacterium tuberculosisvaccine candidates by comprehensive data mining and bioinformatic analyses
Authors: Zvi Anat , Ariel Naomi , Fulkerson John , Sadoff Jerald C , Shafferman Avigdor
Published: May 2008

Background

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%–80%), and directed essentially against early phase infection.

Methods

A genome-scale dataset was constructed by analyzing published data of: (1) global gene expression studies under conditions which simulate intra-macrophage stress, dormancy, persistence and/or reactivation; (2) cellular and humoral immunity, and vaccine potential. This information was compiled along with revised annotation/bioinformatic characterization of selected gene products and in silico mapping of T-cell epitopes. Protocols for scoring, ranking and prioritization of the antigens were developed and applied.

Results

Cross-matching of literature and in silico-derived data, in conjunction with the prioritization scheme and biological rationale, allowed for selection of 189 putative vaccine candidates from the entire genome. Within the 189 set, the relative distribution of antigens in 3 functional categories differs significantly from their distribution in the whole genome, with reduction in the Conserved hypothetical category (due to improved annotation) and enrichment in Lipid and in Virulence categories. Other prominent representatives in the 189 set are the PE/PPE proteins; iron sequestration, nitroreductases and proteases, all within the Intermediary metabolism and respiration category; ESX secretion systems, resuscitation promoting factors and lipoproteins, all within the Cell wall category. Application of a ranking scheme based on qualitative and quantitative scores, resulted in a list of 45 best-scoring antigens, of which: 74% belong to the dormancy/reactivation/resuscitation classes; 30% belong to the Cell wall category; 13% are classical vaccine candidates; 9% are categorized Conserved hypotheticals, all potentially very potent T-cell antigens.

Conclusion

The comprehensive literature and in silico-based analyses allowed for the selection of a repertoire of 189 vaccine candidates, out of the whole-genome 3989 ORF products. This repertoire, which was ranked to generate a list of 45 top-hits antigens, is a platform for selection of genes covering all stages of M. tuberculosis infection, to be incorporated in rBCG or subunit-based vaccines.
Low-level expression of HER2 and CK19 in normal peripheral blood mononuclear cells: relevance for detection of circulating tumor cells
Authors: You Fanglei , Roberts Lisa A , Kang S Peter , Nunes Raquel A , Dias Cinara , Iglehart J Dirk , Solomon Natalie A , Friedman Paula N , Harris Lyndsay N
Published: May 2008

Background

Detection of circulating tumor cells (CTC) in the blood of cancer patients may have prognostic and predictive significance. However, background expression of 'tumor specific markers' in peripheral blood mononuclear cells (PBMC) may confound these studies. The goal of this study was to identify the origin of Cytokeratin 19 (CK19) and HER-2 signal in PBMC and suggest an approach to enhance techniques involved in detection of CTC in breast cancer patients.

Methods

PBMC from healthy donors were isolated and fractionated into monocytes, lymphocytes, natural killer cells/granulocytes and epithelial populations using immunomagnetic selection and fluorescent cell-sorting for each cell type. RNA isolated from each fraction was analyzed for CK19, HER2 and Beta 2 microglobulin (B2M) using real-time qRT-PCR. Positive selection for epithelial cells and negative selection for NK/granulocytes were used in an attempt to reduce background expression of CK19 and HER2 markers.

Results

In normal PBMC, CK19 was expressed in the lymphocyte population while HER-2 expression was highest in the NK/granulocyte population. Immunomagnetic selection for epithelial cells reduced background CK19 signal to a frequency of <5% in normal donors. Using negative selection, the majority (74–98%) of HER2 signal could be removed from PBMC. Positive selection methods are variably effective at reducing these background signals.

Conclusion

We present a novel method to improve the specificity of the traditional method of detecting CTC by identifying the source of the background signals and reducing them by negative immunoselection. Further studies are warranted to improve sensitivity and specificity of methods of detecting CTC will prove to be useful tools for clinicians in determining prognosis and monitoring treatment responses of breast cancer patients.
Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort
Authors: Azzato Elizabeth M , Driver Kristy E , Lesueur Fabienne , Shah Mitul , Greenberg David , Easton Douglas F , Teschendorff Andrew E , Caldas Carlos , Caporaso Neil E , Pharoah Paul DP
Published: May 2008

Introduction

Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division.

Methods

We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis.

Results

The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding.

Conclusion

It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.
Calling on a million minds for community annotation in WikiProteins
Authors: Mons Barend , Ashburner Michael , Chichester Christine , van Mulligen Erik , Weeber Marc , den Dunnen Johan , van Ommen Gert-Jan , Musen Mark , Cockerill Matthew , Hermjakob Henning , Mons Albert , Packer Abel , Pacheco Roberto , Lewis Suzanna , Berkeley Alfred , Melton William , Barris Nickolas , Wales Jimmy , Meijssen Gerard , Moeller Erik , Roes Peter Jan , Borner Katy , Bairoch Amos
Published: May 2008

WikiProteins enables community annotation in a Wiki-based system. Extracts of major data sources have been fused into an editable environment that links out to the original sources. Data from community edits create automatic copies of the original data. Semantic technology captures concepts co-occurring in one sentence and thus potential factual statements. In addition, indirect associations between concepts have been calculated. We call on a 'million minds' to annotate a 'million concepts' and to collect facts from the literature with the reward of collaborative knowledge discovery. The system is available for beta testing at http://www.wikiprofessional.org.
Unraveling the genomic mosaic of a ubiquitous genus of marine cyanobacteria
Authors: Dufresne Alexis , Ostrowski Martin , Scanlan David J , Garczarek Laurence , Mazard Sophie , Palenik Brian P , Paulsen Ian T , de Marsac Nicole Tandeau , Wincker Patrick , Dossat Carole , Ferriera Steve , Johnson Justin , Post Anton F , Hess Wolfgang R , Partensky Frédéric
Published: May 2008

Background

The picocyanobacterial genus Synechococcus occurs over wide oceanic expanses, having colonized most available niches in the photic zone. Large scale distribution patterns of the different Synechococcus clades (based on 16S rRNA gene markers) suggest the occurrence of two major lifestyles ('opportunists'/'specialists'), corresponding to two distinct broad habitats ('coastal'/'open ocean'). Yet, the genetic basis of niche partitioning is still poorly understood in this ecologically important group.

Results

Here, we compare the genomes of 11 marine Synechococcus isolates, representing 10 distinct lineages. Phylogenies inferred from the core genome allowed us to refine the taxonomic relationships between clades by revealing a clear dichotomy within the main subcluster, reminiscent of the two aforementioned lifestyles. Genome size is strongly correlated with the cumulative lengths of hypervariable regions (or 'islands'). One of these, encompassing most genes encoding the light-harvesting phycobilisome rod complexes, is involved in adaptation to changes in light quality and has clearly been transferred between members of different Synechococcus lineages. Furthermore, we observed that two strains (RS9917 and WH5701) that have similar pigmentation and physiology have an unusually high number of genes in common, given their phylogenetic distance.

Conclusion

We propose that while members of a given marine Synechococcus lineage may have the same broad geographical distribution, local niche occupancy is facilitated by lateral gene transfers, a process in which genomic islands play a key role as a repository for transferred genes. Our work also highlights the need for developing picocyanobacterial systematics based on genome-derived parameters combined with ecological and physiological data.
Dynamic instability of the major urinary protein gene family revealed by genomic and phenotypic comparisons between C57 and 129 strain mice
Authors: Mudge Jonathan M , Armstrong Stuart D , McLaren Karen , Beynon Robert J , Hurst Jane L , Nicholson Christine , Robertson Duncan H , Wilming Laurens G , Harrow Jennifer L
Published: May 2008

Background

The major urinary proteins (MUPs) of Mus musculus domesticus are deposited in urine in large quantities, where they bind and release pheromones and also provide an individual 'recognition signal' via their phenotypic polymorphism. Whilst important information about MUP functionality has been gained in recent years, the gene cluster is poorly studied in terms of structure, genic polymorphism and evolution.

Results

We combine targeted sequencing, manual genome annotation and phylogenetic analysis to compare the Mup clusters of C57BL/6J and 129 strains of mice. We describe organizational heterogeneity within both clusters: a central array of cassettes containing Mup genes highly similar at the protein level, flanked by regions containing Mup genes displaying significantly elevated divergence. Observed genomic rearrangements in all regions have likely been mediated by endogenous retroviral elements. Mup loci with coding sequences that differ between the strains are identified - including a gene/pseudogene pair - suggesting that these inbred lineages exhibit variation that exists in wild populations. We have characterized the distinct MUP profiles in the urine of both strains by mass spectrometry. The total MUP phenotype data is reconciled with our genomic sequence data, matching all proteins identified in urine to annotated genes.

Conclusion

Our observations indicate that the MUP phenotypic polymorphism observed in wild populations results from a combination of Mup gene turnover coupled with currently unidentified mechanisms regulating gene expression patterns. We propose that the structural heterogeneity described within the cluster reflects functional divergence within the Mup gene family.
Prevalence and Treatment Patterns of Physical Impairments in Patients With Metastatic Breast Cancer
Authors: Cheville Andrea L. , Troxel Andrea B. , Basford Jeffrey R. , Kornblith Alice B.
Published: May 2008

Purpose

Physical impairments cause profound functional declines in patients with cancer. Although common rehabilitation measures can address many impairments, the extent of their delivery is unknown. We studied these issues by quantifying physical impairments in patients with metastatic breast cancer and by assessing how they are addressed.

Patients and Methods

A consecutive sample of 163 community-dwelling patients with metastatic breast cancer was stratified by Karnofsky performance score and administered the Medical Outcomes Study Physical Function Subscale and the Older Americans Resource Study Activities of Daily Living subscales. Cancer-related physical impairments were identified through a physical examination, the 6-Minute Walk Test, and the Functional Independence Measure Mobility Subscale. Patients were questioned regarding the nature, type, and setting of treatments for impairments. Physical rehabilitation needs were determined through a consensus process involving physiatrists and physical/occupational therapists specializing in cancer.

Results

Ninety-two percent of patients (150 of 163) had at least one physical impairment. Among 530 identified impairments, 484 (92%) required a physical rehabilitation intervention and 469 (88%) required physical therapy (PT) and/or occupational therapy (OT). Only 30% of impairments requiring rehabilitation services and 21% of those requiring PT/OT received treatment. Impairments detected during hospitalization were overwhelmingly more likely to receive a rehabilitation intervention (odds ratio [OR] = 87.9; 95% CI, 28.5 to 271.4), and PT/OT (OR = 558.8; 95% CI, 187.0 to 1,669.6). Low socioeconomic and minority status were significantly associated with nontreatment.

Conclusion

Remediable physical impairments were prevalent and poorly addressed among patients with metastatic breast cancer, drastically so in the outpatient setting. Undertreatment was particularly prominent among minority and socioeconomically disadvantaged groups.
Quality of Life Scores Predict Survival Among Patients With Head and Neck Cancer
Authors: Karvonen-Gutierrez Carrie A. , Ronis David L. , Fowler Karen E. , Terrell Jeffrey E. , Gruber Stephen B. , Duffy Sonia A.
Published: May 2008

Purpose

The purpose of this study was to examine whether quality of life (QOL) scores predict survival among patients with head and neck cancer, controlling for demographic, health behavior, and clinical variables.

Patients and Methods

A self-administered questionnaire was given to 495 patients being treated for head and neck cancer while they were waiting to be seen for a clinic appointment. Data collected from the survey included demographics, health behaviors, and QOL as measured by Short Form-36 (SF-36) physical and mental component scores and the Head and Neck QOL scores. Clinical measures were collected by chart abstraction. Kaplan-Meier plots and univariate and multivariate Cox proportional hazards models were used to determine the association between QOL scores and survival time.

Results

After controlling for age, time since diagnosis, marital status, education, tumor site and stage, comorbidities, and smoking, the SF-36 physical component score and three of the four Head and Neck QOL scales (pain, eating, and speech domains) were associated with survival. Controlling for the same variables, the SF-36 mental component score and the emotional domain of the Head and Neck QOL were not associated with survival.

Conclusion

QOL instruments may be valuable screening tools to identify patients who are at high risk for poor survival. Those with low QOL scores could be followed more closely, with the potential to identify recurrence earlier and perform salvage treatments, thereby possibly improving survival for this group of patients.
Influence of Clinical Communication on Patients' Decision Making on Participation in Clinical Trials
Authors: Albrecht Terrance L. , Eggly Susan S. , Gleason Marci E.J. , Harper Felicity W.K. , Foster Tanina S. , Peterson Amy M. , Orom Heather , Penner Louis A. , Ruckdeschel John C.
Published: May 2008

Purpose

To investigate how communication among physicians, patients, and family/companions influences patients' decision making about participation in clinical trials.

Patients and Methods

We video recorded 235 outpatient interactions occurring among oncologists, patients, and family/companions (if present) at two comprehensive cancer centers. We combined interaction analysis of the real-time video-recorded observations (collected at Time 1) with patient self-reports (Time 2) to determine how communication about trial offers influenced accrual decisions.

Results

Clinical trials were explicitly offered in 20% of the interactions. When offers were made and patients perceived they were offered a trial, 75% of patients assented. Observed messages (at Time 1) directly related to patients' self-reports regarding their decisions (2 weeks later), and how they felt about their decisions and their physicians. Specifically, messages that help build a sense of an alliance (among all parties, including the family/companions), provide support (tangible assistance and reassurance about managing adverse effects), and provide medical content in language that patients and family/companions understand are associated with the patient's decision and decision-making process.

Conclusion

In two urban, National Cancer Institute–designated comprehensive cancer centers, a large percentage of patients are not offered trials. When offered a trial, most patients enroll. The quality and quantity of communication occurring among the oncologist, patient, and family/companion when trials are discussed matter in the patient's decision-making process. These findings can help increase physician awareness of the ways that messages and communication behaviors can be observed and evaluated to improve clinical practice and research.
Estrogen Receptor Expression and Efficacy of Docetaxel-Containing Adjuvant Chemotherapy in Patients With Node-Positive Breast Cancer: Results From a Pooled Analysis
Authors: Andre Fabrice , Broglio Kristine , Roche Henri , Martin Miguel , Mackey John R. , Penault-Llorca Frederique , Hortobagyi Gabriel N. , Pusztai Lajos
Published: May 2008

Purpose

Several adjuvant chemotherapy trials suggested that cytotoxic treatment is less effective in patients with estrogen receptor (ER) –positive breast cancers. The aim of the present study was to assess the efficacy of adjuvant docetaxel and anthracycline therapy according to ER expression in two randomized clinical trials.

Patients and Methods

Pooled data from two randomized trials, BCIRG001 and PACS01, were examined. Hazard ratios for recurrence and survival were estimated by Cox proportional hazards models and were adjusted for clinical variables. Interaction between docetaxel and ER expression was tested.

Results

ER status was available for 3,329 patients (95% of all randomly assigned patients), of whom 75% (n = 2,493) were ER positive. Docetaxel therapy was associated with a 30% reduction in the risk of death (hazard ratio [HR] = 0.70; 95% CI, 0.54 to 0.91) in ER-positive patients and a 31% reduction (HR = 0.69; 95% CI, 0.52 to 0.94) in ER-negative patients. Docetaxel therapy was associated with a 21% reduction in the risk of recurrence (HR = 0.79; 95% CI, 0.66 to 0.93) in ER-positive patients and a 31% reduction (HR = 0.69; 95% CI, 0.54 to 0.97) in ER-negative patients. The interaction between docetaxel therapy and ER status was not statistically significant for either overall survival (P = .87) or disease-free survival (P = .30). ER expression was also not predictive for docetaxel efficacy when it was analyzed as a semi-continuous variable based on percent of positive cells by immunohistochemistry (test for heterogeneity, P = .56 and .86 for overall survival and disease-free survival, respectively).

Conclusion

In the pooled analysis of these two trials, docetaxel did not have a statistically significantly different effect on the risk of recurrence or death in ER-positive and ER-negative patients.
Phase III Study of Valspodar (PSC 833) Combined With Paclitaxel and Carboplatin Compared With Paclitaxel and Carboplatin Alone in Patients With Stage IV or Suboptimally Debulked Stage III Epithelial Ovarian Cancer or Primary Peritoneal Cancer
Authors: Lhommé Catherine , Joly Florence , Walker Joan L. , Lissoni Andrea A. , Nicoletto Maria O. , Manikhas Gregory M. , Baekelandt Mark M.O. , Gordon Alan N. , Fracasso Paula M. , Mietlowski William L. , Jones Gary J. , Dugan Margaret H.
Published: May 2008

Purpose

To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer.

Patients and Methods

Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m2, and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m2 and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability.

Results

With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC–and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC–treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions.

Conclusion

The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.
Phase I Trial of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir and Chemoradiation for Locally Advanced Pancreatic Cancer
Authors: Brunner Thomas B. , Geiger Matthias , Grabenbauer Gerhard G. , Lang-Welzenbach Marga , Mantoni Tine S. , Cavallaro Alexander , Sauer Rolf , Hohenberger Werner , McKenna W. Gillies
Published: May 2008

Purpose

Preclinically, HIV protease inhibitors radiosensitize tumors with activated PI3-kinase/Akt pathway. We determined the toxicity of nelfinavir chemoradiotherapy in borderline resectable and unresectable pancreatic cancer.

Patients and Methods

Oral nelfinavir (2 × 1,250 mg) was started 3 days before and continued throughout chemoradiotherapy to 50.4 Gy (boost, 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested (200 mg/m2 and 300 mg/m2 on days 1, 8, 22, and 29). Cisplatin was administered on the same days at 30 mg/m2. Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging positron emission tomography (PET)/computed tomography (CT) and CA19-9 levels served to assess response, and responding tumors were resected.

Results

At each DL, five of six patients completed chemoradiotherapy, and two of 12 patients had incomplete chemoradiotherapy because of clinical depression (DL1) and peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) as a result of biliary stent occlusion and acute cholecystitis as a result of peritoneal metastasis (DL2). Stent occlusions led to dose-limiting toxicities of grade 3 liver enzyme and bilirubin elevations (two patients at DL1, one patient at DL2). Grade 3 nausea and vomiting occurred in a DL2 patient, and weight loss occurred in a DL1 patient who refused supportive feeding. Secondary complete resection was possible in six of 10 patients with complete chemoradiotherapy, including one tumor with pathologic sterilization. Partial CT responses were observed in five of 10 patients who completed chemoradiotherapy. Of nine patients assessable by PET,responses were complete in five patients and partial patients, and stable disease was observed in two patients.

Conclusion

The combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer.
Identical Outcome After Autologous or Allogeneic Genoidentical Hematopoietic Stem-Cell Transplantation in First Remission of Acute Myelocytic Leukemia Carrying Inversion 16 or t(8;21): A Retrospective Study From the European Cooperative Group for Blood and Marrow Transplantation
Authors: Gorin Norbert-Claude , Labopin Myriam , Frassoni Francesco , Milpied Noel , Attal Michel , Blaise Didier , Meloni Giovanna , Iori Anna P. , Michallet Mauricette , Willemze Roel , Deconninck Eric , Harousseau Jean-Luc , Polge Emmanuelle , Rocha Vanderson
Published: May 2008

Purpose

Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities. They presently do not undergo transplantation in first remission (CR1), but there is concern about late relapses.

Patients and Methods

From 1990 to 2004, 325 adult patients received transplantations in CR1 (159 patients with inv16 and 166 patients with t(8;21), including 35 and 60 patients, respectively, with additional chromosomal abnormalities). Genoidentical allografts were performed in 64 patients with inv16 and 81 patients with t(8;21), and autografts were performed in 95 patients with inv16 and 85 patients with t(8;21).

Results

In patients with inv16, after allogeneic and autologous transplantation, the 5-year leukemia-free survival (LFS) rates were 59% and 66% (P = .5), the relapse incidence (RI) rates were 27% and 32% (P = .45), and the transplantation-related mortality (TRM) rates were 14% and 2% (P = .003), respectively. Female patients had a lower RI and a higher LFS. Additional chromosomal abnormalities, compared with no additional abnormalities, were associated with lower RI rate (12% v 34%, respectively; P = .01) and higher 5-year LFS rate (78% v 59%, respectively; P = .04). In patients with t(8;21), after allogeneic and autologous transplantation, the 5-year LFS rates were 60% and 66% (P = .69), the RI rates were 15% and 28% (P = .03), and the TRM rates were 24% and 6% (P = .003), respectively. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. The TRM was lower and the RI was higher in patients with autologous transplantations versus allogeneic transplantations.

Conclusion

Both autologous and allogeneic transplantation resulted in similar outcomes.
Predictive Biomarkers of Chemotherapy Efficacy in Colorectal Cancer: Results From the UK MRC FOCUS Trial
Authors: Braun Michael S. , Richman Susan D. , Quirke Philip , Daly Catherine , Adlard Julian W. , Elliott Faye , Barrett Jennifer H. , Selby Peter , Meade Angela M. , Stephens Richard J. , Parmar Mahesh K.B. , Seymour Matthew T.
Published: May 2008

Purpose

Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer.

Methods

The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival.

Results

One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, < 10%; moderate, 10% to 50%; or high, > 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio [HR], 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker.

Conclusion

Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.
High Expression of Macrophage Colony-Stimulating Factor in Peritumoral Liver Tissue Is Associated With Poor Survival After Curative Resection of Hepatocellular Carcinoma
Authors: Zhu Xiao-Dong , Zhang Ju-Bo , Zhuang Peng-Yuan , Zhu Hong-Guang , Zhang Wei , Xiong Yu-Quan , Wu Wei-Zhong , Wang Lu , Tang Zhao-You , Sun Hui-Chuan
Published: May 2008

Purpose

To investigate prognostic values of the intratumoral and peritumoral expression of macrophage colony-stimulating factors (M-CSF) in hepatocellular carcinoma (HCC) patients after curative resection.

Patients and Methods

Expression of M-CSF and density of macrophages (MΦ) were assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissue from 105 patients who had undergone hepatectomy for histologically proven HCC. Prognostic value of these and other clinicopathologic factors was evaluated.

Results

Neither intratumoral M-CSF nor MΦ density was associated with overall survival (OS) or disease-free survival (DFS). High peritumoral M-CSF and MΦ density, which correlated with large tumor size, presence of intrahepatic metastasis, and high TNM stage, were independent prognostic factors for both OS (P = .001 and P < .001, respectively) and DFS (P = .001 and P = .003, respectively) and affected incidence of early recurrence. In a small HCC subset, peritumoral M-CSF was also correlated with both OS and DFS (P = .038 and P = .001, respectively). The combination of peritumoral M-CSF and MΦ had a better power to predict the patients' death and disease recurrence (P < .001 for both).

Conclusion

High peritumoral M-CSF and MΦ were associated with HCC progression, disease recurrence, and poor survival after hepatectomy, highlighting the importance of peritumoral tissue in the recurrence and metastasis of HCC. M-CSF and MΦ may be targets of postoperative adjuvant therapy.
Incidence of Venous Thromboembolism in Patients With Ovarian Cancer Undergoing Platinum/Paclitaxel–Containing First-Line Chemotherapy: An Exploratory Analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group
Authors: Fotopoulou Christina , duBois Andreas , Karavas Alexandros N. , Trappe Ralf , Aminossadati Behnaz , Schmalfeldt Barbara , Pfisterer Jacobus , Sehouli Jalid
Published: May 2008

Purpose

Venous thromboembolism (VTE) has been associated with negative prognosis in cancer patients. Most series reporting on VTE have included different tumor types not differentiating between recurrent or primary disease. Data regarding the actual impact of VTE on primary advanced ovarian cancer (AOC) are limited.

Patients and Methods

Between 1995 and 2002, the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study group (AGO–OVAR) recruited 2,743 patients with AOC in three prospectively randomized trials on platinum paclitaxel-based chemotherapy after primary surgery. Pooled data analysis was performed to evaluate incidence, predictors, and prognostic impact of VTE in AOC. Survival curves were calculated for the VTE incidence. Univariate analysis and Cox regression analysis were performed to identify independent predictors of VTE and mortality.

Results

Seventy-six VTE episodes were identified, which occurred during six to 11 cycles of adjuvant chemotherapy; 50% of them occurred within 2 months postoperatively. Multivariate analysis identified body mass index higher than 30 kg/m2 and increasing age as independent predictors of VTE. International Federation of Gynecology and Obstetrics stage and surgical radicality did not affect incidence. Overall survival was significantly reduced in patients with VTE (median, 29.8 v 36.2 months; P = .03). Multivariate analysis identified pulmonary embolism (PE), but not deep vein thrombosis alone, to be of prognostic significance. In addition, VTE was not identified to significantly affect progression-free survival.

Conclusion

Patients with AOC have their highest VTE risk within the first 2 months after radical surgery. Only VTE complicated by symptomatic PE have been identified to have a negative impact on survival. Studies evaluating the role of prophylactic anticoagulation during this high risk postoperative period are warranted.
Genetic Analysis of Krüppel-Like Zinc Finger 11 Variants in 5864 Danish Individuals: Potential Effect on Insulin Resistance and Modified Signal Transducer and Activator of Transcription-3 Binding by Promoter Variant −1659G>C
Authors: Gutiérrez-Aguilar Ruth , Froguel Philippe , Hamid Yasmin H. , Benmezroua Yamina , Jørgensen Torben , Borch-Johnsen Knut , Hansen Torben , Pedersen Oluf , Neve Bernadette
Published: May 2008

Context: The transcription factor Krüppel-like zinc finger 11 (KLF11) has been suggested to contribute to genetic risk of type 2 diabetes (T2D). Our previous results showed that four KLF11 variants, in strong linkage disequilibrium (LD block including +185 A>G/Gln62Arg and −1659 G>C) were associated with T2D in a north European case-control study. Here we further analyzed these variants for T2D association in a general Danish population and assess their possible effect on gene function.

Methods: We genotyped Gln62Arg variant, representative for the LD block, in 5864 subjects of the INTER99 study to assess association to T2D and glucose metabolism-related quantitative traits. We studied effects of LD-block variants on KLF11 function and in particular, the effect of −1659G>C on transcriptional regulation of KLF11 using EMSA, chromatin immunoprecipitation, gene reporter assays, and small interfering RNA transfection.

Results: We could not confirm T2D association of the KLF11 LD block, however, in glucose-tolerant subjects; it was significantly associated with higher fasting serum insulin and C-peptide levels and increased homeostasis model assessment insulin resistance indexes (P = 0.00004, P = 0.006, and P = 0.00002, respectively). In addition, binding of signal transducer and activator of transcription (STAT)-3 to the wild-type (−1659G>C) allele stimulated gene transcription, whereas STAT3 did not bind onto the mutant allele.

Conclusions: We showed that KLF11 may interfere with glucose homeostasis in a Danish general population and that STAT3-mediated up-regulation of KLF11 transcription was impaired by the −1659G>C variant. Overall, KLF11 variants may have a deleterious effect on insulin sensitivity, although that may not be sufficient to lead to T2D.