bluuebunny/crossref_metadata_2025 huggingface dataset:
Geriatric day hospital: opportunity or threat? A qualitative exploratory study of the referral behaviour of Belgian general practitioners
Authors: Vanden Bussche Piet , Desmyter Fien , Duchesnes Christiane , Massart Valérie , Giet Didier , Petermans Jean , Vyncke Veerle , Ven Den Noortgate Nele , Willems Sara
Published: July 2010

Background

In order to address the challenges of an ageing population the Belgian government decided to allocate resources to the creation of geriatric day hospitals (GDHs). Although GDHs are meant to be a strategy to support general practitioners (GPs) caring for the frail elderly, few Belgian GPs seem to refer to a GDH. This study aims to explore the barriers and facilitating factors of GPs' referral to GDHs.

Methods

A qualitative study using focus group discussions (FGDs) was conducted. Fifteen FGDs were organized in the different Belgian regions (Flanders, Wallonia, Brussels).

Results

Contextual factors such as the unsatisfactory cooperation between hospital and GPs and organizational barriers such as the lack of communication on referral procedures between hospital and primary health care (PHC) were identified. Lack of basic knowledge about the concept or the local organization of GDH seemed to be a problem. Unclear task descriptions, responsibilities and activities of a GDH formed prominent points of discussion in all FGDs. Nevertheless a lot of possible advantages and disadvantages of GDHs for the patient and for the GP were mentioned.

Conclusions

In the case of poor referral to GDHs, focusing on improving overall collaboration between primary and secondary health care is essential. This can be achieved by actively delivering adequate information, permanent communication and more involvement of PHC in the organization and functioning of GDHs. The absence of a transparent health care system with delineated role definitions, seems to hinder the integration of new initiatives like GDHs in the care process. Strategies to enhance referral to GDHs should use a comprehensive approach.
Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer
Authors: Lara Ester , Calvanese Vincenzo , Huidobro Covadonga , Fernández Agustin F , Moncada-Pazos Ángela , Obaya Álvaro J , Aguilera Oscar , González-Sancho José Manuel , Sánchez Laura , Astudillo Aurora , Muñoz Alberto , López-Otín Carlos , Esteller Manel , Fraga Mario F
Published: July 2010

Background

Wnt factors control cell differentiation through semi-independent molecular cascades known as the β-catenin-dependent (canonical) and -independent (non-canonical) Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood.

Results

Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouringROR2promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic.

Conclusions

Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour.
Elevation of sulfatides in ovarian cancer: An integrated transcriptomic and lipidomic analysis including tissue-imaging mass spectrometry
Authors: Liu Ying , Chen Yanfeng , Momin Amin , Shaner Rebecca , Wang Elaine , Bowen Nathan J , Matyunina Lilya V , Walker L DeEtte , McDonald John F , Sullards M Cameron , Merrill Alfred H
Published: July 2010

Background

Sulfatides (ST) are a category of sulfated galactosylceramides (GalCer) that are elevated in many types of cancer including, possibly, ovarian cancer. Previous evidence for elevation of ST in ovarian cancer was based on a colorimetric reagent that does not provide structural details and can also react with other lipids. Therefore, this study utilized mass spectrometry for a structure-specific and quantitative analysis of the types, amounts, and tissue localization of ST in ovarian cancer, and combined these findings with analysis of mRNAs for the relevant enzymes of ST metabolism to explore possible mechanisms.

Results

Analysis of 12 ovarian tissues graded as histologically normal or having epithelial ovarian tumors by liquid chromatography electrospray ionization-tandem mass spectrometry (LC ESI-MS/MS) established that most tumor-bearing tissues have higher amounts of ST. Because ovarian cancer tissues are comprised of many different cell types, histological tissue slices were analyzed by matrix-assisted laser desorption ionization-tissue-imaging MS (MALDI-TIMS). The regions where ST were detected by MALDI-TIMS overlapped with the ovarian epithelial carcinoma as identified by H & E staining and histological scoring. Furthermore, the structures for the most prevalent species observed via MALDI-TIMS (d18:1/C16:0-, d18:1/C24:1- and d18:1/C24:0-ST) were confirmed by MALDI-TIMS/MS, whereas, a neighboring ion(m/z 885.6) that was not tumor specific was identified as a phosphatidylinositol. Microarray analysis of mRNAs collected using laser capture microdissection revealed that expression of GalCer synthase and Gal3ST1 (3'-phosphoadenosine-5'-phosphosulfate:GalCer sulfotransferase) were approximately 11- and 3.5-fold higher, respectively, in the ovarian epithelial carcinoma cells versus normal ovarian stromal tissue, and they were 5- and 2.3-fold higher in comparison with normal surface ovarian epithelial cells, which is a likely explanation for the higher ST.

Conclusions

This study combined transcriptomic and lipidomic approaches to establish that sulfatides are elevated in ovarian cancer and should be evaluated further as factors that might be important in ovarian cancer biology and, possibly, as biomarkers.
Costing the scaling-up of human resources for health: lessons from Mozambique and Guinea Bissau
Authors: Tyrrell Amanda K , Russo Giuliano , Dussault Gilles , Ferrinho Paulo
Published: July 2010

Introduction

In the context of the current human resources for health (HRH) crisis, the need for comprehensive Human Resources Development Plans (HRDP) is acute, especially in resource-scarce sub-Saharan African countries. However, the financial implications of such plans rarely receive due consideration, despite the availability of much advice and examples in the literature on how to conduct HRDP costing. Global initiatives have also been launched recently to standardise costing methodologies and respective tools.

Methods

This paper reports on two separate experiences of HRDP costing in Mozambique and Guinea Bissau, with the objective to provide an insight into the practice of costing exercises in information-poor settings, as well as to contribute to the existing debate on HRH costing methodologies. The study adopts a case-study approach to analyse the methodologies developed in the two countries, their contexts, policy processes and actors involved.

Results

From the analysis of the two cases, it emerged that the costing exercises represented an important driver of the HRDP elaboration, which lent credibility to the process, and provided a financial framework within which HRH policies could be discussed. In both cases, bottom-up and country-specific methods were designed to overcome the countries' lack of cost and financing data, as well as to interpret their financial systems. Such an approach also allowed the costing exercises to feed directly into the national planning and budgeting process.

Conclusions

The authors conclude that bottom-up and country-specific costing methodologies have the potential to serve adequately the multi-faceted purpose of the exercise. It is recognised that standardised tools and methodologies may help reduce local governments' dependency on foreign expertise to conduct the HRDP costing and facilitate regional and international comparisons. However, adopting pre-defined and insufficiently flexible tools may undermine the credibility of the costing exercise, and reduce the space for policy negotiation opportunities within the HRDP elaboration process.
Mass spectrometry-based analysis of therapy-related changes in serum proteome patterns of patients with early-stage breast cancer
Authors: Pietrowska Monika , Polanska Joanna , Marczak Lukasz , Behrendt Katarzyna , Nowicka Elzbieta , Stobiecki Maciej , Polanski Andrzej , Tarnawski Rafal , Widlak Piotr
Published: July 2010

Background

The proteomics approach termed proteome pattern analysis has been shown previously to have potential in the detection and classification of breast cancer. Here we aimed to identify changes in serum proteome patterns related to therapy of breast cancer patients.

Methods

Blood samples were collected before the start of therapy, after the surgical resection of tumors and one year after the end of therapy in a group of 70 patients diagnosed at early stages of the disease. Patients were treated with surgery either independently (26) or in combination with neoadjuvant chemotherapy (5) or adjuvant radio/chemotherapy (39). The low-molecular-weight fraction of serum proteome was examined using MALDI-ToF mass spectrometry, and then changes in intensities of peptide ions registered in a mass range between 2,000 and 14,000 Da were identified and correlated with clinical data.

Results

We found that surgical resection of tumors did not have an immediate effect on the mass profiles of the serum proteome. On the other hand, significant long-term effects were observed in serum proteome patterns one year after the end of basic treatment (we found that about 20 peptides exhibited significant changes in their abundances). Moreover, the significant differences were found primarily in the subgroup of patients treated with adjuvant therapy, but not in the subgroup subjected only to surgery. This suggests that the observed changes reflect overall responses of the patients to the toxic effects of adjuvant radio/chemotherapy. In line with this hypothesis we detected two serum peptides (registered m/z values 2,184 and 5,403 Da) whose changes correlated significantly with the type of treatment employed (their abundances decreased after adjuvant therapy, but increased in patients treated only with surgery). On the other hand, no significant correlation was found between changes in the abundance of any spectral component or clinical features of patients, including staging and grading of tumors.

Conclusions

The study establishes a high potential of MALDI-ToF-based analyses for the detection of dynamic changes in the serum proteome related to therapy of breast cancer patients, which revealed the potential applicability of serum proteome patterns analyses in monitoring the toxicity of therapy.
Investigating the synchronization of hippocampal neural network in response to acute nicotine exposure
Authors: Akkurt David , Akay Yasemin M , Akay Metin
Published: July 2010

Previous studies suggested that γ oscillations in the brain are associated with higher order cognitive function including selective visual attention, motor task planning, sensory perception, working memory and dreaming REM sleep. These oscillations are mainly observed in cortical regions and also occur in neocortical and subcortical areas and the hippocampus. In this paper, we investigate the influence of acute exposure to nicotine on the complexity of hippocampal γ oscillations.

Using the approximate entropy method, the influence of acute nicotine exposure on the hippocampal γ oscillations was investigated. The hippocampal γ oscillations have been generated in response to the 100 Hz stimulus and isolated using the visual inspection and spectral analysis method. Our central hypothesis is that acute exposure to nicotine significantly reduces the complexity of hippocampal γ oscillations. We used brain-slice recordings and the approximate entropy method to test this hypothesis. The approximate entropy (complexity) values of the hippocampal γ oscillations are estimated from the 14 hippocampal slices. Our results show that it takes at least 100 msec to see any hippocampal activities in response to the 100 Hz stimulus. These patterns noticeably changed after 100 msec until 300 msec after the stimulus Finally, they were less prominent after 300 msec. We have analyzed the isolated hippocampal γ oscillations (between 150 and 250 msec after the stimulus) using the approximate entropy (ApEn) method. Our results showed that the ApEn (complexity) values of hippocampal γ oscillations during nicotine exposure were reduced compared to those of hippocampal γ oscillations during control, and washout. This reduction was much more significant in response to acute nicotine exposure (p < 0.05) compared to those during control and washout conditions. These results suggest that the neural firing becomes regular and the hippocampal networks become synchronized in response to nicotine exposure.
Factors associated with mosquito pool positivity and the characterization of the West Nile viruses found within Louisiana during 2007
Authors: Christofferson Rebecca C , Roy Alma F , Mores Christopher N
Published: July 2010

Background

West Nile virus (WNV) is an arbovirus of public health importance in the genus Flavivirus, a group of positive sense RNA viruses. The NS3 gene has a high level of substitutions and is phylogenetically informative. Likewise, substitutions in the envelope region have been postulated to enable viruses to subvert immune responses. Analysis of these genes among isolates from positive mosquitoes collected in Louisiana illustrates the variation present in the regions and provides improved insight to a phylogenetic model. Employing a GIS eco-regionalization method, we hypothesized that WNV pool positivity was correlated with regional environmental characteristics. Further, we postulated that the phylogenetic delineations would be associated with variations in regional environmental conditions.

Results

Type of regional land cover was a significant effect (p < 0.0001) in the positive pool prediction, indicating that there is an ecological component driving WNV activity. Additionally, month of collection was significant (p < 0.0001); and thus there is a temporal component that contributes to the probability of getting a positive mosquito pool. All virus isolates are of the WNV 2002 lineage. There appears to be some diversity within both forested and wetland areas; and the possibility of a distinct clade in the wetland samples.

Conclusions

The phylogenetic analysis shows that there has been no reversion in Louisiana from the 2002 lineage which replaced the originally introduced strain. Our pool positivity model serves as a basis for future testing, and could direct mosquito control and surveillance efforts. Understanding how land cover and regional ecology effects mosquito pool positivity will greatly help focus mosquito abatement efforts. This would especially help in areas where abatement programs are limited due to either funding or man power. Moreover, understanding how regional environments drive phylogenetic variation will lead to a greater understanding of the interactions between ecology and disease prevalence.
GTC: A web server for integrating systems biology data with web tools and desktop applications
Authors: Tenenbaum Dan , Bare J Christopher , Baliga Nitin S
Published: July 2010

Gaggle Tool Creator (GTC) is a web application which provides access to public annotation, interaction, orthology, and genomic data for hundreds of organisms, and enables instant analysis of the data using many popular web-based and desktop applications.
Nm23-H1 suppresses hepatocarcinoma cell adhesion and migration on fibronectin by modulating glycosylation of integrin beta1
Authors: She Shangyang , Xu Boying , He Min , Lan Xiuwan , Wang Qiuyan
Published: July 2010

Background

Nm23 gene was isolated as a metastatic suppressor gene. The antimetastatic effect of Nm23 has been an enigma for more than 10 years. Little is known about its molecular mechanisms. In this study we overexpressed Nm23-H1 in H7721 cells and observed reduction of cell adhesion, migration and extension of actin stress fibers in cells stimulated by fibronectin (Fn).

Methods

pcDNA3/Nm23-H1 was introduced into H7721 cells, and expression of Nm23-H1 was monitored by RT-PCR and western blot. Cell adhesion, actin extension and wound-induced migration assays were done on dishes coated with fibronectin. Phosphorylation of focal adhesion kinase (FAK) and total amount of integrin alpha5 and beta1 in Nm23-H1 transfected cells and control cells were measured by western blot. Flow cytometry was used to detect expression of surface alpha5 and beta1 integrin. N-glycosylation inhibitor tunicamycin was used to deglycosylate the integrin beta1 subunit.

Results

Overexpression of nm23-H1 in H7721 cells reduced cell adhesion, migration and extension of actin stress fibers on dishes coated with Fn. Phosphorylation of FAK in Nm23-H1 transfected cells was also attenuated. Integrin alpha5 and beta1 gene messages were unaltered in nm23-H1 overexpressed cells as detected by RT-PCR. However, while cell surface integrin alpha5 was unchanged, surface expression of beta1 integrin was downregulated. Western blot also showed that the total amounts of integrin alpha5 and beta1 were unaltered, but the level of mature integrin beta1 isoform was decreased significantly. Furthermore, partially glycosylated precursor beta1 was increased, which indicated that the impaired glycosylation of integrin beta1 precursor might contribute to the loss of cell surface integrin beta1 in nm23-H1 overexpressed cells.

Conclusion

These results suggest that by modulating glycosylation of integrin beta1, nm23-H1 down-regulates integrin beta1 subunit on cell surface and mediates intracellular signaling and subsequent suppression of the invasive process, including cell adhesion and migration.
Targeted gene therapy of nasopharyngeal cancer in vitro and in vivo by enhanced thymidine kinase expression driven by human TERT promoter and CMV enhancer
Authors: Shen Cong-Xiang , Wen Zhong , Qian Yu-Hong , Mu Shao-Feng , Guan Xiao-Fang
Published: July 2010

Background/Aim

To explore the therapeutic effects of thymidine kinase (TK) expressed by enhanced vector pGL3-basic- hTERTp-TK-EGFP-CMV driven by human telomerase reverse transcriptase promoter (hTERTp) as well as cytomegalovirus immediate early promoter enhancer (CMV).

Materials/Methods

Enhanced TK-EGFP expression was confirmed by fluorescent microscopy, real time PCR and telomerase activity. Its effects were examined by survival of tumor cells NPC 5-8F and MCF-7, index of xenograft implanted in nude mice and histology.

Results

Compared with non-enhanced vector pGL3-basic-TK-hTERTp-EGFP, TK expressed by the enhanced vector significantly decreased NPC 5-8F and MCF-7 cell survival rates after ganciclovir (GCV) treatment (p < 0.001) and tumor progress in nude mice with NPC xenograft and treated with GCV, without obvious toxicity to mouse liver and kidney.

Conclusion

The enhanced TK expression vector driven by hTERTp with CMV enhancer has brighter clinical potentials in nasopharyngeal carcinoma therapy than the non-enhanced vector.
Planning for pre‐exposure prophylaxis to prevent HIV transmission: challenges and opportunities
Authors: Kim Susan C , Becker Stephen , Dieffenbach Carl , Hanewall Blair S , Hankins Catherine , Lo Ying‐Ru , Mellors John W , O'Reilly Kevin , Paxton Lynn , Roffenbender Jason S , Warren Mitchell , Piot Peter , Dybul Mark R
Published: July 2010

There are currently several ongoing or planned trials evaluating the efficacy of pre‐exposure prophylaxis (PrEP) as a preventative approach to reducing the transmission of HIV. PrEP may prove ineffective, demonstrate partial efficacy, or show high efficacy and have the potential to reduce HIV infection in a significant way. However, in addition to the trial results, it is important that issues related to delivery, implementation and further research are also discussed. As a part of the ongoing discussion, in June 2009, the Bill & Melinda Gates Foundation sponsored a Planning for PrEP conference with stakeholders to review expected trial results, outline responsible educational approaches, and develop potential delivery and implementation strategies. The conference reinforced the need for continued and sustained dialogue to identify where PrEP implementation may fit best within an integrated HIV prevention package. This paper identifies the key action points that emerged from the Planning for PrEP meeting.
Respiratory symptoms and disease characteristics as predictors of pulmonary function abnormalities in patients with rheumatoid arthritis: an observational cohort study
Authors: Pappas Dimitrios A , Giles Jon T , Connors Geoffrey , Lechtzin Noah , Bathon Joan M , Danoff Sonye K
Published: July 2010

Introduction

Lung involvement is a common extra-articular manifestation of rheumatoid arthritis (RA) that confers significant morbidity and mortality. The objective of the present study is to assess which respiratory symptoms and patient and disease characteristics are most highly associated with pulmonary function test (PFT) abnormalities in an RA patient cohort without clinical cardiovascular disease.

Methods

A total of 159 individuals with RA and without clinically evident cardiovascular disease were evaluated. Respiratory symptoms were assessed with the Lung Tissue Research Consortium questionnaire and all patients underwent evaluation with PFTs. Demographic, lifestyle, RA disease and treatment characteristics were collected. Subclinical coronary artery disease was assessed by cardiac computed tomography. Multivariable regression analysis was used to identify pulmonary symptoms and nonpulmonary parameters associated with PFT abnormalities. Areas under the receiver operating characteristic curves (AUC) were calculated to evaluate the discrimination of these variables for identifying patients with PFT abnormalities.

Results

Respiratory symptoms were reported by 42% of the patient population. Although only 6% carried a prior diagnosis of lung disease, PFT abnormalities were identified in 28% of the subjects. Symptoms combined with other patient and RA characteristics (body mass index, current smoking, anti-cyclic citrullinated peptide antibodies, and current prednisone use) performed satisfactorily in predicting the PFT abnormalities of obstruction (AUC = 0.91, 95% confidence interval = 0.78 to 0.98), restriction (AUC = 0.79, 95% confidence interval = 0.75 to 0.93) and impaired diffusion (AUC = 0.85, 95% confidence interval = 0.59 to 0.92). Co-morbid subclinical coronary artery disease did not modify these relationships.

Conclusions

Assessment of respiratory symptoms along with a limited number of clinical parameters may serve as a useful and inexpensive clinical tool for identifying RA patients in need of further pulmonary investigation.
Does an increase in body mass index over 10 years affect knee structure in a population-based cohort study of adult women?
Authors: Brennan Sharon L , Cicuttini Flavia M , Pasco Julie A , Henry Margaret J , Wang Yuanyuan , Kotowicz Mark A , Nicholson Geoff C , Wluka Anita E
Published: July 2010

Introduction

Although obesity is a modifiable risk factor for knee osteoarthritis (OA), the effect of weight gain on knee structure in young and healthy adults has not been examined. The aim of this study was to examine the relationship between body mass index (BMI), and change in BMI over the preceding 10-year period, and knee structure (cartilage defects, cartilage volume and bone marrow lesions (BMLs)) in a population-based sample of young to middle-aged females.

Methods

One hundred and forty-two healthy, asymptomatic females (range 30 to 49 years) in the Barwon region of Australia, underwent magnetic resonance imaging (MRI) during 2006 to 2008. BMI measured 10 years prior (1994 to 1997), current BMI and change in BMI (accounting for baseline BMI) over this period, was assessed for an association with cartilage defects and volume, and BMLs.

Results

After adjusting for age and tibial plateau area, the risk of BMLs was associated with every increase in one-unit of baseline BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.009), current BMI (OR 1.13 (95% CI 1.04 to 1.23) P = 0.005), and per one unit increase in BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.01). There was a trend for a one-unit increase in current BMI to be associated with increased risk of cartilage defects (OR 1.06 (95% CI 1.00 to 1.13) P = 0.05), and a suggestion that a one-unit increase in BMI over 10 years may be associated with reduced cartilage volume (-17.8 ml (95% CI -39.4 to 3.9] P = 0.10). Results remained similar after excluding those with osteophytes.

Conclusions

This study provides longitudinal evidence for the importance of avoiding weight gain in women during early to middle adulthood as this is associated with increased risk of BMLs, and trend toward increased tibiofemoral cartilage defects. These changes have been shown to precede increased cartilage loss. Longitudinal studies will show whether avoiding weight gain in early adulthood may play an important role in diminishing the risk of knee OA.
Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule
Authors: Ghebeh Hazem , Lehe Cynthia , Barhoush Eman , Al-Romaih Khaldoon , Tulbah Asma , Al-Alwan Monther , Hendrayani Siti-Faujiah , Manogaran Pulicat , Alaiya Ayodele , Al-Tweigeri Taher , Aboussekhra Abdelilah , Dermime Said
Published: July 2010

Introduction

B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients.

Methods

In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells.

Results

Among tested chemotherapeutic agents, doxorubicin was the most effective in downregulating cell surface expression of B7-H1 in vitro. These results were validated in vivo in a xenograft mouse model, as well as in murine heart tissue known to constitutively express B7-H1. The doxorubicin-dependent cell surface downregulation of B7-H1 was accompanied by an upregulation of B7-H1 in the nucleus. This re-distribution of B7-H1 was concurrent with a similar translocation of phosphorylated AKT to the nucleus. Inhibition of the PI3K/AKT pathway abrogated the doxorubicin-mediated nuclear up-regulation of B7-H1, suggesting an involvement of PI3K/AKT pathway in the nuclear up-regulation of B7-H1. Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells. The novel discovery of B7-H1 expression in the nuclei of breast cancer cells suggests that B7-H1 has functions other than inhibition of T cells.

Conclusions

Our findings explain the previously reported immunomodulatory effect of anthracyclines on cancer cells, and provide a link between immunoresistance and chemoresistance. Finally these results suggest the use of dual combinatorial agents to inhibit B7-H1 beside chemotherapy, in breast cancer patients.
Physicians' and nurses' opinions on selective decontamination of the digestive tract and selective oropharyngeal decontamination: a survey
Authors: Jongerden Irene P , de Smet AnneMarie G , Kluytmans Jan A , te Velde Leo F , Dennesen Paul J , Wesselink Ronald M , Bouw Martijn P , Spanjersberg Rob , Bogaers-Hofman Diana , van der Meer Nardo J , de Vries Jaap W , Kaasjager Karin , van Iterson Mat , Kluge Georg H , van der Werf Tjip S , Harinck Hubertus I , Bindels Alexander J , Pickkers Peter , Bonten Marc J
Published: July 2010

Introduction

Use of selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) in intensive care patients has been controversial for years. Through regular questionnaires we determined expectations concerning SDD (effectiveness) and experience with SDD and SOD (workload and patient friendliness), as perceived by nurses and physicians.

Methods

A survey was embedded in a group-randomized, controlled, cross-over multicenter study in the Netherlands in which, during three 6-month periods, SDD, SOD or standard care was used in random order. At the end of each study period, all nurses and physicians from participating intensive care units received study questionnaires.

Results

In all, 1024 (71%) of 1450 questionnaires were returned by nurses and 253 (82%) of 307 by physicians. Expectations that SDD improved patient outcome increased from 71% and 77% of respondents after the first two study periods to 82% at the end of the study (P = 0.004), with comparable trends among nurses and physicians. Nurses considered SDD to impose a higher workload (median 5.0, on a scale from 1 (low) to 10 (high)) than SOD (median 4.0) and standard care (median 2.0). Both SDD and SOD were considered less patient friendly than standard care (medians 4.0, 4.0 and 6.0, respectively). According to physicians, SDD had a higher workload (median 5.5) than SOD (median 5.0), which in turn was higher than standard care (median 2.5). Furthermore, physicians graded patient friendliness of standard care (median 8.0) higher than that of SDD and SOD (both median 6.0).

Conclusions

Although perceived effectiveness of SDD increased as the trial proceeded, both among physicians and nurses, SOD and SDD were, as compared to standard care, considered to increase workload and to reduce patient friendliness. Therefore, education about the importance of oral care and on the effects of SDD and SOD on patient outcomes will be important when implementing these strategies.

Trial registration

ISRCTN35176830.
Upregulation of the pro-apoptotic genes BID and FAS in septic shock patients
Authors: Turrel-Davin Fanny , Guignant Caroline , Lepape Alain , Mougin Bruno , Monneret Guillaume , Venet Fabienne
Published: July 2010

Introduction

Lymphocyte apoptosis has been suggested to play a central role in sepsis pathophysiology, and studies in animal models demonstrated that blocking this pathway improves outcome. However, no routine biomarkers of apoptosis are so far available in patients. Thus, the aim of our study was to assess the different biomarkers of apoptosis putatively usable on a routine basis in septic shock.

Methods

Thirteen septic shock patients (sampled twice between days 1 to 2 and days 3 to 5 after diagnosis of shock) and 15 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis was measured in lymphocyte subpopulations using flow cytometry (Annexin-V binding, activated caspase-3 and Bcl-2 expressions). Representative pro-apoptotic and anti-apoptotic gene expressions were assessed by quantitative reverse-transcription PCR. Monocyte HLA-DR expression and lymphocyte subpopulation cell counts were measured as markers of sepsis-induced immune dysfunctions. To test for statistical significance, the Mann-Whitney U test was used with correction by the number of tests performed.

Results

Flow cytometric measurements of apoptosis in septic shock patients showed an increased Annexin-V binding on CD4+ T cells and an increased active caspase-3 expression on B cells only at days 3 to 5 (sixfold change and twofold change, respectively). Gene expression analysis showed an increased BCL-XL mRNA and an upregulation of the pro-apoptotic genes BID and FAS in septic shock patients (10-fold change and fivefold change, respectively) compared with healthy controls.

Conclusions

The present study highlights the difficulties encountered in monitoring apoptosis on a routine basis in septic patients, whereas in the same sampling conditions and on the same patients, HLA-DR expression and lymphocyte subpopulation cell counts showed characteristics described in the literature. However, pro-apoptotic genes BID and FAS appear to constitute promising apoptosis markers in our hands.
Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective
Authors: Moran John L , Graham Petra L , Rockliff Sue , Bersten Andrew D
Published: July 2010

Introduction

Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.

Methods

RCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of Abstracts of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus.

Results

Corticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ≥1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids.

Conclusions

Although a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.
Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ
Authors: Rudloff Udo , Jacks Lindsay M. , Goldberg Jessica I. , Wynveen Christine A. , Brogi Edi , Patil Sujata , Van Zee Kimberly J.
Published: July 2010

Purpose

While the mortality associated with ductal carcinoma in situ (DCIS) is minimal, the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) is relatively high. Radiation therapy (RT) and antiestrogen agents reduce the risk of IBTR and are considered standard treatment options after BCS. However, they have never been proven to improve survival, and in themselves carry rare but serious risks. Individualized estimation of IBTR risk would assist in decision making regarding the various treatment options for women with DCIS.

Patients and Methods

From 1991 to 2006, 1,868 consecutive patients treated with BCS for DCIS were identified. A multivariate Cox proportional hazards model was constructed using the 1,681 in whom data were complete. Ten clinical, pathologic, and treatment variables were built into a nomogram estimating probability of IBTR at 5 and 10 years after BCS. The model was validated for discrimination and calibration using bootstrap resampling.

Results

The DCIS nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated good calibration and discrimination, with a concordance index of 0.704 (bootstrap corrected, 0.688) and a concordance probability estimate of 0.686. Factors with the greatest influence on risk of IBTR in the model included adjuvant RT or endocrine therapy, age, margin status, number of excisions, and treatment time period.

Conclusion

The DCIS nomogram integrates 10 clinicopathologic variables to provide an individualized risk estimate of IBTR in a woman with DCIS treated with BCS. This tool may assist in individual decision making regarding various treatment options and help avoid over- and undertreatment of noninvasive breast cancer.
Biologic Correlation of 2-[18F]-Fluoro-2-Deoxy-D-Glucose Uptake on Positron Emission Tomography in Thymic Epithelial Tumors
Authors: Kaira Kyoichi , Endo Masahiro , Abe Masato , Nakagawa Kazuo , Ohde Yasuhisa , Okumura Takehiro , Takahashi Toshiaki , Murakami Haruyasu , Tsuya Asuka , Nakamura Yukiko , Naito Tateaki , Hayashi Isamu , Serizawa Masakuni , Koh Yasuhiro , Hanaoka Hirofumi , Tominaga Hideyuki , Oriuchi Noboru , Kondo Haruhiko , Nakajima Takashi , Yamamoto Nobuyuki
Published: July 2010

Purpose

The usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) can help predict the grade of malignancy and staging in thymic epithelial tumors. However, no satisfactory biologic explanation exists for this phenomenon. The aim of this study was to investigate the underlying biologic mechanisms of [18F]FDG uptake.

Patients and Methods

Forty-nine patients with thymic epithelial tumors who underwent [18F]FDG PET were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial growth factor (VEGF), microvessels (CD31 and CD34), cell cycle control marker (p53), and apoptosis marker (bcl-2). We also conducted an in vitro study of [18F]FDG uptake in a thymic tumor cell line.

Results

There was a positive correlation between [18F]FDG uptake and GLUT1 (P < .0001), HIF-1α (P = .0036), VEGF (P < .0001), microvessel density (MVD; P < .0001), and p53 (P = .0002). GLUT3 and bcl-2 showed no positive correlation with [18F]FDG uptake. The expression of Glut1, HIF-1α, VEGF, CD31, CD34, and p53 was also significantly associated with the grade of malignancy and poor outcome in thymic epithelial tumors, whereas this relationship was not observed in GLUT3 and bcl-2. Our in vitro study demonstrated that upregulation of GLUT1 and HIF-1α was closely associated with [18F]FDG uptake into thymic tumor cell.

Conclusion

[18F]FDG uptake in thymic epithelial tumors is determined by the presence of glucose metabolism (GLUT1), hypoxia (HIF-1α), angiogenesis (VEGF and MVD), and cell cycle regulator (p53).
Hematopoietic Stem-Cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure
Authors: Duval Michel , Klein John P. , He Wensheng , Cahn Jean-Yves , Cairo Mitchell , Camitta Bruce M. , Kamble Rammurti , Copelan Edward , de Lima Marcos , Gupta Vikas , Keating Armand , Lazarus Hillard M. , Litzow Mark R. , Marks David I. , Maziarz Richard T. , Rizzieri David A. , Schiller Gary , Schultz Kirk R. , Tallman Martin S. , Weisdorf Daniel
Published: July 2010

Purpose

Patients with acute leukemia refractory to induction or reinduction chemotherapy have poor prognoses if they do not undergo hematopoietic stem-cell transplantation (HSCT). However, HSCT when a patient is not in complete remission (CR) is of uncertain benefit. We hypothesized that pretransplantation variables may define subgroups that have a better prognosis.

Patients and Methods

Overall, 2,255 patients who underwent transplantation for acute leukemia in relapse or with primary induction failure after myeloablative conditioning regimen between 1995 and 2004 were reported to the Center for International Blood and Marrow Transplant Research. The median follow-up of survivors was 61 months. We performed multivariate analysis of pretransplantation variables and developed a predictive scoring system for survival.

Results

The 3-year overall survival (OS) rates were 19% for acute myeloid leukemia (AML) and 16% for acute lymphoblastic leukemia (ALL). For AML, five adverse pretransplantation variables significantly influenced survival: first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics. For ALL, survival was worse with the following: first refractory or second or greater relapse, ≥ 25% marrow blasts, cytomegalovirus-seropositive donor, and age of 10 years or older. Patients with AML who had a predictive score of 0 had 42% OS at 3 years, whereas OS was 6% for a score ≥ 3. Patients with ALL who had a score of 0 or 1 had 46% 3-year OS but only 10% OS rate for a score ≥ 3.

Conclusion

Pretransplantation variables delineate subgroups with different outcomes. HSCT during relapse can achieve long-term survival in selected patients with acute leukemia.
Pyridoxine Is Not Effective to Prevent Hand-Foot Syndrome Associated With Capecitabine Therapy: Results of a Randomized, Double-Blind, Placebo-Controlled Study
Authors: Kang Yoon-Koo , Lee Sung Sook , Yoon Dok Hyun , Lee So Young , Chun Young Ju , Kim Min Sun , Ryu Min-Hee , Chang Heung-Moon , Lee Jae-Lyun , Kim Tae Won
Published: July 2010

Purpose

To determine whether concurrent pyridoxine therapy can prevent the development of hand-foot syndrome (HFS) in patients being treated with capecitabine.

Methods

Chemotherapy-naive patients with GI tract cancers scheduled for capecitabine-containing chemotherapy were randomly assigned to concurrent oral pyridoxine (200 mg/d) or placebo. Patients were stratified by chemotherapy regimen and monitored until development of National Cancer Institute Common Toxicity Criteria grade 2 or worse HFS or capecitabine-containing chemotherapy ended. Patients in the placebo group who developed grade 2 or worse HFS were randomly assigned again to receive pyridoxine or placebo in the next chemotherapy cycle to determine whether pyridoxine could improve HFS.

Results

The median number of chemotherapy cycles to grade 2 or worse HFS was three in both groups. Grade 2 or worse HFS developed in 55 (30.6%) of 180 placebo-treated patients and in 57 (31.7%) of 180 pyridoxine patients. The cumulative dose of capecitabine to grade 2 or worse HFS was not different between the two groups (median not reached in either group; hazard ratio [HR] = 0.95; P = .788). Randomization of the 44 patients in the placebo group with grade 2 or worse HFS to placebo or pyridoxine for the next cycle resulted in no significant difference in the proportion showing improvement of HFS (42.9% v 47.8%; HR = 1.12; P = .94). By multivariate analysis, age ≥ 56 years (HR = 1.768; 95% CI, 1.190 to 2.628; P = .005) was an independent risk factor for grade 2 or worse HFS, and combined use of docetaxel (HR = 2.046; 95% CI, 0.880 to 4.755; P = .096) was of borderline significance.

Conclusion

Pyridoxine is not effective in prevention of capecitabine-associated HFS.
Therapy-Related Myeloid Neoplasms in Patients With Acute Promyelocytic Leukemia Treated With All-Trans-Retinoic Acid and Anthracycline-Based Chemotherapy
Authors: Montesinos Pau , González José D. , González José , Rayón Chelo , de Lisa Elena , Amigo Maria L. , Ossenkoppele Gert J. , Peñarrubia María J. , Pérez-Encinas Manuel , Bergua Juan , Debén Guillermo , Sayas María J. , de la Serna Javier , Ribera Josep M. , Bueno Javier , Milone Gustavo , Rivas Concha , Brunet Salut , Löwenberg Bob , Sanz Miguel
Published: July 2010

Purpose

We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR).

Patients and Methods

From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy.

Results

Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with ≥ 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months.

Conclusion

t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.
Neoadjuvant Paclitaxel, Ifosfamide, and Cisplatin Chemotherapy for Metastatic Penile Cancer: A Phase II Study
Authors: Pagliaro Lance C. , Williams Dallas L. , Daliani Danai , Williams Michael B. , Osai William , Kincaid Michael , Wen Sijin , Thall Peter F. , Pettaway Curtis A.
Published: July 2010

Purpose

Men with penile squamous cell carcinoma and regional lymph node involvement have a low probability of survival with lymphadenectomy alone. A multimodal approach to treatment is desirable for such patients. We performed a phase II study of neoadjuvant chemotherapy with the objective of determining the response rate, time to progression (TTP), and overall survival (OS) among patients with bulky adenopathy.

Patients and Methods

Eligible patients had stage N2 or N3 (stage III or stage IV) penile cancer without distant metastases. Neoadjuvant treatment (four courses every 3-4 weeks) consisted of paclitaxel 175 mg/m2 administered over 3 hours on day 1; ifosfamide 1,200 mg/m2 on days 1 to 3; and cisplatin 25 mg/m2 on days 1 to 3. Clinical and pathologic responses were assessed, and patient groups were compared for TTP and OS.

Results

Thirty men received chemotherapy of whom 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. Three patients had no remaining tumor on histopathology. Nine patients (30.0%) remained alive and free of recurrence (median follow-up, 34 months; range, 14-59 months), and two patients died of other causes without recurrence. Improved TTP and OS were significantly associated with a response to chemotherapy (P < .001 and P = .001, respectively), absence of bilateral residual tumor (P = .002 and P = .017, respectively), and absence of extranodal extension (P = .001 and P = .004, respectively) or skin involvement (P = .009 and P = .012, respectively).

Conclusion

The neoadjuvant regimen of paclitaxel, ifosfamide, and cisplatin induced clinically meaningful responses in patients with bulky regional lymph node metastases from penile cancer.