bluuebunny/crossref_metadata_2025 huggingface dataset:
An Incremental Step in Patient Safety: Reducing the Risks of Retained Foreign Bodies by the Use of an Integrated Laparotomy Pad/Retractor
Authors: Enker Warren E. , Martz Joseph E. , Picon Antonio , Wexner Steven D. , Fleshman James W. , Koulos John , Goldman Noah
Published: July 2008

Retained foreign body is a recognized complication of abdominal, pelvic, and thoracic surgery and a cause of medical malpractice. Efforts to reduce its incidence include safe exposure and the use of fewer laparotomy pads. The EZ DASH is an absorbent 12-thickness laparotomy pad covering a malleable stainless steel mesh, providing both the needed retraction and a reduction in the use of individual pads. EZ DASH has been introduced into clinical use in 183 consecutive cases by specialty surgeons (colorectal, gynecology, and gynecologic oncology services) at multiple medical centers. The retractor may be shaped to the individual needs of an operating field, eg, the pelvis, and the small bowel secured behind the retractor, held in place by the tension of its mesh and the security of the abdominal wall. Positioning has been intuitive and secure, and the intraoperative use of sponges and of operating time have both been noticeably reduced. Among 183 cases, 91% of uses were felt to reduce OR time by ≤5 to ≥10 minutes. Ninety-three percent of EZ DASH cases used fewer individual laparotomy pads for small bowel retraction. Ninety-five percent of uses suggested a value added to the case by the operating surgeon with an expressed desire to use the product repeatedly. The EZ DASH is a simple method of obtaining small bowel retraction and laparotomy pad absorption with a reduction in the need for individual pads, providing excellent exposure for the operative field and reducing the risk of retained foreign body.
The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity
Authors: James Chloe , Mazurier Frederic , Dupont Sabrina , Chaligne Ronan , Lamrissi-Garcia Isabelle , Tulliez Micheline , Lippert Eric , Mahon François-Xavier , Pasquet Jean-Max , Etienne Gabriel , Delhommeau François , Giraudier Stephane , Vainchenker William , de Verneuil Hubert
Published: July 2008

The JAK2V617F somatic point mutation has been described in patients with myeloproliferative disorders (MPDs). Despite this progress, it remains unknown how a single JAK2 mutation causes 3 different MPD phenotypes, polycythemia vera (PV), essential thrombocythemia, and primitive myelofibrosis (PMF). Using an in vivo xenotransplantation assay in nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice, we tested whether disease heterogeneity was associated with quantitative or qualitative differences in the hematopoietic stem cell (HSC) compartment. We show that the HSC compartment of PV and PMF patients contains JAK2V617F-positive long-term, multipotent, and self-renewing cells. However, the proportion of JAK2V617F and JAK2 wild-type SCID repopulating cells was dramatically different in these diseases, without major modifications of the self-renewal and proliferation capacities for JAK2V617F SCID repopulating cells. These experiments provide new insights into the pathogenesis of JAK2V617F MPD and demonstrate that a JAK2 inhibitor needs to target the HSC compartment for optimal disease control in classical MPD.
A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma
Authors: Rosiñol Laura , Pérez-Simón José Antonio , Sureda Anna , de la Rubia Javier , de Arriba Felipe , Lahuerta Juan José , González José David , Díaz-Mediavilla Joaquín , Hernández Belén , García-Frade Javier , Carrera Dolores , León Angel , Hernández Miguel , Abellán Pascual Fernández , Bergua Juan Miguel , San Miguel Jesús , Bladé Joan
Published: July 2008

One hundred ten patients with multiple myeloma (MM) failing to achieve at least near-complete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)–identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P = .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P = .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantation-related mortality (16% vs 5%, P = .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. This trial is registered at ClinicalTrials.gov ID number NCT00560053
Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis
Authors: Shin Jay W. , Huggenberger Reto , Detmar Michael
Published: July 2008

Lymphatic vessel growth and activation, mediated by vascular endothelial growth factor (VEGF)–C and/or VEGF-A, have important roles in metastasis and in chronic inflammation. We aimed to comprehensively identify downstream molecular targets induced by VEGF-A or VEGF-C in lymphatic endothelium by analyzing the time-series transcriptional profile of treated human dermal lymphatic endothelial cells (LECs). We identified a number of genes, many not previously known to be involved in lymphangiogenesis, that were characterized either as early response genes, transiently induced genes, or progressively induced genes. Endothelial-specific molecule-1 (ESM-1) was one of the genes that were most potently induced by both VEGF-A and VEGF-C. Whereas ESM-1 induction by VEGF-A was mainly dependent on activation of VEGFR-2, VEGF-C–mediated induction depended on the activity of both VEGFR-2 and VEGFR-3. Incubation of LECs with ESM-1 increased the stimulatory effects of both VEGF-A and VEGF-C on LEC proliferation and migration, whereas ESM-1 alone had no effect. Importantly, VEGF-A (or VEGF-C) induction of LEC proliferation and migration were significantly inhibited by siRNA-mediated silencing of ESM-1 in vitro and in vivo. These studies reveal ESM-1 as a novel mediator of lymphangiogenesis and as a potential target for the inhibition of pathologic lymphatic vessel activation.
Altered gene expression changes in Arabidopsis leaf tissues and protoplasts in response to Plum pox virus infection
Authors: Babu Mohan , Griffiths Jonathan S , Huang Tyng-Shyan , Wang Aiming
Published: July 2008

Background

Virus infection induces the activation and suppression of global gene expression in the host. Profiling gene expression changes in the host may provide insights into the molecular mechanisms that underlie host physiological and phenotypic responses to virus infection. In this study, theArabidopsisAffymetrix ATH1 array was used to assess global gene expression changes inArabidopsis thalianaplants infected withPlum pox virus(PPV). To identify early genes in response to PPV infection, anArabidopsissynchronized single-cell transformation system was developed.Arabidopsisprotoplasts were transfected with a PPV infectious clone and global gene expression changes in the transfected protoplasts were profiled.

Results

Microarray analysis of PPV-infectedArabidopsisleaf tissues identified 2013 and 1457 genes that were significantly (Q≤ 0.05) up- (≥ 2.5 fold) and downregulated (≤ -2.5 fold), respectively. Genes associated with soluble sugar, starch and amino acid, intracellular membrane/membrane-bound organelles, chloroplast, and protein fate were upregulated, while genes related to development/storage proteins, protein synthesis and translation, and cell wall-associated components were downregulated. These gene expression changes were associated with PPV infection and symptom development. Further transcriptional profiling of protoplasts transfected with a PPV infectious clone revealed the upregulation of defence and cellular signalling genes as early as 6 hours post transfection. A cross sequence comparison analysis of genes differentially regulated by PPV-infectedArabidopsisleaves against uniEST sequences derived from PPV-infected leaves ofPrunus persica, a natural host of PPV, identified orthologs related to defence, metabolism and protein synthesis. The cross comparison of genes differentially regulated by PPV infection and by the infections of other positive sense RNA viruses revealed a common set of 416 genes. These identified genes, particularly the early responsive genes, may be critical in virus infection.

Conclusion

Gene expression changes in PPV-infectedArabidopsisare the molecular basis of stress and defence-like responses, PPV pathogenesis and symptom development. The differentially regulated genes, particularly the early responsive genes, and a common set of genes regulated by infections of PPV and other positive sense RNA viruses identified in this study are candidates suitable for further functional characterization to shed lights on molecular virus-host interactions.
Immunity related genes in dipterans share common enrichment of AT-rich motifs in their 5' regulatory regions that are potentially involved in nucleosome formation
Authors: Hernandez-Romano Jesus , Carlos-Rivera Francisco J , Salgado Heladia , Lamadrid-Figueroa Hector , Valverde-Garduño Veronica , Rodriguez Mario H , Martinez-Barnetche Jesus
Published: July 2008

Background

Understanding the transcriptional regulation mechanisms in response to environmental challenges is of fundamental importance in biology. Transcription factors associated to response elements and the chromatin structure had proven to play important roles in gene expression regulation. We have analyzed promoter regions of dipteran genes induced in response to immune challenge, in search for particular sequence patterns involved in their transcriptional regulation.

Results

5' upstream regions of D. melanogaster and A. gambiae immunity-induced genes and their corresponding orthologous genes in 11 non-melanogaster drosophilid species and Ae. aegypti share enrichment in AT-rich short motifs. AT-rich motifs are associated with nucleosome formation as predicted by two different algorithms. In A. gambiae and D. melanogaster, many immunity genes 5' upstream sequences also showed NFκB response elements, located within 500 bp from the transcription start site. In A. gambiae, the frequency of ATAA motif near the NFκB response elements was increased, suggesting a functional link between nucleosome formation/remodelling and NFκB regulation of transcription.

Conclusion

AT-rich motif enrichment in 5' upstream sequences in A. gambiae, Ae. aegypti and the Drosophila genus immunity genes suggests a particular pattern of nucleosome formation/chromatin organization. The co-occurrence of such motifs with the NFκB response elements suggests that these sequence signatures may be functionally involved in transcriptional activation during dipteran immune response. AT-rich motif enrichment in regulatory regions in this group of co-regulated genes could represent an evolutionary constrained signature in dipterans and perhaps other distantly species.
Natriuretic peptides modify Pseudomonas fluorescens cytotoxicity by regulating cyclic nucleotides and modifying LPS structure
Authors: Veron Wilfried , Orange Nicole , Feuilloley Marc GJ , Lesouhaitier Olivier
Published: July 2008

Background

Nervous tissues express various communication molecules including natriuretic peptides, i.e. Brain Natriuretic Peptide (BNP) and C-type Natriuretic Peptide (CNP). These molecules share structural similarities with cyclic antibacterial peptides. CNP and to a lesser extent BNP can modify the cytotoxicity of the opportunistic pathogen Pseudomonas aeruginosa. The psychrotrophic environmental species Pseudomonas fluorescens also binds to and kills neurons and glial cells, cell types that both produce natriuretic peptides. In the present study, we investigated the sensitivity of Pseudomonas fluorescens to natriuretic peptides and evaluated the distribution and variability of putative natriuretic peptide-dependent sensor systems in the Pseudomonas genus.

Results

Neither BNP nor CNP modified P. fluorescens MF37 growth or cultivability. However, pre-treatment of P. fluorescens MF37 with BNP or CNP provoked a decrease of the apoptotic effect of the bacterium on glial cells and an increase of its necrotic activity. By homology with eukaryotes, where natriuretic peptides act through receptors coupled to cyclases, we observed that cell-permeable stable analogues of cyclic AMP (dbcAMP) and cyclic GMP (8BcGMP) mimicked the effect of BNP and CNP on bacteria. Intra-bacterial concentrations of cAMP and cGMP were measured to study the involvement of bacterial cyclases in the regulation of P. fluorescens cytotoxicity by BNP or CNP. BNP provoked an increase (+49%) of the cAMP concentration in P. fluorescens, and CNP increased the intra-bacterial concentrations of cGMP (+136%). The effect of BNP and CNP on the virulence of P. fluorescens was independent of the potential of the bacteria to bind to glial cells. Conversely, LPS extracted from MF37 pre-treated with dbcAMP showed a higher necrotic activity than the LPS from untreated or 8BcGMP-pre-treated bacteria. Capillary electrophoresis analysis suggests that these different effects of the LPS may be due, at least in part, to variations in the structure of the macromolecule.

Conclusion

These observations support the hypothesis that P. fluorescens responds to natriuretic peptides through a putative sensor system coupled to a cyclase that could interfere with LPS synthesis and thereby modify the overall virulence of the micro-organism.
Antimalarial drug use in general populations of tropical Africa
Authors: Gardella Florence , Assi Serge , Simon Fabrice , Bogreau Hervé , Eggelte Teunis , Ba Fatou , Foumane Vincent , Henry Marie-Claire , Kientega Pélagie Traore , Basco Léonardo , Trape Jean-François , Lalou Richard , Martelloni Maryse , Desbordes Marc , Baragatti Meïli , Briolant Sébastien , Almeras Lionel , Pradines Bruno , Fusai Thierry , Rogier Christophe
Published: July 2008

Background

The burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine resistance. Antimalarial drug use and drug pressure are critical factors contributing to the selection and spread of resistance. The present study explores the geographical, socio-economic and behavioural factors associated with the use of antimalarial drugs in Africa.

Methods

The presence of chloroquine (CQ), pyrimethamine (PYR) and other antimalarial drugs has been evaluated by immuno-capture and high-performance liquid chromatography in the urine samples of 3,052 children (2–9 y), randomly drawn in 2003 from the general populations at 30 sites in Senegal (10), Burkina-Faso (10) and Cameroon (10). Questionnaires have been administered to the parents of sampled children and to a random sample of households in each site. The presence of CQ in urine was analysed as dependent variable according to individual and site characteristics using a random – effect logistic regression model to take into account the interdependency of observations made within the same site.

Results

According to the sites, the prevalence rates of CQ and PYR ranged from 9% to 91% and from 0% to 21%, respectively. In multivariate analysis, the presence of CQ in urine was significantly associated with a history of fever during the three days preceding urine sampling (OR = 1.22, p = 0.043), socio-economic level of the population of the sites (OR = 2.74, p = 0.029), age (2–5 y = reference level; 6–9 y OR = 0.76, p = 0.002), prevalence of anti-circumsporozoite protein (CSP) antibodies (low prevalence: reference level; intermediate level OR = 2.47, p = 0.023), proportion of inhabitants who lived in another site one year before (OR = 2.53, p = 0.003), and duration to reach the nearest tarmacked road (duration less than one hour = reference level, duration equal to or more than one hour OR = 0.49, p = 0.019).

Conclusion

Antimalarial drug pressure varied considerably from one site to another. It was significantly higher in areas with intermediate malaria transmission level and in the most accessible sites. Thus, P. falciparum strains arriving in cross-road sites or in areas with intermediate malaria transmission are exposed to higher drug pressure, which could favour the selection and the spread of drug resistance.
Old and new cluster designs in emergency field surveys: in search of a one-fits-all solution
Authors: Bilukha Oleg O
Published: July 2008

Introduction

Cluster surveys are frequently used to measure key nutrition and health indicators in humanitarian emergencies. The survey design of 30 clusters of 7 children (30 × 7) was initially proposed by the World Health Organization for measuring vaccination coverage, and later a design of 30 clusters of 30 children (30 × 30) was introduced to measure acute malnutrition in emergency settings. Recently, designs of 33 clusters of 6 children (33 × 6) and 67 clusters of 3 children (67 × 3) have been proposed as alternatives that enable measurement of several key indicators with sufficient precision, while offering substantial savings in time. This paper explores expected effects of using 67 × 3, 33 × 6, or 30 × 7 designs instead of a "standard" 30 × 30 design on precision and accuracy of estimates, and on time required to complete the survey.

Analysis

The 67 × 3, 33 × 6, and 30 × 7 designs are expected to be more statistically efficient for measuring outcomes having high design effects (e.g., vaccination coverage, vitamin A distribution coverage, or access to safe water sources), and less efficient for measuring outcomes with more within-cluster variability, such as global acute malnutrition or anemia. Because of small sample sizes, these designs may not provide sufficient levels of precision to measure crude mortality rates. Given the small number (3 to 7) of survey subjects per cluster, it may be hard to select representative samples of subjects within clusters.

The smaller sample size in these designs will likely result in substantial time savings. The magnitude of the savings will depend on several factors, including the average travel time between clusters. The 67 × 3 design will provide the least time savings. The 33 × 6 and 30 × 7 designs perform similarly to each other, both in terms of statistical efficiency and in terms of time required to complete the survey.

Conclusion

Cluster designs discussed in this paper may offer substantial time and cost savings compared to the traditional 30 × 30 design, and may provide acceptable levels of precision when measuring outcomes that have high intracluster homogeneity. Further investigation is required to determine whether these designs can consistently provide accurate point estimates for key outcomes of interest. Organizations conducting cluster surveys in emergency settings need to build their technical capacity in survey design to be able to calculate context-specific sample sizes individually for each planned survey.
Aberrant right subclavian artery and calcified aneurysm of kommerell's diverticulum: an alternative approach
Authors: Alvarez Jose Rubio J , Quiroga Sierra JL , Nazar Adrio B , Comendador Martinez JM , Carro Garcia J
Published: July 2008

We report a 72 year-old man with dysphagia and dizziness. Aortography and Computed tomographic scans revealed the aberrant right subclavian artery arising from a calcified aneurysm of the Kommerell's diverticulum and bilateral carotid artery disease with atherosclerotic narrowing. Surgical relief was accomplished by excluding the aneurysm from circulation through the aortic arch and a 10 mm graft was interposed between the aberrant artery and the ascending aorta.
Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF
Authors: Bourgogne Agathe , Garsin Danielle A , Qin Xiang , Singh Kavindra V , Sillanpaa Jouko , Yerrapragada Shailaja , Ding Yan , Dugan-Rocha Shannon , Buhay Christian , Shen Hua , Chen Guan , Williams Gabrielle , Muzny Donna , Maadani Arash , Fox Kristina A , Gioia Jason , Chen Lei , Shang Yue , Arias Cesar A , Nallapareddy Sreedhar R , Zhao Meng , Prakash Vittal P , Chowdhury Shahreen , Jiang Huaiyang , Gibbs Richard A , Murray Barbara E , Highlander Sarah K , Weinstock George M
Published: July 2008

Background

Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies.

Results

The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections.

Conclusion

E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.
Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors
Authors: Lukas Thomas J , Miao Haixi , Chen Lin , Riordan Sean M , Li Wenjun , Crabb Andrea M , Wise Alexandria , Du Pan , Lin Simon M , Hernandez M Rosario
Published: July 2008

Background

Epidemiological and genetic studies indicate that ethnic/genetic background plays an important role in susceptibility to primary open angle glaucoma (POAG). POAG is more prevalent among the African-descent population compared to the Caucasian population. Damage in POAG occurs at the level of the optic nerve head (ONH) and is mediated by astrocytes. Here we investigated differences in gene expression in primary cultures of ONH astrocytes obtained from age-matched normal and glaucomatous donors of Caucasian American (CA) and African American (AA) populations using oligonucleotide microarrays.

Results

Gene expression data were obtained from cultured astrocytes representing 12 normal CA and 12 normal AA eyes, 6 AA eyes with POAG and 8 CA eyes with POAG. Data were normalized and significant differential gene expression levels detected by using empirical Bayesian shrinkage moderated t-statistics. Gene Ontology analysis and networks of interacting proteins were constructed using the BioGRID database. Network maps included regulation of myosin, actin, and protein trafficking. Real-time RT-PCR, western blots, ELISA, and functional assays validated genes in the networks.

Conclusion

Cultured AA and CA glaucomatous astrocytes retain differential expression of genes that promote cell motility and migration, regulate cell adhesion, and are associated with structural tissue changes that collectively contribute to neural degeneration. Key upregulated genes include those encoding myosin light chain kinase (MYLK), transforming growth factor-β receptor 2 (TGFBR2), rho-family GTPase-2 (RAC2), and versican (VCAN). These genes along with other differentially expressed components of integrated networks may reflect functional susceptibility to chronic elevated intraocular pressure that is enhanced in the optic nerve head of African Americans.
Risk Factors for the Incidence of Breast Cancer: Do They Affect Survival From the Disease?
Authors: Barnett Gillian C. , Shah Mitul , Redman Karen , Easton Douglas F. , Ponder Bruce A.J. , Pharoah Paul D. P.
Published: July 2008

Purpose

Risk factors that influence the incidence of breast cancer may also affect survival after diagnosis.

Methods

Data from 4,560 women with invasive breast cancer who had taken part in the population-based Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) breast cancer study were used to investigate the influence on survival of variables related to pregnancy, menarche and menopause, prior use of exogenous hormones, height, weight, body mass index (BMI), smoking history, and alcohol intake.

Results

In univariate analyses, there was no association between prognosis and age at menarche and menopause, menopausal status at diagnosis, smoking history, or prior use of the oral contraceptive pill. Women whose most recent pregnancy was more than 30 years ago had a 35% reduced risk of dying (95% CI, 8% to 54%) compared with women who had a full-term pregnancy in the past 15 years, and the use of hormone replacement therapy for more than 4 years was associated with a similar risk reduction. BMI was associated with a 3% (95% CI, 1% to 4%) increase in mortality per unit increase. Improved prognosis was seen with increasing current alcohol consumption, with a 2% (95% CI, 1% to 3%) reduction in the risk of death per unit of alcohol consumed per week.

Conclusion

The apparent benefit of alcohol intake has not been described before, and our data need to be interpreted with some caution. However, our finding that an increase in BMI is associated with a poorer prognosis supports previously published data and suggests that advice on weight loss should be given to all obese patients with breast cancer.
Effect of Esthetic Outcome After Breast-Conserving Surgery on Psychosocial Functioning and Quality of Life
Authors: Waljee Jennifer F. , Hu Emily S. , Ubel Peter A. , Smith Dylan M. , Newman Lisa A. , Alderman Amy K.
Published: July 2008

Purpose

Although breast-conserving surgery (BCS) is often assumed to result in minimal deformity, many patients report postoperative breast asymmetry. Understanding the effect of asymmetry on psychosocial functioning is essential for patients to make an informed choice for surgery.

Patients and Methods

All women who underwent BCS at the University of Michigan Medical Center (Ann Arbor, MI) during a 4-year period were surveyed using a mailed questionnaire (N = 714; response rate = 79.5%). Women were queried regarding five aspects of psychosocial functioning: quality of life (QOL), depression, fear of recurrence, stigmatization, and perceived change in health status. Postoperative breast asymmetry was assessed using items from the Breast Cancer Treatment and Outcomes Survey. Multiple regression was used to examine the relationship between breast asymmetry and each outcome, controlling for age, time from surgery in years, race, education level, disease stage, surgical treatment, and the occurrence of postoperative complications.

Results

Women with pronounced breast asymmetry were significantly more likely to feel stigmatized as a result of their breast cancer treatment (odds ratio [OR] = 4.58; 95% CI, 2.77 to 7.55) and less likely to report unchanged or improved health after treatment (OR = 0.43; 95% CI, 0.27 to 0.66). Minimal breast asymmetry was associated with higher QOL scores (86.3 v 82.4, P < .001). Finally, women with pronounced breast asymmetry were more likely to exhibit depressive symptoms (minimal asymmetry, 16.2%; moderate asymmetry, 18.0%; pronounced asymmetry, 33.7%, Wald test = 16.6; P = .002).

Conclusion

Pronounced breast asymmetry after BCS is significantly correlated with poor psychosocial functioning. Identifying patients at risk for postoperative asymmetry at the time of consultation may allow for improved referral for supportive counseling, prosthetics, and reconstruction.
Novel Intraoperative Molecular Test for Sentinel Lymph Node Metastases in Patients With Early-Stage Breast Cancer
Authors: Julian Thomas B. , Blumencranz Peter , Deck Kenneth , Whitworth Pat , Berry Donald A. , Berry Scott M. , Rosenberg Anne , Chagpar Anees B. , Reintgen Douglas , Beitsch Peter , Simmons Rache , Saha Sukamal , Mamounas Eleftherios P. , Giuliano Armando
Published: July 2008

Purpose

An accurate, intraoperative sentinel lymph node (SLN) test could decrease delayed axillary dissections. Molecular tests may be more sensitive than current intraoperative tests but historically have not been rapid enough and have not been properly validated. We present the results from a large, prospective evaluation of the first rapid molecular SLN test, the Breast Lymph Node (BLN) Assay.

Methods

A beta trial (n = 304) to determine the threshold levels of mammaglobin and cytokeratin 19 correlating with metastasis greater than 0.2 mm and a validation trial (n = 416) to validate the threshold cutoffs were conducted. Alternating portions from each SLN were processed for histology and the BLN Assay.

Results

BLN Assay performance against extensive permanent-section histology verified by central pathology review was similar to that expected of standard permanent-section histology: sensitivity, 87.6%; specificity, 94.2%; positive predictive value, 86.2%; and negative predictive value (NPV), 94.9%. In 319 patients with both frozen-section hematoxylin and eosin results and BLN Assay results, the BLN Assay had higher sensitivity (95.6%) and NPV (98.2%) than frozen section (sensitivity, 85.6%; NPV, 94.5%). The assay can be performed in approximately 36 to 46 minutes for one to three nodes.

Conclusion

The BLN Assay allows a rapid evaluation of 50% of each SLN. Comparison with permanent-section histology on adjacent node pieces evaluated by expert pathologists indicated that the BLN Assay was more sensitive than current intraoperative techniques while maintaining high specificity. These data indicate that the assay may be clinically useful for intraoperative or postoperative axillary lymph node dissection decisions.
Young Age at Diagnosis Correlates With Worse Prognosis and Defines a Subset of Breast Cancers With Shared Patterns of Gene Expression
Authors: Anders Carey K. , Hsu David S. , Broadwater Gloria , Acharya Chaitanya R. , Foekens John A. , Zhang Yi , Wang Yixin , Marcom P. Kelly , Marks Jeffrey R. , Febbo Phillip G. , Nevins Joseph R. , Potti Anil , Blackwell Kimberly L.
Published: July 2008

Purpose

Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined.

Patients and Methods

Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: ≤ 45 years, n = 200; older: ≥ 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed.

Results

Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERα mRNA (P < .0001), ERβ (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERβ and higher EGFR mRNA expression were significant predictors of inferior DFS.

Conclusion

This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.
Analysis of Maryland Cancer Patient Participation in National Cancer Institute–Supported Cancer Treatment Clinical Trials
Authors: Baquet Claudia R. , Ellison Gary L. , Mishra Shiraz I.
Published: July 2008

Purpose

We examined the relationship of sociodemographic factors, urban/rural residence, and county-level socioeconomic factors on accrual of Maryland patients with cancer to National Cancer Institute (NCI) –sponsored cancer treatment clinical trials.

Patients and Methods

Data were analyzed for the period 1999 to 2002 for 2,240 Maryland patients with cancer accrued onto NCI-sponsored treatment trials. The extent to which Maryland patients with cancer and patients residing in lower socioeconomic and/or rural areas were accrued to cancer trials and were representative of all patients with cancer in Maryland was determined. Data were obtained from several sources, including NCI's Cancer Therapy Evaluation Program for Maryland patients with cancer in Cooperative Group therapeutic trials, Maryland Cancer Registry data on cancer incidence, and United States Census and the Department of Agriculture.

Results

For Maryland patients with cancer accrued onto NCI-sponsored treatment trials between 1999 and 2002, subgroups accrued at a higher rate included pediatric and adolescent age groups, white patients, female patients (for sex-specific tumors), patients with private health insurance, and patients residing in the Maryland National Capitol region. Moreover, between 1999 and 2002, there was an estimated annual decline (8.9% per year; P < .05) in the percentage of black patients accrued onto cancer treatment trials. Logistic regression models uncovered different patterns of accrual for female patients and male patients on county-level socioeconomic factors.

Conclusion

Results highlight disparities in the accrual of Maryland patients with cancer onto NCI-sponsored treatment trials based on patient age, race/ethnicity, geography of residence, and county-level socioeconomic factors. Findings provide the basis for development of innovative tailored and targeted educational efforts to improve trial accrual, particularly for the underserved.
Results of the First Phase I Clinical Trial of the Novel Ii-Key Hybrid Preventive HER-2/neuPeptide (AE37) Vaccine
Authors: Holmes Jarrod P. , Benavides Linda C. , Gates Jeremy D. , Carmichael Mark G. , Hueman Matthew T. , Mittendorf Elizabeth A. , Murray James L. , Amin Asna , Craig Dianna , von Hofe Eric , Ponniah Sathibalan , Peoples George E.
Published: July 2008

Purpose

HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4+T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four–amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients.

Patients and Methods

The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 μg, 500 μg, 1,000 μg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 μg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [3H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790).

Results

All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 μg; GM-CSF, 250 μg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36.

Conclusion

The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu–specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.
Obesity and Risk of Cancer in Postmenopausal Korean Women
Authors: Song Yun-Mi , Sung Joohon , Ha Mina
Published: July 2008

Purpose

To evaluate an association between obesity, measured by body mass index (BMI; kg/m2), and risk of cancer at individual and all sites in postmenopausal women.

Methods

A cohort of 170,481 postmenopausal Korean women who were age 40 to 64 years at baseline measurement of BMI was observed prospectively from 1994 to 2003 for cancer incidence. Multivariable adjusted proportional hazard models were used for evaluating the association.

Results

Women with a BMI of 30 kg/m2or higher had a 23% higher risk of cancer than women with a BMI between 21.0 and 22.9 kg/m2(hazard ratio = 1.23; 95% CI, 1.08 to 1.41). According to the increase in BMI level, significant positive trends existed in cancers of colon, breast, corpus uteri, and kidney with hazard ratios of 1.05 (95% CI, 1.02 to 1.08), 1.07 (95% CI, 1.05 to 1.10), 1.13 (95% CI, 1.07 to 1.20), and 1.08 (95% CI, 1.02 to 1.15), respectively, for the increase of BMI by 1 kg/m2. When the analysis was limited to never-smokers, women with a BMI of 25 kg/m2or higher showed a significantly increased risk of cancers of the colon, breast, corpus uteri, and kidney and leukemia compared with the normal BMI (18.5 to 22.9 kg/m2) group.

Conclusion

Although variations exist between the individual cancer sites, obesity was associated with an overall increased risk of cancer in postmenopausal Korean women. To reduce the risk of cancer, active strategies to prevent obesity should be implemented in postmenopausal women.
Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors
Authors: Kulke Matthew H. , Lenz Heinz-Josef , Meropol Neal J. , Posey James , Ryan David P. , Picus Joel , Bergsland Emily , Stuart Keith , Tye Lesley , Huang Xin , Li Jim Z. , Baum Charles M. , Fuchs Charles S.
Published: July 2008

Purpose

Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line–derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients.

Patients and Methods

Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed.

Results

Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment.

Conclusion

Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.
Severe Sequence-Specific Toxicity When Capecitabine Is Given After Fluorouracil and Leucovorin
Authors: Hennig Ivo M. , Naik Jay D. , Brown Sarah , Szubert Alex , Anthoney David A. , Jackson David P. , Melcher Alan M. , Crawford S. Michael , Bradley Christopher , Brown Julia M.B. , Seymour Matthew T.
Published: July 2008

Purpose

Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients.

Patients and Methods

Patients scheduled for adjuvant single-agent fluoropyrimidine therapy were randomly assigned to receive once-weekly FU/LV (425 mg/m2 FU, 45 mg LV) for 6 weeks, followed by two 3-week cycles of capecitabine (1,250 mg/m2 twice daily, days 1 through 14), or the same treatments but in reverse order. After 12 weeks, the patients were asked which treatment they preferred, and received the preferred treatment for an additional 12 weeks. The primary end point was patient preference.

Results

After 40 of the planned 74 patients had been randomly assigned, real-time adverse event monitoring led to early trial closure because of excess sequence-specific toxicity. Eleven of 14 patients (79%) receiving capecitabine as their second treatment experienced grade ≥ 3 toxicity. This compared with five of 18 patients (28%) receiving capecitabine as the first treatment, and no patients receiving FU/LV as the first treatment (zero of 16) or the second treatment (zero of 12). Similar imbalances were seen in the proportion of patients requiring interruption of treatment.

Conclusion

In chemotherapy-naïve patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.
Impact of Intensity-Modulated Radiation Therapy on Local Control in Primary Soft-Tissue Sarcoma of the Extremity
Authors: Alektiar Kaled M. , Brennan Murray F. , Healey John H. , Singer Samuel
Published: July 2008

Purpose

One of the concerns about intensity-modulated radiation therapy (IMRT) is that its tight dose distribution, an advantage in reducing RT morbidity to surrounding normal structures, might compromise tumor coverage. The purpose of this study is to determine if such concern is warranted in soft-tissue sarcoma (STS) of the extremity.

Methods

Between 02/02 and 05/05, 41 adult patients with primary STS of the extremity were treated with limb-sparing surgery and adjuvant IMRT. The margins were positive/within 1 mm in 21. Tumor size was more than 10 cm in 68% of patients and grade was high in 83%. Preoperative IMRT was given to 7 patients (50 Gy) and postoperative IMRT (median dose, 63 Gy) was given to 34 patients. Complete gross resection including periosteal stripping/bone resection was required in 11, and neurolysis/nerve resection in 24.

Results

With a median follow-up time of 35 months, two (4.8%) of 41 patients developed local recurrence. The 5-year actuarial local control rate was 94% (95% CI, 86% to 100%). The local control rate was also 94% for patients with negative or positive/close margin. Other prognostic factors such as age, size, and grade did not impact local control either. The 5-year distant control rate was 61% (95% CI, 45% to 76%) and the overall survival rate was 64% (95% CI, 45% to 84%).

Conclusion

IMRT in STS of the extremity provides excellent local control in a group of patients with high risk features. This suggests that the precision with which IMRT dose is distributed has a beneficiary effect in sparing normal tissue and improving local control.
Estrogen Supplementation Selectively Enhances Hypothalamo-Pituitary Sensitivity to Ghrelin in Postmenopausal Women
Authors: Kok Petra , Paulo Remberto C. , Cosma Mihaela , Mielke Kristi L. , Miles John M. , Bowers Cyril Y. , Veldhuis Johannes D.
Published: July 2008

Context: Sex-steroid hormones amplify pulsatile GH secretion by unknown mechanisms. Ghrelin is the most potent natural GH secretagogue discovered to date. A plausible unifying postulate is that estradiol (E2) enhances hypothalamo-pituitary sensitivity to ghrelin (a physiological effect). The hypothesis is relevant to understanding the basis of hyposomatotropism in aging and other relatively hypogonadal states.

Objective: Our objective was to test the hypothesis that E2 supplementation potentiates ghrelin’s stimulation of pulsatile GH secretion.

Setting: The study was conducted at an academic medical center.

Subjects: Healthy postmenopausal women (n = 20) were included in the study.

Interventions: Separate-day iv infusions of saline vs. five graded doses of ghrelin were performed in volunteers prospectively randomly assigned to receive (n = 8) or not receive (n = 12) transdermal E2 for 21 d were performed.

Measures: GH secretion was estimated by deconvolution analysis and abdominal visceral fat mass determined by computerized axial tomography were calculated.

Results: E2 supplementation augmented ghrelin’s stimulation of basal (nonpulsatile) GH secretion by 3.6-fold (P = 0.022), increased GH responses to low-dose ghrelin by 2.9-fold (P = 0.035), did not alter ghrelin efficacy, and elicited more regular patterns of acylated ghrelin concentrations during saline infusion (P = 0.033). Abdominal visceral fat negatively determined responses to ghrelin (R = −0.346; P < 0.005).

Conclusions: Transdermal E2 supplementation potentiates GH secretion stimulated by physiological but not pharmacological concentrations of acylated ghrelin, and concomitantly regularizes patterns of bioactive ghrelin secretion in postmenopausal women. Accordingly, the estrogen milieu appears to control sensitivity of the hypothalamopituitary unit to acylated ghrelin.