bluuebunny/crossref_metadata_2025 huggingface dataset:
The neighborhood food environment: sources of historical data on retail food stores
Authors: Wang May C , Gonzalez Alma A , Ritchie Lorrene D , Winkleby Marilyn A
Published: July 2006

With the rapidly increasing prevalence of obesity in the United States, and the minimal success of education-based interventions, there is growing interest in understanding the role of the neighborhood food environment in determining dietary behavior. This study, as part of a larger study, identifies historical data on retail food stores, evaluates strengths and limitations of the data for research, and assesses the comparability of historical retail food store data from a government and a commercial source.

Five government and commercial listings of retail food stores were identified. The California State Board of Equalization (SBOE) database was selected and then compared to telephone business directory listings. The Spearman's correlation coefficient was used to assess the congruency of food store counts per census tract between the SBOE and telephone business directory databases. The setting was four cities in Northern California, 1979–1990.

The SBOE and telephone business directory databases listed 127 and 351 retail food stores, respectively. The SBOE listed 36 stores not listed by the telephone business directories, while the telephone business directories listed 260 stores not listed by the SBOE. Spearman's correlation coefficients between estimates of stores per census tract made from the SBOE listings and those made from the telephone business directory listings were approximately 0.5 (p < .0001) for the types of stores studied (chain supermarkets, small grocery stores, and chain convenience markets). We conclude that, depending on the specific aims of the study, caution and considerable effort must be exercised in using and applying historical data on retail food stores.
The Effects of Protein Phosphatase Inhibitors on the Duration of Central Sensitization of Rat Dorsal Horn Neurons following Injection of Capsaicin
Authors: Zhang Xuan , Wu Jing , Fang Li , Willis William D
Published: July 2006

Protein kinases and phosphatases catalyze opposing reactions of phosphorylation and dephosphorylation, which may modulate the function of crucial signaling proteins in central nervous system. This is an important mechanism in the regulation of intracellular signal transduction pathways in nociceptive neurons. To explore the role of protein phosphatase in central sensitization of spinal nociceptive neurons following peripheral noxious stimulation, using electrophysiological recording techniques, we investigated the role of two inhibitors of protein phosphatase type 2A (PP2A), fostriecin and okadaic acid (OA), on the responses of dorsal horn neurons to mechanical stimuli in anesthetized rats following intradermal injection of capsaicin. Central sensitization was initiated by injection of capsaicin into the plantar surface of the left paw. A microdialysis fiber was implanted in the spinal cord dorsal horn for perfusion of ACSF and inhibitors of PP2A, fostriecin and okadaic acid. We found that in ACSF pretreated animals, the responses to innocuous and noxious stimuli following capsaicin injection increased over a period of 15 min after injection and had mostly recovered by 60 min later. However, pre- or post-treatment with the phosphatase inhibitors, fostriecin or OA, significantly enhanced the effects of capsaicin injection by prolonging the responses to more than 3 hours. These results confirm that blockade of protein phosphatase activity may potentiate central sensitization of nociceptive transmission in the spinal cord following capsaicin injection and indicate that protein phosphatase type 2A may be involved in determining the duration of capsaicin-induced central sensitization.
Genetic Polymorphisms in Monoamine Neurotransmitter Systems Show Only Weak Association with Acute Post-Surgical Pain in Humans
Authors: Kim Hyungsuk , Lee Hyewon , Rowan Janet , Brahim Jaime , Dionne Raymond A
Published: July 2006

Background

Candidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans.

Results

Variations in the catecholamine metabolizing enzyme genes ( MAOA and COMT) showed significant associations with the maximum post-operative pain rating while the serotonin transporter gene ( SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene ( SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample.

Conclusion

These results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype.
Mastitis and related management factors in certified organic dairy herds in Sweden
Authors: Hamilton Cecilia , Emanuelson Ulf , Forslund Kristina , Hansson Ingrid , Ekman Torkel
Published: July 2006

Background

Mastitis is one of the major threats to animal health, in organic farming as well as conventional. Preliminary studies of organic dairy herds have indicated better udder health in such herds, as compared to conventional herds. The aim of this paper was to further study mastitis and management related factors in certified organic dairy herds.

Methods

An observational study of 26 certified organic dairy herds in mid-eastern Sweden was conducted during one year. A large-animal practitioner visited the herds three times and clinically examined and sampled cows, and collected information about general health and management routines. Data on milk production and disorders treated by a veterinarian in the 26 herds, as well as in 1102 conventional herds, were retrieved from official records. Multivariable logistic regression was used to assess associations between herd type (organic vs. conventional) and incidence of disorders.

Results

The organic herds that took part in the study ranged in size from 12 to 64 cows, in milk production from 3772 to 10334 kg per cow and year, and in bulk milk somatic cell counts from 83000 to 280000 cells/ml. The organic herds were found to have a lower incidence of clinical mastitis, teat injuries, and a lower proportion of cows with a high somatic cell count (as indicated by the UDS, Udder Disease Score) compared to conventional herds. The spectrum of udder pathogenic bacteria was similar to that found in other Swedish studies. Treatment of mastitis was found to be similar to what is practised in conventional herds. Homeopathic remedies were not widely used in the treatment of clinical mastitis.

The calves in most of these organic herds suckled their dams for only a few days, which were not considered to substantially affect the udder health. The main management factor that was different from conventional herds was the feeding strategy, where organic herds used a larger share of forage.

Conclusion

Udder health in Swedish organic herds appears to be better than in conventional herds of comparable size and production. The major difference in management between the two types of farms is the proportion of concentrates fed. The mechanisms explaining the association between intensity of feeding and udder health in dairy cows require further research.
Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation
Authors: Hardy Rowan S , Filer Andrew , Cooper Mark S , Parsonage Greg , Raza Karim , Hardie Debbie L , Rabbitt Elizabeth H , Stewart Paul M , Buckley Christopher D , Hewison Martin
Published: July 2006

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Expression, activity and function of 11β-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11β-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-α or IL-1β (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-γ was without effect, and there was no difference in 11β-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production – a characteristic feature of synovial derived fibroblasts – was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11β-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11β-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.
Association of FCGR2A and FCGR2A-FCGR3Ahaplotypes with susceptibility to giant cell arteritis
Authors: Morgan Ann W , Robinson Jim I , Barrett Jennifer H , Martin Javier , Walker Amy , Babbage Sarah J , Ollier William ER , Gonzalez-Gay Miguel A , Isaacs John D
Published: July 2006

The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.
Coexpression and interaction of CXCL10 and CD26 in mesenchymal cells by synergising inflammatory cytokines: CXCL8 and CXCL10 are discriminative markers for autoimmune arthropathies
Authors: Proost Paul , Struyf Sofie , Loos Tamara , Gouwy Mieke , Schutyser Evemie , Conings René , Ronsse Isabelle , Parmentier Marc , Grillet Bernard , Opdenakker Ghislain , Balzarini Jan , Van Damme Jo
Published: July 2006

Leukocyte infiltration during acute and chronic inflammation is regulated by exogenous and endogenous factors, including cytokines, chemokines and proteases. Stimulation of fibroblasts and human microvascular endothelial cells with the inflammatory cytokines interleukin-1β (IL-1β) or tumour necrosis factor alpha (TNF-α) combined with either interferon-α (IFN-α), IFN-β or IFN-γ resulted in a synergistic induction of the CXC chemokine CXCL10, but not of the neutrophil chemoattractant CXCL8. In contrast, simultaneous stimulation with different IFN types did not result in a synergistic CXCL10 protein induction. Purification of natural CXCL10 from the conditioned medium of fibroblasts led to the isolation of CD26/dipeptidyl peptidase IV-processed CXCL10 missing two NH2-terminal residues. In contrast to intact CXCL10, NH2-terminally truncated CXCL10(3–77) did not induce extracellular signal-regulated kinase 1/2 or Akt/protein kinase B phosphorylation in CXC chemokine receptor 3-transfected cells. Together with the expression of CXCL10, the expression of membrane-bound CD26/dipeptidyl peptidase IV was also upregulated in fibroblasts by IFN-γ, by IFN-γ plus IL-1β or by IFN-γ plus TNF-α. This provides a negative feedback for CXCL10-dependent chemotaxis of activated T cells and natural killer cells. Since TNF-α and IL-1β are implicated in arthritis, synovial concentrations of CXCL8 and CXCL10 were compared in patients suffering from crystal arthritis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis. All three groups of autoimmune arthritis patients (ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis) had significantly increased synovial CXCL10 levels compared with crystal arthritis patients. In contrast, compared with crystal arthritis, only rheumatoid arthritis patients, and not ankylosing spondylitis or psoriatic arthritis patients, had significantly higher synovial CXCL8 concentrations. Synovial concentrations of the neutrophil chemoattractant CXCL8 may therefore be useful to discriminate between autoimmune arthritis types.
Hormone-related risk factors for breast cancer in women under age 50 years by estrogen and progesterone receptor status: results from a case–control and a case–case comparison
Authors: Ma Huiyan , Bernstein Leslie , Ross Ronald K , Ursin Giske
Published: July 2006

Introduction

It has been suggested that hormonal risk factors act predominantly on estrogen receptor and progesterone receptor (ER/PR)-positive breast cancers. However, the data have been inconsistent, especially in younger women.

Methods

We evaluated the impact of age at menarche, pregnancy history, duration of breastfeeding, body mass index, combined oral contraceptive use, and alcohol consumption on breast cancer risk by ER/PR status in 1,725 population-based case patients and 440 control subjects aged 20 to 49 years identified within neighborhoods of case patients. We used multivariable unconditional logistic regression methods to conduct case–control comparisons overall as well as by ER/PR status of the cases, and to compare ER+PR+ with ER-PR- case patients.

Results

The number of full-term pregnancies was inversely associated with the risk of ER+PR+ breast cancer (ptrend = 0.005), whereas recent average alcohol consumption was associated with an increased risk of ER+PR+ breast cancer (ptrend = 0.03). Neither of these two factors was associated with the risk of ER- PR- breast cancer. Late age at menarche and a longer duration of breastfeeding were both associated with decreased breast cancer risk, irrespective of receptor status (all ptrend≤ 0.03).

Conclusion

Our results suggest that the number of full-term pregnancies and recent alcohol consumption affect breast cancer risk in younger women predominantly through estrogen and progesterone mediated by their respective receptors. Late age at menarche and breastfeeding may act through different hormonal mechanisms.
Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients
Authors: Calza Stefano , Hall Per , Auer Gert , Bjöhle Judith , Klaar Sigrid , Kronenwett Ulrike , Liu Edison T , Miller Lance , Ploner Alexander , Smeds Johanna , Bergh Jonas , Pawitan Yudi
Published: July 2006

Background

Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization.

Methods

We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes – basal-like, ERBB2, luminal A/B and normal-like – and characterized these subtypes extensively with the use of conventional clinical variables.

Results

We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders.

Conclusion

We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability.
Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study
Authors: Ambrosone Christine B , Tian Chunqiao , Ahn Jiyoung , Kropp Silke , Helmbold Irmgard , von Fournier Dietrich , Haase Wulf , Sautter-Bihl Marie Luise , Wenz Frederik , Chang-Claude Jenny
Published: July 2006

Introduction

The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity.

Methods

Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998–2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables.

Results

Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04–4.99). No associations were noted for the other GST genotypes.

Conclusion

These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes.
Unloading work of breathing during high-frequency oscillatory ventilation: a bench study
Authors: van Heerde Marc , Roubik Karel , Kopelent Vitek , Plötz Frans B , Markhorst Dick G
Published: July 2006

Introduction

With the 3100B high-frequency oscillatory ventilator (SensorMedics, Yorba Linda, CA, USA), patients' spontaneous breathing efforts result in a high level of imposed work of breathing (WOB). Therefore, spontaneous breathing often has to be suppressed during high-frequency oscillatory ventilation (HFOV). A demand-flow system was designed to reduce imposed WOB.

Methods

An external gas flow controller (demand-flow system) accommodates the ventilator fresh gas flow during spontaneous breathing simulation. A control algorithm detects breathing effort and regulates the demand-flow valve. The effectiveness of this system has been evaluated in a bench test. The Campbell diagram and pressure time product (PTP) are used to quantify the imposed workload.

Results

Using the demand-flow system, imposed WOB is considerably reduced. The demand-flow system reduces inspiratory imposed WOB by 30% to 56% and inspiratory imposed PTP by 38% to 59% compared to continuous fresh gas flow. Expiratory imposed WOB was decreased as well by 12% to 49%. In simulations of shallow to normal breathing for an adult, imposed WOB is 0.5 J l-1 at maximum. Fluctuations in mean airway pressure on account of spontaneous breathing are markedly reduced.

Conclusion

The use of the demand-flow system during HFOV results in a reduction of both imposed WOB and fluctuation in mean airway pressure. The level of imposed WOB was reduced to the physiological range of WOB. Potentially, this makes maintenance of spontaneous breathing during HFOV possible and easier in a clinical setting. Early initiation of HFOV seems more possible with this system and the possibility of weaning of patients directly on a high-frequency oscillatory ventilator is not excluded either.
Corticosteroids influence the mortality and morbidity of acute critical illness
Authors: Rady Mohamed Y , Johnson Daniel J , Patel Bhavesh , Larson Joel , Helmers Richard
Published: July 2006

Introduction

Use of corticosteroids for adrenal supplementation and attenuation of the inflammatory and immune response is widespread in acute critical illness. The study hypothesis was that exposure to corticosteroids influences the mortality and morbidity in acute critical illness.

Methods

This case–control retrospective study was performed in a single multidisciplinary intensive care unit at a tertiary care institution and consisted of 10,285 critically ill patients admitted between 1 January 1999 and 31 December 2004. Demographics, comorbidities, acute illness characteristics including severity measured by Sequential Organ Failure Assessment, concurrent medications, therapeutic interventions and incidence of infections were obtained from electronic medical records, were examined with multiple regression analysis and were adjusted for propensity of corticosteroid exposure. The primary outcome was hospital death, and the secondary outcome was transfer to a care facility at hospital discharge.

Results

Corticosteroid exposure in 2,632 (26%) patients was characterized by younger age, more females, higher Charlson comorbidity and maximal daily Sequential Organ Failure Assessment scores compared with control patients. Corticosteroids potentiated metabolic and neuromuscular sequels of critical illness with increased requirements for diuretics, insulin, protracted weaning from mechanical ventilation, need for tracheostomy and discharge to a care facility. Early exposure to corticosteroids predisposed to recurrent and late onset of polymicrobial and fungal hospital-acquired infections. Corticosteroids increased the risk for death or disability after adjustments for comorbidities and acute illness characteristics.

Conclusion

Corticosteroids increased the risk for death or disability in critical illness. Hospital-acquired infections and metabolic and neuromuscular sequels of critical illness were exacerbated by corticosteroids. Careful appraisal of the indications for use of corticosteroids is necessary to balance the benefits and risks from exposure in acute critical illness.
Pooled Analysis of Phase II Window Studies in Children With Contemporary High-Risk Metastatic Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group
Authors: Lager Joanne J. , Lyden Elizabeth R. , Anderson James R. , Pappo Alberto S. , Meyer William H. , Breitfeld Philip P.
Published: July 2006

Purpose

The Soft Tissue Sarcoma Committee of the Children's Oncology Group has conducted five upfront window trials in patients with newly diagnosed metastatic rhabdomyosarcoma to identify promising new treatment agents.

Patients and Methods

This pooled analysis identified a total of 420 patients (115 from Intergroup Rhabdomyosarcoma Study III [IRS-III] and 305 from the five window trials). We assessed window therapy response rate, failure-free survival (FFS), and overall survival (OS).

Results

Response rates (complete + partial response) assessed at week 6 of window therapy ranged from 41% to 55% and did not predict FFS (P = .073) or OS (P = .31). FFS was influenced by trial (P = .048); patients enrolled onto IRS-III and the ifosfamide/etoposide and ifosfamide/doxorubicin trials fared best. When grouped and compared with topoisomerase I poison trials, ifosfamide/topoisomerase II inhibitor trials had superior FFS (P = .013). However, there was no difference in survival.

Conclusion

Upfront phase II window trials can efficiently provide robust estimates of activity for new agents and combinations in newly diagnosed patients with high-risk rhabdomyosarcoma. Our data indicate that, for some phase II window trials, the risk of treatment failure may be increased but that the trend towards lower survival for some of the window trials compared with IRS-III is not statistically significant. Window nonresponders did not suffer worse FFS or OS than patients who responded to window therapy. Finally, these results provide a rationale for incorporating ifosfamide, etoposide, doxorubicin, and topoisomerase I poisons in future trials of high-risk metastatic rhabdomyosarcoma.
Phase II Study of Pemetrexed for Second-Line Treatment of Transitional Cell Cancer of the Urothelium
Authors: Sweeney Christopher J. , Roth Bruce J. , Kabbinavar Fairooz F. , Vaughn David J. , Arning Michael , Curiel Rafael E. , Obasaju Coleman K. , Wang Yanping , Nicol Steven J. , Kaufman Donald S.
Published: July 2006

Purpose

To assess the antitumor activity and toxicity of pemetrexed as second-line chemotherapy in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium.

Patients and Methods

Eligible patients had a performance status of 0 or 1, adequate organ function, previous treatment with one prior chemotherapy regimen for locally advanced or metastatic TCC of the urothelium or relapsed within 1 year of adjuvant or neoadjuvant treatment. Patients received pemetrexed 500 mg/m2 intravenously on day 1 every 21 days, with vitamin B12, folic acid, and dexamethasone prophylaxis.

Results

Forty-seven patients were enrolled and included in the intent-to-treat efficacy analysis. Responses: 3 (6.4%) complete responses and 10 (21.3%) partial responses produced an overall response rate of 27.7%. Ten patients (21.3%) had stable disease and 22 patients (46.8%) progressed. The median time to progressive disease was 2.9 months (95% CI, 1.7 months to 4.6 months) and median overall survival was 9.6 months (95% CI, 5.1 months to 14.6 months). Median duration of response was 5.0 months (95% CI, 3.9 months to 13.8 months). Of the 47 patients assessable for safety, grade 3 or 4 hematologic events were thrombocytopenia (8.5%; 0.0%), neutropenia (4.3%; 4.3%) and anemia (2.1%; 2.1%), respectively. Nonlaboratory toxicities included grade 4 stomatitis/pharyngitis, sepsis syndrome (one patient each), and grade 3 fatigue (three patients) and diarrhea (two patients).

Conclusion

Single-agent pemetrexed is safe and active as second-line treatment of patients with advanced TCC of the urothelium. Additional evaluation in the first- or second-line setting in TCC of the urothelium is warranted.
Prognostic Factors for Local Control and Survival After Radiotherapy of Metastatic Spinal Cord Compression
Authors: Rades Dirk , Fehlauer Fabian , Schulte Rainer , Veninga Theo , Stalpers Lukas J.A. , Basic Hiba , Bajrovic Amira , Hoskin Peter J. , Tribius Silke , Wildfang Ingeborg , Rudat Volker , Engenhart-Cabilic Rita , Karstens Johann H. , Alberti Winfried , Dunst Juergen , Schild Steven E.
Published: July 2006

Purpose

To evaluate potential prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression (MSCC).

Patients and Methods

The following potential prognostic factors were investigated retrospectively in 1,852 patients irradiated for MSCC: age, sex, performance status, primary tumor, interval between tumor diagnosis and MSCC (≤ 15 v > 15 months), number of involved vertebrae (one to two v ≥ three), other bone metastases, visceral metastases, pretreatment ambulatory status, time of developing motor deficits before radiotherapy (faster, 1 to 14 v slower, > 14 days), and radiation schedule (short-course v long-course radiotherapy).

Results

On univariate analysis, improved local control of MSCC was associated significantly with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma), no visceral metastases, and long-course radiotherapy. On multivariate analysis, absence of visceral metastases and radiation schedule maintained significance. On univariate analysis, improved survival was associated significantly with female sex, favorable histology, no visceral or other bone metastases, good performance status, being ambulatory before radiotherapy, longer interval between tumor diagnosis and MSCC, and slower development of motor deficits before radiotherapy. Long-course radiotherapy showed a trend. On multivariate analysis, histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MSCC, and time of developing motor deficits maintained significance.

Conclusion

Poorer local control after radiotherapy for MSCC is associated with visceral metastases and short-course radiotherapy. Long-course radiotherapy seems preferable for patients with more favorable prognoses, given that these patients may live long enough to develop MSCC recurrences. Long-term survival after radiotherapy for MSCC may be predicted if several prognostic factors are considered.
Phase II Multicenter Trial of Bevacizumab Plus Fluorouracil and Leucovorin in Patients With Advanced Refractory Colorectal Cancer: An NCI Treatment Referral Center Trial TRC-0301
Authors: Chen Helen X. , Mooney Margaret , Boron Matthew , Vena Don , Mosby Kimberly , Grochow Louise , Jaffe Carl , Rubinstein Lawrence , Zwiebel James , Kaplan Richard S.
Published: July 2006

Purpose

To provide bevacizumab (BV) -based therapy to patients with advanced colorectal cancers (CRC) who had exhausted standard chemotherapy options, and to evaluate the response to BV combined with fluorouracil (FU) and leucovorin (LV) in this patient population.

Patients and Methods

This was a multicenter, single-arm treatment trial conducted under the National Cancer Institute Treatment Referral Center network nationwide. Patients were treated with BV 5 mg/kg every 2 weeks combined with FU/LV; FU was administered by bolus or continuous infusion. Eligibility criteria included advanced CRC that had progressed after irinotecan- and oxaliplatin-based chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 2, and absence of thromboembolism. The primary end point was objective response rate (RR) in the first 100 assessable patients. All patients received follow-up for toxicity and survival.

Results

Due to rapid accrual, a total of 350 patients were enrolled at 32 participating sites nationwide by October 2003. In the initially planned cohort of 100 assessable patients, the objective RR was 4% (95% CI, 1.1% to 9.9%) by investigators' assessment and 1% (95% CI, 0% to 5.5%) based on independent review; median progression-free survival was 3.5 months and median overall survival was 9.0 months. The safety profile was similar to prior BV trials in CRC. Grade 3 to 4 hemorrhage occurred in 5% of patients, including 3.8% with bleeding in the GI tract. Other adverse events such as hypertension, thrombosis, and bowel perforation were also observed at rates consistent with other studies.

Conclusion

For patients with advanced CRC that had progressed after both irinotecan-based and oxaliplatin-based chemotherapy regimens, the combination of BV and FU/LV was associated with rare objective responses.
Differential Impact of Combination Antiretroviral Therapy in Preventing Kaposi's Sarcoma With and Without Visceral Involvement
Authors: Grabar Sophie , Abraham Bruno , Mahamat Aba , Del Giudice Pascal , Rosenthal Eric , Costagliola Dominique
Published: July 2006

Purpose

To study the impact of different potent combined antiretroviral treatment (cART) on the incidence of HIV-associated Kaposi's sarcoma (KS) with and without visceral involvement.

Patients and Methods

Patients were selected from the French Hospital Database on HIV, a large hospital cohort. The risk of KS was estimated by using Cox proportional hazards models adjusting for age, the CD4 cell nadir, the HIV exposure category, prior AIDS, cART, and the type of cART regimen. cART regimens were distinguished according to whether they contained protease inhibitor (PI), non-nucleoside analog (NNRTI), both, or only nucleoside analog (NRTI). Separate analyzes were conducted according to the initial visceral involvement of KS.

Results

Among the 54,999 patients included in this study (182,756 person-years of follow-up), 1,634 patients were diagnosed with KS during follow-up, of whom 421 had visceral involvement at diagnosis. The KS incidence rate fell from 32 per 1,000 person-years in 1993 to 1994 to 3 per 1,000 person-years after 1999. PI-containing and NNRTI-containing cART regimens were associated with similar reductions in the risk of KS (hazard ratio, 0.68; 95%CI, 0.61 to 0.75; HR, 0.62; 95% CI, 0.54 to 0.71, respectively). The risk of visceral KS fell more strongly than the risk of cutaneous KS (> 50% and < 30%, respectively).

Conclusion

The incidence of KS, and especially visceral KS, has fallen sharply since the advent of cART. This effect is likely due to immune restoration rather than to a specific effect on the tumoral process, as PI-containing and NNRTI-containing regimens had similar preventive efficacy.
Association of T-Cell Regulatory Gene Polymorphisms With Susceptibility to Gastric Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Cheng Tsu-Yao , Lin Jaw-Town , Chen Li-Tzong , Shun Chia-Tung , Wang Hsiu-Po , Lin Ming-Tsang , Wang Tsang-En , Cheng Ann-Lii , Wu Ming-Shiang
Published: July 2006

Purpose

Helicobacter pylori infection and host susceptibility interact to develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and activation of specific T cells might play a crucial role in this process. Recent investigations show that the CTLA4, CD28, and ICOS genes are located on chromosome 2q33 and their polymorphisms confer susceptibility to infectious and immune diseases through deregulation of T-cell stimulation. We aimed to determine the role of CTLA4, CD28, and ICOS polymorphisms in gastric MALT lymphoma.

Patients and Methods

Genotyping for CTLA4 (49 A/G, −318 C/T, and CT60 A/G), CD28 (IVS3+ 17T/C), and ICOS (c.602 A/C and c.1624C/T) was performed for 62 patients with gastric MALT lymphoma and compared with 250 unrelated healthy controls.

Results

H pylori infection was significantly higher in patients with gastric MALT lymphoma (90.3%) compared with controls (66.4%; P < .001). The CTLA4 −318 C/T genotype was associated with a lower risk of developing gastric MALT lymphoma (odds ratio [OR] = 0.3; P = .022), whereas CTLA4 49 G/G genotype was linked to a higher risk (OR = 4.1; P = .044). In patients with H pylori infection, CTLA4 49 G/G genotype was associated with an even higher risk (OR = 6.4; P = .047). Carriage of the tightly linked −318C –49G haplotype conferred a four-fold higher susceptibility to MALT lymphoma (OR = 4.2; P = .042). Complete remission after H pylori eradication was related to tumor stage but not to genotypes or haplotypes.

Conclusion

These results indicate a genetic link of CTLA4 gene polymorphisms to development of gastric MALT lymphoma and indirectly support the crucial role of host activated T cells in the MALT lymphomagenesis.
Prospective Comparative Study of Integrated Positron Emission Tomography-Computed Tomography Scan Compared With Remediastinoscopy in the Assessment of Residual Mediastinal Lymph Node Disease After Induction Chemotherapy for Mediastinoscopy-Proven Stage IIIA-N2 Non–Small-Cell Lung Cancer: A Leuven Lung Cancer Group Study
Authors: De Leyn Paul , Stroobants Sigrid , De Wever Walter , Lerut Toni , Coosemans Willy , Decker Georges , Nafteux Philippe , Van Raemdonck Dirk , Mortelmans Luc , Nackaerts Kristiaan , Vansteenkiste Johan
Published: July 2006

Purpose

Mediastinal restaging after induction therapy for non–small-cell lung cancer remains a difficult and controversial issue. The goal of this prospective study was to compare the performance of integrated positron emission tomography (PET) –computed tomography (CT) and remediastinoscopy in the evaluation of mediastinal lymph node metastasis after induction chemotherapy.

Patients and Methods

Thirty consecutive stage IIIA-N2 non–small-cell lung cancer patients surgically treated at our institution were entered onto this prospective study. N2 disease was proven by cervical mediastinoscopy, at which a mean number of 3.8 lymph node levels were biopsied. After completion of induction chemotherapy, the mediastinum was reassessed by integrated PET-CT and remediastinoscopy. All patients underwent thoracotomy with attempted complete resection and systematic nodal dissection.

Results

PET-CT showed no evidence of nodal disease (N0) in 13 patients, Hilar nodal disease (N1) disease in three patients, and residual mediastinal disease (N2) in 14 patients. Remediastinoscopy was positive in only five patients. The preinduction involved lymph node level could be accurately re-evaluated in 18 patients. This was not the case in the other 12 because of extensive fibrosis and adhesions. In 17 patients, persistent N2 disease was found at thoracotomy. The sensitivity, specificity, and accuracy of PET-CT were 77%, 92%, and 83%, respectively. These parameters for remediastinoscopy were 29%, 100%, and 60%, respectively. Sensitivity (P < .0001) and accuracy (P = .012) were significantly better for PET-CT.

Conclusion

After a thorough staging mediastinoscopy, postinduction remediastinoscopy had a disappointing sensitivity because of adhesions and fibrosis. Integrated PET-CT yielded a better result than that obtained in previous studies with side-by-side PET and CT images.
O6-Methylguanine-DNA Methyltransferase Expression Strongly Correlates With Outcome in Childhood Malignant Gliomas: Results From the CCG-945 Cohort
Authors: Pollack Ian F. , Hamilton Ronald L. , Sobol Robert W. , Burnham Judith , Yates Allan J. , Holmes Emiko J. , Zhou Tianni , Finlay Jonathan L.
Published: July 2006

Purpose

O6-Methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined.

Methods

We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens.

Results

Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% ± 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% ± 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location.

Conclusion

Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.
Radiation Therapy After Mastectomy Between 1991 and 1999 in Elderly Women: Response to Clinical Trial Information
Authors: Punglia Rinaa S. , Weeks Jane C. , Neville Bridget A. , Earle Craig C.
Published: July 2006

Purpose

No systematic study has analyzed the changing patterns of use of postmastectomy radiation therapy (PMRT) during the period of information dissemination regarding the benefit of radiation therapy in this setting. We sought to study the receipt of PMRT in elderly women in this period, using a population-based cohort of women with breast cancer.

Patients and Methods

Using data from the linked Surveillance, Epidemiology, and End Results–Medicare database, we analyzed the use of radiation therapy between 1991 and 1999 in 19,699 women with stage I to III breast cancer who received mastectomy as definitive surgery. Multivariable logistic regression was used to investigate the association of diagnosis year and the use of PMRT, after controlling for clinical and sociodemographic factors.

Results

During the entire period studied, 2,160 (11.0%) patients treated with mastectomy received PMRT. The use of PMRT significantly increased in women diagnosed in 1996 (odds ratio [OR], 1.26; P = .04), 1997 (OR, 1.70; P < .0001), 1998 (OR, 1.57; P < .0001), and 1999 (OR, 1.77; P < .0001), relative to those diagnosed in 1991 after controlling for cancer, and sociodemographic and treatment characteristics. There were significant differences in the temporal trends of radiation use among different regions of the country (P < .0001), and between teaching versus nonteaching institutions (P = .04).

Conclusion

The use of PMRT in elderly women increased significantly during the period of data dissemination about its efficacy; however, the trends in adoption varied among different practice settings.
α1β1-integrin engagement to distinct laminin-1 domains orchestrates spreading, migration and survival of neural crest cells through independent signaling pathways
Authors: Desban Nathalie , Lissitzky Jean-Claude , Rousselle Patricia , Duband Jean-Loup
Published: July 2006

Integrin engagement regulates cell adhesion, shape, migration, growth, and differentiation, but molecular mechanisms coordinating these functions in cells remain unclear. Because of their migratory and differentiation potential, neural crest cells constitute a powerful paradigm to address this question. Here, we describe that laminin-1, a major component of their migration routes, promotes crest cell spreading, migration and survival through two distinct integrin-binding domains that are situated on both sides of its α1 subunit and can be separated in the LN-1 elastase proteolytic fragments E1' and E8. Interaction with either domain was mediated by the same integrin α1β1 but produced distinct, complementary responses through specific signaling cascades. FAK activation upon E8 binding induced spreading, formation of actin bundles and focal adhesions, stimulated oriented migration, but failed to support survival. Conversely, Erk activation upon E1' binding promoted long-term survival and random migration without actin reorganization. Consistent with this, interaction with laminin-5 or laminin-10/11, which do not harbor integrin-binding domains in the N-terminal side of their α chains, failed to support survival. Thus, the signaling activity and function of integrins might depend on binding domains in their ligands, thereby revealing ligand control of integrin function as a possible mechanism for the modulation and coordination of cell response to adhesive signals.
Noninvasive Raman Spectroscopy of Human Tissue in vivo
Authors: Matousek Pavel , Draper Edward R. C. , Goodship Allen E. , Clark Ian P. , Ronayne Kate L. , Parker Anthony W.
Published: July 2006

We report the first transcutaneous Raman spectrum of human bone in vivo obtained at skin-safe laser illumination levels. The spectrum of thumb distal phalanx was obtained using spatially offset Raman spectroscopy (SORS), which provides chemically specific information on deep layers of human tissue, well beyond the reach of existing comparative approaches. The spectroscopy is based on collecting Raman spectra away from the point of laser illumination using concentric rings of optical fibers. As a generic analytical tool this approach paves the way for a range of uses including disease diagnosis, noninvasive probing of pharmaceutical products, biofilms, catalysts, paints, and in dermatological applications.
Multivariate Curve Resolution Applied to Infrared Reflection Measurements of Soil Contaminated with an Organophosphorus Analyte
Authors: Gallagher Neal B. , Blake Thomas A. , Gassman Paul L. , Shaver Jeremy M. , Windig Willem
Published: July 2006

Multivariate curve resolution (MCR) is a powerful technique for extracting chemical information from measured spectra of complex mixtures. A modified MCR technique that utilized both measured and second-derivative spectra to account for observed sample-to-sample variability attributable to changes in soil reflectivity was used to estimate the spectrum of dibutyl phosphate (DBP) adsorbed on two different soil types. This algorithm was applied directly to measurements of reflection spectra of soils coated with analyte without resorting to soil preparations such as grinding or dilution in potassium bromide. The results provided interpretable spectra that can be used to guide strategies for detection and classification of organic analytes adsorbed on soil. Comparisons to the neat DBP liquid spectrum showed that the recovered analyte spectra from both soils showed spectral features from methyl, methylene, hydroxyl, and P=O functional groups, but most conspicuous was the absence of the strong PO–(CH2)3CH3 stretch absorption at 1033 cm−1. These results are consistent with those obtained previously using extended multiplicative scatter correction.