bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling
Authors: Finsen Alexandra Vanessa , Woldbaek Per Reidar , Li Jian , Wu Jiaping , Lyberg Torstein , Tønnessen Theis , Christensen Geir
Published: February 2004

Finsen, Alexandra Vanessa, Per Reidar Woldbaek, Jian Li, Jiaping Wu, Torstein Lyberg, Theis Tonnessen, and Geir Christensen. Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling. Physiol Genomics 16: 301-308, 2004. First published November 18, 2003; 10.1152/physi-olgenomics. 00144.2002.—The purpose of this study was to identify essential genes involved in myocardial growth and remodeling following myocardial infarction (MI). Left ventricular noninfarcted tissues from six mice subjected to MI under general anesthesia and from six sham-operated mice were obtained 1 wk after primary surgery and analyzed by means of cDNA filter arrays. Out of a total of 1,176 genes, 641 were consistently expressed, twenty-three were upregulated and thirteen downregulated. Five genes were only expressed following MI. Syndecan-3, a transmembranous heparan sulfate proteoglycan, was found to be upregulated together with a transcriptional activator of syndecans, Wilms tumor protein 1 (WT-1). Northern blotting demonstrated a significant upregulation of syndecan-1, -2, -3, and -4, WT-1, fibronectin, and basic fibroblast growth factor (FGF) receptor 1. Furthermore, Western blot analysis showed statistically significant increases in protein levels for syndecan-3 and -4. In conclusion, we have identified a subset of genes with increased expression in noninfarcted left ventricular tissue following MI, including syndecans 1–4, WT-1, fibronectin, collagen 6A, and FGF receptor 1. Since the syndecans link the cytoskeleton to the extracellular matrix and function as required coreceptors for FGF, we suggest a role for the syndecans in cardiac remodeling following MI.
Defining a metabolic phenotype in the brain of a transgenic mouse model of spinocerebellar ataxia 3
Authors: Griffin J. L. , Cemal C. K. , Pook M. A.
Published: February 2004

Many of the spinocerebellar ataxias (SCAs) are caused by expansions of CAG trinucleotide repeats encoding abnormal stretches of polyglutamine. SCA3 or Machado-Joseph disease (MJD) is the commonest dominant inherited ataxia disease, with pathological phenotypes apparent with a CAG triplet repeat length of 61–84. In this study a mouse model of SCA3 has been examined which was produced using a human yeast artificial chromosome containing the MJD gene with a CAG triplet expansion of 84 repeats. These mice have previously been shown to possess a mild progressive cerebellar deficit. NMR-based metabolomics/metabonomics in conjunction with multivariate pattern recognition identified a number of metabolic perturbations in SCA3 mice. These changes included a consistent increase in glutamine concentration in tissue extracts of the cerebellum and cerebrum and spectra obtained from intact tissue using magic angle spinning 1H-NMR spectroscopy. Furthermore, these profiles demonstrated metabolic abnormalities were present in the cerebrum, a region not previously implicated in SCA3. As well as an increase in glutamine both brain regions demonstrated decreases in GABA, choline, phosphocholine and lactate (representing the summation of lactate in vivo, and postmortem glycolysis of glucose and glycogen). The metabolic changes are discussed in terms of the formation of neuronal intranuclear inclusions associated with SCA3. This study suggests high-resolution 1H-NMR spectroscopy coupled with pattern recognition may provide a rapid method for assessing the phenotype of animal models of human disease.
The Arg16/Gly β2-adrenergic receptor polymorphism is associated with altered cardiovascular responses to isometric exercise
Authors: Eisenach John H. , McGuire Antonio M. , Schwingler Rachel M. , Turner Stephen T. , Joyner Michael J.
Published: February 2004

A polymorphism in the gene encoding the β2-adrenergic receptor (arginine or glycine at amino acid position 16) is associated with altered vasodilator responses to β2-agonists, which may modulate the pressor response to endogenous catecholamines during stress. To test the hypothesis that the Arg16/Gly polymorphism is associated with differences in acute pressor responses to sympathoexcitation, we measured mean arterial pressure (MAP, Finapres) and heart rate (HR, ECG) during mental stress (MS), cold pressor test (CPT), and handgrip (HG) to fatigue in 31 healthy, nonobese, normotensive adults (mean age ± SE: 31 ± 1; 16 females). Subjects were homozygous for Gly16 ( n = 16) or Arg16 ( n = 15). Both groups had similar baseline MAP (Arg16, 86 ± 3 mmHg; Gly16, 89 ± 2 mmHg; P = 0.4) and HR (Arg16, 68 ± 2 beats/min; Gly16, 65 ± 3 beats/min; P = 0.3). For MS and CPT, MAP and HR did not differ between genotype groups. Handgrip also produced similar increases in MAP; however, the change in HR was greater in the Gly16 homozygotes ( PANOVA= 0.001, genotype-by-time interaction). During HG, peak HR at fatigue was 100 ± 4 beats/min for Gly16 (54% increase from rest) vs. 93 ± 3 beats/min for Arg16 (37% increase). We conclude that the cardiovascular responses to MS and CPT do not differ between Gly16 and Arg16 homozygotes. However, the greater HR response to exercise in the Gly16 homozygotes may serve to maintain the pressor response (increased cardiac output) in the face of augmented peripheral vasodilation (decreased total peripheral resistance) in this group.
X-linked loci influence spatial navigation performance in Dahl rats
Authors: Ruiz-Opazo Nelson , Tonkiss John
Published: February 2004

Elucidation of natural genetic variations underlying strain or individual differences in cognitive function has remained elusive. Here we report the identification of two genetic loci that influence spatial navigation in Dahl rats. In the Morris water maze test, Dahl R rats exhibited efficient spatial navigation, whereas Dahl S rats displayed poor spatial navigation (accuracy). Analysis of F1 male progeny of reciprocal crosses between Dahl S and Dahl R strains implicated the X chromosome with the impairment in spatial navigation observed in Dahl S rats. Quantitative trait locus (QTL) analysis of an (RXS) F2 male population phenotyped for spatial navigation detected two QTLs on chromosome X influencing spatial navigation performance. One QTL ( Nav-1, centered at DXRat21, significant for linkage) influenced acquisition performance without affecting spatial accuracy performance; and the second QTL ( Nav-2, centered at DXRat25, significant for linkage) affected spatial accuracy performance with no detectable effect on acquisition performance. Our results demonstrate X linkage of spatial navigation performance in Dahl rats and provide evidence for the existence of independent genetic determinants for defined behavioral components of spatial navigation.
Insights into the physiological role of WT1 from studies of genetically modified mice
Authors: Discenza Maria Teresa , Pelletier Jerry
Published: February 2004

Discenza, Maria Teresa, and Jerry Pelletier. Insights into the physiological role of WT1 from studies of genetically modified mice. Physiol Genomics 16: 287-300, 2004; 10.1152/physiolgenomics.00164.2003.—The identification of WT1 gene mutations in children with WAGR and Denys-Drash syndromes pointed toward a role for WT1 in genitourinary system development. Biochemical analysis of the different WT1 protein isoforms showed that WT1 is a transcription factor and also has the ability to bind RNA. Analysis of WT1 complexes identified several target genes and protein partners capable of interacting with WT1. Some of these studies placed WT1, its downstream targets, and protein partners in a transcriptional regulatory network that controls urogenital system development. We review herein studies on WT1 knockout and transgenic models that have been instrumental in defining a physiological role for WT1 in normal and abnormal urogenital development.
Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]
Authors: Kinasewitz Gary T , Yan S Betty , Basson Bruce , Comp Philip , Russell James A , Cariou Alain , Um Suzane L , Utterback Barbara , Laterre Pierre-Francois , Dhainaut Jean-François ,   for the PROWESS Sepsis Study Group
Published: February 2004

Introduction

PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care).

Methods

Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism.

Results

Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin–antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days.

Conclusion

Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups.
Mammaglobin Is Associated With Low-Grade, Steroid Receptor-Positive Breast Tumors From Postmenopausal Patients, and Has Independent Prognostic Value for Relapse-Free Survival Time
Authors: Span Paul N. , Waanders Esmé , Manders Peggy , Heuvel Joop J.T.M. , Foekens John A. , Watson Mark A. , Beex Louk V.A.M. , Sweep Fred C.G.J.
Published: February 2004

Purpose

The tumor mRNA expression levels of mammaglobin, a novel breast-specific and breast cancer-associated marker, were correlated with disease outcome in 280 patients with primary breast cancer.

Patients and Methods

Mammaglobin expression levels were assessed by quantitative reverse transcriptase polymerase chain reaction in frozen tumor tissue from breast cancer patients with a median age of 60 years (range, 30 to 88 years) and a median follow-up of 85 months (range, 2 to 169 months).

Results

High expression levels were associated with low-grade tumors (P = .018), with positive estrogen and progesterone receptor status (P < .001), and postmenopausal status (P = .010). In the analysis of all patients, low tumor mammaglobin expression levels predicted an early relapse both in Cox univariate (hazard ratio [HR], 0.52; 95% CI, 0.34 to 0.79; P = .002) and multivariate regression analyses corrected for the traditional prognostic factors (HR, 0.55; 95% CI, 0.35 to 0.88; P = .012). The association of mammaglobin expression with the rate of relapse was particularly favorable in patients who received adjuvant tamoxifen treatment (HR, 0.35; 95% CI, 0.17 to 0.71; P = .004).

Conclusion

These results demonstrate that the assessment of the tumor mRNA expression level of the breast-specific protein mammaglobin could be useful to stratify patients for individual adjuvant treatment strategies.
Paclitaxel 175 or 225 mg per Meters Squared With Carboplatin in Advanced Ovarian Cancer: A Randomized Trial
Authors: Bolis Giorgio , Scarfone Giovanna , Polverino Gianpiero , Raspagliesi Francesco , Tateo Saverio , Richiardi Giovanni , Melpignano Mauro , Franchi Massimo , Mangili Giorgia , Presti Mauro , Villa Antonella , Conta Enrico , Guarnerio Paolo , Cipriani Sonia , Parazzini Fabio
Published: February 2004

Purpose

To analyze the effect of different doses of paclitaxel with fixed doses of carboplatin in the treatment of ovarian cancer.

Patients and Methods

Patients with histologically confirmed epithelial ovarian cancer, International Federation of Gynecology and Obstetrics stages IIB to IV, were eligible for this randomized, multicenter study. Women were randomly assigned to treatment with (1) carboplatin at the dose (in milligrams) corresponding to the following formula: target area under the free carboplatin plasma concentration versus time curve (AUC) = 6 × (glomerular filtration rate + 25) mg/m2 (AUC6) plus paclitaxel 175 mg/m2 for six cycles every 21 days or (2) carboplatin AUC6 plus paclitaxel 225 mg/m2 for six cycles every 21 days. A total of 502 women entered the study.

Results

Pathologic complete response was documented in 132 patients (63.8%) in the 175 mg/m2 group and in 127 cases (55.7%) in the 225 mg/m2 group (χ2 P = .090). The 4-year progression-free survival rate was 41.5% (SE = 3.5) in the 175-mg group and 39.2% (SE = 3.5) in the 225-mg group. The corresponding 4-year survival rates were 46.2% (based on 115 deaths) and 47.3% (based on 113 deaths), respectively.

Conclusion

This randomized trial suggests that paclitaxel 175 mg/m2 plus carboplatin AUC6 is the schedule with a more favorable profile than paclitaxel 225 mg/m2 plus carboplatin AUC6.
Enrollment of African Americans Onto Clinical Treatment Trials: Study Design Barriers
Authors: Adams-Campbell Lucile L. , Ahaghotu Chiledum , Gaskins Melvin , Dawkins Fitzroy W. , Smoot Duane , Polk Octavius D. , Gooding Robert , DeWitty Robert L.
Published: February 2004

Purpose

African Americans have the highest cancer mortality rates and poorest survival and are more often uninsured and underinsured compared with other ethnic groups. Minority participation in clinical trials has traditionally been low, with reports ranging from 3% to 20%. The present study systematically assesses 235 consecutively diagnosed African American cancer patients regarding recruitment onto cancer treatment clinical trials at Howard University Cancer Center between January 1, 2001, and December 31, 2002. Our intent is to determine the rate-limiting factors associated with enrolling African Americans onto clinical trials at a historically black medical institution.

Patients and Methods

Two hundred thirty-five consecutively diagnosed African American cancer patients were assessed for participation in clinical trials at Howard University Hospital and Cancer Center. The study population comprised 165 women and 70 men.

Results

The overall eligibility rate was 8.5% (20 of 235 patients); however, among those eligible, the enrollment rate (ie, enrollment among the eligible population) was 60.0% (12 of 20 patients). Comorbidities rendered 17.1% of the patient population ineligible for the trials. Advanced disease stage, associated with poor performance status, premature death, and short life expectancy, made an additional 10% of the patient population ineligible. Respiratory failure, HIV positivity, and anemia accounted for 37.8% of the comorbidities in this population. Cardiovascular diseases and renal insufficiency represented 16.2% of the comorbidities.

Conclusion

It was evident that study design exclusion and inclusion criteria rendered the majority of the study population ineligible. Among African Americans, comorbidity is a major issue that warrants considerable attention.
An Assessment of the Utilization of Complementary and Alternative Medication in Women With Gynecologic or Breast Malignancies
Authors: Navo Marisa A. , Phan Julie , Vaughan Christy , Palmer J. Lynn , Michaud Laura , Jones Kellie L. , Bodurka Diane C. , Basen-Engquist Karen , Hortobagyi Gabriel N. , Kavanagh John J. , Smith Judith A.
Published: February 2004

Purpose

To describe and assess the current utilization of complementary and alternative medicines (CAMs) in women with a diagnosis of either gynecologic or breast cancer and evaluate their reasons for use.

Patients and Methods

This study included 250 female patients from the Multidisciplinary Breast Center and 250 patients from the Gynecologic Oncology Center of The University of Texas M.D. Anderson Cancer Center (Houston, TX). Patients were selected by having an odd-numbered medical record number, and they were contacted before their clinic visit. The goals of the study were explained, and verbal consent was obtained. Patients who agreed to participate were asked to bring a written list and the medication bottles of all over-the-counter prescriptions and CAMs with them to clinic. In clinic, the investigator obtained a written informed consent and administered the survey. All patients and surveys were assessable.

Results

The most frequently used herbal products and megavitamins/minerals were identified from the patient medication histories. Overall, we found the proportion of patients using CAM to be 48% (95% CI, 44% to 53%; 241 of 500 patients). CAM use was related to patients' educational status: 62% had postgraduate degrees, 50% had college degrees, 56% had some college, and 33% had a high school education or less. Also, among patients using CAMs, only 53.5% had spoken to a healthcare provider regarding CAM therapy.

Conclusion

The use of CAM is common among women with cancer. Studies need to be conducted to establish if there are any potential drug interactions and/or therapeutic benefit of CAM products. Moreover, there is a need to educate patients and healthcare providers on appropriate and safe use of CAM products.
Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the Literature
Authors: Liede Alexander , Karlan Beth Y. , Narod Steven A.
Published: February 2004

Major risks conferred by BRCA1 and BRCA2 in women are for cancers of the breast, ovary, fallopian tube, and peritoneum. Male carriers of mutations in BRCA1 or BRCA2 are also susceptible to cancer; however, their risks remain poorly understood and their optimal clinical management has not yet been defined. This article reviews studies that estimate risk associated with mutations in BRCA1 or BRCA2, with a focus on the cancer sites most relevant to men. Male BRCA1 mutation carriers are at increased risk of cancers of the prostate and breast. Evidence supporting increased susceptibility to colon cancer is limited. In contrast to women, who have a greater lifetime risk of cancer with mutations of the BRCA1 gene, BRCA2 is the more important gene for men. The spectrum of cancers is wide for BRCA2 and some studies report that the overall cancer risk for male BRCA2 carriers exceeds the risk for female carriers. In particular, the relative risk to male BRCA2 mutation carriers is high before age 65 years, largely attributable to breast, prostate, and pancreatic cancers. BRCA2 mutation carriers are also at risk of stomach cancer and melanoma (of the skin and eye). Additional research into risks to male BRCA1 or BRCA2 mutation carriers is necessary, specifically to determine the magnitude of excess cancer risk among BRCA2 carriers and to increase our understanding of the basis for the observed site-specificity in cancer development.
Human Kallikrein 13 Protein in Ovarian Cancer Cytosols: A New Favorable Prognostic Marker
Authors: Scorilas Andreas , Borgoño Carla A. , Harbeck Nadia , Dorn Julia , Schmalfeldt Barbara , Schmitt Manfred , Diamandis Eleftherios P.
Published: February 2004

Purpose

Human kallikrein 13 (hK13; encoded by the KLK13 gene) is a secreted serine protease expressed in endocrine tissues, including the prostate, testis, breast, and ovary. We have previously reported steroid hormone regulation of the KLK13 gene and its clinical value as a marker of favorable prognosis in breast cancer at the mRNA level. We hypothesized that hK13 may represent a potential biomarker for ovarian carcinomas.

Patients and Methods

Using a newly developed enzyme-linked immunosorbent assay (ELISA), hK13 levels were quantified in 131 ovarian tumor extracts and correlated with various clinicopathological variables and outcome (progression-free survival [PFS], overall survival [OS]), over a median follow-up period of 42 months.

Results

hK13 concentration in ovarian tumor cytosols ranged from 0 to 18.4 ng/mg of total protein. An optimal cutoff value of 0.13 ng/mg (67th percentile) was selected, based on the ability of hK13 values to predict the PFS of the study population, to categorize tumors as hK13-positive or negative. Women with hK13-positive tumors most often had early stage (stage I/II) disease, no residual tumor after surgery and optimal debulking success (P < .05). Univariate and multivariate Cox regression analyses revealed that patients with hK13-positive tumors had a significantly longer PFS and OS than hK13-negative patients (P < .05). Kaplan-Meier survival curves further confirmed a reduced risk of relapse and death in women with hK13-positive tumors (P = .007 and P = .002, respectively).

Conclusion

These results indicate that hK13 is an independent marker of favorable prognosis in ovarian cancer.
Change in Neurocognitive Functioning After Treatment With Cranial Radiation in Childhood
Authors: Spiegler Brenda J. , Bouffet Eric , Greenberg Mark L. , Rutka James T. , Mabbott Donald J.
Published: February 2004

Purpose

To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors.

Patients and Methods

Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression.

Results

Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary.

Conclusion

Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias.
NF-κB in the Vascular Progression of Melanoma
Authors: Kashani-Sabet Mohammed , Shaikh Ladan , Miller James R. , Nosrati Mehdi , Ferreira Carlos M.M. , Debs Robert J. , Sagebiel Richard W.
Published: February 2004

Purpose

To examine a model of melanoma progression based on vascular factors and the role of NF-κB in the vascular progression of melanoma.

Patients and Methods

A data set of 526 patients from the University of California San Francisco Melanoma Center with 2 years of follow-up or first relapse was studied. The impact of the presence or absence of various prognostic factors on overall survival of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. A matched-pair analysis of NF-κB expression was performed in cases with vascular involvement and increased tumor vascularity versus matched controls lacking these factors.

Results

Cox regression analysis of factors evaluated by the American Joint Committee on Cancer Melanoma Staging Committee reproduced the powerful impact of tumor thickness and ulceration in this data set. With the inclusion of vascular factors such as tumor vascularity and vascular involvement, ulceration was no longer significant in predicting overall survival. By multivariate analysis, vascular involvement and tumor vascularity were the strongest predictors of melanoma outcome. Tumor vascularity seems to be a precursor of both vascular involvement and ulceration. A matched-pair tissue array analysis demonstrated the significant correlation between overexpression of NF-κB–p65 and the development of vascular factors.

Conclusion

Vascular factors play an important role in the progression of malignant melanoma. Ulceration may be a surrogate marker for the interactions between melanoma and the tumor vasculature. NF-κB seems to play an important role in the development of these factors.
Measuring Quality of Life in Routine Oncology Practice Improves Communication and Patient Well-Being: A Randomized Controlled Trial
Authors: Velikova Galina , Booth Laura , Smith Adam B. , Brown Paul M. , Lynch Pamela , Brown Julia M. , Selby Peter J.
Published: February 2004

Purpose

To examine the effects on process of care and patient well-being, of the regular collection and use of health-related quality-of-life (HRQL) data in oncology practice.

Patients and Methods

In a prospective study with repeated measures involving 28 oncologists, 286 cancer patients were randomly assigned to either the intervention group (regular completion of European Organization for Research and Treatment of Cancer-Core Quality of Life Questionnaire version 3.0, and Hospital Anxiety and Depression Scale on touch-screen computers in clinic and feedback of results to physicians); attention-control group (completion of questionnaires, but no feedback); or control group (no HRQL measurement in clinic before encounters). Primary outcomes were patient HRQL over time, measured by the Functional Assessment of Cancer Therapy-General questionnaire, physician-patient communication, and clinical management, measured by content analysis of tape-recorded encounters. Analysis employed mixed-effects modeling and multiple regression.

Results

Patients in the intervention and attention-control groups had better HRQL than the control group (P = .006 and P = .01, respectively), but the intervention and attention-control groups were not significantly different (P = .80). A positive effect on emotional well-being was associated with feedback of data (P = .008), but not with instrument completion (P = .12). A larger proportion of intervention patients showed clinically meaningful improvement in HRQL. More frequent discussion of chronic nonspecific symptoms (P = .03) was found in the intervention group, without prolonging encounters. There was no detectable effect on patient management (P = .60). In the intervention patients, HRQL improvement was associated with explicit use of HRQL data (P = .016), discussion of pain, and role function (P = .046).

Conclusion

Routine assessment of cancer patients' HRQL had an impact on physician-patient communication and resulted in benefits for some patients, who had better HRQL and emotional functioning.
Phase II Trial of Biweekly Infusional Fluorouracil, Folinic Acid, and Oxaliplatin in Patients With Advanced Gastric Cancer
Authors: Al-Batran Salah-Eddin , Atmaca Akin , Hegewisch-Becker Susanna , Jaeger Dirk , Hahnfeld Sabine , Rummel Mathias J , Seipelt Gernot , Rost Andreas , Orth Jacqueline , Knuth Alexander , Jaeger Elke
Published: February 2004

Purpose

To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer.

Patients and Methods

Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m2 (24-hour continuous infusion), FA 500 mg/m2 (2-hour intravenous infusion), and oxaliplatin 85 mg/m2 (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed.

Results

All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths.

Conclusion

Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.
Prognosis of Premenopausal Breast Cancer and Childbirth Prior to Diagnosis
Authors: Phillips Kelly-Anne , Milne Roger L. , Friedlander Michael L. , Jenkins Mark A. , McCredie Margaret R.E. , Giles Graham G. , Hopper John L.
Published: February 2004

Purpose

The time interval between last childbirth and subsequent breast cancer diagnosis is emerging as an important prognostic factor for premenopausal women.

Patients and Methods

We studied, prospectively, 750 women diagnosed with primary invasive breast cancer before age 45 years who participated in the population-based Australian Breast Cancer Family Study (ABCFS).

Results

Median follow-up time was 4.9 years (range, 0.8 to 10.8 years). Compared with nulliparous women, women who gave birth within 2 years prior to diagnosis were more likely to have axillary node-positive (58% v 41%; P = .01), and estrogen receptor-negative (58% v 39%; P = .005) tumors. The unadjusted hazard ratios for death were 2.3 (95% CI, 1.3 to 3.8; P = .002), 1.7 (95% CI, 1.1 to 2.6; P = .03), and 0.9 (95% CI, 0.6 to 1.5; P = .8) for patients who gave birth less than 2 years, 2 to 5 years, and 5 or more years before diagnosis, respectively. After adjusting for tumor characteristics, these hazard ratios were reduced to 1.9 (95%CI, 1.1 to 3.2; P = .02), 1.3 (95% CI, 0.8 to 2.1; P = .3), and 0.9 (95%CI, 0.5 to 1.4; P = .5). Modeling showed that, compared with nulliparous women, the mortality hazard ratio in parous women was 1.9, decreasing by 8% (95%CI, 4% to 13%; P < .001) for each year between last birth and breast cancer diagnosis.

Conclusion

Proximity of last childbirth to subsequent breast cancer diagnosis is a predictor of mortality independent of histopathological tumor characteristics. Clinicians should be aware that women diagnosed with breast cancer within a few years following childbirth may have a worse outcome than that suggested solely by the standard histopathological prognostic factors of their cancer.
Impact of Body Mass Index on Outcomes and Treatment-Related Toxicity in Patients With Stage II and III Rectal Cancer: Findings From Intergroup Trial 0114
Authors: Meyerhardt Jeffrey A. , Tepper Joel E. , Niedzwiecki Donna , Hollis Donna R. , McCollum A. David , Brady Denise , O'Connell Michael J. , Mayer Robert J. , Cummings Bernard , Willett Christopher , Macdonald John S. , Benson Al B. , Fuchs Charles S.
Published: February 2004

Purpose

To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer.

Patients and Methods

We evaluated a nested cohort of 1,688 patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy.

Results

Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% CI, 1.27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P < .0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% CI, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% CI, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals.

Conclusion

Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified.
Primary Cutaneous B-Cell Lymphoma Treated With Radiotherapy: A Comparison of the European Organization for Research and Treatment of Cancer and the WHO Classification Systems
Authors: Smith Benjamin D. , Glusac Earl J. , McNiff Jennifer M. , Smith Grace L. , Heald Peter W. , Cooper Dennis L. , Wilson Lynn D.
Published: February 2004

Purpose

To determine the relationship between the WHO and European Organization for Research and Treatment of Cancer (EORTC) pathologic classifications for primary cutaneous B-cell lymphoma (CBCL) and the implication of this relationship on initial treatment.

Patients and Methods

Patients with primary CBCL treated with radiotherapy were identified retrospectively. Initial biopsy specimens were reviewed by two dermatopathologists and classified according to the EORTC and WHO systems. Primary outcomes were recurrence-free and overall survival.

Results

Thirty-four patients were identified; initial biopsy specimens were adequate for classification in 32 patients. Four different composite histopathologic subtypes of lymphoma were identified: 53% (17 of 32) follicle center cell by EORTC and diffuse large B-cell by WHO (FCC/DLB), 25% (eight of 32) follicle center cell by EORTC and follicular by WHO (FCC/Fol), 13% (four of 32) marginal zone by EORTC and WHO (MZ/MZ), and 9% (three of 32) large B-cell of the leg by EORTC and diffuse large B-cell by WHO (Leg/DLB). Five-year relapse-free survival ranged from 62% to 73% for FCC/DLB, FCC/Fol, and MZ/MZ but was 33% for Leg/DLB (P = .6). Five-year overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P = .07). At 5 years, 21% of all patients had developed extracutaneous disease.

Conclusion

Two-thirds of primary cutaneous FCC lymphomas by EORTC criteria satisfy WHO criteria for DLB lymphoma. Unlike DLB lymphoma presenting in nodal or noncutaneous sites, these lesions are associated with an indolent course and may be treated with local radiotherapy alone.
EBV-Positive Gastric Adenocarcinomas: A Distinct Clinicopathologic Entity With a Low Frequency of Lymph Node Involvement
Authors: van Beek Josine , zur Hausen Axel , Klein Kranenbarg Elma , van de Velde Cornelis J.H. , Middeldorp Jaap M. , van den Brule Adriaan J.C. , Meijer Chris J.L.M. , Bloemena Elisabeth
Published: February 2004

Purpose

Epstein-Barr virus (EBV) is detected in a substantial subgroup of gastric adenocarcinomas worldwide. We have previously reported that these EBV-positive gastric carcinomas carry distinct genomic aberrations. In the present study, we analyzed a large cohort of EBV-positive and EBV-negative gastric adenocarcinomas for their clinicopathologic features to determine whether they constitute a different clinical entity.

Patients and Methods

Using a validated polymerase chain reaction/enzyme immunoassay–based prescreening method in combination with EBER1/2-RNA in situ hybridization, EBV was detected in the tumor cells of 7.2% (n = 41) of the gastric carcinomas from the Dutch D1D2 trial (N = 566; mean follow-up, 9 years). EBV status was correlated with clinicopathologic features collected for the Dutch D1D2 trial.

Results

EBV-positive gastric carcinomas occurred significantly more frequently in males (P < .0001) and in younger patients (P = .012). Most were of the intestinal type according to the Laurén classification (P = .047) or tubular according to the WHO classification (P = .006) and located in the proximal part of the stomach (P < .0001). A significantly lower tumor-node-metastasis system-stage (P = .026) was observed in the patients with EBV-carrying carcinomas, which was solely explained by less lymph node (LN) involvement (P = .034) in these cases. In addition, a better prognosis, as reflected by a longer disease-free period (P = .04) and a significant better cancer-related survival (P = .02), was observed for these patients, which could be explained by less LN involvement, less residual disease, and younger patient age.

Conclusion

EBV-carrying gastric adenocarcinomas are a distinct entity of carcinomas, characterized not only by unique genomic aberrations, but also by distinct clinicopathologic features associated with significantly better prognosis.
Randomized, Double-Blind, Dose-Finding Study of Dexamethasone in Preventing Acute Emesis Induced by Anthracyclines, Carboplatin, or Cyclophosphamide:
Authors:   The Italian Group for Antiemetic Research
Published: February 2004

Purpose

Different doses and schedules of dexamethasone, combined with a 5-HT3 antagonist, are used to prevent acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide. Therefore, we planned a randomized, double-blind, dose finding study aimed to identify the preferred dose and schedule of dexamethasone.

Patients and Methods

All consecutive chemotherapy-naive patients enrolled onto study were randomly assigned to receive for the prevention of acute emesis, during the first 24 hours, one of the following dexamethasone regimens, in combination with ondansetron 8 mg intravenously (IV): for arm A, 8 mg IV before chemotherapy plus 4 mg orally every 6 hours for four doses, starting at the same time of the chemotherapy; for arm B, 24 mg IV single dose before chemotherapy; and for arm C, 8 mg IV single dose before chemotherapy. All patients received from day 2 to 5 oral dexamethasone 4 mg bid.

Results

A total of 587 patients were enrolled, and 585 were assessed according to the intention-to-treat principle (195 patients in each arm). The rate of complete protection from acute vomiting and nausea, respectively, was not significantly different among the three groups (arm A, 84.6% and 66.7%; arm B, 83.6% and 56.9%; arm C, 89.2% and 61.0%), nor was the rate of complete protection from delayed vomiting and nausea, respectively (arm A, 81.0% and 46.7%; arm B, 81.3% and 45.1%; arm C, 79.8% and 46.1%). The incidence of delayed vomiting and nausea was strictly dependent on the presence of acute vomiting and nausea. Adverse events were mild and not significantly different among the three groups.

Conclusion

Dexamethasone 8 mg single dose IV before chemotherapy, in combination with a 5-HT3 antagonist, should be considered the preferred dose to prevent acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide.
Individualized Patient Dosing in Phase I Clinical Trials: The Role of Escalation With Overdose Control in PNU-214936
Authors: Cheng Jonathan D. , Babb James S. , Langer Corey , Aamdal Steinar , Robert Francisco , Engelhardt Lars Rupert , Fernberg Olov , Schiller Joan , Forsberg Goran , Alpaugh R. Katherine , Weiner Louis M. , Rogatko André
Published: February 2004

Purpose

A patient-specific dose-escalation scheme using a Bayesian model of Escalation with Overdose Control (EWOC) was conducted to establish the maximum tolerated dose (MTD) of PNU-214936 in advanced non–small-cell lung cancer (NSCLC). PNU-214936 is a murine Fab fragment of the monoclonal antibody 5T4 fused to a mutated superantigen staphylococcal enterotoxin A (SEA).

Patients and Methods

Seventy-eight patients with NSCLC were treated with an individualized dose of PNU-214936 calculated using EWOC, based on their anti-SEA antibody level, and given as a 3-hour infusion on 4 consecutive days.

Results

Fever (82%; grade 3 to 4, 2.6%) and hypotension (57%; grade 3 to 4, 9%) were the most common toxicities. Eight dose-limiting toxicities occurred, as defined as any grade 4 toxicity occurring within the first 5 days. The MTD was defined as a function of pretreatment anti-SEA antibody level. MTD ranged from 103 ng/kg for patients with anti-SEA concentrations ≤ 10 pmol/mL, to 601 ng/kg for patients with anti-SEA concentrations of 91 to 150 pmol/mL. A minor tumor response was demonstrated in five of 66 assessable patients.

Conclusion

EWOC determined phase I doses of PNU-214936 that were adjusted for patient anti-SEA antibody level, while safeguarding against overdose. Furthermore, the method permitted the construction of a dosing algorithm that would allow patients in subsequent clinical investigations to be treated with a dose of PNU-214936 that is tailored to their specific tolerance for the agent, as reflected by their pretreatment anti-SEA.
A non-chromosomal factor allows viability ofSchizosaccharomyces pombelacking the essential chaperone calnexin
Authors: Collin Philippe , Beauregard Pascale B. , Elagöz Aram , Rokeach Luis A.
Published: February 2004

Calnexin is a molecular chaperone playing key roles in protein folding and the quality control of this process in the endoplasmic reticulum. We, and others, have previously demonstrated that cnx1+, the gene encoding the calnexin homologue in Schizosaccharomyces pombe, is essential for viability. We show that a particular cnx1 mutant induces a novel mechanism allowing the survival of S. pombe cells in the absence of calnexin/Cnx1p. Calnexin independence is dominant in diploid cells and is inherited in a non-Mendelian manner. Remarkably, this survival pathway, bypassing the necessity for calnexin, can be transmitted by transformation of cell extracts into a wild-type naive strain, thus implicating a non-chromosomal factor. Nuclease and UV treatments of cells extracts did not obliterate transmission of calnexin independence by transformation. However, protease digestion of extracts did reduce the appearance of calnexin-independent cells, indicating that a protein element is required for calnexin-less viability. We discuss a model in which this calnexin-less survival mechanism would be activated and perpetuated by a protein component acting as a genetic element.
Zena Werb
Authors: Watt Fiona M.
Published: February 2004

Zena Werb was born in Bergenbelsen, Germany to Polish Jewish parents. As a post-war refugee, with her family she moved from Wroclaw, Poland to Milan, Italy. From there they immigrated to Canada, first to Saskatchewan and then to southern Ontario, where Zena grew up on a farm. She went to the University of Toronto, where she read Honours Biochemistry, receiving a BSc in 1966. Studying with the late Professor Zanvil A. Cohn, Zena received her PhD in cell biology from The Rockefeller University, New York. Her post-doctoral work was at the Strangeways Research Laboratory in Cambridge, UK. After one year on the faculty of Dartmouth Medical School in Hanover, New Hampshire, she joined the University of California, San Francisco, as an Assistant Professor in the Laboratory of Radiobiology. She is currently Professor and Vice-Chair of Anatomy and a member of the Program in Biological Sciences and Biomedical Sciences Program at the University of California, San Francisco.

Zena's research is on the roles of matrix metalloproteinases in normal and pathological tissues, concentrating on mouse models of bone and mammary gland development. She has demonstrated the importance of proteolysis as a mechanism of altering extracellular signaling. She has shown that remodeling of the extracellular matrix and the cellular microenvironment by stromal and inflammatory cells contributes to development of tumors as aberrant organs.
Tracking down lipid flippases and their biological functions
Authors: Pomorski Thomas , Holthuis Joost C. M. , Herrmann Andreas , van Meer Gerrit
Published: February 2004

The various organellar membranes of eukaryotic cells display striking differences in the composition, leaflet distribution and transbilayer movement of their lipids. In membranes such as the endoplasmic reticulum, phospholipids can move readily across the bilayer, aided by membrane proteins that facilitate a passive equilibration of lipids between both membrane halves. In the plasma membrane, and probably also in the late Golgi and endosomal compartments, flip-flop of phospholipids is constrained and subject to a dynamic, ATP-dependent regulation that involves members of distinct protein families. Recent studies in yeast, parasites such as Leishmania, and mammalian cells have identified several candidates for lipid flippases, and whereas some of these serve a fundamental role in the release of lipids from cells, others appear to have unexpected and important functions in vesicular traffic: their activities are required to support vesicle formation in the secretory and endocytic pathways.
Poly(ADP-ribosyl)ated chromatin domains: access granted
Authors: Rouleau Michèle , Aubin Rémy A. , Poirier Guy G.
Published: February 2004

The seemingly static architecture of interphase and mitotic chromatin betrays an otherwise elegantly dynamic entity capable of remodelling itself to facilitate DNA replication, transcription, repair and recombination. Remodelling of local chromatin domains in response to physiological cues proceeds, at least in part, through transient cycles of relaxation and condensation that require use of histone variants and post-translational modifications of histones. Studies have connected poly(ADP-ribosyl)ation of histones with virtually every aspect of DNA metabolism and function over the years, most notably with the response to DNA damage, where convincing evidence supports its essential role granting repair machinery access to damaged DNA. Recent reports extend this notion to transcription and the maintenance of genomic stability, thereby supporting a general role for nuclear poly(ADP-ribosyl)ation in many aspects of genomic activity. The phenomenon might contribute to the `histone code' by dictating levels of local chromatin compaction.
Sexual offenders discharged from prison in England and Wales: A 21‐year reconviction study
Authors: Cann Jenny , Falshaw Louise , Friendship Caroline
Published: February 2004

Purpose. This study examined the reconviction rates of a cohort of sexual offenders released from prison in England and Wales during 1979. A 21‐year follow‐up period was used and sexual, violent and general reconvictions assessed.

Method. The sample consisted of all adult male sexual offenders discharged from prison in England and Wales during 1979 (N = 419). Criminal conviction histories were obtained for the sample from the Offenders Index and sexual, violent and general reconvictions were calculated, over a period of 21 years (1979‐2000).

Results. A quarter (24.6%) of the sample received a reconviction for a sexual offence over the 21‐year follow‐up period, 21.7% received a violent reconviction and 61.8% received a general reconviction. A proportion of the sample received their first sexual reconviction 5, 10 or 15 years after being discharged from custody, thus remaining at risk of reconviction for many years.

Conclusions. The findings from this study give a unique insight into the long‐term offending of discharged sexual offenders in England and Wales and have implications for the supervision of such offenders.