bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defective CD4+CD25+regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-γ
Authors: Kelchtermans Hilde , De Klerck Bert , Mitera Tania , Van Balen Maarten , Bullens Dominique , Billiau Alfons , Leclercq Georges , Matthys Patrick 
Published: January 2005

AbstractMice with a deficiency in IFN-γ or IFN-γ receptor (IFN-γR) are more susceptible to collagen-induced arthritis (CIA), an experimental autoimmune disease that relies on the use of complete Freund's adjuvant (CFA). Here we report that the heightened susceptibility of IFN-γR knock-out (KO) mice is associated with a functional impairment of CD4+CD25+ Treg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II (CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role of Treg cells in the effector phase of CIA. IFN-γR deficiency did not affect the number of CD4+CD25+ T cells in the central and peripheral lymphoid tissues. In addition, CD4+CD25+ T cells isolated from naive IFN-γR KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4+CD25+ T cells became significantly more impaired in IFN-γR-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly specific marker for Treg cells, was lower. We further demonstrated that the effect of endogenous IFN-γ, which accounts for more suppressive activity in wild-type mice, concerns both Treg cells and accessory cells. Our results demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-γ.
Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts
Authors: Samoszuk Michael , Tan Jenny , Chorn Guillaume 
Published: January 2005

Abstract
Introduction
Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts.

Methods
We measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin.

Results
Clonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells.

Conclusion
Serum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers.
Preferred analysis methods for Affymetrix GeneChips revealed by a wholly defined control dataset
Authors: Choe Sung E , Boutros Michael , Michelson Alan M , Church George M , Halfon Marc S 
Published: January 2005

Abstract
Background
As more methods are developed to analyze RNA-profiling data, assessing their performance using control datasets becomes increasingly important.

Results
We present a 'spike-in' experiment for Affymetrix GeneChips that provides a defined dataset of 3,860 RNA species, which we use to evaluate analysis options for identifying differentially expressed genes. The experimental design incorporates two novel features. First, to obtain accurate estimates of false-positive and false-negative rates, 100-200 RNAs are spiked in at each fold-change level of interest, ranging from 1.2 to 4-fold. Second, instead of using an uncharacterized background RNA sample, a set of 2,551 RNA species is used as the constant (1x) set, allowing us to know whether any given probe set is truly present or absent. Application of a large number of analysis methods to this dataset reveals clear variation in their ability to identify differentially expressed genes. False-negative and false-positive rates are minimized when the following options are chosen: subtracting nonspecific signal from the PM probe intensities; performing an intensity-dependent normalization at the probe set level; and incorporating a signal intensity-dependent standard deviation in the test statistic.

Conclusions
A best-route combination of analysis methods is presented that allows detection of approximately 70% of true positives before reaching a 10% false-discovery rate. We highlight areas in need of improvement, including better estimate of false-discovery rates and decreased false-negative rates.
Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors
Authors: Soepenberg Otto , Dumez Herlinde , Verweij Jaap , Semiond Dorothee , deJonge Maja J.A. , Eskens Ferry A.L.M. , Steeg Judith ter , Selleslach Johan , Assadourian Sylvie , Sanderink Ger-Jan , Sparreboom Alex , van Oosterom A.T. 
Published: January 2005

Purpose To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. Patients and Methods Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days. Results Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 × 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 × 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. Conclusion The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 × 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.
Discussions Regarding Reproductive Health for Young Women With Breast Cancer Undergoing Chemotherapy
Authors: Duffy Christine M. , Allen Susan M. , Clark Melissa A. 
Published: January 2005

Purpose Young women who undergo chemotherapy for breast cancer face serious consequences to their reproductive health. Research in this area has previously focused on men, or on childhood cancer survivors. We sought to explore self-report of reproductive health counseling in young women undergoing chemotherapy for breast cancer. Patients and Methods A total of 166 premenopausal women aged ≤ 50 years were recruited from oncology offices in academic and private practices in four northeastern states, as part of a randomized controlled clinical trial aimed at stress reduction. Women were asked a variety of questions regarding diagnosis and treatment, including whether they received any counseling regarding early menopause and fertility issues. Results Sixty-eight percent and 34% of women reported recalling a discussion with a physician regarding early menopause or fertility, respectively. In multivariate analysis, hormonal therapy and early stage of disease were associated with significantly increased odds of recall of a discussion regarding menopause. Difficulty communicating with medical team was associated with increased odds of recalling a discussion regarding fertility, whereas older age and anxiety in medical situations were associated with decreased odds. Conclusion Many women fail to recall discussions regarding the reproductive health impact of chemotherapy. Demographic, psychological, and disease-related variables are related to recalling such discussions. Counseling about premature menopause and fertility changes is an overlooked aspect of preparation for adjuvant chemotherapy in young premenopausal women with breast cancer. Future research should explore this issue further.
Mortality Risk From Squamous Cell Skin Cancer
Authors: Clayman Gary L. , Lee J. Jack , Holsinger F. Christopher , Zhou Xian , Duvic Madeleine , El-Naggar Adel K. , Prieto Victor G. , Altamirano Evelyn , Tucker Susan L. , Strom Sara S. , Kripke Margaret L. , Lippman Scott M. 
Published: January 2005

Purpose To identify nonmelanoma skin cancer patients with squamous cell carcinoma (SCC) who are at greatest risk of disease-specific mortality. Patients and Methods Prospectively enrolled patients with a minimum of one pathologically confirmed skin SCC lesion, definitive treatment of the SCC lesion(s) resulting in no evidence of disease, and at least 2 months of follow-up after definitive treatment were eligible for the present longitudinal analysis. They received comprehensive clinical, pathologic evaluations and follow-up for patterns of failure and mortality. Results We enrolled 210 patients (187 men and 23 women) with a total of 277 skin SCC lesions and a median enrollment age of 68 years (range, 34 to 95 years). Median follow-up of surviving patients was 22 months. Three-year overall and disease-specific survival (DSS) rates were 70% and 85%, respectively. In univariate analyses, the clinical-pathologic factors associated with adverse DSS were local recurrence at presentation (P = .05), invasion beyond subcutaneous tissues (P = .009), perineural invasion (P = .002), lesion size (P = .0003), and depth of invasion (P = .05). Statistical models identified a homogeneous high-risk group of patients with lesions ≥ 4 cm, perineural invasion, and deep invasion beyond subcutaneous structures. Three-year DSS was 100% for patients with no risk factors versus 70% for patients with at least one risk factor. Conclusion Lesion size ≥ 4 cm and histologic evidence of perineural invasion and deep invasion beyond subcutaneous structures were the clinical-pathologic factors most significantly associated with disease-specific mortality in skin SCC.
Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular Lymphoma
Authors: Czuczman M.S. , Koryzna A. , Mohr A. , Stewart C. , Donohue K. , Blumenson L. , Bernstein Z.P. , McCarthy P. , Alam A. , Hernandez-Ilizaliturri F. , Skipper M. , Brown K. , Chanan-Khan A. , Klippenstein D. , Loud P. , Rock M.K. , Benyunes M. , Grillo-Lopez A. , Bernstein S.H. 
Published: January 2005

Purpose To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naïve or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. Patients and Methods This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. Results An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naïve and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. Conclusion Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.
Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer
Authors: Bissett Donald , O’Byrne Ken J. , von Pawel J. , Gatzemeier Ulrich , Price Allan , Nicolson Marianne , Mercier Richard , Mazabel Elva , Penning Carol , Zhang Min H. , Collier Mary A. , Shepherd Frances A. 
Published: January 2005

Purpose Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non–small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. Conclusion Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.
Breast Cancer Treatment Guidelines in Older Women
Authors: Giordano Sharon H. , Hortobagyi Gabriel N. , Kau Shu-Wan C. , Theriault Richard L. , Bondy Melissa L. 
Published: January 2005

Purpose To determine patterns and predictors of concordance with institutional treatment guidelines among older women with breast cancer. Methods The study population included 1,568 patients aged 55 years and older who were treated at M.D. Anderson Cancer Center between July 1997 and January 2002 for stage I to IIIA invasive ductal and lobular breast cancer. Concordance with institutional guidelines was determined for definitive surgical therapy, radiotherapy after breast-conserving surgery, radiation therapy after mastectomy, adjuvant chemotherapy use, and adjuvant hormonal therapy use. The following variables were considered as possible modifiers of concordance: patient age, marital status, race, educational level, Eastern Cooperative Oncology Group performance status, comorbidity score, clinical stage, hormone receptor status, HER2-neu status, tumor grade, pathologic tumor size, lymphatic invasion, and number of lymph nodes involved. Logistic regression modeling was performed to determine the independent effect of each variable on guideline concordance. Results Older women were less likely to receive treatment in concordance with guidelines for definitive surgical therapy (P < .001), postlumpectomy radiation (P = .03), adjuvant chemotherapy (P < .001), and adjuvant hormonal therapy (P < .001). In multivariate analysis, age ≥ 75 years predicted a deviation from guidelines for definitive surgical therapy, adjuvant chemotherapy, and adjuvant hormonal therapy. Nonwhite race was associated with decreased likelihood of adjuvant radiation therapy after breast conservation. Conclusion After adjustment for comorbidity score, race, marital status, educational status, clinical stage, and tumor characteristics, increasing patient age was independently associated with decreased guideline concordance for definitive surgery, adjuvant chemotherapy, and adjuvant hormonal therapy. Future research should focus on delineating the possible reasons for guideline discordance.
EGFR Mutations in Non–Small-Cell Lung Cancer: Analysis of a Large Series of Cases and Development of a Rapid and Sensitive Method for Diagnostic Screening With Potential Implications on Pharmacologic Treatment
Authors: Marchetti Antonio , Martella Carla , Felicioni Lara , Barassi Fabio , Salvatore Simona , Chella Antonio , Camplese Pier P. , Iarussi Teodorico , Mucilli Felice , Mezzetti Andrea , Cuccurullo Franco , Sacco Rocco , Buttitta Fiamma 
Published: January 2005

Purpose It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non–small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. Patients and Methods We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach—direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations. Results There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing. Conclusion Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.
Phenotypic Heterogeneity in Multiple Myeloma Families
Authors: Lynch Henry T. , Watson Patrice , Tarantolo Stefano , Wiernik Peter H. , Quinn-Laquer Brigid , Isgur Bergsagel Karin , Huiart Laetitia , Olopade O.I. , Sobol Hagay , Sanger Warren , Hogg David , Weisenburger Dennis 
Published: January 2005

Purpose To describe a series of families with familial multiple myeloma (MM). Observations were used to generate hypotheses about the role of genetic factors, the mode of inheritance of these factors, and the association of other cancers with familial MM. Patients and Methods This observational study consisted of 39 families with multiple cases of MM or related disorders from four collaborating research centers. Each center followed its usual family study method. Probands were interviewed, and, when possible, cancers were verified by medical records and pathology review. A working pedigree was compiled on each family. Results Seventeen families had affected members in two or more generations, and eight families had two or more affected members in a single generation. Four families had two or more members with plasma cell dyscrasias, with or without a single case of MM. In the remaining 10 families, a single MM case occurred with a family history of other cancers. Other cancers observed in family members included hematologic malignancies and solid tumors. In families with MM in multiple generations, there was a decrease in the age at MM diagnosis in successive generations. Conclusion The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. Population-based epidemiologic studies are crucial, but because of the rarity of familial MM, a concerted case-finding approach may also be fruitful. Therefore, we propose an international consortium to study familial MM, and we invite all interested colleagues to participate.
Relationship Between MYCN Copy Number and Expression in Rhabdomyosarcomas and Correlation With Adverse Prognosis in the Alveolar Subtype
Authors: Williamson Daniel , Lu Yong-Jie , Gordon Tony , Sciot Raf , Kelsey Anna , Fisher Cyril , Poremba Christopher , Anderson John , Pritchard-Jones Kathy , Shipley Janet 
Published: January 2005

Purpose Amplification of the transcription factor MYCN is an important molecular diagnostic tool in stratifying treatment for neuroblastoma. Increased copy number and overexpression of MYCN in the pediatric cancer rhabdomyosarcoma has been described in a number of small studies with conflicting conclusions about its association with clinicopathologic characteristics. We aimed to study the phenomenon in the largest series to date. Patients and Methods Using quantitative polymerase chain reaction, we measured MYCN copy number and expression levels in rhabdomyosarcoma samples from 113 and 92 individuals with a confirmed diagnosis of rhabdomyosarcoma, respectively. Results Increased copy number of MYCN was found to be a feature of both the embryonal and alveolar subtypes. The copy number and expression levels were significantly greater in the alveolar subtype, although the range of expression in both subtypes spanned several orders of magnitude. MYCN copy number showed a significant correlation with expression in the alveolar subtype; this relationship between copy number and expression could be modeled as a logarithmic function. It is notable that relatively high expression frequently occurred in embryonal rhabdomyosarcoma without high copy number and that low expression was found in some cases with high copy number. In patients with alveolar rhabdomyosarcoma, overexpression (greater than median) or gain of genomic copies of MYCN were significantly associated with adverse outcome. Conclusion MYCN deregulation is a feature of rhabdomyosarcoma tumorigenesis, defines groups of patients with a poor prognosis, and is a potential target for novel therapies.