bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiling of Hfe
-/-liver and duodenum in mouse strains with differing susceptibilities to iron loading: identification of transcriptional regulatory targets of Hfe and potential hemochromatosis modifiers
Authors: Coppin Hélène , Darnaud Valérie , Kautz Léon , Meynard Delphine , Aubry Marc , Mosser Jean , Martinez Maria , Roth Marie-Paule 
Published: October 2007

Abstract
Background
Hfe disruption in mouse leads to experimental hemochromatosis by a mechanism that remains elusive. Affymetrix GeneChip® Mouse Genome 430 2.0 microarrays and bioinformatics tools were used to characterize patterns of gene expression in the liver and the duodenum of wild-type and Hfe-deficient B6 and D2 mice (two inbred mouse strains with divergent iron loading severity in response to Hfe disruption), to clarify the mechanisms of Hfe action, and to identify potential modifier genes.

Results
We identified 1,343 transcripts that were upregulated or downregulated in liver and 370 in duodenum of Hfe-/- mice, as compared to wild-type mice of the same genetic background. In liver, Hfe disruption upregulated genes involved in antioxidant defense, reflecting mechanisms of hepatoprotection activated by iron overload. Hfe disruption also downregulated the expression of genes involved in fatty acid β-oxidation and cholesterol catabolism, and of genes participating in mitochondrial iron traffic, suggesting a link between Hfe and the mitochondrion in regulation of iron homeostasis. These latter alterations may contribute to the inappropriate iron deficiency signal sensed by the duodenal enterocytes of these mice, and the subsequent upregulation of the genes encoding the ferrireductase Dcytb and several iron transporters or facilitators of iron transport in the duodenum. In addition, for several genes differentially expressed between B6 and D2 mice, expression was regulated by loci overlapping with previously mapped Hfe-modifier loci.

Conclusion
The expression patterns identified in this study contribute novel insights into the mechanisms of Hfe action and potential candidate genes for iron loading severity.
Phase II Study of Low-Dose Paclitaxel and Cisplatin in Combination With Split-Course Concomitant Twice-Daily Reirradiation in Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of Radiation Therapy Oncology Group Protocol 9911
Authors: Langer Corey J. , Harris Jonathan , Horwitz Eric M. , Nicolaou Nicos , Kies Merrill , Curran Walter , Wong Stuart , Ang Kian 
Published: October 2007

Purpose Recurrent squamous cell carcinoma of the head and neck (SCCHN) or new second primary tumor (SPT) in a previous radiation field, if not curable by surgery or radiation, is almost always fatal. Chemotherapy alone yields a median survival time (MST) of no more than 10 months and 1-year overall survival (OS) of 35% at best. Concurrent reirradiation and chemotherapy is an alternative strategy. Patients and Methods Eligibility for Radiation Therapy Oncology Group (RTOG) protocol 9911 stipulated recurrent SCCHN or SPT in a previous radiation field. Patients received twice-daily radiation (1.5 Gy per fraction bid × 5 days every 2 weeks ×4), plus cisplatin 15 mg/m2 intravenously (IV) daily × 5 and paclitaxel 20 mg/m2 IV daily × 5 every 2 weeks ×4. Granulocyte colony-stimulated factor was administered days 6 through 13 of each 2-week cycle. Results One hundred five patients were enrolled from March 2000 through June 2003; 23% had SPT. Oropharynx (40%) and oral cavity (27%) were the predominant primary sites. Median prior radiation dose was 65.4 Gy. Seventy-four percent of patients completed chemotherapy. Grade 4 or worse acute toxicity occurred in 28%, grade 4 or worse acute hematologic toxicity in 21%. Eight treatment-related deaths (8%) occurred: five in the acute setting, three late (including two carotid hemorrhages). MST was 12.1 months, with estimated 1- and 2-year OS rates of 50.2% and 25.9%. Conclusion Despite a high incidence of grade 5 toxicity, 1- and 2-year OS rates for split-course bid radiation therapy and concurrent cisplatin/paclitaxel exceed results generally seen with chemotherapy alone.
Prediagnosis Smoking, Obesity, Insulin Resistance, and Second Primary Cancer Risk in Male Cancer Survivors: National Health Insurance Corporation Study
Authors: Min Park Sang , Kyung Lim Min , Won Jung Kyu , Ae Shin Soon , Yoo Keun-Young , Ho Yun Young , Yul Huh Bong 
Published: October 2007

PurposeSmoking, obesity, and insulin resistance are well-known risk factors for cancer, yet few epidemiology studies evaluate their role as risk factors for a second primary cancer (SPC).Patients and MethodsWe identified 14,181 men with a first cancer from the National Health Insurance Corporation Study cohort. We obtained data on fasting glucose level, body mass index (BMI), and smoking history from an enrollment interview (1996). We obtained SPC incidence data for 1996 through 2002 from the Korean Central Cancer Registry. We used the standard Poisson regression model to estimate the age- and multivariate-adjusted relative risk (RR) for SPCs in relation to smoking history, BMI, and insulin resistance before diagnosis.ResultsWe observed 204 patients with SPC. The overall age-standardized incidence rate of SPC was 603.2 occurrences per 100,000 person-years, which was about 2.3 times higher than that of first cancer in the general male population. Multivariate regression revealed that lung (RR, 3.69; 95% CI, 1.35 to 10.09) and smoking-related (RR, 2.02; 95% CI, 1.02 to 4.03) SPCs were significantly associated with smoking. Obese patients (BMI ≥ 25 kg/m2) had significantly elevated RRs for colorectal (RR, 3.45; 95% CI, 1.50 to 7.93) and genitourinary (RR, 3.61; 95% CI, 1.36 to 9.54) SPCs. Patients with a fasting serum glucose concentration ≥ 126 mg/dL had a higher RR for hepatopancreatobiliary (RR, 3.33; 95% CI, 1.33 to 8.37) and smoking-related (1.93; 95% CI, 1.01 to 3.68) SPCs.ConclusionPrediagnosis smoking history, obesity, and insulin resistance were risk factors for several SPCs. These findings suggest that more thorough surveillance and screening for SPCs is needed for the cancer survivors with these risk factors.
Predicting Treatment Response of Malignant Gliomas to Bevacizumab and Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A Pilot Study
Authors: Chen Wei , Delaloye Sibylle , Silverman Daniel H.S. , Geist Cheri , Czernin Johannes , Sayre James , Satyamurthy Nagichettiar , Pope Whitney , Lai Albert , Phelps Michael E. , Cloughesy Timothy 
Published: October 2007

Purpose Evaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan. Patients and Methods Patients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival. Results Twenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P = .003), and tended to have a prolonged progression-free survival (P = .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P = .006; 6 weeks, P = .002), compared with the MRI responses (P = .060 for both 6-week and best responses). Conclusion FLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.
Comparison of Menopausal Symptoms During the First Year of Adjuvant Therapy With Either Exemestane or Tamoxifen in Early Breast Cancer: Report of a Tamoxifen Exemestane Adjuvant Multicenter Trial Substudy
Authors: Jones Stephen E. , Cantrell James , Vukelja Svetislava , Pippen John , O'Shaughnessy Joyce , Blum Joanne L. , Brooks Robert , Hartung Nicole L. , Negron Angel G. , Richards Donald A. , Rivera Ragene , Holmes Frankie Ann , Chittoor Sreeni , Whittaker Thomas L. , Bordelon James H. , Ketchel Steven J. , Davis Jennifer C. , Ilegbodu Des , Kochis Jean , Asmar Lina 
Published: October 2007

Purpose Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Patients and Methods Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor–positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Results Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. Conclusion At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.
Evaluation of Alternate Size Descriptors for Dose Calculation of Anticancer Drugs in the Obese
Authors: Sparreboom Alex , Wolff Antonio C. , Mathijssen Ron H.J. , Chatelut Etienne , Rowinsky Eric K. , Verweij Jaap , Baker Sharyn D. 
Published: October 2007

PurposeDespite the rising prevalence of obesity, there is paucity of information describing how doses of anticancer drugs should be adjusted in clinical practice. Here, we assessed the pharmacokinetics of eight anticancer drugs in adults and evaluated the potential utility of alternative weight descriptors in dose calculation for the obese.Patients and MethodsA total of 1,206 adult cancer patients were studied, of whom 162 (13.4%) were obese (body mass index ≥ 30). Pharmacokinetic parameters were calculated using noncompartmental analysis, and compared between lean (body mass index ≤ 25) and obese patients.ResultsThe absolute clearance of cisplatin, paclitaxel, and troxacitabine was significantly increased in the obese (P < .023), but this was not observed for carboplatin, docetaxel, irinotecan, or topotecan (P < .17). For doxorubicin, the systemic clearance was statistically significantly reduced in obese women (P = .013), but not in obese men (P = .52). Evaluation of alternate weight descriptors for dose calculation in the obese, including predicted normal weight, lean body mass, (adjusted) ideal body weight, and the mean of ideal and actual body weight, indicated that, for most of the evaluated drugs, weight scalars used to calculate body-surface area should consider actual body weight regardless of size.ConclusionThe results suggest that a number of widely used empiric strategies for dose adjustments in obese patients, including a priori dose reduction or dose capping, should be discouraged.
High Interleukin-15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia With Involvement of the CNS
Authors: Cario Gunnar , Izraeli Shai , Teichert Anja , Rhein Peter , Skokowa Julia , Möricke Anja , Zimmermann Martin , Schrauder Andre , Karawajew Leonid , Ludwig Wolf-Dieter , Welte Karl , Schünemann Holger J. , Schlegelberger Brigitte , Schrappe Martin , Stanulla Martin 
Published: October 2007

PurposeApplying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients.Patients and MethodsWe evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples.ResultsInterleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31).ConclusionQuantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.
Capecitabine Plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer
Authors: Kulke Matthew H. , Blaszkowsky Lawrence S. , Ryan David P. , Clark Jeffrey W. , Meyerhardt Jeffrey A. , Zhu Andrew X. , Enzinger Peter C. , Kwak Eunice L. , Muzikansky Alona , Lawrence Colleen , Fuchs Charles S. 
Published: October 2007

Purpose The addition of either capecitabine or erlotinib to gemcitabine in the first-line treatment of advanced pancreatic cancer is associated with modest improvements in overall survival. We evaluated an oral regimen of capecitabine and erlotinib in patients with advanced pancreatic cancer who had experienced treatment failure with standard first-line therapy with gemcitabine. Patients and Methods Thirty patients with gemcitabine-refractory metastatic pancreatic cancer were treated with capecitabine, administered at a dose of 1,000 mg/m2 twice daily for 2 weeks, followed by a 1-week break. All patients also received erlotinib 150 mg daily. Patients were observed for evidence of response, toxicity, and survival. EGFR mutational status was assessed in available tumor blocks. Results Treatment with capecitabine and erlotinib in gemcitabine-refractory patients was associated with an overall objective radiologic response rate of 10% and a median survival duration of 6.5 months. In addition, 17% of the treated patients experienced decreases in tumor marker (CA 19-9) levels of more than 50% from baseline. Common toxicities included diarrhea, skin rash, fatigue, and hand-foot syndrome. EGFR mutations were detected in two of five available tumors; no association between treatment response and EGFR mutational status was evident. Conclusion The combination of capecitabine and erlotinib is active in patients with gemcitabine-refractory pancreatic cancer. This regimen may represent an acceptable treatment option in patients who experience treatment failure with standard first-line therapy with gemcitabine or for whom gemcitabine may not be an appropriate first-line treatment option.
Long-Term Survival Associated With Complete Resection After Induction Chemotherapy in Stage IIIA (N2) and IIIB (T4N0-1) Non–Small-Cell Lung Cancer Patients: The Spanish Lung Cancer Group Trial 9901
Authors: Garrido Pilar , González-Larriba José Luis , Insa Amelia , Provencio Mariano , Torres Antonio , Isla Dolores , Sanchez José Miguel , Cardenal Felipe , Domine Manuel , Barcelo Jose Ramon , Tarrazona Vicente , Varela Andres , Aguilo Rafael , Astudillo Julio , Muguruza Ignacio , Artal Angel , Hernando-Trancho Florentino , Massuti Bartomeu , Sanchez-Ronco Maria , Rosell Rafael 
Published: October 2007

Purpose To assess the activity of induction chemotherapy followed by surgery in stage IIIA and selected stage IIIB non–small-cell lung cancer patients. Patients and Methods Mediastinoscopy proof of either positive N2 (IIIA) or T4N0-1 (IIIB) disease was required. Induction therapy was three cycles of cisplatin/gemcitabine/docetaxel, followed by surgery. Results From December 1999 to March 2003, 136 patients were entered onto the study; the clinical response rate in 129 assessable patients was 56%. The overall complete resection rate was 68.9% of patients eligible for surgery (72% of stage IIIA patients and 66% of stage IIIB patients) and 48% of all assessable patients. Eight (12.9%) of 62 completely resected patients had a pathologic complete response. Seven patients (7.8%) died during the postoperative period. The median overall survival time was 15.9 months, 3-year survival rate was 36.8%, and 5-year survival rate was 21.1%, with no significant differences in survival between stage IIIA and stage IIIB patients. Median survival time was 48.5 months for 62 completely resected patients, 12.9 months for 13 incompletely resected patients, and 16.8 months for 15 nonresected patients (P = .005). Three- and 5-year survival rates were 60.1% and 41.4% for completely resected patients, 23.1% and 11.5% for incompletely resected patients, and 31.1% and 0% for nonresected patients, respectively. In the multivariate analysis, complete resection (hazard ratio [HR] = 0.35; P < .0001), clinical response (HR = 0.32; P < .0001), and age younger than 60 years (HR = 0.64; P = .027) were the most powerful prognostic factors. Conclusion Induction chemotherapy followed by surgery is effective in stage IIIA and in selected stage IIIB patients attaining complete resection.
Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme
Authors: Vredenburgh James J. , Desjardins Annick , Herndon James E. , Marcello Jennifer , Reardon David A. , Quinn Jennifer A. , Rich Jeremy N. , Sathornsumetee Sith , Gururangan Sridharan , Sampson John , Wagner Melissa , Bailey Leighann , Bigner Darell D. , Friedman Allan H. , Friedman Henry S. 
Published: October 2007

Purpose The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. Patients and Methods This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. Results The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). Conclusion Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.
Combined Immunochemotherapy With Reduced Whole-Brain Radiotherapy for Newly Diagnosed Primary CNS Lymphoma
Authors: Shah Gaurav D. , Yahalom Joachim , Correa Denise D. , Lai Rose K. , Raizer Jeffrey J. , Schiff David , LaRocca Renato , Grant Barbara , DeAngelis Lisa M. , Abrey Lauren E. 
Published: October 2007

Purpose Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR. Patients and Methods Thirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m2; day 2, MTX 3.5 gm/m2 and vincristine 1.4 mg/m2. Procarbazine 100 mg/m2/d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed. Results With a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed. Conclusion The addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.