bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intratumor Heterogeneity and Precision of Microarray-Based Predictors of Breast Cancer Biology and Clinical Outcome
Authors: Barry William T. , Kernagis Dawn N. , Dressman Holly K. , Griffis Ryan J. , Hunter J'Vonne D. , Olson John A. , Marks Jeff R. , Ginsburg Geoffrey S. , Marcom Paul K. , Nevins Joseph R. , Geradts Joseph , Datto Michael B. 
Published: April 2010

Purpose Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. Patients and Methods Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. Results Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). Conclusion Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.
Phase III Trial of Bevacizumab Plus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma (AVOREN): Final Analysis of Overall Survival
Authors: Escudier Bernard , Bellmunt Joaquim , Négrier Sylvie , Bajetta Emilio , Melichar Bohuslav , Bracarda Sergio , Ravaud Alain , Golding Sophie , Jethwa Sangeeta , Sneller Vesna 
Published: April 2010

Purpose A phase III trial of bevacizumab combined with interferon alfa-2a (IFN) showed significant improvements in progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC). Here, we report overall survival (OS) data. Patients and Methods Six hundred forty-nine patients with previously untreated mRCC were randomly assigned to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN (9 MIU subcutaneously three times a week; n = 327) or IFN plus placebo (n = 322) in a multicenter, randomized, double-blind, phase III trial. The primary end point was OS. Final analysis of the secondary end point (PFS) was reported earlier. Results Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo (unstratified hazard ratio [HR] = 0.91; 95% CI, 0.76 to 1.10; P = .3360; stratified HR = 0.86; 95% CI, 0.72 to 1.04; P = .1291). Patients (> 55%) in both arms received at least one postprotocol antineoplastic therapy, possibly confounding the OS analysis. Patients receiving postprotocol therapy including a tyrosine kinase inhibitor had longer median OS (bevacizumab plus IFN arm: 38.6 months; IFN plus placebo arm: 33.6 months; HR = 0.80; 95% CI, 0.56 to 1.13). Tolerability was similar to that reported previously. Conclusion Bevacizumab plus IFN is active as first-line treatment in patients with mRCC. Most patients with mRCC receive multiple lines of therapy, so considering the overall sequence of therapy when selecting first-line therapy may optimize patient benefit.
Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer
Authors: Dikken Johan L. , Jansen Edwin P.M. , Cats Annemieke , Bakker Berdine , Hartgrink Henk H. , Kranenbarg Elma Meershoek-Klein , Boot Henk , Putter Hein , Peeters Koen C.M.J. , van de Velde Cornelis J.H. , Verheij Marcel 
Published: April 2010

Purpose The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. Patients and Methods Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. Results With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. Conclusion After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.
Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117
Authors: Bradley Jeffrey D. , Bae Kyounghwa , Graham Mary V. , Byhardt Roger , Govindan Ramaswamy , Fowler Jack , Purdy James A. , Michalski Jeff M. , Gore Elizabeth , Choy Hak 
Published: April 2010

Purpose Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non–small-cell lung cancer (NSCLC). Phase II results are reported here. Patients and Methods Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m2 and carboplatin at area under the curve 2 mg/m2. The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be ≤ 30%. Results Of the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months (range, 0.9 to 57.9 months) for all patients and 25.4 months (range, 13.1 to 57.9 months) for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5% (95% CI, 65.7% to 85.2%). The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade ≥ 3 lung toxicity (two patients had grade 5 lung toxicity). Conclusion The median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial.
Multivariate Analysis of Prognostic Factors Among 2,313 Patients With Stage III Melanoma: Comparison of Nodal Micrometastases Versus Macrometastases
Authors: Balch Charles M. , Gershenwald Jeffrey E. , Soong Seng-jaw , Thompson John F. , Ding Shouluan , Byrd David R. , Cascinelli Natale , Cochran Alistair J. , Coit Daniel G. , Eggermont Alexander M. , Johnson Timothy , Kirkwood John M. , Leong Stanley P. , McMasters Kelly M. , Mihm Martin C. , Morton Donald L. , Ross Merrick I. , Sondak Vernon K. 
Published: April 2010

Purpose To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma. Patients and Methods Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed. Results Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P < .001). Tremendous heterogeneity in survival was observed, particularly in the microscopically detected nodal metastasis subset (from 23% to 87% for 5-year survival). Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P < .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P < .01). Conclusion In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma.
IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Marcucci Guido , Maharry Kati , Wu Yue-Zhong , Radmacher Michael D. , Mrózek Krzysztof , Margeson Dean , Holland Kelsi B. , Whitman Susan P. , Becker Heiko , Schwind Sebastian , Metzeler Klaus H. , Powell Bayard L. , Carter Thomas H. , Kolitz Jonathan E. , Wetzler Meir , Carroll Andrew J. , Baer Maria R. , Caligiuri Michael A. , Larson Richard A. , Bloomfield Clara D. 
Published: April 2010

Purpose To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication–negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. Conclusion IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.
Nomograms for Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection
Authors: Yang Hwai-I , Sherman Morris , Su Jun , Chen Pei-Jer , Liaw Yun-Fan , Iloeje Uchenna H. , Chen Chien-Jen 
Published: April 2010

Purpose Counseling patients with chronic hepatitis B virus (HBV) on their individual risk of liver disease progression is challenging. This study aimed to develop nomograms for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B. Patients and Methods Two thirds of the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer–Hepatitis B Virus (REVEAL-HBV) study cohort was allocated for model derivation (n = 2,435), and the remaining third was allocated for model validation (n = 1,218). Previously confirmed independent risk predictors included in three Cox proportional hazards regression models were sex, age, family history of hepatocellular carcinoma, alcohol consumption habit, serum ALT level, hepatitis B envelope antigen (HBeAg) serostatus, serum HBV DNA level, and HBV genotype. Regression coefficients were rounded into integer risk scores, and predicted risk over 5- and 10-year periods for each risk score was calculated and depicted in nomograms. The predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC) and the correlation between predicted and observed hepatocellular carcinoma risk. Results All selected risk predictors were statistically significant in all models. In each model, either HBeAg seropositivity or HBeAg seronegativity with high viral load (HBV DNA level ≥ 100,000 copies/mL) and genotype C infection had the highest risk scores. All AUROCs for risk prediction nomogram were ≥ 0.82 in both model derivation and validation sets. The correlation coefficients between the observed hepatocellular carcinoma risk and the nomogram-predicted risk were greater than 0.90 in all model derivation and validation sets. Conclusion These easy-to-use nomograms based on noninvasive clinical characteristics can accurately predict the risk of hepatocellular carcinoma in patients with chronic hepatitis B. They may facilitate risk communication between patients and clinicians.
Impact of IDH1 R132 Mutations and an IDH1 Single Nucleotide Polymorphism in Cytogenetically Normal Acute Myeloid Leukemia: SNP rs11554137 Is an Adverse Prognostic Factor
Authors: Wagner Katharina , Damm Frederik , Göhring Gudrun , Görlich Kerstin , Heuser Michael , Schäfer Irina , Ottmann Oliver , Lübbert Michael , Heit Wolfgang , Kanz Lothar , Schlimok Günter , Raghavachar Aruna A. , Fiedler Walter , Kirchner Hartmut H. , Brugger Wolfram , Zucknick Manuela , Schlegelberger Brigitte , Heil Gerhard , Ganser Arnold , Krauter Jürgen 
Published: April 2010

Purpose We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. Results IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3–internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. Conclusion IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.
Neuromuscular Blocker Mix-up in the Pharmacy; ISMP and Doctor's Digest Launch New iPhone Application; “UD” for “Ut Dictum”—an Ambiguous and Dangerous Abbreviation; Order by Metric Weight, Not Volume
Authors: Cohen Michael R. , Smetzer Judy L. 
Published: April 2010

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Differences in Pharmacy Interventions at a Psychiatric Hospital: Comparison of Staff Pharmacists, Pharmacy Faculty, and Student Pharmacists
Authors: Marino Jehan , Caballero Joshua , Llosent Marlene , Hinkes Roberta 
Published: April 2010

Purpose Previous evidence suggests psychiatric pharmacists have improved patient symptoms and provide valuable information. However, there are limited recent data regarding clinical pharmacists performing interventions in a psychiatric setting and its effects on costs. Additionally, there are no data that differentiate between psychiatric hospital staff pharmacists' (HSP), faculty clinical pharmacists' (FCP), and student pharmacists' (SP) interventions. Therefore, the objective of this study is to evaluate and describe interventions made by HSPs, FCPs, and SPs in a psychiatric hospital and cost savings. Methods A retrospective review of interventions made in a psychiatric hospital over 18 months was performed. Descriptive statistics and cost analysis were also determined through Pharmacy OneSource. Results A total of 2,220 interventions were made. Among HSPs (n = 4), there were 1,734 interventions including clarifications of orders (n = 592) and MAR discrepancies (n = 385). FCPs (n = 2) contributed 358 interventions consisting of dose recommendations/adjustments (n = 78), drug lab/level recommendations (n = 47), and therapeutic recommendations (n = 37). Additionally, SPs (n = 27) made 128 interventions including patient medication history (n = 31), drug information (n = 30), and counseling patients (n = 25). Annual cost savings were estimated at $125,500 with approximately 90% contributed by HSPs. Conclusion Pharmacy personnel contributed a considerable amount of interventions providing a cost savings to the hospital. Also, HSPs provided a greater number of interventions resulting in decreased costs. In our setting, HSPs, FCPs, and SPs contribute different clinical therapeutic interventions that may optimize patient care.
Ustekinumab
Authors: Cada Dennis J. , Levien Terri L. , Baker Danial E. 
Published: April 2010

Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing inservices. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent in print and are also available online. Monographs can be customized to meet the needs of a facility. Subscribers to The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The April 2010 monograph topics are on liraglutide, dalfampridine, collagenase clostridium histolyticum for injection, roflumilast, and belimumab. The DUE is on liraglutide.
Molecular characterisation of ‘transmembrane protein 192’ (TMEM192), a novel protein of the lysosomal membrane
Authors: Schröder Bernd , Wrocklage Christian , Hasilik Andrej , Saftig Paul 
Published: April 2010

AbstractTransmembrane protein 192 (TMEM192) has been previously identified in proteomic analyses of lysosomal membranes. TMEM192 does not exhibit any significant homology to known protein families and possesses four potential transmembrane segments. To approach the molecular role of TMEM192, a detailed biochemical characterisation of this protein was performed. Expression constructs of fusion proteins containing TMEM192 and appended epitope tags were constructed. In HeLa cells these proteins were detected in membranes of lysosomes/late endosomes. To examine endogenous TMEM192, a TMEM192-specific antibody was generated and validated. With this antibody colocalisation of endogenous TMEM192 with lysosomal and late endosomal markers was demonstrated. Using Percoll density gradient centrifugation and immunoblotting, co-sedimentation of major portions of both TMEM192 and the lysosomal proteins LAMP-2 and cathepsin D into high-density fractions was observed. Interestingly, in contrast to many other lysosomal proteins no N-glycosylation of TMEM192 could be detected. Western blotting of reduced and non-reduced samples and co-immunoprecipitation experiments indicated TMEM192 to be a homodimer with one or more interchain disulphide bridges. TMEM192 was found to be strongly expressed in human kidney, liver, lung and pancreas tissue. The widespread tissue distribution could suggest an important role of TMEM192 for lysosomal function.