bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Phase III Study of Gemcitabine and Vinorelbine Versus Gemcitabine, Vinorelbine, and Cisplatin in the Treatment of Advanced Non-Small-Cell Lung Cancer: From the German and Swiss Lung Cancer Study Group
Authors: Laack E. , Dickgreber N. , Müller T. , Knuth A. , Benk J. , Lorenz C. , Gieseler F. , Dürk H. , Engel-Riedel W. , Dalhoff K. , Kortsik C. , Graeven U. , Burk M. , Dierlamm T. , Welte T. , Burkholder I. , Edler L. , Hossfeld D.K. 
Published: June 2004

Purpose To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1 and 8 + cisplatin 75 mg/m2 on day 2 every 3 weeks). Primary end point of the study was overall survival. Results Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P = .73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P = .35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P = .004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. Conclusion In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.
Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)
Authors: Ejlertsen Bent , Mouridsen Henning T. , Langkjer Sven T. , Andersen Jorn , Sjöström Johanna , Kjaer Mogens 
Published: June 2004

Purpose To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. Patients and Methods A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, or epirubicin 90 mg/m2 IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m2 (950 mg/m2 from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. Results Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. Conclusion Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.
Capecitabine Plus Paclitaxel As Front-Line Combination Therapy for Metastatic Breast Cancer: A Multicenter Phase II Study
Authors: Gradishar William J. , Meza Luis A. , Amin Bipinkumar , Samid Dvorit , Hill Todd , Chen Yin-Miao , Lower Elyse E. , Marcom P. Kelly 
Published: June 2004

Purpose The goal of this multicenter, open-label phase II study was the clinical evaluation of combination therapy with the oral fluoropyrimidine capecitabine and the taxane paclitaxel in patients with metastatic breast cancer (MBC). Patients and Methods Forty-seven patients with MBC received oral capecitabine at 1,650 mg/m2/d (825 mg/m2 twice daily) on days 1 through 14, and intravenous infusion of paclitaxel at 175 mg/m2 on day 1 of each 21-day treatment cycle. Treatment continued until disease progression, intolerable toxicity, or patient's decision to discontinue. Patients (35 to 76 years old) had a median Karnofsky performance status of 90%. Forty-four patients (94%) received study treatment as first-line therapy for metastatic disease. Results Objective responses occurred in 24 (51%) patients; seven (15%) complete responses and 17 (36%) partial responses. Stable disease lasting 180 days or more was observed in nine (19%); the clinical response rate was 70%. Median duration of response was 12.6 months, median time to disease progression was 10.6 months, and median overall survival time was 29.9 months. The most common treatment-related adverse events, regardless of severity, were alopecia, hand-foot syndrome, nausea, and fatigue. Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only grade 3 or 4 treatment-related adverse events that occurred in more than 10% of patients. Conclusion The combination of capecitabine plus paclitaxel is a highly active and generally well-tolerated regimen for first-line treatment of MBC.
Differential Activation of Epidermal Growth Factor (EGF) Receptor Downstream Signaling Pathways by Betacellulin and EGF
Authors: Saito Tsugumichi , Okada Shuichi , Ohshima Kihachi , Yamada Eijiro , Sato Minoru , Uehara Yutaka , Shimizu Hiroyuki , Pessin Jeffrey E. , Mori Masatomo 
Published: June 2004

AbstractTo determine the downstream signaling pathways regulated by betacellulin (BTC) in comparison with epidermal growth factor (EGF), we used Chinese hamster ovary cells overexpressing the human EGF receptor (ErbB1/EGFR). The overall time-dependent activation of EGFR autophosphorylation was identical in cells treated with 1 nm BTC or 1.5 nm EGF. Analysis of site-specific EGFR phosphorylation demonstrated that the BTC and EGF tyrosine phosphorylation of Y1086 was not significantly different. In contrast, the autophosphorylation of Y1173 was markedly reduced in BTC-stimulated cells, compared with EGF stimulation that directly correlated with a reduced BTC stimulation of Shc tyrosine phosphorylation, Ras, and Raf-1 activation. On the other hand, Y1068 phosphorylation was significantly increased after BTC stimulation, compared with EGF in parallel with a greater extent of Erk phosphorylation. Expression of a dominant interfering MEK kinase 1 (MEKK1) and Y1068F EGFR more efficiently blocked the enhanced Erk activation by BTC, compared with EGF. Interestingly BTC had a greater inhibitory effect on apoptosis, compared with EGF, and expression of Y1068F EGFR abolished this enhanced inhibitory effect. Together, these data indicated that although BTC and EGF share overlapping signaling properties, the ability of BTC to enhance Erk activation occurs independent of Ras. The increased BTC activation results from a greater extent of Y1068 EGFR tyrosine phosphorylation and subsequent increased recruitment of the Grb2-MEKK1 complex to the plasma membrane, compared with EGF stimulation. The increased Erk activation by BTC associated with antiapoptotic function.
Ovarian Follicle Development Requires Smad3
Authors: Tomic Dragana , Miller Kimberly P. , Kenny Hilary A. , Woodruff Teresa K. , Hoyer Patricia , Flaws Jodi A. 
Published: June 2004

AbstractSmad3 is an important mediator of the TGFβ signaling pathway. Interestingly, Smad3-deficient (Smad3−/−) mice have reduced fertility compared with wild-type (WT) mice. To better understand the molecular mechanisms underlying the reduced fertility in Smad3−/− animals, this work tested the hypothesis that Smad3 deficiency interferes with three critical aspects of folliculogenesis: growth, atresia, and differentiation. Growth was assessed by comparing the size of follicles, expression of proliferating cell nuclear antigen, and expression of cell cycle genes in Smad3−/− and WT mice. Atresia was assessed by comparing the incidence of atresia and expression of bcl-2 genes involved in cell death and cell survival in Smad3−/− and WT mice. Differentiation was assessed by comparing the expression of FSH receptor (FSHR), estrogen receptor (ER) α, ERβ, and inhibin α-, βA-, and βB-subunits in Smad3−/− and WT mice. Because growth, atresia, and differentiation are regulated by hormones, estradiol, FSH, and LH levels were compared in Smad3−/− and WT mice. Moreover, because alterations in folliculogenesis can affect the ability of mice to ovulate, the number of corpora lutea and ovulated eggs in response to gonadotropin treatments were compared in Smad3−/− and WT animals. The results indicate that Smad3 deficiency slows follicle growth, which is characterized by small follicle diameters, low levels of proliferating cell nuclear antigen, and low expression of cell cycle genes (cyclin-dependent kinase 4 and cyclin D2). Smad3 deficiency also causes atretic follicles, degenerated oocytes, and low expression of bcl-2. Furthermore, Smad3 deficiency affects follicular differentiation as evidenced by decreased expression of ERβ, increased expression of ERα, and decreased expression of inhibin α-subunits. Smad3 deficiency causes low estradiol and high FSH levels. Finally, Smad3−/− ovaries have no corpora lutea, and they do not ovulate after ovulatory induction with exogenous gonadotropins. Collectively, these data provide the first evidence that reduced fertility in Smad3−/− mice is due to impaired folliculogenesis, associated with altered expression of genes that control cell cycle progression, cell survival, and cell differentiation. The findings that Smad3−/− follicles have impaired growth, increased atresia, and altered differentiation in the presence of high FSH levels, normal expression of FSHR, and lower expression of cyclin D2, suggest a possible interaction between Smad3 and FSH signaling downstream of FSHR in the mouse ovary.
The Role of Uncoupling Protein 1 in the Metabolism and Adiposity of RIIβ-Protein Kinase A-Deficient Mice
Authors: Nolan Michael A. , Sikorski Maria A. , McKnight G. Stanley 
Published: June 2004

AbstractMice lacking the RIIβ regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RIIβ−/− mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RIIβ null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RIIβ and UCP1 (RIIβ−/−/Ucp1−/−) were created, and the key parameters of metabolism and body composition were studied. We discovered that RIIβ−/− mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RIIβ−/− mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RIIβ null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RIIβ mutant mice.
Comparison of Natural Product Use Between Primary Care and Nephrology Patients
Authors: Grabe Darren W , Garrison Gina Daubney 
Published: June 2004

BACKGROUND: The use of natural products is increasing, but healthcare professionals may underestimate the use of these agents by patients. It is unknown whether natural product use differs between primary care and specialty clinic patients, such as those in a nephrology clinic. OBJECTIVE: To compare patterns of natural product use between primary care and nephrology clinic patients. METHODS: One thousand adult patients from each clinic were randomly mailed an anonymous questionnaire to determine current and past use of natural products. RESULTS: A total of 491 surveys were returned, for an overall response rate of 26% (25% primary care; 28% nephrology clinic). Current use of natural products was similar between the primary care and nephrology groups (34% vs 29%, respectively; p = NS). Primary care patients were more likely to have taken a natural product in the past (57% vs 45%; p < 0.05); Echinacea was the most common product taken by those patients (26%). Green tea was the most common natural product taken by nephrology clinic patients (18%). More primary care patients took Echinacea compared with nephrology clinic patients (26% vs 12%; p < 0.01). Adverse reactions led to discontinuation of the natural product in 7% of respondents. CONCLUSIONS: Active use of natural products was similar between the survey respondents. Documentation and monitoring of natural product use by healthcare professionals working with primary care and nephrology clinic patients are recommended.
Intensive Insulin Therapy for Critically III Patients
Authors: Lewis Kelly S , Kane-Gill Sandra L , Bobek Mary Beth , Dasta Joseph F 
Published: June 2004

OBJECTIVE: To evaluate the clinical outcomes of glycemic control of intensive insulin therapy and recommend its place in the management of critically ill patients. DATA SOURCES: Searches of MEDLINE (1966—March 2004) and Cochrane Library, as well as an extensive manual review of abstracts were performed using the key search terms hyperglycemia, insulin, intensive care unit, critically ill, outcomes, and guidelines and algorithms. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and deemed relevant if they included and assessed clinical outcomes. DATA SYNTHESIS: Mortality among patients with prolonged critical illness exceeds 20%, and most deaths are attributable to sepsis and multisystem organ failure. Hyperglycemia is common in critically ill patients, even in those with no history of diabetes mellitus. Maintaining normoglycemia with insulin in critically ill patients has been shown to improve neurologic, cardiovascular, and infectious outcomes. Most importantly, morbidity and mortality are reduced with aggressive insulin therapy. This information can be implemented into protocols to maintain strict control of glucose. CONCLUSIONS: Use of insulin protocols in critically ill patients improves blood glucose control and reduces morbidity and mortality in critically ill populations. Glucose levels in critically ill patients should be controlled through implementation of insulin protocols with the goal to achieve normoglycemia, regardless of a history of diabetes. Frequent monitoring is imperative to avoid hypoglycemia.
Approximate Equivalent Rosuvastatin Doses for Temporary Statin Interchange Programs
Authors: Kendrach Michael G , Kelly-Freeman Maisha 
Published: June 2004

OBJECTIVE: To estimate approximate doses of rosuvastatin equivalent to the other hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for a temporary substitution program. DATA SOURCES: A literature search was conducted to locate clinical trials directly comparing rosuvastatin with other statins that evaluated the magnitude of cholesterol lowering. DATA SYNTHESIS: The mean low-density lipoprotein and total cholesterol values from the clinical trials were assessed. Study results indicate that rosuvastatin is not equivalent to other statins on a milligram-to-milligram basis. CONCLUSIONS: Rosuvastatin appears to be at least 2 and 4 times as potent as atorvastatin and simvastatin, respectively, and at least 8 times as potent as pravastatin and lovastatin.
The Paperless Labeling Initiative: A Proof-of-Concept Study
Authors: Ruchalski Charles 
Published: June 2004

BACKGROUND: Traditional paper professional package inserts (PPIs) are used on a daily basis by a variety of healthcare providers to locate and disseminate drug information. Unfortunately, paper PPIs are sometimes not accessible to the healthcare provider, appear unreadable due to varied font sizes, and are often considered not to be user-friendly. In December 2000, the Food and Drug Administration proposed regulations that would revise the format of PPIs. OBJECTIVE: To determine whether electronic delivery of PPI information is achievable in community pharmacy practice settings. METHODS: Electronic PPIs are an alternative means of delivering this information. This 12-week proof-of-concept study evaluated the Health Information Designs/Thomson Healthcare and Etreby Computer Company for electronic delivery of PPIs in 6 chain and 4 independent community pharmacies, with 5 pharmacies evaluating each system. Participating pharmacists were asked 9 questions designed to determine the feasibility of implementing electronic PPI delivery, as well as pharmacist satisfaction with each system. RESULTS: Pharmacists deemed both systems to be accessible and user-friendly. Pharmacists from both groups felt that the electronic PPIs were challenging to read and that printing took too long. CONCLUSIONS: Future studies in a more diverse selection of dispensing sites, including pharmacies (community and hospital based), clinics, and physician practices, need to be performed to maximize the use of electronic PPIs.
Bevacizumab: An Angiogenesis Inhibitor with Efficacy in Colorectal and Other Malignancies
Authors: Zondor Stacey D , Medina Patrick J 
Published: June 2004

OBJECTIVE: To review the pharmacology, pharmacokinetics, and pivotal clinical trials for bevacizumab, emphasizing its use in colorectal cancer. DATA SOURCES: A PubMed/MEDLINE search was conducted (1966—April 2004) using the following terms: bevacizumab, Avastin, anti-VEGF, anti-angiogenesis, and colorectal cancer. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Preclinical and clinical trials that used bevacizumab for the treatment of colorectal cancer and other malignancies were selected from the data sources. All published, randomized clinical trials evaluating bevacizumab in colorectal cancer were included in this review. DATA SYNTHESIS: Despite advances in chemotherapy, current therapeutic options for metastatic disease provide only temporary benefit for most patients. Bevacizumab is the first anti-cancer agent shown to provide benefit for patients with cancer by inhibiting angiogenesis. Bevacizumab has shown significant activity in the treatment of many cancers, including metastatic colorectal cancer. When used in combination with fluorouracil-based chemotherapy, bevacizumab improves overall response rates, time to progression, and survival in patients with metastatic colorectal cancer. Common toxicities associated with bevacizumab include hypertension, bleeding episodes, and thrombotic events. CONCLUSIONS: Although clinical knowledge on the effectiveness of bevacizumab is limited, early data indicate that it is a promising agent, with a novel mechanism of action, for patients with metastatic cancer, including colorectal cancer.
Rhabdomyolysis Caused by Commiphora mukul, a Natural Lipid-Lowering Agent
Authors: Bianchi Antonio , Cantù Paola , Firenzuoli Fabio , Mazzanti Gabriela , Menniti-Ippolito Francesca , Raschetti Roberto 
Published: June 2004

OBJECTIVE: To report a case of rhabdomyolysis caused by Commiphora mukul, a natural lipid-lowering agent. CASE SUMMARY: A 55-year-old man was taking an extract of C. mukul 300 mg 3 times daily to lower his cholesterol level. He developed rhabdomyolysis with hemoglobinuria after 2 weeks of treatment. Laboratory tests showed creatine kinase 144 600 IU/L (reference range 24–195), myoglobin >3000 ng/mL (28–72), lactate dehydrogenase 7157 IU/L (230–460), aspartate aminotransferase 1115 IU/L (10–35), and alanine aminotransferase 205 IU/L (10–35). Analysis of a urine sample was 2+ positive for hemoglobin. All parameters returned to normal after the herbal preparation was discontinued. DISCUSSION: The Naranjo probability scale indicates C. mukul as the possible cause of rhabdomyolysis in our patient. Drug-induced rhabdomyolysis is an established but rare adverse effect of high doses of cholesterol-lowering agents (statins) or interactions between drugs (eg, statins and fibrates). As of May 28, 2004, to our knowledge, this is the first reported case of rhabdomyolysis following C. mukul ingestion. CONCLUSIONS: Our report describes a case of rhabdomyolysis possibly caused by C. mukul and underlines the need for active surveillance of natural products.
Selective Serotonin-Reuptake Inhibitors for the Treatment of Hot Flashes
Authors: Koch Yvonne De Sloover , Ernst Michael E 
Published: June 2004

OBJECTIVE: To review the literature evaluating the use of selective serotonin-reuptake inhibitors (SSRIs) for the treatment of hot flashes. DATA SOURCES: Biomedical literature was accessed through MEDLINE (1966—June 2003), MD Consult, and references of reviewed articles. Key search terms used were hot flashes, vasomotor symptoms, antidepressants, and SSRIs. DATA SYNTHESIS: Recent evidence from the Women's Health Initiative precludes the use of traditional hormonal therapy in some women. Nonhormonal therapies are possible options, but conflicting evidence of efficacy exists. CONCLUSIONS: Although further studies are warranted, preliminary data suggest that SSRIs are generally modestly successful in reducing the frequency and severity of hot flashes.