bluuebunny/crossref_metadata_2025 huggingface dataset:
Proof-of-Principle Phase II MRI Studies in Stroke
Authors:   MR Stroke Collaborative Group
Published: August 2006

Background and Purpose—

Since the failure of a number of phase III trials of neuroprotection in ischemic stroke, the need for smaller phase II studies with MRI surrogates has emerged. There is, however, little information available about sample size requirements for such phase II trials and rarely enough patients in single studies to make robust estimates. We have formed an international collaborative group to assemble larger datasets and from these have generated sample size tables for MRI-based infarct expansion as the outcome measure.

Methods—

Twelve centers from Australia, Europe, and North America contributed data from patients with hemispheric ischemic stroke. Infarct expansion was defined from initial diffusion-weighted images and later fluid-attenuated inversion recover or T
2
images. Sample size estimates were calculated from data on infarct expansion ratios treated as dichotomous or continuous variables. A nonparametric approach was used because the distribution of infarct expansion was resistant to all forms of transformation.

Results—

As an example, a 20% absolute reduction in infarct expansion ratio (≤1), 80% power, and α=0.05 requires 99 patients in each arm. To achieve an equivalent effect size with a continuous approach requires 61 patients.

Conclusions—

These tables will be useful in planning phase II trials of therapy with the use of MRI outcome measures. For positive studies, biologically plausible surrogates such as these may provide a rationale for proceeding to phase III trials.
The Notion of Argument in Prepositional Phrase Attachment
Authors: Merlo Paola , Ferrer Eva Esteve
Published: August 2006

In this article we refine the formulation of the problem of prepositional phrase (PP) attachment as a four-way disambiguation problem. We argue that, in interpreting PPs, both knowledge about the site of the attachment (the traditional noun-verb attachment distinction) and the nature of the attachment (the distinction of arguments from adjuncts) are needed. We introduce a method to learn arguments and adjuncts based on a definition of arguments as a vector of features. In a series of supervised classification experiments, first we explore the features that enable us to learn the distinction between arguments and adjuncts. We find that both linguistic diagnostics of argumenthood and lexical semantic classes are useful. Second, we investigate the best method to reach the four-way classification of potentially ambiguous prepositional phrases. We find that whereas it is overall better to solve the problem as a single four-way classification task, verb arguments are sometimes more precisely identified if the classification is done as a two-step process, first choosing the attachment site and then labeling it as argument or adjunct.
Curbing the Demand for Mass Destruction
Authors: Curtis Charles B.
Published: August 2006

We live in an age when the supply of weapons and materials of mass destruction easily meets the demand of Islamist extremists all too willing to use them. It is essential but not enough to reduce and secure the supply of weapons and materials of mass destruction. A comprehensive approach to catastrophic terrorism requires that we manage both the supply and demand for weapons of mass destruction. Nonproliferation strategies that focus solely on supply are merely buying us time.
Assessing U.S. Strategy in the War on Terror
Authors: Van Evera Stephen
Published: August 2006

Al Qaeda and its jihadi allies pose a large threat to U.S. national security. Such a grave menace requires a strong response. Yet the United States has so far waged only a one-dimensional war against al Qaeda, fighting hard on one front when it should be fighting on four. Specifically, the Bush administration has focused heavily on an offensive campaign against al Qaeda overseas while neglecting three other critical fronts: bolstering homeland defense, securing weapons and materials of mass destruction from possible theft or purchase by terrorists, and winning the war of ideas. And the administration has sometimes done too little even on the offensive, instead diverting itself into a costly and counterproductive sideshow in Iraq. The public credits President Bush for toughness on terror. In fact, his administration has pursued a half-hearted war on terror, failing to devote the political and financial resources it requires.
Impact of Disease States on the Pharmacokinetics and Pharmacodynamics of Angiotensin‐Converting Enzyme Inhibitors
Authors: LeBlanc Jaclyn M. , Dasta Joseph F. , Pruchnicki Maria C. , Schentag Jerome J.
Published: August 2006

The pharmacokinetics and pharmacodynamics of angiotensin‐converting enzyme inhibitors (ACE) in elderly patients and patients with renal and hepatic impairment were examined, and a role for an AUC/EC50 ratio to guide dosing was evaluated. A Medline and International Pharmaceutical Abstracts search was used to identify human studies and abstracts. Relevant data were evaluated and summarized. Dosing regimens were compared using an AUC/EC50 ratio. Most studies evaluating ACE inhibitors in renal impairment report a strong linear correlation between creatine clearance and drug elimination. AUC and EC50 values for these drugs in elderly subjects appear similar to younger and hypertensive patients. There is increased AUC in some patients with hepatic impairment. Pharmacodynamic data are conflicting. Prolonged ACE inhibition is evident in renal impairment but not necessarily other disease states. ACE inhibitor dosing for hypertension is reasonable based on pharmacokinetics and EC50 values. Further individualization of therapy may improve outcomes, and using the threshold AUC/EC50 ratio may help guide appropriate dosing.
Bioavailability of Amlodipine Besylate/Atorvastatin Calcium Combination Tablet
Authors: Chung Menger , Calcagni Albert , Glue Paul , Bramson Candace
Published: August 2006

The bioequivalence of combination tablets containing amlodipine besylate/atorvastatin calcium with coadministered matching doses of amlodipine besylate and atorvastatin calcium tablets was investigated in randomized, 2‐way crossover studies in healthy volunteers (N = 126). Subjects received a single dose of the amlodipine/atorvastatin tablet or coadministered matching doses of amlodipine and atorvastatin at the highest (10/80 mg; n = 62) and lowest (5/10 mg; n = 64) dose strengths. Atorvastatin geometric mean ratios for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) for the highest and lowest dose strengths were 94.1 and 98.8, and 104.5 and 103.8, respectively. Amlodipine geometric mean ratios for Cmax and AUC for the highest and lowest dose strengths were 100.8 and 103.4, and 100 and 102.7, respectively. The 90% confidence intervals for all comparisons were within 80% to 125%, demonstrating bioequivalence for amlodipine and atorvastatin at both dose strengths. Use of amlodipine/atorvastatin combination tablets may provide a more integrated approach to treatment of cardiovascular risk.
Influence of Simulated Weightlessness on the Intramuscular and Oral Pharmacokinetics of Promethazine in 12 Human Volunteers
Authors: Gandia Peggy , Saivin Sylvie , Le‐Traon Anne Pavy , Guell Antonio , Houin Georges
Published: August 2006

The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (Cmax), time to Cmax (tmax), and area under plasma concentration versus time curve from 0 to infinity (AUCinf) were determined, and the bioequivalence was tested between bed‐rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed‐rest and ambulatory position. Simulated weightlessness did not influence the ratio AUCbed rest/AUCambulatory after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3‐fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.
Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Rivaroxaban—an Oral, Direct Factor Xa Inhibitor—Are Not Affected by Aspirin
Authors: Kubitza Dagmar , Becka Michael , Mueck Wolfgang , Zuehlsdorf Michael
Published: August 2006

Rivaroxaban (BAY 59‐7939) is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This was a randomized, 2‐way crossover study in healthy male subjects, with an aspirin run‐in period, to examine whether aspirin influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban. All treatments were well tolerated; drug‐related adverse events were mild and transient. Aspirin did not alter the effects of rivaroxaban on Factor Xa activity or clotting tests. Platelet aggregation and bleeding time were not affected by rivaroxaban, and rivaroxaban did not influence the effects of aspirin on these parameters to a clinically relevant extent. Aspirin did not affect the pharmacokinetics of rivaroxaban, including the fraction unbound. This study suggests that there is no clinically relevant interaction between rivaroxaban and aspirin and that the 2 drugs could be administered concomitantly at the doses used in this study.
Historical Traces of Hundi, Sociocultural Understanding, and Criminal Abuses of Hawala
Authors: Sharma Divya
Published: August 2006

This article presents a descriptive and exploratory analysis of informal money transfer systems like Hundi and Hawala starting with a historical account of Hundi, its decline, and re-emergence as a Hawala-like system in South Asia and the Middle East. Hawala is a consequence of a number of factors, such as poor banking infrastructure, global migration, economic crimes, and political corruption. It gained global notoriety after it was suspected that the September 11, 2001, attacks on the United States were carried out with the money that was transferred from the Middle East through Hawala. The article highlights legal, illegal, and criminal abuses of Hawala. By understanding the larger sociocultural, economic, and historical framework, the model of Hawala can be applied to other forms of informal banking that could eventually help in regulating these systems without alienating immigrant and refugee populations. The article makes use of both primary and secondary data.
Striving for Mutual Collaboration
Authors: Miller Pete
Published: August 2006

The ability to navigate complex challenges that arise when universities, schools, and communities collaborate with each other is an increasingly important characteristic for effective educational leaders to possess. This case focuses on the planning process that occurred when Mountain University and its neighboring schools and communities attempted to work together for reciprocal benefit. With its use of the work of Paulo Freire, this case can be used to develop discussion on the role of educational leaders in the development of university-school-community partnerships that are mutually dependent on the input of all participants.
Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils
Authors: Szczur Kathleen , Xu Haiming , Atkinson Simon , Zheng Yi , Filippi Marie-Dominique
Published: August 2006

Neutrophil transmigration into tissue is a multiple-step process that results from a coordinated rearrangement of the cytoskeleton and adhesion complexes. Assembly and disassembly of actin and adhesion structures dictate motility behavior, while polarity and gradient sensing provide directionality to the cell movement. Here, using mice deficient in the CDC42 regulator CDC42 GTPase-activating protein (CDC42GAP), we demonstrate that CDC42 activity separately regulates neutrophil motility and directionality. CDC42GAP–/– neutrophils showed increased motility, while directed migration was defective. Podosome-like structures present at the leading edge in wild-type neutrophils were significantly reduced in CDC42GAP–/– cells. CDC42GAP–/– neutrophils also showed increased lateral and tail filopodia-like formation, and excess membrane protrusions. We further suggest that CDC42GAP-mediated extracellular signal–regulated kinase (ERK) activity regulates motility associated with podosome-like structures at the cell leading edge, while CDC42GAP-induced p38MAPK phosphorylation regulates directed migration by antagonizing filopodia assembly. Overall, this study reveals that CDC42 activity regulates both motility and directionality in neutrophils, but via distinct mitogen-activated protein kinase (MAPK) pathways.
Inhaled steroid/long-acting β2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients
Authors: Lötvall Jan , Langley Stephen , Woodcock Ashley
Published: August 2006

Background

The combination of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide™ GSK, UK) and formoterol/budesonide (FBC, Symbicort™, AstraZeneca, UK) are commercially available.

Objectives

The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose.

Methods

Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400–1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800–1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide™ followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment.

Results

In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2–24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively

Conclusion

Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.
Rhinosinusitis derived Staphylococcal enterotoxin B plays a possible role in pathogenesis of food allergy
Authors: Liu Tao , Wang Bin-Quan , Zheng Peng-Yuan , He Shao-Heng , Yang Ping-Chang
Published: August 2006

Background

Staphylococcal enterotoxin B (SEB) is a potent immunomodulator and implicated with pathogenesis of inflammatory diseases mediated by Th1 or Th2 dominant immune responses. The objective of this study is to determine a possible association between rhinosinusitis derived SEB and pathogenesis of food allergy (FA).

Methods

The study included chronic rhinosinusitis (CRS) patients with FA (N = 46) or without FA (N = 33). Controls included FA patients without CRS (N = 26) and healthy volunteers (N = 25). In CRS patients, we assessed the parameters associated with FA including prick skin test (PST) reactivity to food allergens, serum levels of allergen-specific IgE and cytokines (IL-4, IL-13, IFN-Î3), and the number/reactivity of food-allergen specific Th1/Th2 cells in the peripheral blood before and 2 months after sinus surgery. Changes of these parameters were evaluated in comparison with changes in SEB concentration in the sinus lavage and stool samples and also in vitro reactivity to SEB. In CRS patients with FA, we also assessed changes in reactivity to oral challenge of offending food before and after sinus surgery.

Results

Two months following sinus surgery, we observed statistically significant reduction in PST and oral challenge reactivity in CRS patients with FA in parallel to decrease in serum levels of Th2 cytokines (IL-4 and IL-13) and allergen specific IgE. Improvement of reactivity to food allergens was positively associated with decline in SEB concentrations in the sinus lavage and stool samples. In vitro study results also indicated a role of SEB in aggravation of Th2 skewed responses to food allergens. Such changes were not observed in CRS-non FA patients or control FA patients.

Conclusion

The rhinosinusitis derived SEB plays a certain role in the pathogenesis of FA by augmenting and/or maintaining polarized Th2 responses. Removal of SEB-producing pathogens from the rhinosinuses may be beneficial for attenuating the FA symptoms in patients with CRS-FA.
Transactivation and signaling functions of Tat are not correlated: biological and immunological characterization of HIV-1 subtype-C Tat protein
Authors: Siddappa Nagadenahalli Byrareddy , Venkatramanan Mohanram , Venkatesh Prasanna , Janki Mohanbabu Vijayamma , Jayasuryan Narayana , Desai Anita , Ravi Vasanthapuram , Ranga Udaykumar
Published: August 2006

Background

Of the diverse subtypes of Human Immunodeficiency Virus Type-1 (HIV-1), subtype-C strains cause a large majority of infections worldwide. The reasons for the global dominance of HIV-1 subtype-C infections are not completely understood. Tat, being critical for viral infectivity and pathogenesis, may differentially modulate pathogenic properties of the viral subtypes. Biochemical studies on Tat are hampered by the limitations of the current purification protocols. Tat purified using standard protocols often is competent for transactivation activity but defective for a variety of other biological functions. Keeping this limitation in view, we developed an efficient protein purification strategy for Tat.

Results

Tat proteins obtained using the novel strategy described here were free of contaminants and retained biological functions as evaluated in a range of assays including the induction of cytokines, upregulation of chemokine coreceptor, transactivation of the viral promoter and rescue of a Tat-defective virus. Given the highly unstable nature of Tat, we evaluated the effect of the storage conditions on the biological function of Tat following purification. Tat stored in a lyophilized form retained complete biological activity regardless of the storage temperature. To understand if variations in the primary structure of Tat could influence the secondary structure of the protein and consequently its biological functions, we determined the CD spectra of subtype-C and -B Tat proteins. We demonstrate that subtype-C Tat may have a relatively higher ordered structure and be less flexible than subtype-B Tat. We show that subtype-C Tat as a protein, but not as a DNA expression vector, was consistently inferior to subtype-B Tat in a variety of biological assays. Furthermore, using ELISA, we evaluated the anti-Tat antibody titers in a large number of primary clinical samples (n = 200) collected from all four southern Indian states. Our analysis of the Indian populations demonstrated that Tat is non-immunodominant and that a large variation exists in the antigen-specific antibody titers.

Conclusion

Our report not only describes a simple protein purification strategy for Tat but also demonstrates important structural and functional differences between subtype-B and -C Tat proteins. Furthermore, this is the first report of protein purification and characterization of subtype-C Tat.
Identification and classification of human cytomegalovirus capsids in textured electron micrographs using deformed template matching
Authors: Ryner Martin , Strömberg Jan-Olov , Söderberg-Nauclér Cecilia , Homman-Loudiyi Mohammed
Published: August 2006

Background

Characterization of the structural morphology of virus particles in electron micrographs is a complex task, but desirable in connection with investigation of the maturation process and detection of changes in viral particle morphology in response to the effect of a mutation or antiviral drugs being applied. Therefore, we have here developed a procedure for describing and classifying virus particle forms in electron micrographs, based on determination of the invariant characteristics of the projection of a given virus structure. The template for the virus particle is created on the basis of information obtained from a small training set of electron micrographs and is then employed to classify and quantify similar structures of interest in an unlimited number of electron micrographs by a process of correlation.

Results

Practical application of the method is demonstrated by the ability to locate three diverse classes of virus particles in transmission electron micrographs of fibroblasts infected with human cytomegalovirus. These results show that fast screening of the total number of viral structures at different stages of maturation in a large set of electron micrographs, a task that is otherwise both time-consuming and tedious for the expert, can be accomplished rapidly and reliably with our automated procedure. Using linear deformation analysis, this novel algorithm described here can handle capsid variations such as ellipticity and furthermore allows evaluation of properties such as the size and orientation of a virus particle.

Conclusion

Our methodological procedure represents a promising objective tool for comparative studies of the intracellular assembly processes of virus particles using electron microscopy in combination with our digitized image analysis tool. An automated method for sorting and classifying virus particles at different stages of maturation will enable us to quantify virus production in all stages of the virus maturation process, not only count the number of infectious particles released from un infected cell.
Local tumor control and toxicity in HIV-associated anal carcinoma treated with radiotherapy in the era of antiretroviral therapy
Authors: Oehler-Jänne Christoph , Seifert Burkhardt , Lütolf Urs M , Ciernik I Frank
Published: August 2006

Purpose

To investigate the outcome of HIV-seropositive patients under highly active antiretroviral treatment (HAART) with anal cancer treated with radiotherapy (RT) alone or in combination with standard chemotherapy (CT).

Patients and methods

Clinical outcome of 81 HIV-seronegative patients (1988 – 2003) and 10 consecutive HIV-seropositive patients under HAART (1997 – 2003) that were treated with 3-D conformal RT of 59.4 Gy and standard 5-fluorouracil and mitomycin-C were retrospectively analysed. 10 TNM-stage and age matched HIV-seronegative patients (1992 – 2003) were compared with the 10 HIV-seropositive patients. Pattern of care, local disease control (LC), overall survival (OS), cancer-specific survival (CSS), and toxicity were assessed.

Results

RT with or without CT resulted in complete response in 100 % of HIV-seropositive patients. LC was impaired compared to matched HIV-seronegative patients after a median follow-up of 44 months (p= 0.03). OS at 5 years was 70 % in HIV-seropositive patients receiving HAART and 69 % in the matched controls. Colostomy-free survival was 70 % (HIV+) and 100 % (matched HIV-) and 78 % (all HIV-). No HIV-seropositive patient received an interstitial brachytherapy boost compared to 42 % of all HIV-seronegative patients and adherence to chemotherapy seemed to be difficult in HIV-seropositive patients. Acute hematological toxicity reaching 50 % was high in HIV-seropositive patients receiving MMC compared with 0 % in matched HIV-seronegative patients (p= 0.05) or 12 % in all HIV-seronegative patients. The rate of long-term side effects was low in HIV-seropositive patients.

Conclusion

Despite high response rates to organ preserving treatment with RT with or without CT, local tumor failure seems to be high in HIV-positive patients receiving HAART. HIV-seropositive patients are subject to treatment bias, being less likely treated with interstitial brachytherapy boost probably due to HIV-infection, and they are at risk to receive less chemotherapy.
Type I interferon production in HIV-infected patients
Authors: Hosmalin Anne , Lebon Pierre
Published: August 2006

Type I IFNs display multiple biological effects. They have a strong antiviral action, not only directly but also indirectly through activation of the immune system. They may also have actions that are deleterious for the host. The cells that produce type I IFN are mostly plasmacytoid dendritic cells (pDC), but this depends on the viral stimulus. The migration and distribution of pDC into lymphoid organs, driven by chemokine interactions with their ligands, determines interaction with different cell types. In HIV infection, IFN production in vitro is impaired during primary infection and later in association with opportunistic infections. Circulating pDC numbers are decreased in parallel. These parameters may be used to help assess the prognosis of the disease and to monitor treatment.
Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer
Authors: Kröger Nicolaus , Frick Markus , Gluz Oleg , Mohrmann Svjetlana , Metzner Bernd , Jackisch Christian , Ko Yon , Lindemann Hans-Walter , Meier Carl Richard , Lohrmann Hans Peter , Ruffert Ute , Hänel Matthias , Bodenstein Heinrich , Neubauer Andreas , Ehninger Gerhard , Wolf Hans-Heinrich , Kolbe Kathrin , Burock Karin , Zander Axel R. , Nitz Ulrike
Published: August 2006

Purpose

To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients.

Patients and Methods

Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation.

Results

One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival.

Conclusion

Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.
Influence of Hormone Replacement Therapy on Tamoxifen-Induced Vasomotor Symptoms
Authors: Sestak Ivana , Kealy Roseann , Edwards Robert , Forbes John , Cuzick Jack
Published: August 2006

Purpose

Tamoxifen is an effective drug, but its role in prevention is limited by its adverse effect profile. Non–life-threatening adverse effects, such as vasomotor symptoms, have an important influence in its use for prevention. Vasomotor symptoms were evaluated according to follow-up time, severity, and use of hormone replacement therapy (HRT) in a retrospective analysis.

Patients and Methods

In the International Breast Cancer Intervention Study-I study, 7,154 women at increased risk of breast cancer were randomly assigned to either tamoxifen 20 mg/d or placebo for 5 years. Women gave detailed information on any vasomotor symptoms at each 6-month follow-up visit.

Results

Hot flushes were reported more often in the tamoxifen group than in the placebo group (70.6% v 57.1%, respectively; odds ratio, 1.80; 95% CI, 1.63 to 1.99). Severe hot flushes were more strongly related to tamoxifen. In the tamoxifen arm, more women taking HRT at entry experienced hot flushes in the first 6 months than those who did not take HRT (60.8% v 49.2%, respectively; P = .09). In contrast, women on placebo taking HRT at entry experienced fewer hot flushes than women who stopped HRT (22.9% v 34.3%, respectively; P = .03). Furthermore, for women who first began HRT in the first 6 months of the trial compared with women who did not begin HRT, HRT seemed to be much more effective in controlling hot flushes in months 6 to 12 in the placebo arm (47.9% v 20.4%, respectively) than in the tamoxifen arm (51.4% v 39.0%, respectively).

Conclusion

HRT use at entry or during the trial was not effective in alleviating hot flushes for women in the tamoxifen arm. Our retrospective study suggests that estrogen-based HRT has limited effectiveness among women receiving tamoxifen.
Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared With Gemcitabine Alone in Advanced Pancreatic Cancer
Authors: Heinemann Volker , Quietzsch Detlef , Gieseler Frank , Gonnermann Michael , Schönekäs Herbert , Rost Andreas , Neuhaus Horst , Haag Caroline , Clemens Michael , Heinrich Bernard , Vehling-Kaiser Ursula , Fuchs Martin , Fleckenstein Doris , Gesierich Wolfgang , Uthgenannt Dirk , Einsele Hermann , Holstege Axel , Hinke Axel , Schalhorn Andreas , Wilkowski Ralf
Published: August 2006

Purpose

To compare the effectiveness and tolerability of gemcitabine plus cisplatin with single-agent gemcitabine as first-line chemotherapy for locally advanced or metastatic pancreatic cancer.

Patients and Methods

Patients with advanced adenocarcinoma of the pancreas were randomly assigned to receive either gemcitabine 1,000 mg/m2 and cisplatin 50 mg/m2 given on days 1 and 15 of a 4-week cycle (GemCis arm) or gemcitabine alone at a dose of 1,000 mg/m2 on days 1, 8, and 15 of a 4-week regimen (Gem arm). The primary end point was overall survival; secondary end points were progression-free survival, response rate, safety, and quality of life.

Results

One hundred ninety-five patients were enrolled and showed baseline characteristics well balanced between treatment arms. Combination treatment in the GemCis arm was associated with a prolonged median progression-free survival (5.3 months v 3.1 months; hazard ratio [HR] = 0.75; P = .053). Also, median overall survival was superior for patients treated in the GemCis arm as compared with the Gem arm (7.5 v 6.0 months), an advantage which did not, however, reach statistical significance (HR = 0.80; P = .15). Tumor response rates were comparable between treatment arms (10.2% v 8.2%). The rate of stable disease was, however, greater in the combination arm (60.2% v 40.2%; P < .001). Grade 3 to 4 hematologic toxicity did not exceed 15% in both treatment arms.

Conclusion

These results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin. Median overall survival and progression-free survival were more favorable in the combination arm as compared with gemcitabine alone, although the difference did not attain statistical significance.
Symptom Improvement in Lung Cancer Patients Treated With Erlotinib: Quality of Life Analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21
Authors: Bezjak Andrea , Tu Dongsheng , Seymour Lesley , Clark Gary , Trajkovic Aleksandra , Zukin Mauro , Ayoub Joseph , Lago Sergio , de Albuquerque Ribeiro Ronaldo , Gerogianni Alexandra , Cyjon Arnold , Noble Jonathan , Laberge Francis , Chan Raymond Tsz-Tong , Fenton David , von Pawel Joachim , Reck Martin , Shepherd Frances A.
Published: August 2006

Purpose

This report describes the quality of life (QOL) findings of a randomized placebo controlled study of erlotinib, an epidermal growth factor receptor inhibitor, in patients with non–small-cell lung cancer (NSCLC).

Patients and Methods

This double-blind phase III trial randomly assigned 731 patients with NSCLC who had progressed after prior chemotherapy to erlotinib 150 mg daily or placebo, with survival as the primary study outcome. QOL was assessed by European Organisation for Research and Treatment of Cancer QLQ-C30 and the lung cancer module QLQ-LC13. The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea, and pain.

Results

Survival was significantly longer (hazard ratio, 0.70; P < .0001) in the erlotinib arm. Compliance with QOL was 87% at baseline and more than 70% during treatment. Patients receiving erlotinib had significantly longer median time to deterioration for all three symptoms (4.9 v 3.7 months for cough [P = .04]; 4.7 v 2.9 months for dyspnea [P = .04], and 2.8 v 1.9 months for pain [P = .03]). QOL response analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by a significant improvement in the physical function (31% erlotinib v 19% placebo, P = .01), and global QOL (35% v 26%, P < .0001). Patients with complete or partial response were more likely to have improvement in the QOL response than patients with stable or progressive disease (P < .01).

Conclusion

Erlotinib not only improves survival in previously treated patients with NSCLC, but also improves tumor-related symptoms and important aspects of QOL.
Shaping Your Career to Maximize Personal Satisfaction in the Practice of Oncology
Authors: Shanafelt Tait , Chung Harold , White Heather , Lyckholm Laurie Jean
Published: August 2006

The practice of oncology can be a source of both great satisfaction and great stress. Although many oncologists experience burnout, depression, and dissatisfaction with work, others experience tremendous career satisfaction and achieve a high overall quality of life. Identifying professional goals, optimizing career fit, identifying and managing stressors specific to practice type, and achieving the optimal personal work–life balance can increase the likelihood of individual oncologists' achieving personal and professional satisfaction. In this article, we will explore how oncologists can accomplish these tasks and will examine several pervasive professional myths that often distort perspective. The article concludes in a conversation with four oncologists regarding what they find most meaningful about their work, how they manage career-specific stressors, and how they achieve balance between their personal and professional lives.
Comparison of Long-Term Neurocognitive Outcomes in Young Children With Acute Lymphoblastic Leukemia Treated With Cranial Radiation or High-Dose or Very High-Dose Intravenous Methotrexate
Authors: Spiegler Brenda J. , Kennedy Kimberly , Maze Ronnen , Greenberg Mark L. , Weitzman Sheila , Hitzler Johann K. , Nathan Paul C.
Published: August 2006

Purpose

Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established.

Patients and Methods

Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 × 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory.

Results

Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures.

Conclusion

Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.
Lack of Benefit of Maintenance Paclitaxel in First-Line Chemotherapy in Metastatic Breast Cancer
Authors: Gennari Alessandra , Amadori Dino , De Lena Mario , Nanni Oriana , Bruzzi Paolo , Lorusso Vito , Manzione Luigi , Conte Pier Franco
Published: August 2006

Purpose

This randomized study compared maintenance paclitaxel with control in metastatic breast cancer patients not experiencing progression after first-line anthracycline/paclitaxel combination chemotherapy.

Methods

Between April 1998 and October 2003, 459 metastatic breast cancer patients received first-line combination chemotherapy with epirubicin or doxorubicin plus paclitaxel. Of these, 255 who had a response or stable disease were then randomly assigned onto the Maintenance Paclitaxel 1 (MANTA1) study, comparing eight courses of maintenance paclitaxel versus control (ie, no additional chemotherapy administration). The primary end point was progression-free survival.

Results

The study was prematurely concluded after a futility analysis, which was performed on 215 of the 238 patients randomly assigned within December 2002. Of these, 109 patients were assigned to maintenance paclitaxel and 106 were assigned to stopping chemotherapy. No significant difference in median progression-free survival was observed (8.0 months for maintenance paclitaxel and 9.0 months for control). There was no significant difference in median survival time (28.0 v 29.0 months). When the Bayesian method for monitoring clinical trials was applied to these data, even under an enthusiastic prior distribution, in the posterior distribution there was only an 8.6% chance of observing a 3-month improvement in median progression-free survival in the group receiving maintenance paclitaxel. After these results study accrual was closed.

Conclusion

Compared with control, the administration of additional courses of paclitaxel in patients who achieve disease control after six to eight courses of first-line anthracycline plus paclitaxel combination chemotherapy does not improve progression-free survival.
The Aminoterminal Insulin-Like Growth Factor (IGF) Binding Domain of IGF Binding Protein-3 Cannot Be Functionally Substituted by the Structurally Homologous Domain of CCN3
Authors: Yan Xiaolang , Baxter Robert C. , Perbal Bernard , Firth Sue M.
Published: August 2006

IGF binding proteins (IGFBPs) are a family of structurally homologous proteins that bind IGFs with high affinities and can modulate IGF activity. The IGF binding site has been shown to comprise residues in both the aminoterminal and carboxyterminal domains. In recent years several proteins including members of the CCN (connective tissue growth factor, Cyr61, and nephroblastoma overexpressed) family were recognized as having structural homology in their aminoterminal domains to the IGFBPs. Despite their low or undetectable IGF binding ability, a proposal was made to rename them as IGFBP-related proteins. To test whether the aminoterminal domain of a CCN protein can fulfill the high-affinity IGF binding function of an IGFBP, we created a chimera in which the aminoterminal domain of IGFBP-3 was substituted with the aminoterminal domain of CCN3 (previously known as Nov). The CCN3-IGFBP-3 chimera bound IGFs and inhibited IGF activity very weakly, similar to CCN3 itself. Although structurally similar, the aminoterminal domain of CCN3 is unable to replace the aminoterminal domain of IGFBP-3 in forming a high-affinity IGF-binding site. These results argue against a direct role of CCN3 in the regulation of IGF bioavailability and indicate that the nomenclature of IGFBP-related proteins (which implies functional relationship to the classical IGFBPs) is inappropriate for CCN proteins.
Phosphoinositide-Specific Inositol Polyphosphate 5-Phosphatase IV Inhibits Inositide Trisphosphate Accumulation in Hypothalamus and Regulates Food Intake and Body Weight
Authors: Bertelli Daniela F. , Araújo Eliana P. , Cesquini Maristela , Stoppa Graziela R. , Gasparotto-Contessotto Miriam , Toyama Marcos H. , Felix Jorge V. C. , Carvalheira José B. , Michelini Lisete C. , Chiavegatto Silvana , Boschero Antonio C. , Saad Mario J. A. , Lopes-Cendes Iscia , Velloso Licio A.
Published: August 2006

The enzyme phosphatidylinositol 3-kinase (PI3-kinase) exerts an important role in the transduction of the anorexigenic and thermogenic signals delivered by insulin and leptin to first-order neurons of the arcuate nucleus in the hypothalamus. The termination of the intracellular signals generated by the activation of PI3-kinase depends on the coordinated activity of specific inositol phosphatases. Here we show that phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) is highly expressed in neurons of the arcuate and lateral nuclei of the hypothalamus. Upon intracerebroventricular (ICV) treatment with insulin, 5ptase IV undergoes a time-dependent tyrosine phosphorylation, which follows the same patterns of canonical insulin signaling through the insulin receptor, insulin receptor substrate-2, and PI3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we used a phosphorthioate-modified antisense oligonucleotide specific for this enzyme. The treatment of rats with this oligonucleotide for 4 d reduced the hypothalamic expression of 5ptase IV by approximately 80%. This was accompanied by an approximately 70% reduction of insulin-induced tyrosine phosphorylation of 5ptase IV and an increase in basal accumulation of phosphorylated inositols in the hypothalamus. Finally, inhibition of hypothalamic 5ptase IV expression by the antisense approach resulted in reduced daily food intake and body weight loss. Thus, 5ptase IV is a powerful regulator of signaling through PI3-kinase in hypothalamus and may become an interesting target for therapeutics of obesity and related disorders.
Regulation of the RAP1/RAF-1/Extracellularly Regulated Kinase-1/2 Cascade and Prolactin Release by the Phosphoinositide 3-Kinase/AKT Pathway in Pituitary Cells
Authors: Romano David , Pertuit Morgane , Rasolonjanahary Ramahefarizo , Barnier Jean-Vianney , Magalon Karine , Enjalbert Alain , Gerard Corinne
Published: August 2006

In pituitary cells, prolactin (PRL) synthesis and release are controlled by multiple transduction pathways. In the GH4C1 somatolactotroph cell line, we previously reported that MAPK ERK-1/2 are a point of convergence between the pathways involved in the PRL gene regulation. In the present study, we focused on the involvement of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the MAPK ERK-1/2 regulation and PRL secretion in pituitary cells. Either specific pharmacological PI3K and Akt inhibitors (LY294002, Akt I, and phosphoinositide analog-6) or Akt dominant-negative mutant (K179M) enhanced ERK-1/2 phosphorylation in unstimulated GH4C1 cells. Under the same conditions, PI3K and Akt inhibition also both increased Raf-1 kinase activity and the levels of GTP-bound (active form) monomeric G protein Rap1, which suggests that a down-regulation of the ERK-1/2 cascade is induced by the PI3K/Akt signaling pathway in unstimulated cells. On the contrary, ERK-1/2 phosphorylation, Raf-1 activity, and Rap1 activation were almost completely blocked in IGF-I-stimulated cells previously subjected to PI3K or Akt inhibition. Although the PRL promoter was not affected by either PI3K/Akt inhibition or activation, PRL release increased in response to the pharmacological PI3K/Akt inhibitors in unstimulated GH4C1 and rat pituitary primary cells. The IGF-I-stimulated PRL secretion was diminished, on the contrary, by the pharmacological PI3K/Akt inhibitors. Taken together, these findings indicate that the PI3K/Akt pathway exerts dual regulatory effects on both the Rap1/Raf-1/ERK-1/2 cascade and PRL release in pituitary cells, i.e. negative effects in unstimulated cells and positive ones in IGF-I-stimulated cells.
Metabolic Activation of Glucose Low-Responsive β-Cells by Glyceraldehyde Correlates with Their Biosynthetic Activation in Lower Glucose Concentration Range But Not at High Glucose
Authors: Martens G. A. , Wang Q. , Kerckhofs K. , Stangé G. , Ling Z. , Pipeleers D.
Published: August 2006

Insulin synthesis and release activities of β-cells can be acutely regulated by glucose through its glycolytic and mitochondrial breakdown involving a glucokinase-dependent rate-limiting step. Isolated β-cell populations are composed of cells with intercellular differences in acute glucose responsiveness that have been attributed to differences in glucokinase (GK) expression and activity. This study first shows that glyceraldehyde can be used as GK-bypassing oxidative substrate and then examines whether the triose can metabolically activate β-cells with low glucose responsiveness. Glyceraldehyde 1 mm induced a similar cellular 14CO2 output and metabolic redox state as glucose 4 mm. Using flow cytometric analysis, glyceraldehyde (0.25–2 mm) was shown to concentration-dependently increase the percent metabolically activated cells at all tested glucose concentrations (2.5–20 mm). Its ability to activate β-cells that are unresponsive to the prevailing glucose level was further illustrated in glucose low-responsive cells that were isolated by flow sorting. Metabolic activation by glyceraldehyde was associated with an activation of nutrient-driven translational control proteins and an increased protein synthetic response to glucose, however not beyond the maximal rates that are inducible by glucose alone. It is concluded that glucose low-responsive β-cells can be metabolically activated by the GK-bypassing glyceraldehyde, increasing their acute biosynthetic response to glucose but not their maximal glucose-inducible biosynthetic capacity, which is considered subject to chronic regulation.