bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of PAF-induced expression of CD11b and shedding of L-selectin on human neutrophils and eosinophils by the type IV selective PDE inhibitor, rolipram
Authors: Berends C , Dijkhuizen B , de Monchy JG , Dubois AE , Gerritsen J , Kauffman HF
Published: February 2003

We quantitatively determined whether the selective phosphodiesterase (PDE) inhibitor, rolipram, inhibits changes in the adhesion molecules CD11b and L-selectin on platelet-activating factor (PAF)-stimulated human neutrophils and eosinophils in vitro. Incubations were performed in human whole blood obtained from healthy volunteers, to restrict activation by purification procedures and to simulate in vivo conditions, in which different cell types may interact, more closely. Receptor expression was measured after fixation of cells, using monoclonal antibodies and flow cytometry. Concentration-dependent inhibition of the PAF-induced CD11b expression and L-selectin shedding for neutrophils and eosinophils was observed with rolipram, dibutyryl cyclic adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), and isoproterenol. However, these inhibitions did not exceed 50%. Preincubation with rolipram (10(-8) M) and subsequent incubation with isoproterenol (0.5x10(-8) M) or PGE2 (10(-8) M) induced a cumulative, but not synergistic, effect. Using the combination of rolipram with isoproterenol or PGE2, inhibition of PAF-induced L-selectin shedding from eosinophils was as high as 71+/-28 and 67+/-21%, respectively. Other inhibitions were below 50%. In conclusion, rolipram inhibits CD11b expression and L-selectin shedding of platelet-activating factor-stimulated neutrophils and eosinophils in whole blood in a concentration-dependent fashion. Inhibitions did not exceed 50%, even at high concentrations. The inhibition of platelet-activating factor induced shedding of L-selectin from eosinophils with a combination of rolipram and prostaglandin E2 or isoproterenol, however, was found to be approximately 70%. Inhibition of rolling adhesion of eosinophils may, therefore, be a mode of action of type IV phosphodiesterase inhibitors.
Bronchial and skin reactivity in asthmatic patients with and without atopic dermatitis
Authors: Brinkman L , Raaijmakers JA , Bruijnzeel-Koomen CA , Koenderman L , Lammers JW
Published: February 2003

It is unclear whether the presence and severity of atopic dermatitis (AD) is predictive for the occurrence and severity of early and late asthmatic responses to inhaled allergens. The aim of this study was to compare the bronchial effects of allergen inhalation challenge in allergic asthma (AA) and atopic dermatitis. We therefore studied these responses in: nine patients with mild-to-moderate AA without AD; eight patients with mild-to-moderate AA and mild AD; eight patients with severe AD and mild AA; and eight patients with severe AD without AA. Allergen challenge was performed by inhaling doubling doses until the dose provoking a 20% fall in forced expiratory volume in one second (PC20) was reached. The late asthmatic reaction (LAR) was defined as a fall of >20% in peak expiratory flow (PEF) between 3 and 8 h after the challenge. All but four of the patients with severe AD without AA developed an early asthmatic response (EAR). A LAR was seen in all patients with severe AD and mild AA, in four patients with mild AD and mild-to-moderate AA, and in three patients with mild-to-moderate AA without AD. The LAR was most pronounced in patients with a combination of mild AA and severe AD. This could be explained, in part, by a decreased skin sensitivity in these patients, which made the Cockcroft formula for prediction of PC20 allergen less accurate in such patients. We conclude that patients with severe atopic dermatitis and mild asthma are at risk for developing pronounced late asthmatic responses after allergen exposure. This suggests that eosinophils activated in atopic dermatitis also predispose to airway inflammation.
Perception of airway narrowing in a general population sample
Authors: Salome CM , Xuan W , Gray EJ , Belooussova E , Peat JK
Published: February 2003

In epidemiological studies, defining asthma as the presence of airway hyperresponsiveness (AHR) plus recent symptoms leaves two groups of subjects whose clinical significance is unclear: those with asymptomatic AHR, and those with symptoms only. The aim of the study was to determine whether subjects with symptoms only differ from the normal and asthmatic groups in the perception of airway obstruction. Six hundred and ninety seven adults completed a questionnaire of symptoms and underwent bronchial challenge with histamine to induce airway obstruction. Recent symptoms included wheeze and morning chest tightness in the last 12 months. AHR was defined as a provoking dose of histamine causing > or = 20% fall in forced expiratory volume in one second (PD20FEV1) <3.9 micromol. At the end of the challenge test, subjects who felt wheezy or tight in the chest marked a value from 0 to 10 on a modified Borg scale, to describe the severity of the sensation. Subjects with asymptomatic AHR did not differ significantly from subjects with AHR plus recent symptoms (current asthma) either in the mean fall in FEV1 or in the median Borg score. In subjects with symptoms only, the mean Borg score was not significantly different from that of the asthmatic subjects, although mean fall in FEV1 differed significantly (p<0.0001). In subjects with symptoms only, chest tightness correlated significantly with the fall in forced vital capacity (FVC) (p= 0.011), but not with the fall in FEV1. Subjects with asymptomatic airways hyperresponsiveness were not poor perceivers of airway narrowing, but may underreport their symptoms. Subjects with symptoms only may have enhanced perception of small changes in lung function, particularly in forced vital capacity.
Breathing pattern during bronchial challenge in humans
Authors: Meessen NE , van der Grinten CP , Luijendijk SC , Folgering HT
Published: February 2003

Increases in minute ventilation (V'E) have been observed during exacerbations of asthma and in response to administration of histamine. However, it is not yet clear how the breathing pattern is affected, and whether the increase in V'E is found in general. In the present study, the effects of inhalation of histamine on respiratory frequency (fR), tidal volume (VT), V'E, and on functional residual capacity (FRC) were evaluated in 63 humans. Forty four subjects were hyperresponsive (BHR+). In each of these subjects, the doses of histamine applied for the present study (mean 3.5 mg x mL(-1)) caused a decrease in forced expiratory volume in one second (FEV1) that was greater than 20% of the control value. The dose of histamine applied in the 19 nonhyperresponsive subjects (BHR-) was substantially larger (8.0 mg x mL(-1)) whilst for this dose the decrease in FEV1 was less than 20% of control value. After histamine, fR was significantly increased in both subgroups of subjects, BHR+ and BHR-. The increase in V'E was significant in BHR- but not significant in BHR+. In general, the changes in V'E,fR and VT were not uniform; comparable numbers of subjects responded with increases (n=33) and decreases (n=30) in V'E. For fR 40 subjects responded with an increase and 23 with a decrease, and for VT these numbers were 26 and 37, respectively. The increase in FRC after histamine was significantly larger in BHR+ subjects than in BHR-. These findings may be interpreted to indicate that different mechanisms with opposite effects may be operating simultaneously, e.g. excitation of central inspiratory activity by stimulation of rapidly-adapting pulmonary stretch receptors, which will promote increases in respiratory frequency, tidal volume and minute ventilation, and bronchoconstriction with increased airway resistance, which will promote decreases in these parameters. As a consequence, depending on the net result of these opposite contributions to, e.g. minute ventilation, administration of histamine will cause an increase in minute ventilation in one subject and a decrease in another.
Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project
Authors: Anderson HR , Spix C , Medina S , Schouten JP , Castellsague J , Rossi G , Zmirou D , Touloumi G , Wojtyniak B , Ponka A , Bacharova L , Schwartz J , Katsouyanni K
Published: February 2003

We investigated the short-term effects of air pollution on hospital admissions for chronic obstructive pulmonary disease (COPD) in Europe. As part of a European project (Air Pollution and Health, a European Approach (APHEA)), we analysed data from the cities of Amsterdam, Barcelona, London, Milan, Paris and Rotterdam, using a standardized approach to data eligibility and statistical analysis. Relative risks for daily COPD admissions were obtained using Poisson regression, controlling for: seasonal and other cycles; influenza epidemics; day of the week; temperature; humidity and autocorrelation. Summary effects for each pollutant were estimated as the mean of each city's regression coefficients weighted by the inverse of the variance, allowing for additional between-cities variance, as necessary. For all ages, the relative risks (95% confidence limits (95% CL)) for a 50 microg x m(-3) increase in daily mean level of pollutant (lagged 1-3 days) were (95% CL): sulphur dioxide 1.02 (0.98, 1.06); black smoke 1.04 (1.01, 1.06); total suspended particulates 1.02 (1.00, 1.05), nitrogen dioxide 1.02 (1.00, 1.05) and ozone (8 h) 1.04 (1.02, 1.07). The results confirm that air pollution is associated with daily admissions for chronic obstructive pulmonary disease in European cities with widely varying climates. The results for particles and ozone are broadly consistent with those from North America, though the coefficients for particles are substantially smaller. Overall, the evidence points to a causal relationship but the mechanisms of action, exposure response relationships and pollutant interactions remain unclear.
Chronic respiratory disease morbidity in construction workers: patterns and prognostic significance for permanent disability and overall mortality
Authors: Rothenbacher D , Arndt V , Fraisse E , Daniel U , Fliedner TM , Brenner H
Published: February 2003

The aim of this study was to determine chronic respiratory disease morbidity in construction workers, and to assess the prognostic value of various morbidity measures on permanent disability and on all-cause mortality. Subjects in this analysis were male employees in the German construction industry, aged 40-64 yrs, who were examined by the occupational health service between August 1986 and December 1988. Prevalence of respiratory disorders as characterized by: 1) pathological findings on lung auscultation; 2) reduced forced expiratory volume in one second (FEV1); and 3) a medical diagnosis of chronic respiratory disease (International Classification of Diseases 9th revision (ICD-9) 490496) was assessed among occupational groups of construction workers, and compared with prevalence among white-collar employees. Active follow-up was conducted between October 1992 and July 1994 to ascertain working and life status (completeness: 92 and 96%, respectively). The prognostic value of the morbidity measures on permanent disability and on all-cause mortality was assessed using the Cox proportional hazards model. In the entire cohort, crude prevalence was 7.6% for pathological findings on lung auscultation, 8.8% for a reduced FEV1 (<70% of predicted value), and 6.1% for a recorded diagnosis of chronic respiratory disease. There was strong variation of prevalence with age, smoking status and, less clearly, occupation. The relative risk for permanent disability varied between 1.9 and 3.2, and for mortality between 2.0 and 2.9, respectively, when men with the various measures of bronchopulmonary disorders were compared with other men. The morbidity measures utilized allow the identification of employees at higher risk of disability and death, and this may facilitate targeting of specific prevention and rehabilitation measures.
Nasal potential difference in cystic fibrosis patients presenting borderline sweat test
Authors: Delmarco A , Pradal U , Cabrini G , Bonizzato A , Mastella G
Published: February 2003

The diagnosis of cystic fibrosis (CF) can be difficult if the sweat test and routine deoxyribonucleic acid (DNA) analysis are inconclusive. Under these circumstances, measurement of nasal potential difference (NPD) was proposed as a complementary diagnostic tool, as demonstrated in subjects bearing the G551S or 3849+10KbC-->T mutations. The purpose of the present study was to verify the diagnostic value of this technique in CF patients with a borderline sweat test. NPD was measured in 18 patients with a borderline sweat test, in whom CF diagnosis was based on the presence of one CF gene mutation in each chromosome (CF borderline). These patients were compared both to non-CF controls and CF patients with an abnormal sweat test (CF controls). Basal NPD values of CF borderline patients (mean value -39+/-6 mV, range -29 to -52 mV; n=18) were in the pathological range of CF controls (-39+/-8 mV, range -28 to -57 mV; n=37), and both were statistically different from values obtained in non-CF controls (-15+/-4 mV, range -6 to -23 mV; n=24; p<0.0001). Mutation analysis confirmed a high frequency of the 3849+10KbC-->T mutation in this group of CF borderline patients (positive in 14 out of 18 subjects), whereas other mutations, such as AF508, Q552X, N1303K and R1162X, were also found to be associated with this atypical CF phenotype. These results confirm the presence of pathological values of basal NPD in CF patients with borderline sweat test, and also extend this finding to subjects bearing genotypes other than the G551S and 3849+10KbC-->T mutations. The present findings, therefore, confirm the usefulness of measurement of basal nasal potential difference in all those patients in whom diagnosis of cystic fibrosis can be suspected but the sweat test remains inconclusive.
Parapneumonic effusion and empyema
Authors: Hamm H , Light RW
Published: February 2003

Parapneumonic effusions account for about one third of all pleural effusions. Approximately 40% of patients with pneumonia develop a concomitant effusion, which is associated with an increased morbidity and mortality. In order to select the most appropriate therapy for the individual patient, the effusion should be categorized as being in the exudative, fibropurulent, or organizational stage, and all necessary information should be compiled to decide whether the effusion is likely to take an uncomplicated or a complicated course. There is a considerable variation in the aggressiveness and course of parapneumonic effusions, and, therefore, the spectrum of the appropriate therapy may vary from a conservative approach in uncomplicated effusions to aggressive surgical intervention in advanced multiloculated empyemas. This review discusses current diagnostic and therapeutic options and offers guidelines for treating the various stages of parapneumonic effusions and empyemas.
Comparison of guidelines and self-management plans in asthma
Authors: Meijer RJ , Kerstjens HA , Postma DS
Published: February 2003

Since the rise in asthma mortality and morbidity, many guidelines and self-management plans have been published. Many of these guidelines and self-management plans are not, however, based on results of previous studies but on the opinion of experts. We compared the five most frequently cited asthma guidelines concerning treatment steps and self-management plans with special regard to peak expiratory flow (PEF)-guided plans in asthma. We also compared results of published studies with asthma-management in the context of the guidelines. Classification of asthma severity differed considerably between the guidelines. This was also true for PEF-guided patient self-management plans. Although there was agreement on the type of drug to be used, guidelines varied with respect to when to use the drug, the "best" strategy to increase the dose, and the maximum dose. The studies available on self-management do not make it possible to determine which part of the programme is most important or cost-effective. The latter is an important issue.
Bronchial vascular congestion and angiogenesis
Authors: Charan NB , Baile EM , Pare PD
Published: February 2003

The bronchial vasculature is the systemic arterial blood supply to the lung. Although small relative to the pulmonary blood flow, the bronchial vasculature serves important functions and is modified in a variety of pulmonary and airway diseases. Congestion of the bronchial vasculature may narrow the airway lumen in inflammatory airway diseases, and formation of new bronchial vessels (angiogenesis) is implicated in the pathology of a variety of chronic inflammatory, infectious and ischaemic pulmonary diseases. The remarkable ability of the bronchial vasculature to remodel has implications for disease pathogenesis. The contributions of the bronchial vasculature to the pathogenesis of pulmonary disease are reviewed in this article.
Bronchial Kaposi's sarcoma after single lung transplantation
Authors: Sleiman C , Mal H , Roue C , Groussard O , Baldeyrou P , Olivier P , Fournier M , Pariente R
Published: February 2003

Kaposi's sarcoma (KS) has been reported in 6% of malignancies of solid organ transplant recipients. Most of the observations have been in recipients of renal allografts but, so far, KS has not been described in lung transplantation. We report a case of bronchial KS occurring in a black patient 6 months after single lung-transplantation. Skin lesions were absent and, interestingly, KS lesions were observed solely in the trachea and the native lung. Following reduction of the immunosuppressive regimen a complete remission was obtained 1 year later. Up to the present time, this clinical remission is very encouraging, but close surveillance remains necessary to detect rejection episodes or the reappearance of KS following manipulation of the immunosuppressive therapy.
Bronchiolitis obliterans organizing pneumonia in three children with acute leukaemias treated with cytosine arabinoside and anthracyclines
Authors: Battistini E , Dini G , Savioli C , Morando A , Gandolfo A , Kotitsa Z , Garaventa A , Rossi GA
Published: February 2003

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinicopathological entity with well-defined diagnostic criteria, which can be idiopathic or produced by a variety of biological processes. We describe the occurrence of BOOP in three children, one with acute lymphoblastic leukaemia and two with acute promyelocytic leukaemia. In the three patients, BOOP developed 10-20 days after a course of therapy with cytosine arabinoside and anthracyclines. The possible relationships between the small conducting airway lesions, lung toxic reaction to the drugs and/or nonidentified infectious agents are discussed.
Design and tuning of valve position controllers with industrial applications
Authors: Allison Bruce J. , Ogawa Shiro
Published: February 2003

Mid-ranging refers to control problems where there are two manipulated inputs and only one output to control. Most mid-ranging controllers in industrial use today are based on the valve position control concept. Presently, design and tuning of valve position control schemes is largely done ad hoc. As a result, much time is spent devising control strategies that may work well in one application, but not nearly so well in another. To address this problem, we set out to devise a systematic approach to the design and tuning of valve position controllers. The new method was tested in simulation, and pilot plant and paper mill examples were used to demonstrate the performance of the method in several real-life applications. Overall, the proposed design was able to reject disturbances quicker and mid-range faster, and with less oscillation than conventional schemes. This approach may be applied to virtually any mid-ranging control application and is easily implemented on any distributed control system.
A discrete double-controller scheme for delayed processes with both load and set-point disturbances
Authors: Guo Bingjun , Jutan Arthur
Published: February 2003

Using a double-controller strategy and a design approach related to Dahlin’s controller, a new sampled data control scheme is presented that is suitable for handling both set-point change and load disturbances. This control scheme has two controllers, a set-point controller and a load controller, which result in the separation of the load response from the set-point response in a closed-loop system. These two controllers can be designed independently to achieve good system performance for both set-point tracking and load rejection. The control scheme is applicable to processes that can be approximated by first-order plus time delay dynamics. For set-point changes, the set-point controller is a generalized Dahlin controller that has an extra tuning parameter TLC and has more ‘exibility and more robustness than Dahlin’s controller. For load disturbances, the load controller is also a generalized Dahlin controller and shows a significant improvement over the performance of Dahlin’s controller. The new double-controller scheme also alleviates a difficult compromise that the generalized Dahlin controller makes between the set-point tracking performance and load rejection performance. A simulation study is used to evaluate the performance of this new double-controller scheme in the presence of noise and model errors, and to compare it to Dahlin’s controller and the generalized Dahlin controller. The results show that the proposed double-controller scheme is superior to both Dahlin’s controller and the generalized Dahlin controller.
Randomized, Multicenter, Phase II Trial of Two Multicomponent Regimens in Androgen-Independent Prostate Cancer
Authors: Millikan Randall , Thall Peter F. , Lee Sang-Joon , Jones Donnah , Cannon M.W. , Kuebler J. Phillip , Wade James , Logothetis Christopher J.
Published: February 2003

Purpose: Several multicomponent regimens have been reported to be useful in advanced androgen-independent prostate cancer. We used a randomized phase II design to evaluate and compare two such regimens. Patients were accrued primarily in the community setting.

Patients and Methods: Patients with progressive, androgen-independent prostate cancer were randomly assigned to one of two treatments: either ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide (TEE). Patients were prospectively stratified on the basis of disease volume. The primary end points were response and overall survival time.

Results: A total of 75 patients were registered; 71 are included in the analysis. By the criterion of an 80% prostate-specific antigen reduction maintained for at least 8 weeks, 11 (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI], 10.5 to 21.2 months) in the TEE arm and 23.4 months (95% CI, 12.9 to 30.6 months) for patients treated with KA/VE. Many patients (24%) failed to complete at least 6 weeks of therapy, including five (8%) treatment-related early deaths.

Conclusion: Each of these regimens produced clinically significant responses, and the observed median survival (18.9 months for all 71 patients) compares favorably with previously published results, especially in the community setting. Nonetheless, it is apparent that these first-generation regimens must be applied judiciously, and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting.
Lung Cancer Risk Reduction After Smoking Cessation: Observations From a Prospective Cohort of Women
Authors: Ebbert J.O. , Yang P. , Vachon C.M. , Vierkant R.A. , Cerhan J.R. , Folsom A.R. , Sellers T.A.
Published: February 2003

Purpose: We conducted this study because the duration of excess lung cancer risk among former smokers has been inconsistently reported, doubt has been raised regarding the population impact of smoking cessation, and differential risk reduction by histologic cell type after smoking cessation needs to be confirmed.

Methods: The Iowa Women’s Health Study is a prospective cohort study of 41,836 Iowa women aged 55 to 69 years. In 1986, mailed questionnaires were used to collect detailed smoking history. Age-adjusted lung cancer incidence through 1999 was analyzed according to years of smoking abstinence. Relative risks were estimated using Cox regression analysis.

Results: There were 37,078 women in the analytic cohort. Compared with the never smokers, former smokers had an elevated lung cancer risk (relative risk, 6.6; 95% confidence interval, 5.0 to 8.7) up to 30 years after smoking cessation for all former smokers. However, a beneficial effect of smoking cessation was observed among recent and distant former smokers. The risk of adenocarcinoma remained elevated up to 30 years for both former heavier and former lighter smokers.

Conclusion: The risk for lung cancer is increased for both current and former smokers compared with never smokers and declines for former smokers with increasing duration of abstinence. The decline in excess lung cancer risk among former smokers is prolonged compared with other studies, especially for adenocarcinoma and for heavy smokers, suggesting that more emphasis should be placed on smoking prevention and lung cancer chemoprevention.
Impact of Smoking on Cancer Stage at Diagnosis
Authors: Kobrinsky Nathan L. , Klug Marilyn G. , Hokanson Peggy Jo , Sjolander Diane E. , Burd Larry
Published: February 2003

Background: Studies evaluating the relationship between smoking and cancer spread are limited.

Methods: We studied the relationship between cancer stage at diagnosis (local, regional, or metastatic) and smoking history (current, previous, or nonsmoker). For lung cancer, patterns of spread were also studied.

Results: In a tumor registry for eastern North Dakota, northwestern Minnesota, and northern South Dakota, 11,716 cases were identified from 1986 to 2001. Current smokers (relative risk [RR], 2.11; 95% confidence interval, 1.93 to 2.32; P < .001) and previous smokers (RR, 1.56; 95% confidence interval, 1.42 to 1.72; P < .001) had an increased risk of metastatic disease at diagnosis. Current smokers (RR, 1.39; 95% confidence interval, 1.29 to 1.51; P < .001), but not previous smokers, also had an increased risk of regional disease. An increase in metastatic disease was most evident for prostate cancer (RR, 1.53; P = .003). An increase in regional disease was most evident for head and neck (RR, 3.53; P < .001), prostate (RR, 1.83; P = .030), and breast cancer (RR, 1.22; P = .005). Compared with previous smokers, current smokers with metastatic lung cancer were more likely to have involvement of the brain (33.6% v 23.0%; P = .004), bone marrow, adrenal gland, and pericardium (24.7% v 15.9%; P = .004).

Conclusion: Previous or current smoking is a risk factor for increased cancer stage in a wide range of malignancies. Further study is required to determine whether this association is causal.
Intensive Induction Chemotherapy With CBOP/BEP in Patients With Poor Prognosis Germ Cell Tumors
Authors: Christian J.A. , Huddart R.A. , Norman A. , Mason M. , Fossa S. , Aass N. , Nicholl E.J. , Dearnaley D.P. , Horwich A.
Published: February 2003

Purpose: Despite a high cure rate in patients with testicular cancer, there remain patients in the poor prognosis group who have a less favorable outcome. Intensive induction chemotherapy using a regimen consisting of carboplatin, bleomycin, vincristine, and cisplatin, followed by bleomycin, etoposide, and cisplatin (CBOP/BEP), developed at the Royal Marsden Hospital, is designed to overcome the rapid proliferation seen in germ cell tumors. This study assesses the outcome of patients with poor-prognosis nonseminomatous germ cell tumors (NSGCT) treated with CBOP/BEP.

Patients and Methods: Patients with NSGCT from three centers, classified as poor prognosis according to International Germ Cell Classification Consensus Group criteria, were treated with CBOP/BEP regimen during the period from 1989 to 2000. Data on treatment toxicity, relapse-free survival (RFS), and overall survival (OS) were collected prospectively on a hospital database.

Results: Fifty-four male patients with poor prognosis NSGCT were treated with CBOP/BEP. The RFS at 3 and 5 years for all patients was 83.2% (95% confidence interval [CI], 68.8% to 91.3%). After a median follow-up of 4 years, the OS of the 54 patients was 91.5% (95% CI, 78.6% to 96.8%) at 3 years and 87.6% (95% CI, 71.3% to 94.9%) at 5 years. Three-year OS in patients with a primary mediastinal germ cell tumor was 77.1% (95% CI, 34.5% to 93.9%) compared with 95.4% (95% CI, 82.8% to 98.8%) in patients with a testicular primary tumor (P = .24).

Conclusion: The results reported here compare favorably with the historical results of alternative regimens used in the management of poor-prognosis NSGCT. We suggest a phase III trial to confirm our findings.
Genetic Tumor Markers With Prognostic Impact in Dukes’ Stages B and C Colorectal Cancer Patients
Authors: Diep Chieu B. , Thorstensen Lin , Meling Gunn Iren , Skovlund Eva , Rognum Torleiv O. , Lothe Ragnhild A.
Published: February 2003

Purpose: To examine several genetic changes in primary colorectal carcinomas (CRCs) from patients with 10 years of follow-up and associate the findings with clinicopathologic variables.

Material and Methods: DNA from 220 CRCs were analyzed for allelic imbalances at 12 loci on chromosome arms 1p, 14q, 17p, 18q, and 20q, and the microsatellite instability (MSI) status was determined. The clinical significance of the tumor protein 53 (TP53) mutations was re-evaluated.

Results: Patients with tumors containing 17p or 18q deletions had shorter survival than those without these alterations (P = .021, P = .008, respectively). This was also significant for the Dukes’ B group (P = .025, P = .010, respectively). Furthermore, patients with tumors showing losses of both chromosome arms revealed an even poorer disease outcome than those with either 17p or 18q loss. Patients with low increase in 20q copy number in their tumors had longer survival compared with those without changes (P = .009) or those with a high increase of copy number (P = .037). This was also evident for the Dukes’ C group (P = .018, P = .030, respectively). MSI was seemingly a beneficial marker for survival (P = .071). A significant association between mutations affecting the L3 zinc-binding domain of TP53 and survival was confirmed in this cohort after 10 years of follow-up, and also was found to apply for patients in the Dukes’ B group. Several associations were found among genetic and pathologic data.

Conclusion: The present study indicates that 17p, 18q, and 20q genotypes, and TP53 mutation status add information in the subclassification of Dukes’ B and C patients and may have impact on the choice of treatment.
Treatment of Children With Nonmetastatic Paratesticular Rhabdomyosarcoma: Results of the Malignant Mesenchymal Tumors Studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology
Authors: Stewart Richard J. , Martelli Hélène , Oberlin Odile , Rey Annie , Bouvet Nathalie , Spicer Richard D. , Godzinski Jan , Stevens Michael C.G.
Published: February 2003

Purpose: To report the results of the Malignant Mesenchymal Tumors studies (MMT 84 and 89) of the International Society of Pediatric Oncology (SIOP) in males with nonmetastatic paratesticular rhabdomyosarcoma.

Patients and Methods: From 1984 to 1994, 96 males were treated in SIOP protocols. Radical inguinal orchidectomy was recommended, but initial retroperitoneal lymph node dissection was not performed. Disease was staged according to the SIOP tumor-node-metastasis staging system. Treatment was stratified by stage. In the MMT 89 study, males with completely resected tumors at diagnosis received less chemotherapy (vincristine and dactinomycin) than patients in the MMT 84 study (ifosfamide, vincristine, and dactinomycin).

Results: Median age at diagnosis was 65 months. Thirty-one tumors were larger than 5 cm, and 13 males were older than 10 years with a tumor larger than 5 cm. At a median follow-up of 7 years, 87 patients were alive; 79 were in first complete remission and eight were in second complete remission. Relapse occurred in 16 patients (17%). At 5 years, the overall survival (OS) rate was 92%, with an event-free survival (EFS) rate of 82%. OS and EFS were significantly worse for males with tumors greater than 5 cm and for males older than 10 years at diagnosis.

Conclusion: Males with paratesticular RMS have an excellent prognosis except for a selected group of patients older than 10 years or with tumor greater than 5 cm. Intensified chemotherapy incorporating alkylating agents for this subgroup may be preferred to the use of systematic lymphadenectomy to improve survival while minimizing the burden of therapy.
Preoperative Twice-Weekly Paclitaxel With Concurrent Radiation Therapy Followed by Surgery and Postoperative Doxorubicin-Based Chemotherapy in Locally Advanced Breast Cancer: A Phase I/II Trial
Authors: Formenti Silvia C. , Volm Matthew , Skinner Kristin A. , Spicer Darcy , Cohen Deidre , Perez Edith , Bettini Anna C. , Groshen Susan , Gee Conway , Florentine Barbara , Press Michael , Danenberg Peter , Muggia Franco
Published: February 2003

Purpose: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy.

Patients and Methods: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m2 delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan.

Results: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer).

Conclusion: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.
Thymidylate Synthase Protein Expression in Primary Colorectal Cancer: Lack of Correlation With Outcome and Response to Fluorouracil in Metastatic Disease Sites
Authors: Johnston Patrick G. , Benson Al B. , Catalano Paul , Rao M. Sambasiva , O’Dwyer Peter J. , Allegra Carmen J.
Published: February 2003

Purpose: The aim of this study was to investigate the utility of quantitating thymidylate synthase (TS) in the primary tumor as a surrogate for metastatic disease sites to predict the likelihood of response and outcome to fluorouracil (FU) treatment in patients with metastatic colorectal cancer.

Methods: TS protein expression was evaluated using the TS 106 antibody and the avidin biotin labeling immunohistochemical technique in primary tumor samples from 219 patients with metastatic colorectal cancer. The patients were a representative sample of those patients enrolled into the Eastern Cooperative Oncology Group E2290 protocol that evaluated five separate FU-containing regimens in patients with metastatic residual or recurrent colorectal carcinoma.

Results: Our retrospective analysis found that the level and extent of TS protein expression in the primary tumor did not correlate with overall survival in patients with metastatic or recurrent colorectal cancer. A trend toward a direct correlation between the level of TS protein expression and response was noted in tumors that expressed high TS levels. This response advantage for patients expressing high TS levels in the primary tumor was apparent regardless of what FU-based treatment the patient received but was most apparent in the subgroup treated with leucovorin, in which the level of TS expression and response to FU and leucovorin reached statistical significance (P = .034). No significant interaction could be detected between the addition of leucovorin to FU and the level of TS expression in the primary tumor.

Conclusion: This study demonstrated that measurement of TS protein levels in the primary tumor tissue does not aid in predicting outcome or response to FU in a metastatic disease site. These assays must be performed on biopsy tissue from the metastatic disease site that is used to radiologically assess response and outcome to treatment.
American Oncologists’ Views of Internet Use by Cancer Patients: A Mail Survey of American Society of Clinical Oncology Members
Authors: Helft Paul R. , Hlubocky Fay , Daugherty Christopher K.
Published: February 2003

Purpose: Americans are turning more and more frequently to the Internet to obtain health information. The specific effects on patients, doctors, and the clinical encounter are not well known.

Methods: A brief mail survey was sent to a systematic sample of 5% of medical oncologists and hematologist/oncologists listed in the membership directory of the American Society of Clinical Oncology.

Results: Response rate to this mail survey was 46.2%. Oncologists’ median estimate of the proportion of their patients using the Internet to obtain cancer information was 30%. Subjects responded that, on average, 10 minutes were added to each patient encounter in which Internet information was discussed. Responding oncologists reported that use of the Internet had the ability to simultaneously make patients more hopeful, confused, anxious, and knowledgeable. Forty-four percent of responding oncologists reported that they sometimes or rarely had difficulty discussing Internet information, and only 9% of subjects reported that they sometimes or always felt threatened when patients brought Internet information to discuss. In narrative responses, oncologists reported both positive and negative effects of Internet use by patients.

Conclusion: In this brief mail survey to a systematic sample of American oncologists in academic and community practice, respondents reported that a significant proportion of their patients use the Internet to obtain cancer information. Oncologists viewed Internet information as having both positive and negative effects on the clinical encounter. Further research is needed on the effects of patients’ use of the Internet to obtain cancer information involving both patients and oncologists.
Phase II Trial of Autologous Tumor Vaccination, Anti-CD3-Activated Vaccine-Primed Lymphocytes, and Interleukin-2 in Stage IV Renal Cell Cancer
Authors: Chang Alfred E. , Li Qiao , Jiang Guihua , Sayre Donna M. , Braun Thomas M. , Redman Bruce G.
Published: February 2003

Purpose: Previous preclinical and clinical studies have demonstrated that autologous tumor vaccines can induce relatively specific tumor-reactive T cells in draining lymph nodes. The adoptive transfer of these cells can result in tumor regression.

Patients and Methods: Patients with stage IV renal cell cancer (RCC) were vaccinated with irradiated autologous tumor cells admixed with Calmette-Guérin bacillus. Approximately 7 days later, vaccine-primed lymph nodes (VPLNs) were harvested and the lymphoid cells secondarily activated with anti-CD3 monoclonal antibody and expanded in interleukin 2 (IL-2). The activated cells were subsequently infused intravenously along with the concomitant administration of bolus IL-2 (360,000 U/kg intravenously × 15 doses).

Results: Thirty-nine patients were entered onto the study, of whom 34 completed an initial course of cell therapy consisting of a mean (SEM) number of 4.3 (2.2) × 1010VPLN cells. Among subjects who received cell therapy, there were nine responses (four complete responses [CRs] and five partial responses [PRs]), for an overall response rate of 27%. The durations of the CRs were > 48, 45, > 35, and 12 months, and the durations of the PRs were > 63, 48, 15, 12, and 4 months. Cultured tumor cells were available to assess in vitro cytokine release of VPLN cells in 24 subjects. The median cytokine release ratio of interferon gamma (IFNγ) to IL-10 for responders and nonresponders was 992 and 5, respectively, which was significantly different (P = .047).

Conclusion: The treatment protocol resulted in durable tumor responses in patients with advanced RCC. The ratio of IFNγ and IL-10 cytokines released in response to tumor by the VPLN cells was a significant correlate with tumor response.
Phase III Comparison of Two Irinotecan Dosing Regimens in Second-Line Therapy of Metastatic Colorectal Cancer
Authors: Fuchs Charles S. , Moore Melvin R. , Harker Graydon , Villa Luis , Rinaldi David , Hecht J. Randolph
Published: February 2003

Purpose: Randomized trials in fluorouracil (FU)-refractory colorectal cancer demonstrate significant survival advantages for patients receiving irinotecan. We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients.

Patients and Methods: This multicenter, open-label, phase III study randomly assigned patients in a 1:2 ratio to irinotecan given either weekly (125 mg/m2) or once every 3 weeks (350 mg/m2, or 300 mg/m2 in patients who were ≥ 70 years of age, who had Eastern Cooperative Oncology Group performance status equal to 2, or who had prior pelvic irradiation).

Results: With median follow-up of 15.8 months, there was no significant difference in 1-year survival (46% v 41%, respectively; P = .42), median survival (9.9 v 9.9 months, respectively; P = .43), or median time to progression (4.0 v 3.0 months, respectively; P = .54) between the two regimens. Grade 3/4 diarrhea occurred in 36% of patients treated weekly and in 19% of those treated once every 3 weeks (P = .002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34% of those treated once every 3 weeks (P = .35). Treatment-related mortality occurred in five patients (5.3%) receiving irinotecan weekly and three patients (1.6%) given therapy once every 3 weeks (P = .12). Global quality of life was not statistically different between treatment groups.

Conclusion: Irinotecan schedules of weekly and of once every 3 weeks demonstrated similar efficacy and quality of life in patients with FU-refractory, metastatic colorectal cancer. The regimen of once every 3 weeks was associated with a significantly lower incidence of severe diarrhea.
Nicotine Patch Therapy Based on Smoking Rate Followed by Bupropion for Prevention of Relapse to Smoking
Authors: Hurt Richard D. , Krook James E. , Croghan Ivana T. , Loprinzi Charles L. , Sloan Jeff A. , Novotny Paul J. , Kardinal Carl G. , Knost James A. , Tirona Maria Tria , Addo Ferdinand , Morton Roscoe F. , Michalak John C. , Schaefer Paul L. , Porter Patricia A. , Stella Philip J.
Published: February 2003

Purpose: To determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy.

Participants and Methods: Fourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment.

Results: Of 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P = .73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P = .12).

Conclusion: Tailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.
Bidirectional Signaling between the Estrogen Receptor and the Epidermal Growth Factor Receptor
Authors: Levin Ellis R.
Published: February 2003

Interactions between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) contribute to the biological effects of these binding protein families. EGFR stimulates DNA synthesis and gene transcription in the uterus, related in part to estrogen-independent activation of the nuclear ER. This results from signal transduction enacted by the plasma membrane tyrosine kinase growth factor receptor, leading to 1) phosphorylation and activation of the nuclear ER, and 2) phosphorylation of coregulator proteins. More recently, it has been shown that a pool of ERα resides in or associates with the plasma membrane as a cytoplasmic protein. These ERs utilize the membrane EGFR to rapidly signal through various kinase cascades that influence both transcriptional and nontranscriptional actions of estrogen in breast cancer cells. This is congruent with a general theme of receptor signaling, where membrane G protein-coupled receptors activate tyrosine kinase growth factor receptors (EGFR, IGF-I receptor) that subsequently signal to MAPKs and other pathways. Overall, the bidirectional cross-talk between EGFR and cellular pools of ER contributes to reproductive organ physiology and pathophysiology.
A unified approach to the kinematics of a spreader suspended by multiple cables
Authors: Lee J-W , Kim D-H , Oh J-H
Published: February 2003

This paper presents the kinematics of a spreader suspended by four cables, which is widely used in industrial gantry cranes. The approach is based on the minimum energy principle, which provides exact solutions to the kinematics of the spreader. The energy consists of potential energy of the spreader and elastic deformation energy of suspension cables. By minimizing the sum of energy, tensions and elongations of cables are obtained and the kinematics of the spreader is determined in a natural way. Through numerical simulations, various results for the kinematics of the spreader are presented for a typical gantry system for parallel cabling and non-parallel cabling. The results include transition from the four-cable suspension state to a three-cable suspension one. For non-parallel cabling, variation of various physical quantities with respect to the form factor is illustrated.