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  • 2000-2004  (281)
  • 1995-1999  (7,884)
  • 1950-1954  (1,432)
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  • breast cancer
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  • 1
    ISSN: 1530-0358
    Keywords: Barostat ; Colon ; Human ; Ileus ; Manometry ; Motility ; Postoperative ; Rectum ; Surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: Colonic motility is crucial for the resolution of postoperative ileus. However, few data are available on postoperative colonic motility and no data on postoperative colonic tone. We aimed to characterize postoperative colonic tone and motility in patients. METHODS: Nineteen patients were investigated with combined barostat and manometry recordings after left colonic surgery. During surgery a combined recording catheter was placed in the colon with two barostat bags and four manometry channels cephalad to the anastomosis. Recordings were performed twice daily from Day 1 to Day 3 after surgery. RESULTS: Manometry showed an increasing colonic motility index, which was a mean (± standard error of the mean) of 37±5 mmHg/minute on Day 1, 87±19 mmHg/minute on Day 2, and 102±13 mmHg/minute on Day 3 (P〈0.05 for Day 1vs. Day 2 and Day 2vs. Day 3). Low barostat bag volumes indicating a high colonic tone were observed on Day 1 after surgery and increased subsequently (barostat bag I was 19±4, 32±6, and 32±6 ml; barostat bag II was 13±1, 19±3, and 22±5 ml on Days 1, 2, and 3, respectively; for both barostat bagsP〈0.05 for Day 1vs. Day 2 but not Day 2vs. Day 3). CONCLUSIONS: Colonic motility increased during the postoperative course. The low barostat bag volumes indicated a high colonic tone postoperatively which would correspond to a contracted rather than to a distended colon. High colonic tone postoperatively may be relevant for pharmacologic treatment of postoperative ileus.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of hepato-biliary-pancreatic surgery 7 (2000), S. 575-579 
    ISSN: 1436-0691
    Keywords: Key words Precancerous conditions ; Pancreatic duct adenocarcinoma ; Hamster ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Precancerous conditions for ductal adenocarcinoma of the pancreas in hamsters and human beings are discussed. In hamsters, ductal adenocarcinomas induced by nitrosamines are of nonmucin-hypersecreting tubular or papillary tumor types, and genetic alterations resembling these types are found in their human counterparts. Ductal lesions develop step-by-step from hyperplasias to carcinomas, and atypical ductal cell hyperplasias may be precancerous. In humans, ductal lesions, hyperplasias, or dysplasias, with or without mucin hypersecretion, are possible preneoplastic conditions. Genetic or phenotypic markers to determine their likelihood of progressing to pancreatic duct adenocarcinomas are a high priority for future research.
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  • 3
    ISSN: 1436-2813
    Keywords: Key Words: genetic changes ; prognostic factor ; breast cancer ; amplification ; loss of heterozygosity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: ERBB2 , INT2, and MYC genes, in 131 patients with breast carcinoma, 49 of whom had lymph node involvement, but none of whom had distant metastases. Among the several chromosome arms tested, LOH at 17q was correlated with lymph node metastasis. Amplification of the ERBB2, MYC, and INT2 genes was found more frequently in tumors from patients with lymph node metastases than in tumors from those without lymph node metastases. Univariate analysis demonstrated that LOH at 17q and INT2 amplification were factors influencing disease-free survival (DFS). A multivariate analysis was performed on 89 tumors that were able to be evaluated for both LOH at 17q and INT2 amplification, and the results showed that patients who had tumors with these genetic changes were more likely to have a poor prognosis. The findings of this study suggest that investigating genetic changes, in addition to conventional clinicopathologic factors, may contribute to defining groups of breast cancer patients with differences in prognosis.
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  • 4
    ISSN: 1432-2307
    Keywords: Keywords Lung ; Ozone ; Centriacinar ; Human ; Autopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Semiquantitative measurements of chronic inflammation of the centriacinar region (proximal acinus of lung) were compared between 20 Miami and 18 Los Angeles residents (ages 11–30 years) for whom smoking histories were available. Mean extent and severity scores of four lung sites were higher for Los Angeles than Miami residents, with effect of city statistically significant for extent (P=0.02). Also, maximum scores for extent and severity by city were significantly greater for Los Angeles residents (P=0.02, each), but not by smoking history. Smokers did have higher scores for mean extent and severity (by lung site and smoking history), but neither this nor inclusion of smoking and city in the model reached significance. With respect to maximum extent and maximum severity scores, a stratified comparison of cities by smoking history showed a trend (not significant) toward higher scores for Los Angeles residents. Mean extent and severity scores for the lower lobe were higher for basilar sections than for apical sections (each P〈0.001). Cumulative data indicate that expanded pathologic studies are essential for efforts to complete a convergence of epidemiological and experimental data implicating exceedences of the Federal ozone standard as a contributor to human lung injury.
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  • 5
    ISSN: 1569-8041
    Keywords: BRCA1 ; breast cancer ; p53 ; survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The association between BRCA1 germ-linemutations and breast cancer prognosis is controversial. A historical cohortstudy was designed to determine the prognosis for women with axillary lymphnode negative hereditary breast cancer. Patients and methods:We tested pathology blocks from 118Ashkenazi Jewish women with axillary lymph node negative breast cancer for thepresence of the two common BRCA1 founder mutations, 185delAG and5382insC. Patients were followed up for a median of 76 months. SomaticTP53mutations were screened for by immunohistochemistry, and directsequencing was performed in the BRCA1-positive tumours. Results:Sixteen breast cancer blocks (13.6%) carried aBRCA1 mutation. Young age of onset, high nuclear grade, negativeestrogen receptor status and over-expression of p53 were highly associatedwith BRCA1-positive status (P-values all 〈0.01).BRCA1 mutation carriers had a higher mortality than non-carriers(five-year overall survival, 50% and 89.6%, respectively,P = 0.0001). Young age of onset, estrogen receptor negative status,nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Coxmultivariate analyses showed that only germ-line BRCA1 mutationstatus was an independent prognostic factor for overall survival (P= 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrierstatus was a significant prognostic factor of death (risk ratio 5.8,95% confidence interval: 1.5–22, P = 0.009). Sequencingof BRCA1-related breast cancers revealed one TP53missensemutation not previously reported in breast cancer. Conclusions:Using a historical cohort approach, we haveidentified BRCA1 mutation status as an independent prognostic factorfor node negative breast cancer among the Ashkenazi Jewish women. Thosemanaging women carrying a BRCA1 mutation may need take these findingsinto consideration. Additionally, our preliminary results, taken together withthe work of others suggest a different carcinogenic pathway inBRCA1-related breast cancer, compared to non-hereditary cases.
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  • 6
    ISSN: 1569-8041
    Keywords: BCL-2 ; breast cancer ; HER-2 ; p53 ; predictive factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The selection of therapies for breast cancer is todaybased on prognostic features (chemotherapy, radiotherapy), hormone receptorstatus (hormonal therapy) and HER-2 status (trastuzumab therapy). HER-2,p53and BCL-2are tumour-related proteins that have thepotential to further improve individualisation of patient management, bypredicting response to chemotherapy, hormonal therapy and radiotherapy. Materials and methods:This paper reviews the rationale for theuse of these proteins as predictive factors, as well as the publishedliterature addressing the use of each one to predict response to hormonaltherapy, chemotherapy and radiotherapy. Results:HER-2, p53and BCL-2remaininadequately assessed as predictive factors in breast cancer. HER-2 evaluationis required for the selection of patients for trastuzumab (Herceptin®)therapy, as trials of this therapy have been limited to HER-2 overexpressors.HER-2 overexpression may be predictive of resistance to hormonal therapy.Anthracyclines are effective therapy for breast cancer regardless of HER-2status, but patients whose tumours overexpress HER-2 appear to receive thegreatest relative benefit from this therapy. Studies of HER-2 as a predictorof response to CMF and to radiotherapy are inconclusive at this time. No datayet exist to support the use of p53or BCL-2as predictivefactors in the therapy of breast cancer. Conclusions:At this point in time, there is inadequate evidenceto support the use of HER-2, p53or BCL-2to guide theselection of hormonal therapy, chemotherapy or radiotherapy for breast cancer.
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  • 7
    ISSN: 1569-8041
    Keywords: breast cancer ; camptothecins ; colorectal cancer ; GI147211 ; non-small-cell lung cancer ; topoisomerase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:GI147211 is a water-soluble synthetic analogue ofcamptothecin showing promising in vivoand in vitroantitumor activity and an acceptable toxicity profile. Patients and methods:Between April 1995 and November 1996, 67eligible patients with pretreated breast cancer (25 patients) andchemo-naïve colorectal (19 patients) and non-small-cell lung cancer (23patients) were entered into three multicentric, non-randomized phase IItrials. Treatment schedule consisted of intravenous GI147211 administered ata dose of 1.2 mg/m2/day for five consecutive days every threeweeks. Results:Hematological toxicity was common with grade 3–4neutropenia in 54% of patients and neutropenic fever together or notassociated with infection in 14.5% of patients. Grade 3–4thrombocytopenia and grade 2–4 anemia were observed in 20% andin 68% of patients, respectively. Non-hematological toxicity wasgenerally mild to moderate and consisted mainly of gastrointestinal toxicity,asthenia and alopecia. A dose-escalation to 1.5 mg/m2/d wasfeasible in 17 (25%) patients. The antitumor activity of GI147211 wasmoderate in breast cancer patients (3 partial responses (PRs), response rate(RR) 13%) and minimal in non-small cell lung cancer patients (2 PRs,RR 9%). No objective responses were obtained in colorectal patients. Conclusions:GI147211, at the dose and schedule employed in thisstudy, showed an acceptable safety profile but a modest antitumor activity inthe examined tumor types.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Biomedical microdevices 2 (2000), S. 305-316 
    ISSN: 1572-8781
    Keywords: membranes ; breast cancer ; oncology ; cell column regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract Using microfabrication technology, we have developed a new experimental apparatus and technique which allow isolation of individual cells and which facilitate the study of kinetic volume changes and membrane permeability. The key component of the apparatus is a microdiffusion chamber which was constructed using silicon microfabrication technology and standard photolithography. The central unit of the chamber is a 1 μ m thick silicon nitride membrane with a center hole on the order of 2–3 μ m in diameter. The device is novel in its analysis of a single cell, instead of the traditional array of cells, and its avoidance of the damage artifacts and computational difficulties which are inherent in other, commonly used methods of cellular analysis. The device is used in conjunction with a predictive computer model which simulates the response of the entire membrane or a portion of the membrane to various permeant and impermeant concentrations. This study introduces the apparatus and the model, and illustrates the effectiveness of the new procedure by determining several membrane permeability coefficients for HBL-100 (healthy human breast line). The empirical data and theoretical data were combined to yield a water permability (L p) of 1.1 ± 0.5μ m/(min-atm) (mean ± 1 standard deviation) (N= 5) during the uncoupled transport of water at 22 ±C. In the presence of 6 M glycerol, the water permeability (L p), permeability coefficient (P S), and the reflection coefficient (σS) were determined to be 2.0 ± 0.63 μ m/(min-atm), 2.7E-5 ± 6.1E-6 cm-sec-1, and 0.76 ± 0.5 (N = 6). No previous values of these coefficients could be found for HBL-100 cells.
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  • 9
    ISSN: 1569-8041
    Keywords: biological/pathological characteristics ; breast cancer ; prognosis ; progression ; symptomatic/asymptomatic patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:It is well known that mammographic screening reducesbreast cancer mortality. One possible explanation for this effect is thatscreening makes it possible to detect smaller breast cancers with fewerinvolved nodes, but another hypothesis is that some screening-detected tumorsare in a pathologically and biologically different phase of evolution fromthose that are detected clinically. The aim of the present study was tocompare the biological, pathological and clinical characteristics ofsymptomatic vs. asymptomatic breast cancers. Patients and methods:The study considers a series of 1916consecutive patients who underwent surgery for stage I and II infiltratingbreast cancer at Verona hospitals after having undergone ultrasound andmammography (at least one of which was positive). They were divided into twogroups on the basis of why they decided to undergo the imaging examinations:group A refers to the 1247 patients with a palpable lump, and group B to the616 who were asymptomatic. Results:The patients in group A were older, and had larger tumorsand a higher percentage of positive nodes than those in group B; they also hadsignificantly higher grade tumors, higher Ki-67 levels, and a higherpercentage of ER and PgR negative and c-erbB-2 positive tumors (allof the P-values were significant). A logistic regression analysisadjusted for tumor diameter and age showed a reduction in the significance ofeach of the considered variables, but all of them remained significantlyassociated with the modality of diagnosis except ER, PgR andc-erbB-2. Conclusions:Our results suggest that asymptomatic tumors arebiologically different from their clinically presenting counterparts, thusconfirming the hypothesis that progression towards greater malignancy mayoccur during the natural history of breast cancer.
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  • 10
    ISSN: 1569-8041
    Keywords: 4-OH-IF ; breast cancer ; drug combination ; human cell lines ; primary cultures ; VNB
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Vinorelbine and ifosfamide are active drugs againstbreast cancer, but the best treatment schedule has yet to be defined bypreclinical or clinical studies. The antitumor activity of4-hydroxy-ifosfamide (4-OH-IF), the active form of ifosfamide, and vinorelbine(VNB) and their interaction were investigated in two established breast cancercell lines (MCF-7 and BRC-230) and in 10 primary breast cancer cultures. Materials and methods:Cytotoxic activity was evaluated by ahighly efficient clonogenic assay (HECA). The median-effect principle wasapplied to evaluate synergistic and antagonistic interactions and thecorresponding combination index values were calculated. Cell cycleperturbations were analysed by flow cytometry. Results:In MCF-7 and BRC-230 cell lines the sequence VNB for 4hours followed by 4-OH-IF for 24 hours produced an antagonistic effect.Conversely, the inverse sequential scheme, 4-OH-IF → VNB providedsynergistic effects on both cell lines. The synergism was associated with astrong block in the G2-M phase. Synergistic activity of 4-OH-IF → VNBsequence was confirmed in 7 of 10 primary breast cancercultures. Conclusions:In conclusion, the sequence 4-OH-IF → VNBappeared to be the most effective scheme both in established cell lines andin primary breast cancer cultures.
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  • 11
    ISSN: 1569-8041
    Keywords: adjuvant treatment ; breast cancer ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aim:Immediate adjuvant tamoxifen reduces disease recurrence andimproves survival in patients with early breast cancer. However, is it toolate to administer tamoxifen to patients who have already undergone treatment,but were unable to benefit from this adjuvant therapy? The French NationalCancer Centers (FNCLCC) have investigated the efficacy of delayed tamoxifenadministration in a randomized controlled trial. Patients and methods:From September 1986 to October 1989, womenwith primary breast cancer, who had undergone surgery, radiotherapy, and/orreceived adjuvant chemotherapy but not hormone therapy more than two yearsearlier, were randomized to receive either 30 mg/day tamoxifen or notreatment. The 10-year disease-free and overall survival rates of the twogroups of patients and of various subgroups were determined according to theKaplan–Meyer method and compared by the log-rank test. Results:This intention-to-treat analysis comprised 250 women inthe tamoxifen group and 244 in the control group. Patient characteristics(age, T stage, number of positive nodes, receptor status, and interval sincetumor treatment) were comparable in both groups. Delayed adjuvant tamoxifensignificantly improved overall survival only in node-positive patients and inpatients with estrogen receptor-positive (ER+) or progesteronereceptor-positive (PR+) tumors. Disease-free survival, however, wassignificantly improved in the global population and in several patientsubgroups (node-positive, ER+, PR+). Patients in whom the interval betweenprimary treatment and delayed adjuvant tamoxifen was greater than five yearsalso had significantly improved disease-free survival. Conclusions:Overall and disease-free survival results indicatethat delayed adjuvant tamoxifen administration (30 mg/day) is justified inwomen with early breast cancer, even if this treatment is initiated two ormore years after primary treatment.
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Annals of oncology 11 (2000), S. 1349-1351 
    ISSN: 1569-8041
    Keywords: breast cancer ; radiotherapy ; tumor lysis syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumor lysis syndrome (TLS) is a rare serious acute complication of cancertherapy, reported mainly following chemotherapy in patients with large tumorload and chemosensitive disease. These are mainly patients with non-Hodgkin'slymphoma, leukemia and rarely in solid tumors. It is less frequently describedafter radiotherapy for lymphoid and hematological malignancies. TLS followingradiotherapy for solid tumors is a very rare complication. In thisreport/review we describe a seventy-three-year-old male patient withprogressive metastatic carcinoma of the breast to the lungs, liver and bone.He was referred for radiotherapy because of generalized bony pains. Thepatient was planned for sequential hemi-body irradiation starting with themore symptomatic upper half body. After premedication, he was given 8.5 Gy tothe mid point at the maximum chest separation with anterior lung attenuatorlimiting uncorrected lung dose to 6.15 Gy. A further 3.5 Gy electron boost tothe fungating breast tumor was given to the 100%. Forty-eight hours after irradiation he developed hyperkalemia,hyperphosphatemia, hyperuricemia, hypocalcemia and renal failure. Theseclinical and biochemical changes are typical of tumor lysis syndrome (TLS).Despite hydration, and treating the hyperuricemia, the patient developed comaand died eight days after irradiation. The prophylaxis and management of TLS and in high-risk patients aredescribed to avoid this frequently fatal complication.
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  • 13
    ISSN: 1569-8041
    Keywords: breast cancer ; erbB2 ; HER-2/neu ; tamoxifen ; therapy resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aim:We aimed to study the importance of erbB2 status in earlystage postmenopausal breast cancer for patients who participated in a trialof five vs. two years of adjuvant tamoxifen. Patients and methods:We analysed the erbB2 status of the tumoursfrom 577 patients participating in the trial, either by a DNA amplificationassay (n = 181) or by measurement of the protein level with flowcytometry (n = 396). Results:ErbB2 was overexpressed or gene amplified in 102 of thepatients (18%). Overall, erbB2-positive patients had a significantlylower recurrence-free probability than others, 62% at five years ascompared to 83%, and showed a significantly decreased breast cancersurvival rate (P = 0.0007). ErbB2 status was significantlyassociated with recurrence and death in Cox multivariate analysis, adjustingfor nodal status, tumour size and estrogen receptor status. The relative riskof recurrence (RR) for five vs. two years of tamoxifen was analysed inrelation to erbB2 status for patients still disease-free two years aftersurgery. Whereas erbB2-negative patients showed significant benefit fromprolonged treatment (RR = 0.62, 95% confidence interval (95%CI): 0.42–0.93), no benefit was evident for erbB2-positive patients (RR= 1.1, 95% CI: 0.41–3.2). When the same analysis was restrictedto ER-positive patients a similar difference in relative hazard was obtainedbut the difference was not strictly significant (P = 0.065). Conclusions:For early stage breast cancer patients treated withadjuvant tamoxifen, overexpression of erbB2 is an independent marker of poorprognosis. The results suggest that overexpression decreases the benefit fromprolonged tamoxifen treatment.
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  • 14
    ISSN: 1569-8041
    Keywords: breast cancer ; cyclophosphamide ; elderly ; idarubicin ; oral chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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  • 15
    ISSN: 1569-8041
    Keywords: adjuvant therapy ; breast cancer ; docetaxel ; feasibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background and purpose:Docetaxel is an active agent in thetreatment of metastatic breast cancer. We evaluated the feasibility ofdocetaxel-based sequential and combination regimens as adjuvant therapies forpatients with node-positive breast cancer. Patients and methods:Three consecutive groups of patients withnode-positive breast cancer or locally-advanced disease, aged ≤70 years,received one of the following regimens: a) sequential A → T → CMF:doxorubicin 75 mg/m2 q 3 weeks × 3, followed by docetaxel 100mg/m2 q 3 weeks × 3, followed by i.v. CMF days 1 + 8 q 4weeks × 3; b) sequential accelerated A → T → CMF: A and T wereadministered at the same doses q 2 weeks; c) combination therapy: doxorubicin50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks × 4,followed by CMF × 4. When indicated, radiotherapy was administeredduring or after CMF, and tamoxifen started after the end of CMF. Results:Seventy-nine patients have been treated. Median age was48 years. A 30% rate of early treatment discontinuation was observedin patients receiving the sequential accelerated therapy (23% duringA → T), due principally to severe skin toxicity. Median relativedose-intensity was 100% in the three treatment arms. The incidence ofG3–G4 major toxicities by treated patients, was as follows: skintoxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%;b: 20%; c: 3%. The incidence of neutropenic fever was a:30%; b: 13%; c: 48%. After a median follow-up of 18months, no late toxicity has been reported. Conclusions:The accelerated sequential A → T → CMFtreatment is not feasible due to an excess of skin toxicity. The sequentialnon accelerated and the combination regimens are feasible and under evaluationin a phase III trial of adjuvant therapy.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Medical electron microscopy 33 (2000), S. 109-114 
    ISSN: 1437-773X
    Keywords: Key words Ciliogenesis ; Ciliated cell ; Abnormal cilia ; Basal body ; Ultrastructure ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cilia are motile processes extending from the basal bodies, playing important roles in the mucociliary clearance in the respiratory tract and the transport of the ovum from the ovary to the uterus in mammals. Ciliogenesis is divided into four stages: (1) duplication of centrioles; (2) migration of centrioles to the apical cell surface to become basal bodies; (3) elongation of cilia containing the axoneme; and (4) formation of accessory structures of basal bodies. The orderly course of ciliogenesis appears to be disturbed by various internal and external factors and, as a result, various unusual forms of the ciliary apparatus develop in the cell. Inhibition of basal body migration results in development of intracytoplasmic axonemes, cilia within periciliary sheaths, and intracellular ciliated cysts. Swollen cilia and the bulging type of compound cilia are formed during ciliary budding and elongation. This review also discusses the origin, composition, and function of the centriolar precursor structures.
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  • 17
    ISSN: 1432-0533
    Keywords: Key words Skeletal muscle ; Human ; Differentiation ; Protein kinase C ; Isozymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mechanism of skeletal muscle regeneration in vivo can be well modeled in vitro by culturing skeletal muscle cells. In these cultures mononuclear satellite cells fuse to form polynuclear myotubes by proliferation and differentiation. The aim of this study was to determine how the different protein kinase C (PKC) isozymes were expressed during differentiation of human skeletal muscle in vitro. The expressions of desmin, used as a muscle-specific intermediate filament protein marker of differentiation, and of different PKC isozymes were detected by single and double immunohistochemical labeling, and by Western blot analysis. In skeletal muscle cells we could identify five PKC isozymes (PKCα, -γ, -η, -θ and -ζ). The expressions of PKCα and -ζ did not change significantly during differentiation; their levels of expression were high in the early immature cells and remained unchanged in later phases. In contrast, the expression levels of PKCγ and -η increased with differentiation. Furthermore, the cellular localization of PKCγ markedly altered during differentiation, with a perinuclear-nuclear to cytoplasmic translocation. The change in the level of expression of PKCθ during differentiation showed different pattern; its expression was high during the early phases, but a decreased immunostaining was detected in the matured, well-differentiated myotubes. We conclude, therefore, that cultured human skeletal muscle cells possess a characteristic PKC isozyme pattern, and that the different phases of differentiation are accompanied by different expression patterns of the various isozymes. These data suggest the possible functional and differential roles of PKC isozymes in human skeletal muscle differentiation.
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  • 18
    ISSN: 1432-0568
    Keywords: Keywords Granulosa cells ; Ontogeny ; Ovary ; Rete ovarii ; Cytokeratin ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Cells from the inner and outer granulosa cell layers of the ovarian follicles differ in function, probably because of their different origins from the surface epithelium and from the rete. This suggestion has not so far been thoroughly investigated in the human ovary. We examined fetal ovaries from the early, middle and late gestational periods, ovaries from fertile women, and preovulatory follicular cells obtained from patients under in vitro fertilization therapy (IVF). Indirect immunohistology and immunocytology were used to detect the presence of cytokeratin (CK)-positive epithelial cells. In fetal ovaries from the early gestational period, prominent rete tubules (sometimes with oocytes) appeared to be fused with the sex cords and primordial follicles. Both showed CK-positively, detected with the pan-CK antibody Lu-5. Cytokeratin 19 was clearly expressed in the fusion area. In the fetal and adult ovaries, CK-positive follicular or granulosa cells were noted in the primordial and primary follicles as well as the preovulatory follicles. Cytokeratin was not detected in the granulosa cells of growing follicles, CK-positive and -negative luteal cells were identified in the developing corpus luteum. We conclude for the human ovary: (1) the heterogeneous morphology of granulosa cells may be explained by their twofold origin from the surface epithelium and the rete, (2) the rete tubules appear to be involved in folliculogenesis, (3) the transient absence of CK expression in growing follicles compared to resting and mature follicles or to the developing corpus luteum indicates a particular role of CK-positive cells at the periovulatory period.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 292 (2000), S. 9-15 
    ISSN: 1432-069X
    Keywords: Key words Epidermal T cells ; Function ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The function of human epidermal T cells (ETC) is unknown. In the present study, dermal T cells (DTC), ETC and keratinocytes were cultured from normal human skin. DTC and ETC lines were expanded in medium containing interleukin 2. The autologous keratinocytes were transfected with a human papillomavirus 16 E6 and E7 plasmid to produce an immortal keratinocyte line “HEK001”. Lymphocyte migration and adhesion to HEK001 was assessed in calcein fluorimetric assays. ETC migrated towards HEK001 three to four times more than DTC. ETC adhered to HEK001 two to four times more than DTC. The proportion of ETC expressing the cutaneous lymphocyte-associated antigen was greater than that of DTC (26% and 1%, respectively). The keratinocyte line HEK001 expressed ICAM-1 following stimulation with TNF-α or IFN-γ and following coculture with autologous cutaneous T cells. A blocking anti-ICAM-1 antibody reduced DTC and ETC adhesion to HEK001 by 30% and 50%, respectively. Therefore, cutaneous T cells may upregulate keratinocyte ICAM-1 expression which mediates adhesion to autologous keratinocytes. These results are consistent with the hypothesis that the ETC and DTC populations are distinct. Both directed migration (epidermotropism) and selective retention may be involved in the development and maintenance of the ETC population in normal human skin.
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  • 20
    ISSN: 1432-0584
    Keywords: Key words Erythropoietin ; Endogenous ; Blood volume ; Human ; Intraoperative
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  There is accumulating evidence of a relationship between changes in intravascular blood volume and endogenous erythropoietin (EPO) levels. In this study, eight healthy adult American Society of Anesthesiologists class-I patients due for prolonged elective surgery were randomised either to preoperative hypervolaemic haemodilution using hydroxyethyl starch, followed by intraoperative crystalloid infusion, or to standard intraoperative normovolaemic fluid balance management using crystalloids (control group). Electrolytes, creatinine, urea, osmolality, urine output and blood gases were monitored pre- and intraoperatively for 6 h, Comparable cardiopulmonary and renal homeostasis were maintained in both groups. We found that central venous pressure increased and EPO levels decreased, both significantly, in the hypervolaemic haemodilution group relative to controls. There were no significant intergroup changes in any other parameters. By controlling for other known determinants of EPO levels, our data indicate a relationship between EPO levels and changes in intravascular blood volume in humans, supporting the notion of EPO as a volume-regulated, and possibly volume-regulating, hormone.
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  • 21
    ISSN: 1432-0533
    Keywords: Key words Allograft-inflammatory factor-1 ; Microglia response factor-1 ; Macrophage-inhibiting factor ; related-protein-8/S100A8 ; Traumatic brain injury ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Intracellular calcium (Ca2+) has been shown to function as second messenger and to be associated with activation of different cell types including microglia. Previously, in human focal cerebral infarctions an early expression of macrophage-related protein-8 (MRP8/ S100A8), a member of the Ca2+-binding S100-protein family, in microglia has been reported. On the other hand, a delayed activation of microglia was observed following traumatic brain injury (TBI). We therefore examined immunohistochemically microglial expression of MRP8 and allograft inflammatory factor-1 (AIF-1), identical to microglial response factor-1 (mrf-1) and ionized calcium binding adaptor molecule-1 (iba1) in human brains after TBI and in control brains. Both, MRP8 and AIF-1 are Ca2+-binding peptides which have been associated with microglial activation in experimental models and in human cerebral infarctions. Detection of AIF-1 in controls confirmed constitutive expression of this peptide in a subset of microglial cells. After TBI, the density of AIF-1+ microglia did not increase significantly. Lesional expression of AIF-1 did not significantly differ from other brain regions. Furthermore, following TBI, we found no significant differences in the density of AIF-1+ microglia as compared to controls. Microglial MRP8 expression was not detectable in controls and within the first 3 days post TBI, but increased rapidly after 3 days post TBI, suggesting a subpopulation of microglial cells to be AIF-1–/MRP8+. We conclude that the delayed expression of MRP8 and the lack of AIF-1 up-regulation in microglia after TBI is in contrast to ischemic brain lesions and might reflect different activation cascades of microglia.
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  • 22
    ISSN: 1432-0851
    Keywords: Keywords Melanoma ; Antigens ; Cytotoxic ; T lymphocytes ; Human ; Immunotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Melanoma-reactive HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) lines generated in vitro lyse autologous and HLA-matched allogeneic melanoma cells and recognize multiple shared peptide antigens from tyrosinase, MART-1, and Pmel17/gp100. However, a subset of melanomas fail to be lysed by these T cells. In the present report, four different HLA-A*0201+ melanoma cell lines not lysed by melanoma-reactive allogeneic CTL have been evaluated in detail. All four are deficient in expression of the melanocytic differentiation proteins (MDP) tyrosinase, Pmel17/gp100, gp75/trp-1, and MART-1/Melan-A. This concordant loss of multiple MDP explains their resistance to lysis by melanoma-reactive allogeneic CTL and confirms that a subset of melanomas may be resistant to tumor vaccines directed against multiple MDP-derived epitopes. All four melanoma lines expressed normal levels of HLA-A*0201, and all were susceptible to lysis by xenoreactive-peptide-dependent HLA-A*0201-specific CTL clones, indicating that none had identifiable defects in antigen-processing pathways. Despite the lack of shared MDP-derived antigens, one of these MDP-negative melanomas, DM331, stimulated an effective autologous CTL response in vitro, which was restricted to autologous tumor reactivity. MHC-associated peptides isolated by immunoaffinity chromatography from HLA-A1 and HLA-A2 molecules of DM331 tumor cells included at least three peptide epitopes recognized by DM331 CTL and restricted by HLA-A1 or by HLA-A*0201. Recognition of these CTL epitopes cannot be explained by defined, shared melanoma antigens; instead, unique or undefined antigens must be responsible for the autologous-cell-specific anti-melanoma response. These findings suggest that immunotherapy directed against shared melanoma antigens should be supplemented with immunotherapy directed against unique antigens or other undefined antigens, especially in patients whose tumors do not express MDP.
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  • 23
    ISSN: 1432-1211
    Keywords: Key words MHC class III region ; Mouse ; Human ; G7c ; Lung tumor susceptibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 24
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    Immunogenetics 51 (2000), S. 487-488 
    ISSN: 1432-1211
    Keywords: Key words Immunoglobulin ; J segments ; IGKJ genes ; Alleles ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 25
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    International archives of occupational and environmental health 73 (2000), S. 479-487 
    ISSN: 1432-1246
    Keywords: Key words Biological monitoring ; Formate ; Formic acid ; Human ; Methanol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A toxicokinetic (TK) model was developed to describe the inhalation exposure in humans to methyl formate (MF), a catalyst used in foundries, and to discuss biological monitoring. The TK model consisted of four compartments: MF, the metabolites – methanol (MeOH) and formic acid (FA) – and, in addition, a urinary compartment describing the saturable reabsorption of FA. Levels of MeOH and FA in urine, from an experimental study (100 ppm MF, 8 h at rest), validated the present model. The TK model describes well the general behaviour of MeOH and FA in urine after MF exposure. A nonlinear and a linear relationship respectively, was predicted between MF exposure and FA or MeOH excretion in urine, and this has previously been seen after occupational MF exposure. The present model has been modified to simulate MeOH exposure as well. Generally low exposures (concentration or exercise) produce only marginal increases in FA urinary excretions, but when exposure is elevated, urinary FA excretion increases because of saturation in the mechanism of reabsorption. Using FA urinary excretion as the critical indicator, because of its link to health effects, an occupational exposure limit value for MF of no greater than 50 ppm should be selected (based on predictions with the TK model). MeOH in urine can be considered as a biomarker for MF at low exposure, because of lower background values and of a linear relationship with exposure. At higher exposures, however, FA could be used as a biomarker as it becomes progressively more sensitive. But the use of biological monitoring for MF is difficult because of individual variations in background values. Under the present state of knowledge both FA and MeOH should be used to estimate only group exposures, rather than individual exposures.
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  • 26
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    Psychopharmacology 147 (2000), S. 339-346 
    ISSN: 1432-2072
    Keywords: Key words Sibutramine ; d-Amphetamine ; Abuse potential ; Subjective effect ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Sibutramine (Meridia) is a serotonin and norepinephrine reuptake inhibitor marketed for weight control. Previous studies demonstrated low abuse potential for 20 and 30 mg sibutramine (doses near the therapeutic range); however, no data existed on supratherapeutic doses. This study, therefore, examined 25 and 75 mg sibutramine in humans compared to d-amphetamine (20 mg) as a positive control and placebo as a negative control. Objectives: The study examined the acute subjective, reinforcing, and physiological effects of sibutramine to assess its abuse liability. Methods: Twelve polydrug abusers with no history of drug dependence participated in this double-blind, inpatient/outpatient study. Volunteers participated in four drug sessions, in which they completed subjective effects scales including the Profile of Mood States (POMS), Visual Analog Scales (VAS), and the Addiction Research Center Inventory (ARCI). The Multiple Choice Procedure (MCP) was used to evaluate reinforcing efficacy. Results: Sibutramine 25 mg produced subjective effects that were indistinguishable from placebo. Sibutramine 75 mg produced significant unpleasant effects, such as Anxiety, Confusion, and decreased Vigor. On the MCP, volunteers chose to give up an average of $4.04 from their study pay rather than receive the higher dose of sibutramine again. In contrast, d-amphetamine 20 mg produced positive mood changes and was well liked. Conclusions: These data indicate sibutramine lacks amphetamine-type abuse liability when administered acutely.
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  • 27
    ISSN: 1432-2072
    Keywords: Key words Haloperidol ; Dopamine ; Receptor occupancy ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Positron emission tomography (PET) is increasingly being used to study dopamine receptor occupancy and the clinical effects of antipsychotic medication. Dopamine D2 receptor occupancy has been shown to predict several clinical effects of antipsychotic medication including therapeutic response, motor and endocrine side-effects. Plasma levels may be used as a surrogate marker for central occupancy if the relationship between these two measures may be accurately described. This study was designed to test the capacity of a previously derived relationship equation (%D2 occupancy=plasma level/ED50+plasma level, where ED50= 0.40 ng/ml) to predict striatal D2 occupancy from plasma level. Twenty-one patients receiving treatment with low dose haloperidol underwent a 11C-raclopride PET scan to measure D2 occupancy. The D2 occupancy levels were accurately predicted by use of the previously generated equation with only a small degree of error (3.89% CI 0.45–7.33). Predicted and measured D2 occupancy values correlated closely (Pearson’s r=0.864, P=0.003). The study indicates that reliable prediction of D2 occupancy from plasma levels is possible. This provides a potentially useful surrogate measure of D2 occupancy for research and possibly clinical practice, as the routine use of PET to measure occupancy levels is not feasible.
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  • 28
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    Psychopharmacology 149 (2000), S. 24-33 
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Conditioning ; Cardiovascular effect ; Subjective effect ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Clinical data suggest that stimuli paired with cocaine use acquire emergent stimulus effects, such as the ability to elicit cocaine craving. Objectives: The purpose of this study was to determine the conditioned effects of neutral stimuli paired with cocaine smoking. Methods: Eight experienced adult cocaine smokers participated in 22 experimental sessions while residing on a Clinical Research Center. One set of cues (CS–) was paired with placebo smoked cocaine and one set of cues (CS+) was paired with 25 mg smoked cocaine. Results: After 18 training trials, the effects of cocaine on heart rate and ratings of ”anxious” were greater, and skin temperature and ratings of ”tired” were smaller when compared to the effects of cocaine after the first training trial. When instructed to select a cue to experience after training, seven of eight participants selected the CS+, while only three of the participants selected the CS+ prior to training, i.e., the CS+ functioned as a conditioned reinforcer. Presentation of the CS+ alone without cocaine during extinction trials increased HR, SP, and ratings of ”anxious””tired”, and ”I want cocaine” and decreased skin temperature. These changes elicited by presentation of the CS+ decreased over the course of the extinction sessions. Conclusions: The present results indicate that classical conditioning is one mechanism by which stimuli paired with cocaine acquire emergent stimulus effects.
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  • 29
    ISSN: 1432-1106
    Keywords: Key words Visual perception ; Object recognition ; Functional magnetic resonance imaging ; Neuroimaging ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Electrophysiologic and functional imaging studies have shown that the visual cortex produces differential responses to the presence or absence of structure within visual textures. To further define and characterize regions involved in the analysis of form, functional magnetic resonance imaging (fMRI) was used to detect changes in activation during the viewing of four levels of isodipole textures. The texture levels systematically differed in the density of visual features such as extended contours and blocks of solid color present within the images. A linear relationship between activation level and density of structure was observed in the striate cortex of human subjects. This finding suggests that a special subpopulation of striate cortical neurons participates in the ability to extract and process structural continuity within visual stimuli.
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  • 30
    ISSN: 1432-0738
    Keywords: Key words Diethylhexylphthalate ; Peroxisome proliferation ; Hepatocarcinogenesis ; Species differences ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Diethylhexylphthalate (DEHP) is a phthalate plasticizer that belongs to the peroxisome proliferator (PP) class of rodent nongenotoxic hepatocarcinogens. Previously, we have shown that MEHP (a principal metabolite of DEHP and the proximal PP) induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes in vitro. Here, we present further studies of species differences in response to DEHP. In rats, 4 days of exposure to DEHP (950 mg/kg per day by gavage) induced peroxisomal β-oxidation, DNA synthesis and suppressed apoptosis. In contrast, there was no response of guinea pig liver to DEHP. In rat hepatocytes in vitro, MEHP (250, 500 and 750 μM) induced peroxisomal β-oxidation, DNA synthesis and suppressed apoptosis. In contrast to the pleiotropic response noted in rat hepatocytes, there was no response of human hepatocytes to 250, 500 or 750 μM MEHP. PPs activate the peroxisome proliferator activated receptor alpha (PPARα) that binds to DNA at peroxisome proliferator response elements (PPREs) within the promoters of PP-responsive genes such as rat acyl CoA oxidase (ACO). However, the human ACO gene promoter differs at three bases within the PPRE from the rat ACO promoter and appears refractory to PPs. To address species differences in response to DEHP at the molecular level, we used promoter-reporter gene assays to compare the ability of MEHP to induce gene expression from the rat or the human ACO promoter. MEHP gave a concentration-dependent increase in reporter gene expression from the rat ACO gene promoter with either mouse or human PPARα. In contrast, the human ACO promoter was unable to drive MEHP-induced gene transcription irrespective of the species origin of PPARα. These data provide further weight of evidence at the cellular and molecular levels for a lack of risk to human health from the phthalate DEHP.
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  • 31
    ISSN: 1432-0738
    Keywords: Key words Organophosphate ; Acetylcholinesterase ; Oximes ; Human ; Reactivation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The reactivation of organophosphate-inhibited acetylcholinesterase (AChE) by oximes inevitably results in the formation of highly reactive phosphoryloximes (POX), which are able to re-inhibit the enzyme. In this study, the dependence of POX formation on AChE concentration was investigated with sarin-inhibited human erythrocyte AChE (EryAChE). A marked dependence was found with obidoxime but not with the experimental oxime HI 6, suggesting great differences in the decomposition rates of the respective POXs. At a physiological erythrocyte content the reactivation of EryAChE was markedly affected by POX with obidoxime and pralidoxime (2-PAM) but not with the newer oximes HI 6 and HLö 7. Addition of extensively dialysed, sarin-treated human plasma reduced the reactivation by obidoxime and 2-PAM even more. Obidoxime and 2-PAM were superior to HI 6 and HLö 7 in reactivating butyrylcholinesterase (BChE). This effect was pronounced in diluted plasma, but was obscured in concentrated plasma, probably because of re-inhibition by the generated POX. Addition of native erythrocytes to sarin-treated plasma resulted in marked inhibition of EryAChE in the presence of obidoxime, suggesting a higher affinity of the POX for EryAChE. The results indicate that obidoxime and 2-PAM may reactivate sarin-inhibited AChE insufficiently due to re-inhibition by the POX formed. In addition, the re-inhibition of EryAChE may be aggravated by the POX that is produced during BChE reactivation. These reactions must be regarded as therapeutically detrimental and disqualify those oximes which are capable of forming stable POX by reactivation of BChE.
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  • 32
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    Journal of neurology 247 (2000), S. I28 
    ISSN: 1432-1459
    Keywords: Key words Motor neurone ; Astrocyte ; Human ; Tissue culture ; ALS ; Glutamate ; Calcium ; SOD-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Defining the basis of the selective cell vulnerability of motor neurones (MN) represents the key issue in amyotrophic lateral sclerosis (ALS), and tissue culture models are the ideal system for the identification of the MN specific features at the single cell level. Neurone-astrocyte metabolic interactions, which have a critical role in MN through glutamatergic toxicity, have been mostly defined in vitro. Ca++ metabolism, which appears to play a critical role in inducing MN loss in ALS, has been successfully studied using in vitro cell models. Furthermore, primary cultures demonstrated that apoptotic or necrotic death of neurones after injury depends upon the cell energetic status. Superoxide dismutase-1 (SOD-1) mutations were successfully expressed in cultured rodent MNs, providing a critical assay to sequence the molecular processes responsible for MN degeneration due to the identified genetic defect. The recent identification of genes that separate humans from apes further increases the value of the human in vitro models to better understand specific human cellular properties. Purified human MNs and astrocytes can today be obtained from the human embryonic spinal cord anterior horns. Interactions at the single cell level can be dissected using the cDNA amplification techniques. The effects of molecules affecting MN survival, neurite extension, and metabolism can easily be defined in vitro, gaining a critical mass of information of immediate clinical application in the treatment of patients affected by ALS. Understanding the properties of human MNs in vitro represents today a significant and critical tool that can easily be reached after extension of the available knowledge from non-primate to human research. Human MN culture studies can greatly contribute to identifying the primitive critical cellular events responsible for the MN degeneration observed in ALS and to gaining crucial information ¶on new therapeutical agents.
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  • 33
    ISSN: 1432-2277
    Keywords: Key words Liver transplantation ; Rejection ; Tacrolimus ; Human ; Child
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rejection and efficacy of rescue therapy with tacrolimus were evaluated in 50 children who underwent primary, ABO-compatible, liver transplantation. Six patients who died within the first week and one child who underwent retransplantation from an ABO-incompatible donor were excluded from the study. No patient or graft were lost due to rejection. We observed 48 episodes of rejection in 33 patients. Fourteen patients required conversion to tacrolimus for steroid-resistant rejection with resolution of rejection. One of these children developed PTLD. Other indications for conversion were neurotoxicity and hirsutism. One patient developed blindness of unknown origin after the conversion. Other side effects of tacrolimus were minor and resolved by lowering the dose. Five patients developed rejection after conversion; all achieved resolution with either steroid therapy or increase of tacrolimus dose. In conclusion, our study confirms that tacrolimus is an effective rescue therapy for paediatric liver transplantation.
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  • 34
    ISSN: 1432-2307
    Keywords: Key words Pituitary ; Human ; Somatotroph ; Thyrotroph hyperplasia ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In patients with protracted primary hypothyroidism, the pituitary is enlarged due to the lack of feedback inhibition by thyroid hormone. In the present work, adenohypophysial biopsies from three women with protracted primary hypothyroidism were investigated by routine histology, immunocytochemistry, double immunostaining, immunoelectron microscopy, and combined immunocytochemistry – in situ hybridization. These methods confirmed the presence of massive thyrotroph hyperplasia and the formation of ”thyroidectomy” or ”thyroid deficiency” cells. A number of thyroidectomy cells were found to be immunoreactive for growth hormone (GH). Double immunostaining and immunoelectron microscopy revealed the presence of bihormonal cells containing both GH and thyroid stimulating hormone (TSH). Immunostaining combined with in situ hybridization revealed GH immunoreactive cells expressing TSH mRNA as well as TSH immunopositive cells expressing GH mRNA. Our findings provide conclusive evidence that somatotrophs may transform to thyrotrophs. Thus, in addition to multiplication of thyrotrophs, transdifferentiation of GH cells to thyrotrophs contributes to the increase of TSH-producing cells. The presence of such bihormonal cells best termed ”thyrosomatotrophs” supports the concept that adenohypophysial cells are not irreversibly committed to the production of one single hormone and that their phenotype can change in response to functional demand.
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  • 35
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    Child's nervous system 16 (2000), S. 235-241 
    ISSN: 1433-0350
    Keywords: Key words Magnetic resonance spectroscopy ; Epilepsy ; Brain metabolism ; GABA ; N-Acetyl aspartate ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The current applications of magnetic resonance spectroscopy (MRS) in the clinical management of epileptic patients are reviewed. A major contribution of MRS to epilepsy is its ability to determine lateralisation before surgical resection of the diseased brain region. Phosphorus-31 and proton single-voxel MRS identify abnormalities in high-energy metabolism, neuronal function and neurotransmitter levels, but information can only be obtained from restricted regions of the brain. Spectroscopic imaging techniques (also known as chemical shift imaging) provide a metabolic mapping of the whole brain. They expand the range of applications of MRS to other types of epilepsy (neocortical, frontal) than temporal lobe epilepsy, which is the most often studied. Also, spectral editing techniques in proton MRS make it possible to detect and monitor drug-induced variations of GABA in the human brain, opening new insights into patient response to drug therapy of epilepsy. MRS is playing an increasing role in the noninvasive characterisation and management of epileptic patients.
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  • 36
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    Knee surgery, sports traumatology, arthroscopy 8 (2000), S. 180-185 
    ISSN: 1433-7347
    Keywords: Keywords Proprioception ; Equilibrium ; Posture ; Reproducibility of results ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract The Kinesthetic Ability Trainer (KAT 2000) is a balance platform designed for training and functional testing of the neuromuscular control system. Forty healthy and sports-active persons were tested and 1 month later retested to investigate the reliability of the KAT 2000 testing “one-leg static balance” and “two-leg dynamic balance”. A significant improvement at retesting on the same day was seen in both tests; furthermore the dynamic test result improved significantly with retesting 1 month later. The data obtained made it possible to calculate the 95% confidence limits for an unchanged test result for a single person and a group of persons. The results show a clear learning effect when the persons are retested, especially in the dynamic test. The KAT 2000 can be used as a tool for testing groups of persons both in short- and long-term studies, but it cannot be used for testing single persons due to the great variance in the test results. Further investigations involving injured persons are needed to determine the range of improvement after intervention.
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  • 37
    ISSN: 1432-2013
    Keywords: Key words cDNA ; Human ; Cathepsin P ; Propeptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A cDNA encoding a novel human putative member of the papain family of cysteine peptidases has been cloned. The protease, named cathepsin P, is synthesized as a preproprotein. The presumed propeptide of 38 amino acids is followed by a 242-residue mature protein. The mature protease region is 30% identical to human papain-like cathepsins, with all the residues important for catalysis conserved. No similarity was observed in the propeptide region. On the contrary, the proenzyme shares 51-87% residues with some precursors of cysteine proteases from other species that have not yet been characterized. They all show a nearly completely conserved “CYTRED motif” in the propeptide region, not present in other members of the family, and could therefore constitute a distinct subfamily.
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  • 38
    ISSN: 1569-8041
    Keywords: breast cancer ; combination therapy ; paclitaxel ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:To evaluate the anti-tumour activity and tolerance of thecombination of paclitaxel plus vinorelbine in metastatic breast cancer (MBC)patients previously treated with anthracyclines. Patients and methods:Fifty-six MBC patients who have had at leastone previous anthracycline-containing chemotherapy regimen were enrolled inthis phase II trial. Patients received paclitaxel (135 mg/m2 overone-hour infusion) and vinorelbine (30 mg/m2) both on day 1 of eachthree-week course of therapy (maximum eight courses or until diseaseprogression was evident). Results:Six complete and nineteen partial responses were observedamong the fifty-four assessable patients (response rate of 46%,95% CI: 33%–60%). Responses were observed in alldisease sites and in all subsets of patients. The response rates whenpaclitaxel plus vinorelbine were used as first, second and third-linechemotherapy for metastases were 67%, 41% and 35%,respectively. The response rate among anthracycline-refractory patients was46% (6 of 13). Median time to progression in the overall patient groupwas 28 weeks. The main toxicities (CTC grade 2 or more) were alopecia,myelosuppression and peripheral neuropathy (85%, 46% and19% of patients, respectively). Nine patients (17%) hadneutropenic fever in fifteen of the three hundred twenty-eight coursesadministered (5%). Conclusions:The combination of paclitaxel and vinorelbine on day1 every three weeks is active in MBC patients with prior anthracyclineexposure. The regimen is safe, well tolerated and convenient for the patients.
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  • 39
    ISSN: 1569-8041
    Keywords: breast cancer ; cyclophosphamide ; fluorouracil ; mitoxantrone ; radiation therapy ; secondary leukemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The topoisomerase II-targeted drugs,epipodophyllotoxins and anthracyclines, have been shown to inducetherapy-related AML (t-AML) characterized by a short latency period afterchemotherapy, the absence of prior myelodysplastic syndrome and stereotypedchromosome aberrations. Few reports have been published on patients treatedwith the anthracenedione mitoxantrone which also targets topoisomerase II. Weobserved 10 cases of such t-AML over a 7-year-period in breast cancer patientstreated with mitoxantrone combined with fluorouracil, cyclophosphamide andregional radiotherapy, and in three cases with vindesine. Patients and methods:We retrospectively analyzed patientsreferred to our hospital for AML with a past history of polychemotherapy forbreast cancer, including mitoxantrone, either as adjuvant (8patients)/neoadjuvant (1 patient) therapy or for metastatic disease (1patient). We studied the probability of developing t-AML in a prospectiveseries of 350 patients treated with an adjuvant FNC regimen (mitoxantrone,fluorouracil, cyclophosphamide) and radiation therapy. Results:The median age was 45 years (range 35–67). t-AMLdeveloped 13–36 months (median 16) after beginning chemotherapy forbreast cancer, and 4–28 months (median 10.5) after ending treatment. Asdescribed in t-AML following treatment with epipodophyllotoxins oranthracyclines, we found a majority of FAB M4, M5 and M3 phenotypes (7 of 10),and characteristic karyotype abnormalities that also can be found in denovoAML: breakpoint on chromosome 11q23 (3 patients), inv(16)(p13q22)(2 patients), t(15;17)(q22;q11) (1 patient), t(8;21)(q22;q22) (1 patient) anddel(20q)(q11) (1 patient). The prognosis was poor. All patients died of AMLshortly after diagnosis. Since two patients had been enrolled in a prospectivetrial for the treatment of breast cancer which included 350 patients, theprobability of developing t-AML was calculated to be 0.7% from25–40 months, using the Kaplan–Meier method (95% confidenceinterval (95% CI): 0.1–4.5). Conclusions:The combination of mitoxantrone withcyclophosphamide, fluorouracil, and radiation therapy can induce t-AML, aswith other topoisomerase II-targeted drugs. Despite a low incidence, theprognosis appears to be poor.
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  • 40
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    Annals of oncology 11 (2000), S. 1255-1262 
    ISSN: 1569-8041
    Keywords: age ≤35 years ; breast cancer ; single institution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Early-onset breast cancer may differ with respect toetiology, clinical features and outcome compared with breast cancer in olderwomen. To gain further insight, we retrospectively reviewed the clinicalfeatures and outcome of women ≤35 years with primary breast cancer seen atour institution over a 30-year period. Patients and methods:Charts were reviewed for women with operablebreast cancer diagnosed ≤35 years of age seen at the Princess MargaretHospital (PMH), Toronto from 1965–1994. Results:One thousand eighty-six women with non-metastaticinvasive breast cancer, aged 18.3–35.6 years (median 32.1 years) werereferred to PMH. Symptoms at presentation included: self-detected breast lump(83%), other breast symptom (10%), physician diagnosis(4%) and unknown (3%). Tumor size was known in 936 (〉2 cm in61%) and nodal status in 888 (lymph node positive in 52%).Modified radical mastectomy was performed in 568 (57%) andbreast-conservation surgery (BCS) in 422 (42%). Five hundred sixteen(51%) patients received adjuvant radiotherapy and five hundredthirty-four (53%) adjuvant systemic therapy. Two hundred ninety-three(29%) patients had a family history of breast cancer (FH).Contralateral breast cancer (CBC) occurred more frequently in women with FH(Prange 0.042–0.008). Local recurrence (LR) was 37% and73% at 10 years in those treated by BCS with and without radiotherapy,respectively. At 10 years, disease-free survival (DFS) was 30% andoverall patient survival 48%. Conclusions:In this cohort, breast cancer was usuallyself-diagnosed and tumors were 〉2 cm at presentation in approximatelytwo-thirds of cases, suggesting the possibilities of a delay in diagnosis,more aggressive tumors or both. Our results are compatible with the knownassociation of breast cancer FH with increased CBC. Our data also corroboratesthe suggestion that positive genetic testing in this age group should lead toconsideration of more aggressive ipsilateral and contralateral breastmanagement. In those receiving adjuvant irradiation after BCS, the LR rate washigh, but did not impact on overall survival.
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  • 41
    ISSN: 1569-8041
    Keywords: breast cancer ; carboplatinum ; chemotherapy ; continuous 5-fluorouracil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We performed a trial using the combination of epirubicin 50mg/m2/day 1, carboplatinum AUC 5/day 1 and continuous5-fluorouracil (5-FU) 200 mg/m2/day (every 4 weeks for6 months) to confirm the efficacy and low toxicity profile of thisregimen in breast cancer. In 51 patients with metastatic(n = 33) or locally advanced (n = 18)breast cancer the overall response rate was 86% (95% confidenceinterval (95% CI): 73%–94%): 94% in locallyadvanced and 81% metastatic disease. Grade 3–4 toxicity was low:4% of patients presented with febrile neutropenia, 16% withsevere palmar-plantar syndrome, 10% with Port-a-cath thrombosis. This study confirms the high efficacy of infusional 5-FU-based regimens andjustifies further research into novel promising oral 5-FU derivatives.
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  • 42
    ISSN: 1569-8041
    Keywords: adjuvant chemotherapy ; breast cancer ; doxorubicin ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The purpose of this study was to evaluate the clinicaloutcome of doxorubicin-based adjuvant chemotherapy in elderly breast cancerpatients and to compare results in elderly patients with those in youngerpatients. Patients and methods:We retrospectively reviewed the records ofall patients aged 50 years or older treated in trials of doxorubicin-basedadjuvant chemotherapy between 1974 and 1988. Old age was not an exclusioncriterion for these trials. Patient characteristics, hematologic andnonhematologic side effects, patterns of recurrence, and causes of death weredetermined for patients aged 50–64 years and for patients aged 65 yearsor older, and results were compared between these two groups.Kaplan–Meier survival curves were plotted, and tested by the generalizedWilcoxon test. Results:A total of 390 patients aged 50 years or older weretreated with doxorubicin-based adjuvant chemotherapy during the study period.Of these, 325 were aged 50–64 years (group 1), and 65 were aged 65 yearsor older (group 2). The median follow-up period for group 1 was 185 months(range 29–272+ months), and the median follow-up period for group 2 was169 months (range 128–240+ months). There were no statisticallysignificant differences between the two groups with respect to performancestatus, hormone receptor profile, tumor size, nodal status, or type oflocoregional therapy. There also were no statistically significant differencesbetween the two groups in recurrence patterns, disease-free survival, oroverall survival. The granulocyte and platelet nadirs of cycles 1, 3, and 6were similar between the two groups. No cumulative hematologic side effectswere seen in either group. The occurrence of second malignancies was extremelylow in both groups. In both groups, the majority of deaths were due toprogression of disease. Conclusions:Adjuvant doxorubicin-based chemotherapy is welltolerated in elderly breast cancer patients who have good performance statusand normal cardiac ejection fraction. Adjuvant doxorubicin-based chemotherapyin these patients results in disease-free and overall survival rates similarto those seen in younger patients.
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  • 43
    ISSN: 1569-8041
    Keywords: breast cancer ; hot flashes ; paroxetine ; serotonin uptake inhibitors ; survivors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Many breast cancer survivors suffer debilitating hotflashes. Estrogen, the drug of choice in perimenopausal women, is generallynot recommenced to breast cancer survivors. Nonhormonal treatments are mostlydisappointing. Anecdotal reports in our institution suggested that theselective serotonin-reuptake inhibitor, paroxetine hydrochloride, might beefficacious in alleviating hot flashes. Patients and methods:Thirty women with prior breast cancer whowere suffering at least two hot flashes a day entered a single institutionpilot trial to evaluate paroxetine's efficacy in reducing the frequency andseverity of hot flashes. After completing daily diaries for one week on notherapy, the women received open-label paroxetine, 10 mg daily for one week,followed by four weeks of paroxetine, 20 mg daily. The women completedhot-flash daily diaries throughout the study period, and a health-relatedsymptom-assessment questionnaire and a quality-of-life rating scale in thefirst and sixth week of the study. Results:Twenty-seven women completed the six-week study period.The mean reduction of hot flash frequency was 67% (95%confidence interval (95% CI): 56%–79%). The meanreduction in hot flash severity score was 75% (95% CI:66%–85%). There was a statistically significantimprovement in depression, sleep, anxiety, and quality of life scores.Furthermore, 25 (83%) of the study participants chose to continueparoxetine therapy at the end of study. The most common adverse effect wassomnolence, resulting in drug discontinuation in two women, and dose reductionin two women. One woman discontinued drug due to anxiety. Conclusions:Paroxetine hydrochloride is a promising new treatmentfor hot flashes in breast cancer survivors, and warrants further evaluationin a double-blind randomized placebo-controlled trial.
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  • 44
    ISSN: 1569-8041
    Keywords: breast cancer ; socio-economic status ; stage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:This study describes and compares the pathologicalprognostic factors and surgeon assessment of stage of breast cancer of womenliving in affluent and deprived areas to assess whether clinical stage atpresentation may explain the known poorer survival outcomes for deprivedwomen. Patients and methods:A population-based review of the caserecords of 417 women with breast cancer was carried out. Results:No difference in pathological criteria was found betweenthe 88% of women living in affluent and deprived areas for whom suchdata were available. Clinical assessment of the remaining 50 cases showed thatwomen living in deprived areas were more likely to present with locallyadvanced or metastatic disease. Conclusion:The poorer survival of women from deprived areas withbreast cancer may be explained by more deprived women presenting with advancedcancers.
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  • 45
    ISSN: 1569-8041
    Keywords: breast cancer ; choice ; decision-making process ; patient–physician relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Shared decision-making is increasingly advocated asan ideal model. However, very few studies have tested the feasibility ofgiving patients the opportunity to participate in the choice of treatment. Patients and methods:Women, with non-metastatic breast cancer,eligible for non-intensified adjuvant chemotherapy attending our hospital wereproposed two administrations of chemotherapy and radiotherapy: a sequentialand a concomitant one. Two patient-questionnaires were used to elicitmotivations for their choice and their degree of comfort with the process ofdecision-making and one questionnaire to test physicians' ability to predictpatients' choice. Results:Participation rate in the study was 75.3%(n = 64). Majority (64%) of patients chose the concomitanttreatment. Multivariate analysis revealed that patients with a lower level ofeducation, who discussed the choice with social circle, and who most fearedside-effects were more likely to choose the sequential treatment. Physicianswere able to predict patients' choice in 66% of cases. 89% ofpatients declared that they were "fully satisfied" with having participatedin the choice of treatment and 79% supported shared decision-making. Conclusions:Results are in favour of promoting activeparticipation of cancer-patients in medical decision-making. The adequatedegree of such participation remains however to be elicited and tested fortherapeutic choices implying more difficult trade-offs between quantity andquality of life.
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  • 46
    ISSN: 1569-8041
    Keywords: adjuvant therapy ; breast cancer ; second cancer ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Women treated with tamoxifen for breast cancer are atincreased risk of endometrial cancer. We conducted a retrospective cohortstudy to evaluate the risk of second primary cancers after adjuvant tamoxifentherapy for breast cancer in Japan. Patients and methods:The subjects of the study were 6148 womenwho had been diagnosed with stage I, II, or IIIA unilateral primary breastcancer and had received surgical treatment during the period from January 1982through December 1990 at nine institutions in Japan. The information on eachpatient was obtained from medical records or a prospectively compiled computerdatabase at each institution. Results:Of the 6148 women, 3588 (58.4%) were administeredtamoxifen as an adjuvant treatment and 2560 (41.6%) were notadministered. Median follow-up periods were 7.64 years for tamoxifen-treatedpatients and 8.10 years for non-tamoxifen-treated patients, respectively. Theduration of tamoxifen treatment was mostly two years or less (80.7%),and few patients received tamoxifen for more than five years. The cumulativeincidence rates of all second cancers at 10 years were 4.61% and4.09% among tamoxifen-treated and non-tamoxifen-treated patients(P = 0.62), respectively, and the incidence rate ratio (IRR) forall second cancers was 1.06 (95% confidence interval (CI):0.77–1.47) after adjustment of several covariates. The numbers ofendometrial cancers was 9 and 3 among tamoxifen-treated andnon-tamoxifen-treated patients, respectively, and the IRR was 2.37 (95%CI: 0.64–8.77, P = 0.20). Of the 12 patients who developedendometrial cancer, 4 died of cancer (for 3 of them, the cause of death wasbreast cancer), and the other 8 patients were alive as of March 1996. Stomachcancer was the most frequent second cancer and the IRR was 1.34 (95%CI: 0.76–2.38, P = 0.31). There was no substantialincrease in any other type of gastrointestinal cancer such as colorectal andliver cancers among tamoxifen-treated patients. Conclusions:The incidence and risk of second primary cancersassociated with tamoxifen therapy is low. The potential benefit of adjuvanttamoxifen therapy in breast cancer patients outweighs the risk of secondprimary cancers for Japanese breast cancer patients.
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  • 47
    ISSN: 1569-8041
    Keywords: breast cancer ; docetaxel ; epirubicin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:In a previous phase I trial we evaluated the toxicity anddetermined the maximum tolerated doses of the docetaxel (D)–epirubicin(Epi) combination. We conducted a multicenter phase II study to evaluate theefficacy and tolerability of this regimen as front-line treatment in womenwith advanced breast cancer (ABC). Patients and methods:Fifty-four women with ABC stage IIIB (4patients) or IV (50 patients) received front-line treatment with Epi 70mg/m2 on day 1 and D 90 mg/m2 on day 2. The median agewas 55 years, performance status (WHO) was 0–1 in 49 patients andvisceral disease was present in 45 (83%). Results:All patients were evaluable for toxicity and 50 forresponse. In an intent-to-treat analysis complete remission was observed in5(9%) patients, partial remission in 31 (57%) (overall responserate 66%, 95% confidence interval: 54%–79%),stable disease in 9 (17%) and disease progression in 9 (17%).After a median follow-up of 11.5 months, the median duration of responses was8 months, the median time to disease progression 11.5 months and the mediansurvival has not yet been reached. The probability of one-year survival was65%. Three hundred six cycles of treatment were administered (median6 cycles per patient). Grade 3 and 4 neutropenia was observed in 8(15%) and 31 (57%) patients, respectively, and febrileneutropenia in 19 (35%). Prophylactic rh-G-CSF was used in 45(83%) patients or 226 (74%) cycles. Other hematologic ornon-hematologic toxicities were usually mild. In five (9%) patients theleft ventricular ejection fraction (LVEF) was decreased by more than10% with the treatment. Two patients died during the treatment ofrespiratory failure without associated neutropenia. Conclusions:The combination of docetaxel–epirubicin is aneffective and well tolerated front-line treatment in patients with ABC.
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  • 48
    ISSN: 1569-8041
    Keywords: breast cancer ; p53 ; prognostic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:There is heterogeneity of methods and conflictingresults concerning the prognostic value of p53 in node-negativebreast cancer. The clinical value of a quantitative method for measuringtumoral p53 content still needs to be evaluated. Patients and methods: A long-term retrospective study wasconducted on 297 node-negative patients with a median follow-up greater than10 years (11 years, 101–172 months). Classic prognostic factors wereconsidered including age, tumor size, histoprognostic grade and estradiol (ER)and progesterone receptors (PR). In addition, the value of p53 determination (immunoluminometric assay in tumor cytosol) was assessed forthis long follow-up period. Results: p53 concentrations were significantly linked tothe histological grade (P = 0.001), to tumor size (P = 0.02)and ER status (P = 0.01). Higher p53 tumoral concentrationswere found in tumors with large size, pejorative histological grade andnegative ER status. In contrast, p53 tumoral concentrations were notinfluenced by menopausal or PR status. Multivariate Cox analysis demonstratesthat tumor size was the only significant predictor of disease-free survival(P = 0.049) with a risk factor at 1.38. As regards specific survival,univariate Cox analysis indicates that p53 taken as a continuousvariable is a significant predictor (P = 0.024) together withhistological grade, tumor size and ER status. In a multivariate Cox analysisthere were two significant and independent variables for predicting overallsurvival: tumor size (P = 0.031) and ER status (P = 0.015)with the highest risk factor (RR = 2.14). Conclusions:The present investigation points out that theprognostic power of p53 tumor determination evaluated at more than10 years median survival is not higher than the well-recognized classicprognostic factors in node-negative breast cancer. The present data highlightthe need to assess the prognostic value of potentially new biological factorsin node-negative breast cancer on cohorts of patients followed over periodsin excess of 10 years.
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  • 49
    ISSN: 1569-8041
    Keywords: breast cancer ; genetic counselling ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:With the identification of genes predisposing tohereditary breast cancer, the accurate and consistent estimation of a woman'srisk of developing breast cancer based on her family history is of paramountimportance if national service guidelines are to be developed. Patients and methods:The residual lifetime risk of developingbreast cancer was estimated for 200 women attending a breast cancer geneticassessment clinic by three different methods currently in use in the UK. Riskswere computed on the basis of the Cancer and Steroid Hormone (CASH) study dataand were classified as ‘low/moderate’ (〈20%) or ‘high’(〉20%). These risk categories are representative of those currentlyused to allocate surveillance and genetic testing. Risks were then comparedto estimates derived by other methods used in current clinical practice,including those of Houlston and Murday. Results:The CASH data-based method ascribed 27% to thehigh risk category, as compared to 53% for the combined Houlston andMurday methods. A method based on the number of affected relatives aloneascribed only 14% to the high risk category. Overall, 108 (54%)women were placed in the same risk category by all three methods. Conclusions:This study demonstrates that there is a significantdegree of variability between methods currently used to estimate breast cancerrisk which has serious implications for individual patient management, serviceprovision and multicentre studies evaluating the benefits of genetic testingfor breast cancer susceptibility.
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  • 50
    Electronic Resource
    Electronic Resource
    Springer
    Annals of oncology 11 (2000), S. 495-496 
    ISSN: 1569-8041
    Keywords: breast cancer ; gemcitabine ; metastases ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:Gemcitabine (GEM) and vinorelbine (VNR) are both activeagainst advanced breast cancer (ABC), being able to induce a median ORR of25% and 40%, respectively. Because of their different mechanismof action and good tolerability, the combination of GEM and VNR has beentested in ABC. Patients and methods:Twenty-nine ABC patients pretreated withanthracycline-taxane were treated with GEM 1000 mg/m2 on day 1, 8,15, and VNR 25 mg/m2 on day 1 and 8 every twenty-eight days.Analysis of toxicity pattern, response rate, TTP and OS were carried out. Results:Twenty-nine patients were enrolled into the trial. TheORR was 48% (95% CI: 29–67): a CR was observed in threepatients (10%; 95% CI: 2–27), while eleven patients(38%; 95 CI: 21–58) achieved PR, eight (28%) had a SD, andseven (24%) progressed. Toxicity was mainly hematological and included:grade 3 leukopenia in 48% of cases without episodes of neutropenicfever, grade 3–4 thrombocytopenia in 10%, and grade 2 anemia in7%. Non-hematological toxicities were mild and rather infrequent. Conclusions:The GEM–VNR combination seems to be active inpretreated ABC with an acceptable toxicity pattern, and may well reppresentan interesting therapeutic choice after anthracycline/taxane regimens.
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  • 51
    Electronic Resource
    Electronic Resource
    Springer
    Annals of oncology 11 (2000), S. 469-474 
    ISSN: 1569-8041
    Keywords: breast cancer ; Prognostic factors ; psychosocial factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Research interest in psychosocial predictors of theonset and course of cancer has been active since the 1950s. Recently wereported associations between psychological factors and survival in patientswith metastatic melanoma. We now report a replication of this study in asample of women with metastatic breast cancer. Patients and methods:Ninety-nine patients with metastatic breastcancer completed questionnaires measuring cognitive appraisal of threat,coping, psychological adjustment, perceived aim of treatment, social supportand quality of life, approximately four months after diagnosis. Survival wasmeasured from date of study entry to date of death or censored at the date oflast follow-up for surviving patients. Results:In a multivariate analysis, four factors independentlypredicted outcome. Patients with metastases in the liver, lung or pleurasurvived for a shorter duration (P 〈 0.001); older patients(P 〈 0.001) and those with a better appetite (P 〈0.05) also lived for a shorter time. Patients who minimised the impact ofcancer survived longer (a median of 29.1 vs. 23.9 months after study entry,P 〈 0.01). Conclusions:Minimisation was also significantly associated withoutcome in patients with metastatic melanoma who participated in anidentically designed study, reported elsewhere. This suggests thatminimisation may have a general impact on cancer progression and deservescloser scrutiny in other cancers.
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  • 52
    ISSN: 1569-8041
    Keywords: 5-FU ; breast cancer ; metastatic ; navelbine ; protracted continuous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The protracted continuous infusion (PCI) of5-fluorouracil (5-FU) has proven in several studies an active and welltolerated treatment for advanced, pretreated breast cancer. Navelbine has alsoactivity in this setting. Patients and methods:Heavily pretreated patients with metastaticbreast carcinoma were eligible for the study. Treatment consisted of 5-FU 250mg/m2 given as a PCI by an elastomeric pump and navelbine 20mg/m2 on days 1 and 8, every four weeks. Eighty-three patients(median age 54 years; range 32–82 years) entered the study. The mediannumber of metastatic tumour sites was 2, with visceral involvement in 56patients. Apart from five patients with contraindications, all patients hadbeen pretreated with anthracyclines. Thirty-one patients had received taxanesand seventy-four bolus 5-FU. Results:A median of 5 cycles (range 1–14) per patient wasadministered. The median duration of 5-FU infusion was 17 weeks (range, 4-90).In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and24 partial remissions occurred (response rate, 45%). Median durationof response was 9 months. Toxicity was mild. Median survival was 20 months. Conclusions:PCI–5-FU combined with navelbine offers areasonable chance of tumour regression with modest side effects in patientswith heavily pretreated breast cancer.
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  • 53
    ISSN: 1569-8041
    Keywords: adjuvant chemotherapy ; attitudes ; breast cancer ; consensus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:A worldwide variation in policy is seen regardingadjuvant systemic treatment for node negative breast cancer (NNBC). After thefirst presentations of the 10-year EBCTCG results, a study was carried out inthe Netherlands to assess patterns of care and to obtain the views ofoncologists as to what constitutes a worthwhile benefit from treatment. Methods:A questionnaire regarding patterns of use of andpreferences for adjuvant chemotherapy in younger women was mailed to surgical,medical and radiation oncologists in the Netherlands. Results:Thirty-five percent stated that NNBC patients under 50in their hospital never received adjuvant chemotherapy. The majorityconsidered a 10-year survival gain of 6%–10% sufficientto warrant the use of chemotherapy in patients under 50. Surgical oncologistsrequired a larger benefit from treatment than radiotherapists and medicaloncologists. The more frequently oncologists treated patients in a researchcontext, the less benefit they required from treatment to make it worthwhile. Conclusions:Data such as these are valuable input into theprocess of guideline development, and may help discussion within theprofession as to what benefit offsets the burden of treatment.
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  • 54
    ISSN: 1569-8041
    Keywords: breast cancer ; clinical trial ; docetaxel ; hepatic metastases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Previous phase II studies of docetaxel have indicatedthat hepatic metastases from breast cancer respond well to first-linetreatment with docetaxel. The objective of this prospective, open label phaseII study therefore was specifically to evaluate the activity and safety ofdocetaxel in this indication. Patients and methods:The study recruited 47 women (mean age 50years, range 33–66 years) with hepatic metastases from breast cancer whofulfilled the eligibility criteria. After premedication with steroids,patients received a one-hour intravenous infusion of docetaxel 100mg/m2 at three-weekly intervals for up to eight cycles. Responseto treatment during medication was assessed after three, six and whereappropriate, eight cycles and every three month follow-up thereafter, untildisease progression or death. Results:The best overall response rate (ORR) for evaluablepatients was 64.3% (95% CI: 48.0%–78.5%).In terms of the primary efficacy parameters, the ORR at the sixth cycle oftreatment was 62% (95% CI: 45%–80%) with17% complete responses. The median duration of response was 139 days(95% CI: 111–216 days) and the median survival durationcalculated on an intent-to-treat basis was 335 days (227–568 days,95% CI). One (2%) toxic death was reported. Conclusions:Docetaxel is a highly effective cytotoxic agent inthe treatment of patients with liver metastases from breast cancer.
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  • 55
    ISSN: 1569-8041
    Keywords: breast cancer ; lymph nodes ; sentinel lymph node biopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Sentinel node biopsy (SNB) has been proposed as analternative to axillary lymph-node dissection (ALND) in breast cancer. Beforeimplementing SNB in our practice, we wished to test its validity by comparingit to the standard ALND, both in our hands and with other reported series. Patients and methods:One hundred thirty-two patients wereincluded prospectively. SNB and immediate ALND were performed. For SNB, atechnetium-colloid was used to produce preoperative lymphoscintigraphy andintraoperative gamma-probe search for the SN. Serial sectioning andimmunostains were used on the SN. A comprehensive review of the literature wasdone in order to run a meta-analysis of diagnostic tests using a summaryreceiver operating characteristic curve (SROC) to calculate the pooledparameters of sensitivity and associated 95% confidence interval(95% CI), including our own data. Results:Our technical success rate was 96%. Localsensitivity was 96%, with a 95% CI from85%–99%. Seven patients were upstaged by the SNB. Aliterature search identified 18 studies published from 1996–1999.Estimates of sensitivity ranged from 83%–100%. The pooleddata meta-analysis gave a global sensitivity of 91%, with a 95%CI from 89%–93%. The area under the global SROC curve was0.9967. Conclusions:The minimally invasive SNB was shown to be apractical alternative to ALND. We propose to use local as well as globalsensitivity and associated 95% CI to test the validity of SNB in theclinical setting. Due to limitations of ALND as the golden standard, SNB canin fact be considered a more accurate method for nodal staging.
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  • 56
    ISSN: 1569-8041
    Keywords: docetaxel + gemcitabine ; docetaxel + vinorelbine ; phase I ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:The objective of this study was to determine thedocetaxel MTD when combined with gemcitabine or vinorelbine in advanced breastcancer patients who had received previous anthracycline-based chemotherapy foradvanced disease. Patients and methods:Advanced breast cancer patients aged between18 and 70 with ECOG PS 0–2 who had not responded to, or had relapsedafter, first-line anthracycline-based chemotherapy, were randomized to receiveeither gemcitabine 1000 mg/m2 or vinorelbine 25 mg/m2in combination with escalating doses of docetaxel (starting from 30mg/m2), all on days 1 and 8 every three weeks. Escalation wasstopped if 〉33% of patients treated at a given dose level showed DLTat the first cycle. Results:A total of 34 patients with locally advanced (8) ormetastatic disease (26) were treated, for a total of 94 cycles delivered.Nineteen patients received docetaxel in combination with gemcitabine and 15with vinorelbine. All patients had been pretreated with anthracyclines, and24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of40/m2 proved to be safe when combined on days 1 and 8 withgemcitabine, while a dose of 35 mg/m2 was tolerated in combinationwith vinorelbine. Overall, nine episodes of DLT, all of them neutropenia,occurred at the first cycle. Considering all 94 cyles, grades 3 or 4neutropenia and thrombocytopenia occurred in 15 (44%), and 7(20%) patients. Non-hematologic toxicity was mild, except for threecases of grade 2 peripheral neuropathy. All patients were assessed forresponse on an 'intent-to-treat' basis. Overall, five partial responses wererecorded (docetaxel + gemcitabine = 3 and docetaxel + vinorelbine = 2), fora 15% (95% CI: 5%–31%) overall responserate. Only 1 of 24 (4%) patients who had received weekly dose-densepaclitaxel responded to treatment. Conclusions:The weekly docetaxel administration in combinationwith either gemcitabine or vinorelbine is a well-tolerated treatment forheavily pretreated advanced breast cancer patients. This approach, althoughsometimes capable of achieving a major response, does not seem advisable inadvanced breast cancer patients refractory to both anthracyclines andpaclitaxel.
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  • 57
    ISSN: 1569-8041
    Keywords: breast cancer ; estrogen receptor ; progesterone receptor ; preoperative chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:We recently demonstrated that in premenopausalpatients with estrogen receptors (ER)-absent tumors, early initiation ofsystemic chemotherapy after primary surgery might improve outcome. These dataindicate a different responsiveness to chemotherapy for tumors not expressinghormone receptors. To test this hypothesis we evaluated the responsiveness topreoperative chemotherapy in patients with ER and progesterone receptors(PgR)-absent tumors. Patients and methods:Patients with biopsy-provenT2–T3, N0–2 breast cancertreated at a single institution from January 1995 to August 1999 withpreoperative chemotherapy were retrospectively evaluated. ER and PgR weredetermined immunohistochemically and classified for this purpose as absent(0% of the cells positive) or positive (≥1% of the cells). Results:On 117 evaluable patients 72 had an objective response(61%). A significant difference in response was observed for patientswith ER and PgR absent compared with those with ER and/or PgR-positive tumors(82% vs. 57%,P = 0.03 Fishers's exact test).Pathological complete remission rates were also significantly different in thetwo groups (23% vs. 7%, respectively; P = 0.04). Conclusions:The different degree of response according to hormonereceptors expression supports the hypothesis that tumors not expressing bothER and PgR might represent a different clinical entity in terms ofchemotherapy responsiveness.
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  • 58
    ISSN: 1432-2072
    Keywords: Key words Cerebral blood flow velocity ; EEG ; Caffeine ; Withdrawal ; Physical dependence ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. Objective: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. Methods: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. Results: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. Conclusion: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.
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  • 59
    ISSN: 1432-2072
    Keywords: Key words Opioids ; Self-administration ; Progressive ratio ; Drug abuse ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. Objective: We investigated the influence of morphine dose and an alternative non-drug reinforcer on choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. Methods: Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an IM injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned one-ninth of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single IM injection at the end of the session; money earned was credited to the subject’s account. Results: As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. Conclusion: The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies.
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  • 60
    ISSN: 1615-2573
    Keywords: Key words Basal systemic nitric oxide production rate ; Fasting ; Human ; Plasma nitrate ; Single-compartment model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It is of great interest and value to evaluate the systemic nitric oxide (NO) production rate in humans under various conditions. However, the currently available estimation methods are troublesome and time-consuming. We thus aimed at developing a simple method to estimate the basal systemic NO production rate in humans based on a steady-state analysis, i.e., a balance between the systemic NO production rate and the total nitrate elimination rate. Plasma nitrate concentrations of young healthy volunteers (n = 7 in group 1; n = 9 in group 2) were measured for 2 days. In group 1, all subjects had the same meals for 7 days prior to the plasma nitrate measurement. In group 2, all subjects were allowed free diets. The plasma nitrate concentrations were highly influenced by dietary nitrite/nitrate intake in both groups and reached the steady-state levels after 14-h fasting. Accordingly, the basal systemic NO production rates were estimated from the plasma nitrate concentrations after 14-h fasting (group 1, 630 ± 37 nmol min−1 = 0.78 ± 0.03 μmol kg−1 h−1; group 2, 597 ± 45 nmol min−1 = 0.66 ± 0.05 μmol kg−1 h−1, P = not significant vs group 1). These estimated values were comparable to the values obtained by other methods. In conclusion, the present estimation method with 14-h fasting using a single-compartment analysis was found to be a simple approach to quantitative evaluation and intra- and interindividual comparisons of the basal systemic NO production rates in humans.
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  • 61
    ISSN: 1615-2573
    Keywords: Key words Heat shock protein ; Antibody ; Vascular disease ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Heat shock proteins (Hsp) are families of phylogenetically conserved molecules that have a range of cytoprotective and intracellular functional roles. Reactivity to heat shock proteins has been implicated in the development of autoimmune disease and tissue expression of heat shock proteins and increased levels of anti-Hsp antibodies have also been reported in vascular disease. This study compared circulating levels of Hsp60 and Hsp70 and antihuman Hsp60, antihuman Hsp70, and antimycobacterial Hsp65 antibodies in peripheral (PVD) and renal (RVD) vascular disease with those in age- and sex-matched controls. Levels of Hsp70 were higher in both PVD (median 580 vs 40; P 〈 0.01) and RVD (median 160 vs 0; P 〈 0.03), whereas there were no differences in Hsp60 levels. Anti-Hsp60 antibody levels were elevated in PVD (146 vs 81 arbitrary units/ml; P 〈 0.04), but not RVD. This is the first study to demonstrate increased levels of circulating Hsp70 in pathological disease states; however, its physiological role remains to be determined.
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  • 62
    ISSN: 1439-6327
    Keywords: Key words Temporal summation ; Repeated electrical stimulation ; Experimental pain ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present human study, we aimed to investigate the facilitation of both the subjective pain responses, and the withdrawal reflex to consecutive transcutaneous electrical stimuli as measures of temporal summation. The frequency (0.5–20 Hz) and intensity (0.4–0.8 times the reflex threshold,  ×RT) of the electrical stimuli were systematically varied. When using repeated stimulation, the stimulus intensity that evoked pain was lower than that required by a single stimulus (temporal summation). Temporal summation leading to pain was found to depend significantly upon both frequency and intensity (e.g. stimulation at 1 Hz caused summation at 0.8 × RT, whereas stimulation at 20 Hz caused summation at 0.6 × RT). The strongest reflex facilitation, and hence the strongest pain intensity was obtained for stimulation at 10–20 Hz at an intensity of 0.8 × RT. In conclusion, the results of the present human study demonstrate clearly that a stimulus that is perceived as a localised, repetitive tactile tap can be integrated and cause severe pain. This suggests that pathologically generated sparse nociceptive afferent activity causes strong pain by central integration. This might be one mechanism to explain why clinical conditions can become excruciatingly painful despite the fact that the pathophysiological changes seem to be marginal (e.g. minor nerve trauma).
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  • 63
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    European journal of applied physiology 83 (2000), S. 106-115 
    ISSN: 1439-6327
    Keywords: Key words Central fatigue ; Muscle fatigue ; Human ; Motor cortex ; Motoneuron
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fatigue is a reduction of maximal muscle force or power that occurs with exercise. It is accompanied by changes at multiple levels in the motor pathway and also by changes in the discharge patterns of muscle afferents. Changes in afferent firing can lead to altered perceptions and can also act on the efferent pathway. Changes in the motor pathway include slowing of motor unit firing rates during sustained maximal voluntary contractions (MVCs). Muscle responses to stimulation at different levels of the motor pathway also change. Transcranial magnetic stimulation of the motor cortex and stimulation of descending tracts in the spinal cord in human subjects show an increase in the response of the cortex and a decrease in response of the motoneuron pool during sustained MVCs. In addition, the silent period following magnetic stimulation is prolonged. During relaxation after fatiguing exercise, muscle responses to stimulation of the motor cortex are initially facilitated and are then depressed for many minutes, whereas responses to descending tract stimulation are initially depressed but recover over about 2 min. Although some of the loss of force of fatigue does occur through inadequate drive to the muscle, it is not clear which, if any, of the changes described in the cortex or the motoneurons are responsible for loss of maximal voluntary force and thus contribute to fatigue. Changes may be associated with muscle fatigue without causing it.
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  • 64
    ISSN: 1439-6327
    Keywords: Key words Fatigue ; Glenohumeral joint ; Human ; Occupational musculoskeletal problems ; Proprioception
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Repetitive work to fatigue is soundly associated with work-related musculoskeletal disorders (WMSD), although the underlying mechanisms are poorly understood. In the present study, we tested the hypothesis that fatiguing work leads to proprioceptive deficits, which can be an initiating factor for the occurrence of WMSD. Thus, the position sense of the shoulder was determined for 13 males and 13 females before and after performing repetitive low-intensity arm work to fatigue in a simulated occupational setting. From a starting position of 45° to the sagittal plane, position sense tests consisted of subjects attempting to actively reproduce target positions of horizontal movements to 15° and 30° (shoulder adduction) and to 60° and 75° (shoulder abduction). An analysis of variance revealed that the absolute error was significantly increased following fatigue for the subjects as a group (P 〈 0.001). Furthermore, females had an overall higher error than males (P 〈 0.01). No difference in error was detected for the shorter movements versus the longer movements. However, the overall absolute error for adduction was significantly higher than for abduction (P 〈 0.001). The results of the present study support the hypothesis of diminished proprioceptive acuity following low-intensity work to fatigue. A reduction in position sense acuity could lead to impairment in motor control, which would further impact on position sense. Thus, a vicious cycle may be activated that might result in WMSD. The poorer position sense acuity observed for females may contribute to the explanation of why females demonstrate a higher incidence of WMSD than males.
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  • 65
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    European journal of applied physiology 81 (2000), S. 210-213 
    ISSN: 1439-6327
    Keywords: Key words Cross-sectional area ; Exercise ; Human ; Reflex sympathetic activity ; Skeletal muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This research was performed to study how the cross-sectional area (CSA) changes in the skeletal muscles of exercising (E-leg) and contralateral non-exercising (N-leg) legs and to evaluate to what extent changes in CSA mirror changes in blood flow or extravascular water displacement. Seven healthy volunteers performed plantar flexion exercise at three different exercise intensities for 10 min each. Six plantar flexions followed by a 2-s rest in between allowed repeated measurement of the blood flow to the lower limbs by duplex ultrasonography in the popliteal artery and CSA by magnetic resonance imaging. The CSA was measured using manual planimetry at rest and after 3 and 9 min of the exercise periods. The CSA increased in the E-leg by 4.5% and decreased in the N-leg by −2.4%, from rest to highest exercise intensity. Post-exercise imaging of the E-leg showed a bi-phasic recovery of CSA with a rapid phase followed by a slower phase while the blood flow very rapidly returned almost to basal. The time course of the post-exercise decrease indicated that about 50% of the increase in CSA at the highest exercise intensity might have been a result of extravascular water displacement and 50% of an increase in the vasculature volume related to the flow increase. The CSA reduction in N-leg seems to have been related to vasoconstriction, probably mainly of the capacitance vessels since blood flow was not reduced.
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  • 66
    ISSN: 1439-6327
    Keywords: Key words Local cold ; Extremities ; Cold induced vasodilatation ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hand cooling is a cold pressor test, which induces general sympathetic stimulation. This cooling procedure is often performed to investigate cold induced vasodilatation (CIVD) in one finger. To investigate the effects of this sympathetic stimulation on local CIVD, 12 subjects immersed either the right index finger (T1), right hand (T2) or left hand and right index finger (T3) for 30 min in water at 5°C followed by 15-min recovery. Skin temperature and skin blood flow (Q˙ sk) measured by laser Doppler flowmetry on the right index finger, as well as heart rate (f c) and mean arterial blood pressure ( ), were continuously monitored during the three tests. Cutaneous vascular conductance was calculated as Q˙ sk/ . Concentrations of plasma noradrenaline (NA) and adrenaline (AD) were measured at different times during the tests. The results showed no cardiovascular change in T1, whereas f c and increased significantly at the beginning of both T2 and T3. Similarly, sympathetic stimulation was reflected in the NA concentrations, which increased significantly (P 〈 0.01) during T2 and T3 after 5 min of immersion, and remained elevated until the recovery period. The AD concentration did not change during the three tests. During T2, the CIVD appeared later and slower in comparison with T1 [CIVD onset: 12.81 (SEM 2.30) min in T2 and 5.62 (SEM 0.33) min in T1] . During T3, the CIVD onset was not delayed compared to T1 [6.38 (SEM 0.67) min], but the rewarming was lower [+5.40 (SEM 0.86)°C in T3 and +9.10 (SEM 1.31)°C in T1]. These results showed that CIVD could be altered by sympathetic stimulation but it also appeared that the onset of CIVD could be influenced by local cooling, independently of the general sympathetic stimulation.
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  • 67
    ISSN: 1439-6327
    Keywords: Key words Eccentric-concentric actions ; Electromyography ; Gastrocnemius muscle ; Soleus muscle ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The objective of this study was to investigate muscle and tendon stiffness in the triceps surae muscles in patients who had previously had a stroke. The participants were 12 men showing slight to moderate degrees of muscle tonus in the affected leg. All patients showed minimal or no overt clinical motor symptoms, and all walked without mechanical aid. Muscle strengths in isometric and isokinetic activities were measured, as was passive resistance during plantarflexion in each leg. Walking speed was also measured. Evaluations of physical performance and muscle tone were made. Muscle and tendon stiffness was calculated from measurements whilst passively stretching during electrical stimulation, separately for each leg. Muscle strength was significantly higher in the non-affected than in the affected leg. Muscle stiffness was significantly higher in the affected leg than in the non-affected leg. Tendon stiffness was significantly higher in the non-affected than in the affected leg. The higher muscle stiffness in the affected leg might enhance the possibility for storing elastic energy during preactivation. Lower tendon stiffness in the affected leg might reduce the development of fatigue in movements at low velocities.
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  • 68
    ISSN: 1439-6327
    Keywords: Key words Bed rest ; Resistance training ; Skeletal muscle ; Physiological cross-sectional area ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this study was to investigate the effects of resistance training on the morphological and functional properties of human lower limb muscles during 20 days of 6° head-down-tilt bed rest. Nine men were randomly assigned to the resistance training group (BR-Tr, n=5) or the non-training, control group (BR-Cont, n=4). Isometric leg-press exercises were performed: 3 s × 30 repetitions (30 s rest between repetitions) daily for 20 days during the bed-rest period. Serial axial magnetic resonance images were taken from the right thigh and leg muscles, and muscle volume, muscle length, and fibre length were estimated. The physiological cross-sectional areas (PCSAs) of the knee extensor, knee flexor, ankle plantarflexor, and ankle dorsiflexor (tibialis anterior) muscle groups were determined as muscle volume multiplied by the cosine of the angle of fibre pennation divided by fibre length. Maximum voluntary contraction (MVC) during knee extension was measured. No significant changes were observed in the PCSA of the knee extensor muscles in BR-Tr group, whereas the PCSA in the BR-Cont group decreased by 7.8%. The PCSA of the knee flexor and plantarflexor muscles in the BR-Tr group and BR-Cont group significantly decreased after bed rest (knee flexors, 10.2% and 11.5%; plantarflexors, 13.0% and 12.8%, respectively). However, in both groups bed rest had no effect on the muscle volume and PCSA of the tibialis anterior. MVC was maintained by resistance training in the BR-Tr group (decreased by 1%). In contrast, a decline of strength was observed in the BR-Cont group (−16%), but this result was not statistically significant. These results suggest that isometric leg-press training prevents the deconditioning (i.e. atrophy and decline of strength) of the knee extensor muscle group.
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  • 69
    ISSN: 1573-7276
    Keywords: bone sialoprotein ; osteopontin ; breast cancer ; metastasis ; bone metastases ; immunohistochemistry ; in situ hybridization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bone sialoprotein (BSP) and osteopontin (OPN) are prominent, mineral-associated proteins in the extracellular matrix of bone that have been implicated in the metastatic activity of cancer cells. The expression of BSP, which is normally restricted to mineralizing tissues, has been observed in cancers with a high propensity for forming bone metastases. To investigate the relationship between BSP expression and the formation of bone metastases we have conducted an initial study of the expression of BSP in 10 intraductal breast carcinoma bone metastases using immunostaining and in situ hybridization, and compared the expression with OPN. The metastases were characterized by the infiltration of tumour cells into bone with extensive bone resorption evident. Moderate to strong staining for BSP was observed in all (100%) carcinomas, which also expressed BSP mRNA as determined by in situ hybridization. Variable staining for BSP was also observed in the mineralized bone and expression of BSP mRNA could be observed in osteoblastic cells on the bone surface and in some osteocytes at sites of bone remodelling. Contrary to a previous report, BSP expression could be demonstrated by PCR in three breast cancer cell lines, MCF-7, T47-D and MDA-MB-231. Moreover, in sub-cutaneous tumours formed by MDA-MB-231 breast cancer cells injected into athymic mice, higher immunostaining for BSP was seen in large ulcerating tumours in which mineral deposits were formed. In contrast to BSP, staining for OPN in bone metastases was generally restricted to the interface between tumor cells and bone surface of the carcinomas. While OPN staining was also observed in the cytoplasm of osteoclasts, which showed strong hybridization to a digoxygenin-labelled OPN cRNA probe, expression of OPN was not clearly detectable in the tumour cells. These studies provide the first demonstration of BSP expression by tumour cells in bone metastases and support the concept that BSP may have a role in targeting metastatic cells to bone. Expression of OPN in bone metastases appears to be related to increased bone resorptive activity by osteoclasts.
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  • 70
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    Clinical & experimental metastasis 18 (2000), S. 573-580 
    ISSN: 1573-7276
    Keywords: breast cancer ; cell motility ; KGF ; metastasis ; MCF-7 ; T-47D ; ZR-75-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Endogenous growth factors and cytokines are known to have a major influence on the progression, motility and invasiveness of tumor cells. We have reported previously that conditioned media from mouse fibroblasts increases the motility of breast cancer cells. Further, we determined that keratinocyte growth factor (KGF) was an active factor from mouse fibroblasts responsible for most of the motility response in breast cancer cells. The present study examined the effect of human KGF on the motility of estrogen receptor (ER)-positive and ER-negative human breast cancer cell lines in culture using time-lapse videomicroscopy to quantify cell motility. In the present study we observed that recombinant human KGF enhanced several parameters of cellular motility in ER-positive cells but not in ER-negative cell lines. Further, we observed that the level of KGF receptor (KGFR) expression in ER-positive cells was much greater than in the ER-negative cell lines. The motility response to KGF was found to be both dose-and time-dependent. Of the three ER-positive breast cancer cell lines tested, MCF-7 cells were the most responsive to KGF stimulation. Finally, MCF-7 cells grown in estrogen-depleted media did not respond to KGF. These results suggest that KGF from stromal tissue surrounding a primary tumor mass can enhance tumor cell motility and may be an early signal in the progression of breast cancer cells to a more motile and metastatic phenotype. Thus, KGF, KGFR and/or the KGF signaling pathway may be important therapeutic targets for the treatment or prevention of breast cancer metastasis.
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  • 71
    ISSN: 1573-7276
    Keywords: breast cancer ; chromosome 11q13 ; gap junctions ; metastasis suppressor gene ; motility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Introduction of normal, neomycin-tagged human chromosome 11 (neo11) reduces the metastatic capacity of MDA-MB-435 human breast carcinoma cells by 70–90% without affecting tumorigenicity. Differential display comparing MDA-MB-435 and neo11/435 led to the discovery of a human breast carcinoma metastasis suppressor gene, BRMS1, which maps to chromosome 11q13.1–q13.2. Stable transfectants of MDA-MB-435 and MDA-MB-231 breast carcinoma cells with BRMS1 cDNA still form progressively growing, locally invasive tumors when injected in mammary fat pads of athymic mice but exhibit significantly lower metastatic potential (50–90% inhibition) to lungs and regional lymph nodes. To begin elucidating the mechanism(s) of action, we measured the ability of BRMS1 to perturb individual steps of the metastatic cascade modeled in vitro. Consistent differences were not observed for adhesion to extracellular matrix components (laminin, fibronectin, type IV collagen, type I collagen, Matrigel); growth rates in vitro or in vivo; expression of matrix metalloproteinases, heparanase, or invasion. Likewise, BRMS1 expression did not up regulate expression of other metastasis suppressors, such as NM23, Kai1, KiSS1 or E-cadherin. Motility of BRMS1 transfectants was modestly inhibited (30–60%) compared to parental and vector-only transfectants. Ability to grow in soft agar was also decreased in MDA-MB-435 cells by 80–89%, but the decrease for MDA-MB-231 was less (13–15% reduction). Also, transfection and re-expression of BRMS1 restored the ability of human breast carcinoma cells to form functional homotypic gap junctions. Collectively, these data suggest that BRMS1 suppresses metastasis of human breast carcinoma by complex, atypical mechanisms.
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  • 72
    ISSN: 1573-7373
    Keywords: choroidal metastasis ; leptomeningeal carcinomatosis ; breast cancer ; docetaxel ; mitoxantrone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Choroidal metastases from breast cancer represent an unusual metastatic presentation that has been traditionally treated with radiation therapy. Herein, we report a case of metastatic breast cancer presenting with pulmonary, cutaneous, lymph node and symptomatic choroidal metastases treated with systemic combination chemotherapy incorporating docetaxel and mitoxantrone without induction or consolidation radiation therapy to control visual symptoms from choroidal metastases. The patient experienced a durable complete remission in all metastatic sites that was maintained for 21 months since the initiation of chemotherapy, afterwhich she developed isolated leptomeningeal carcinomatosis managed successfully with intensive intrathecal methotrexate and whole brain irradiation leading to a new complete remission maintained until this report; 11 months after its presentation. This is the first case to our knowledge reporting complete regression of choroidal metastases with docetaxel-based chemotherapy as the only treatment modality and subsequent isolated leptomeningeal carcinomatosis recurrence.
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  • 73
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 351-364 
    ISSN: 1573-7039
    Keywords: Human ; breast cancer ; premalignant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Most human invasive breast cancers (IBCs)4 arise from preexisting benign lesions. There are many types of benign lesions in the human breast and only a few appear to have significant premalignant potential (atypical hyperplasias and in situ carcinomas). These lesions are relatively common and only a small proportion progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect evidence based on epidemiological studies. Although lesions within specific categories look alike, they must possess morphologically silent biological differences motivating some to remain stable and others to progress. Understanding the biological changes responsible for the development and progression of premalignant disease is a very active area of medical research. Progress in this area may provide new opportunities for breast cancer prevention by providing strategies to treat premalignant lesions before they develop or become cancerous. A large number of biological features have been evaluated in this setting during the past decade. This review discusses a few features that appear to be particularly important and have been studied in a relatively comprehensive manner.
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  • 74
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 409-420 
    ISSN: 1573-7039
    Keywords: Pre-malignancy ; breast cancer ; experimental model ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract While a number of agents have been shown to induce mammary carcinogenesis in the rat, premalignant stages of the disease have been best characterized in chemically-induced models, specifically those initiated by either 7,12 dimethylbenz[α]anthracene (DMBA)4 or 1-methyl-1-nitrosourea (MNU). In general, it appears that epithelial cells in mammary terminal end buds or terminal ductules are the targets of carcinogenic initiation, and that a series of morphologically identifiable steps are involved in the development of mammary carcinoma. The premalignant steps include ductal hyperplasia of the usual type and carcinoma in situ of the cribriform or comedo type; atypical ductal hyperplasia has not been reported. Thus the histogenesis of lesions occurring in chemically induced mammary carcinogenesis in the rat is similar to that observed in the human; although, the spectrum of lesions observed in the rat is limited. Opportunities to investigate the biological and molecular characteristics of premalignant breast disease in the rat are presented.
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  • 75
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 139-163 
    ISSN: 1573-7039
    Keywords: breast cancer ; pathology atlas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This article illustrates the most common benign and malignant lesions in the breast, and is intended for the biologist working in the area of breast cancer and breast biology, not for the practicing pathologist. The atlas covers benign proliferative lesions, atypical lesions, variants of in situ cancer, the main types of invasive cancers, spindle cell lesions, and examples of vascular and lymphatic spread. Some entities are included to illustrate a point of particular relevance to the biology and histogenesis of the lesions. Some controversial diagnostic areas are considered, along with the relative risk of developing breast cancer associated with some of the proliferative lesions. The content of this atlas should be read in conjunction with the companion article by Howard and Gusterson in this issue. Their article covers the cellular origin of epithelial and stromal tumors and presents a description of some of the common benign proliferative lesions that are considered to be components of the normal spectrum of changes seen at postmortem or in biopsies.
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  • 76
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 341-349 
    ISSN: 1573-7039
    Keywords: Premalignancy ; risk ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Premalignant breast disease in humans is a concept that admits to a broad range of elements and possible determinants predicting the likelihood of developing breast cancer. Most of these elements are relative, such as the risk of breast cancer for women that is 130 times that of men and peaks at a younger age by about 10 years. Breast cancer is clearly a stochastic, multifactorial process that evolves over many years in which we must make predictions by likelihood. This review will present the most specially defined and reliably proven of these elements, highlighting anatomic and molecular factors.
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  • 77
    ISSN: 1573-7217
    Keywords: adjuvant chemotherapy ; breast cancer ; decision-making ; treatment preference ; decision board instrument
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose.To examine the effects of framing of outcome and probabilities of cancer occurrence on the treatment preference which breast cancer patients indicate for hypothetical patient scenarios. Methods.A modified version of the Decision Board Instrument (Levine et al. 1992) was administered to 35 breast cancer patients with past ACT experience. Patients expressed their choice regarding ACT for six scenarios which were characterized by either negative or positive framing of outcome and by one of the three levels of probability of recurrence (high, medium, low). Results.The framing had no influence on ACT choices over all three probability levels. The majority chose ACT for high and medium risk and one third switched from ACT to No ACT in the low-risk condition. This switch was statistically significant. Conclusion.Hypothetical treatment decisions against ACT occur only when the probability of recurrence is low and the benefit of ACT is small. This finding for patients with past experience of ACT is similar to those reported for other oncological patient groups still in treatment.
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  • 78
    ISSN: 1573-7217
    Keywords: breast cancer ; metastasis ; liver metastasis ; surgical procedure ; hepatectomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have performed a retrospective study to evaluate whether surgical treatment is beneficial in patients with hepatic metastases from breast cancer. Between September 1985 and September 1998, 25 patients with hepatic metastases (14 solitary and 11 multiple), eight of whom had extrahepatic metastases, underwent hepatectomy. All of the detectable liver metastasis were resected in all of the cases. There were no severe postoperative complications. All but one of the patients received adjunctive polychemotherapy after the hepatectomy. After the hepatectomy, recurrent tumors were detected in 18 of the patients, being located in the liver in 12 (67%) of them. Overall, however, hepatectomy ensured that the liver was clinically recurrence-free for a median of 24 months (range 2–132 months). Eleven patients died of recurrent tumors, two died of other causes and the remaining 12 are currently alive. The 2- and 5-year cumulative survival rates after hepatectomy were 71% and 27%, respectively, and the median survival duration was 34.3±3.2 months, much better than the period of 8.5 months for another series of patients treated with standard or non-surgical therapies at our institution. The number and the size of hepatic metastases, the interval between treatment of the primary lesion and hepatectomy, and the existence of extrahepatic metastasis were not adverse prognostic factors. In conclusion, our data, although limited and highly selective, suggest that surgical treatment of hepatic metastases from breast cancer may prolong survival in certain subgroups of patients to a greater extent than standard or non-surgical therapies.
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  • 79
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; continuous variables statistical analysis ; cytokeratins ; multiple correspondence analysis ; prognosis ; tissue cytosol ; tissue polypeptide antigen (TPA)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apoptosis is associated with caspase-mediated proteolysis of Type I (K18 and K19) cytokeratins. We previously showed a positive association between the levels of tissue polypeptide antigen (TPA), that recognizes cytokeratins K8, K18, and K19 fragments, and induced apoptosis in breast cancer cell lines. The aim of the present study was to evaluate the interrelationships between TPA, steroid receptors, and p53, and their joint prognostic role in node-negative breast cancer patients not treated with adjuvant therapies. Age and pT were also considered since they are known prognostic factors. Five hundred and ninety-nine cases with N- breast cancer were evaluated (median follow-up: 60 months). TPA was measured by an immunoradiometric assay and p53 by an immuno-chemiluminescent assay in tumor cytosol. Multiple correspondence analysis was used to study the associations among variables. Their prognostic role (univariate analysis) and their joint effect (multivariate analysis) on RFS were investigated with Cox regression models. TPA showed a direct association with ER and PgR. Higher p53 values were weakly associated to low values of ER, PgR, and TPA. Younger age was related to low and intermediate values of ER and PgR and to low p53 values, while older age was related to high values of ER. Multivariate analysis showed a significant prognostic impact for pT, age, ER, and TPA. Among the interactions considered clinically relevant, only that between ER and age was found. RFS estimated values were poorer in cases with lower than in those with higher TPA values, both in patients expected to have a poor (pT2, young age, low ER) and a better prognosis (pT1, older age, high ER). From the findings of the present study we can draw the following conclusions: The relationship of TPA with prognosis gives an additional contribution to pT, age, and steroid receptors in N- breast cancer; TPA may be considered the first marker of apoptosis measured with a fully standardized quantitative method in tumor cytosol and could be evaluated in prognostic indexes including markers related to different biological mechanisms.
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  • 80
    ISSN: 1573-7217
    Keywords: reversal ; paclitaxel ; resistance ; P-glycoprotein ; breast cancer ; valspodar ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Paclitaxel (Taxol®) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated 〉6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
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  • 81
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    Cancer causes & control 11 (2000), S. 239-247 
    ISSN: 1573-7225
    Keywords: alcohol ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: To study the association between alcohol consumption and breast cancer risk. Methods: A case–cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40–59 at recruitment.) The cohort was recruited between 1980 and 1985, and during follow-up to the end of 1993 a total of 1469 women in the dietary cohort were diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons the analyses were based on 1336 cases and 5238 noncases. Results: When compared to nondrinkers the adjusted incidence rate ratios (95% confidence intervals) for those consuming 〉 0 and  ≤ 10 g of alcohol/day,  〉 10 and  ≤ 20 g/day,  〉 20 and  ≤thinsp;30 g/day,  〉 30 and  ≤ 40 g/day,  〉 40 and  ≤ 50 g/day, and  〉 50 g/day were 1.01 (0.84–1.22), 1.16 (0.91–1.47), 1.27 (0.91–1.78), 0.77 (0.51–1.16), 1.00 (0.57–1.75), and 1.70 (0.97–2.98), respectively; the associated p value for the test for trend was 0.351. Similar findings were obtained when analyses were conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, for screen-detected and interval-detected breast cancer, and by levels of other breast cancer risk factors. Conclusions: The results of this study suggest that alcohol consumption might be associated with increased risk of breast cancer at relatively high levels of intake.
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  • 82
    ISSN: 1573-7225
    Keywords: breast cancer ; insulin growth factor I ; leptin ; postmenopause ; premenopause
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: Because both breast cancer and the hormone leptin are associated with obesity and reproductive phenomena in women, we have examined whether there is a relationship between leptin and breast cancer among premenopausal and postmenopausal women. We have also evaluated in this dataset the association of IGF-I with breast cancer. Methods: Seventy-five cases, diagnosed during mammographic screening, with incident breast cancer were matched for age and type of permanent residence with seventy-five controls from those screened negative in the same study base. Results: There was no evidence for an association between IGF-I and either premenopausal or postmenopausal breast cancer risk or between leptin and postmenopausal breast cancer. Among premenopausal women, however, there was a strong and statistically significant inverse association of leptin with breast cancer. Conclusion: We did not confirm the positive association, reported from other investigations, of IGF-I with premenopausal breast cancer risk. We have found evidence, however, that leptin may be inversely related to breast cancer risk among premenopausal women. The latter finding is not biologically implausible and deserves to be examined in additional datasets.
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  • 83
    ISSN: 1573-7225
    Keywords: breast cancer ; body weight ; case–control study ; postmenopausal ; weight gain ; weight loss
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: Although many studies have shown that higher weight increases the risk of postmenopausal breast cancer, some aspects of this association are unclear. In order to examine the risk associated with different patterns of weight change, we analyzed data from a large case–control study of postmenopausal breast cancer. Methods: Participants included women aged 50–79 years (n = 5031) who are newly diagnosed with invasive breast cancer in Massachusetts, New Hampshire, and Wisconsin. Similarly-aged population controls (n = 5255) were selected at random from driver's license files and Medicare beneficiary lists. Height, weight, and information on other breast cancer risk factors were ascertained by structured telephone interviews from 1992 to 1995, and logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Women in the top quintile groups for height at age 20, recent weight, and recent body mass index had significantly increased risks of breast cancer. Among women who reached their highest adult weight at younger ages (≤45 years), increasing weight loss since that age was associated with a reduced risk of postmenopausal breast cancer (OR 0.90, CI 0.84–0.98, per 5 kg). However, weight loss among women whose highest weight occurred after age 45 was not associated with risk (OR 1.00, CI 0.95–1.05, per 5 kg). Weight gain since the lowest adult weight increased risk by 8% for each 5 kg of gain (OR 1.08, CI 1.06–1.11). Temporary weight cycling (weight loss followed by weight gain) was not associated with increased risk. Conclusions: Weight gain clearly increased risk of postmenopausal breast cancer. These data lend further support to efforts aimed at helping women avoid weight gain as they age.
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  • 84
    ISSN: 1573-7225
    Keywords: breast cancer ; breast density ; mammographic density ; risk factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: Mammographically defined percent breast density is an important risk factor for breast cancer, but the epidemiology of this trait is poorly understood. Although several studies have investigated the associations between reproductive factors and density, few data are available on the associations of breast density and waist-to-hip ratio (WHR), physical activity, education, alcohol and smoking. Methods: We investigated the associations of known and suspected breast cancer risk factors with breast density in a large breast cancer family study. Information was collected on members of 426 families through telephone interviews, mailed questionnaires and mammography. Mammographic films on 1900 women were digitized and breast density was estimated in discrete five-unit increments by one radiologist. Analysis of covariance techniques were used and all analyses were performed stratified by menopausal status. Results: Similar to other reports, nulliparity, late age at first birth, younger age and lower body mass index were associated with increased percent density in both premenopausal and postmenopausal women, and hormone replacement therapy among postmenopausal women. Higher levels of alcohol consumption and low WHR were associated with increased percent density among both premenopausal and postmenopausal women (differences of 3–11% between high and low categories). However, smoking and education were inversely associated with percent density among premenopausal (p = 0.004 and p = 0.003, respectively) but not postmenopausal women (p = 0.52 and p = 0.90). Physical activity was not associated with percent density in either stratum (p values 〉 0.25). Combined, these factors explained approximately 37% of the variability in the percent density measure in premenopausal women and 19% in postmenopausal women. Conclusions: Many of these factors may potentially affect breast cancer risk through their effect on percent breast density.
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  • 85
    ISSN: 1573-7217
    Keywords: breast cancer ; bromodeoxyuridine ; Ki-67 ; nodes ; survival ; S-phase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Proliferation indices are intended to help patients and clinicians make treatment decisions. We have previously demonstrated that a proliferation index based on in vivo labeling of S-phase cells with bromodeoxyuridine (BrdUrd) correlates with Ki-67 labeling index (LI). We now compare the prognostic value of these indices. With written consent, we gave 129 women with biopsy confirmed breast cancer 200 mg/M2 BrdUrd during 30 min immediately preceding surgery. We used IU-4 anti BrdUrd antibody to count the immunohistochemical labeling index (LI) of DNA-incorporated BrdUrd in 2,000 cells and MIB-1 to count Ki-67 (118 cases). Patients received standard surgical and adjuvant treatment. No patients were lost to follow-up and patients were followed a minimum of 2 (median 5.1) years. We compared survival and recurrence in tumors with high vs low labeling indices. We found that women in the low BrdUrd LI group had better disease free survival (92% vs 67% 5-yr DFS p = 0.001) and overall survival (94% vs 70% 5-yr OS, p = 0.0001) than those with a high LI. In comparison, a low Ki-67 index predicted better OS (87% vs 80% 5-yr OS, p = 0.020) and a trend for better DFS (84% vs 72% DFS p = 0.055). The apparent superiority of BrdUrd LI over Ki-67 LI is likely due to chance (p = 0.18). In multivariate survival analyses we found that BrdUrd LI proliferative index significantly improves prediction of DFS or OS even when node status, age or tumor size is in the model. We conclude that markers of proliferation are useful adjuncts in predicting patient prognosis.
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  • 86
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    Breast cancer research and treatment 59 (2000), S. 185-192 
    ISSN: 1573-7217
    Keywords: BRCA1 mutation ; breast cancer ; disease-free survival ; overall survival ; pathology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Reports from different countries have been inconclusive in attempting to relate the BRCA1 mutation status to the survival of breast cancer patients. The purpose of this study was to investigate overall and disease-free survival for German hereditary breast cancer patients. Data on clinical outcome and data on age at diagnosis of breast cancer, histology, tumor size, lymph node status, histological grade, and laterality of 36 breast cancer patients from 12 families with a BRCA1 mutation and from one family with strong evidence for linkage to BRCA1 were compared with those of 49 hereditary breast cancer patients from 23 families that did not harbor a BRCA1 mutation. Overall and disease-free survival was estimated for both groups. BRCA1 mutation carriers had a significantly earlier age of diagnosis than non-carriers (p = 0.0001) and more frequently developed contralateral breast cancer (p = 0.04). Also, BRCA1-associated tumors more frequently were of larger size (p = 0.041) and higher grade of malignancy (p = 0.005) than non-BRCA1-associated tumors. Whereas no difference in overall survival was seen, disease-free survival at 10 years differed significantly with 53.3% for BRCA1 mutation carriers and 76% for non- carriers (p = 0.02). However, after stratification for age and in multivariate analysis for mutation status, age, and bilaterality, it was shown that the worse prognosis for BRCA1 mutation carriers disappeared. Our results suggest that the worse prognosis of BRCA1 mutation carriers in terms of disease-free survival may in large part be due to the age of onset of breast cancer in this population. Thus, BRCA1 mutation status does not appear to be an independent prognostic factor.
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  • 87
    ISSN: 1573-7217
    Keywords: breast cancer ; dose-intensity ; G-CSF ; metastatic ; vinorelbine ; weekly schedule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: In this phase II study, we explored tolerability and activity of vinorelbine administered according to a dose-dense weekly schedule with hematopoietic growth factor support in pretreated, advanced breast cancer patients. Patients and Methods: From January 1994 to March 1996, 40 patients with metastatic breast cancer, pretreated with at least one prior anthracycline-containing regimen, were entered into the study. Patient characteristics: median age 53 years (range 32–70); ECOG performance status 0-1: 34 patients, 2: 6 patients; dominant visceral metastatic disease: 15 patients, dominant non-visceral: 25; anthracycline-refractory/resistant: 2 patients, sensitive: 38 patients. Six patients were treated as first-line therapy for metastatic disease and 34 in second- or subsequent lines. All patients received vinorelbine at the dose of 25 mg/m2/week as a short intravenous infusion, together with routine antiemetic medication. Granulocyte-colony stimulating factor (Lenograstim) at the dose of 150 μg/m2 subcutaneously on day 3 was included in the treatment schedule. Results: The median number of treatment weeks was 23 (range: 4–24), with a delivered dose-intensity (DDI) of 23.8 mg/m2/week (range: 18.7–25, 95.2% of projected dose-intensity). Toxicity was mild, with non-complicated neutropenia being the main toxicity observed (grade 3–4 in 25% of the patients but only 2% of treatment weeks). Overall response rate was 52.5%, with complete responses in 12.5% of patients. Median duration of the response and median time to progression were 10 and 9 months, respectively. Median overall survival was 19 months. Conclusion: Dose-dense weekly vinorelbine is safe and effective with minimal toxicity in pretreated advanced breast cancer patients.
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  • 88
    ISSN: 1573-7217
    Keywords: antibody ; breast cancer ; HER-2/neu ; immunity ; ovarian cancer ; T-cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunomodulatory strategies, such as antibody therapy and cancer vaccines, are increasingly being considered as potential adjuvant therapies in patients with advanced stage breast cancer to either treat minimal residual disease or prevent relapse. However, little is known concerning the incidence and magnitude of the pre-existent breast cancer specific immune response in this patient population. Using the HER-2/neu oncogenic protein as a model, a well-defined tumor antigen in breast cancer, we questioned whether patients with advanced stage HER-2/neu overexpressing breast and ovarian cancers (III/IV) had evidence of pre-existent immunity to HER-2/neu. Forty-five patients with stage III or IV HER-2/neu overexpressing breast or ovarian cancer were evaluated for HER-2/neu specific T cell and antibody immunity. Patients enrolled had not received immunosuppressive chemotherapy for at least 30 days (median 5 months, range 1–75 months). All patients were documented to be immune competent prior to entry by DTH testing using a skin test anergy battery. Five of 45 patients (11%) were found to have a significant HER-2/neu specific T cell response as defined by a stimulation index ≥ 2.0 (range 2.0–7.9). None of eight patients who were HLA-A2 had a detectable IFNγ secreting T-cell precursor frequency to a well-defined HER-2/neu HLA-A2 T cell epitope, p369-377. Three of 45 patients (7%) had detectable HER-2/neu specific IgG antibodies, range 1.2–8.9 μg/ml. These findings suggest that patients with advanced stage HER-2/neu overexpressing breast and ovarian cancer can mount a T cell and/or antibody immune response to their tumor. However, in the case of the HER-2/neu antigen, the pre-existent tumor specific immune response is found only in a minority of patients.
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  • 89
    ISSN: 1573-7217
    Keywords: breast cancer ; prognosis ; Nottingham histologic grade ; S-phase fraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Flow cytometric DNA analysis with assessment of S-phase fraction and DNA ploidy was compared to Nottingham histologic grade. The study population consisted of 654 patients who presented between 1987 and 1996 with primary operable breast cancer and whose tumours had been analysed for S-phase fraction and DNA ploidy at the time of surgery. Grade, tumour size, node status, steroid receptor status, age, S-phase fraction and DNA ploidy were analysed univariately and multi-variately in a Cox proportional hazard analysis. In the univariate analyses all parameters were statistically significantly associated with breast cancer mortality during the follow-up period of 2–11 years. The most powerful predictor of death from breast cancer in the multiple regression analysis was grade. Patients with grade 1 tumours have excellent prognosis. We conclude that tumour grade is a strong prognostic indicator applicable to all breast cancer patients, regardless of size and nodal status, and advocate its general use.
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  • 90
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    Breast cancer research and treatment 63 (2000), S. 23-29 
    ISSN: 1573-7217
    Keywords: breast cancer ; c-erbB-2 ; early onset ; HER-2/neu ; immunohistochemistry ; prognostic factors ; young age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer. A population consisting of 110 young breast cancer patients, ≤ 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein. Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P = 0.002) and for patients with axillary nodal metastases (P = 0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy. The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.
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  • 91
    ISSN: 1573-7217
    Keywords: axillary lymph node dissection ; breast cancer ; sentinel lymph node biopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Several pilot studies have indicated that SLN biopsy can be used to identify axillary lymph node metastases in patients with breast cancer. To confirm this finding, a multicenter study in a variety of practice settings was performed. A total of 674 patients with breast cancer at five institutions were enrolled. The techniques of SLN identification included the vital dye-guided and the vital dye- and gamma probe-guided methods. The SLN was removed, and complete axillary lymph node dissection (ALND) was performed. SLN and ALND specimens were examined separately. The SLN was successfully identified in 214 (94%) of 227 patients using the combined dye- and gamma probe-guided methods. The SLN was identified in 332 (74%) of 447 patients using vital dye-guided method alone. Patient age of at least 51 years, medially located primary tumor, and clinically positive nodes were correlated with failure to identify the SLN. The accuracy of SLN biopsy for the detection of metastatic disease was 96% (522 of 546), and the sensitivity was 90% (203 of 226). Accuracy of 100% was achieved in the patients with tumors less than 1.6 cm in diameter. All 23 false negative results occurred with larger primary tumors. SLN biopsy can accurately predict the presence or absence of axillary lymph node metastases, particularly in patients with small (≤ 1.5 cm) breast cancers.
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  • 92
    ISSN: 1573-7217
    Keywords: bone marrow fibroblasts ; breast cancer ; migration ; matrix metalloproteinases ; MMP-1 ; MMP-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two invasive breast cancer cell lines (MDA-MB-231 and BT-549) were found to be more adherent and have greater migratory capacity on bone marrow fibroblasts than three non-invasive cell lines (MCF-7, T47D and BT-483). Antibodies to the adhesion molecules CD44, E-cadherin, ICAM-1, and integrin chains α2, α3, α4, α5, α6, αv, α1, α3 and α7 failed to inhibit breast cancer cell migration through bone marrow fibroblasts. Inhibitors of matrix metalloproteases, 1, 10-phenanthroline, Ro-9790, TIMP-1 and TIMP-2 were able to attenuate the migration of MDA-MB-231 cells through bone marrow fibroblast monolayers suggesting a role for these enzymes in the migration of breast cancer cells through bone marrow adherent layers. Co-culture of MDA-MB-231 cells and bone marrow fibroblasts resulted in augmentation of the levels of the matrix metalloproteases MMP-1 and MMP-2 in culture supernatants. Soluble factors produced by bone marrow fibroblasts were responsible for the increase in MMP-1 levels. However, maximal MMP-2 production was dependent on direct contract between the breast cancer cells and the bone marrow fibroblasts. Modulation of MMP production by cell–cell contact or soluble factors suggests a mechanism by which breast cancer cells can enhance their ability to invade the bone marrow microenvironment.
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  • 93
    ISSN: 1573-7217
    Keywords: adjuvant chemotherapy ; breast cancer ; mastectomy ; reconstruction ; skin expander-toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Immediate breast reconstruction (IBR) by means of skin expander is currently one of the most widely used methods of breast reconstruction in mastectomized patients. However, given that many breast cancer patients usually receive adjuvant chemotherapy, the adoption of IBR raises new questions concerning possible cumulative toxicity. The present study reports our experience in the use of concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expander after mastectomy for breast cancer and the acute cumulative toxicity of the treatments. Methods. We evaluated a consecutive series of 52 breast cancer patients who have received IBR by skin expander after radical mastectomy and adjuvant chemotherapy concurrently during skin expansion between 1995 and 1998 (IBR/CT group). We identified two series of control patients treated during the same period: 51 consecutive patients undergoing radical mastectomy and IBR without adjuvant chemotherapy (IBR group) and 63 consecutive patients undergoing radical mastectomy and adjuvant chemotherapy without IBR (CT group). For each patient, we evaluated the incidence of surgical complications and chemotherapy's side effects and dose intensity. Results. The interval between surgery and the start of expander inflation was similar in IBR/CT (range 0–19, median 5 days) and IBR groups (range 0–40, median 5 days) and the timing of inflation was not influenced by chemotherapy. The overall incidence of surgical complications in patients undergoing IBR was low: seroma in eight cases, infection in one, skin necrosis in one, expander rupture in two and erythema in three. There were no statistically significant differences in the distribution of complications between the IBR/CT and IBR groups. The dose intensity of chemotherapy was similar between IBR/CT and CT groups, with a median dose intensity of 96% and 95% of the projected dose, respectively. The only statistically significant difference in terms of chemotherapy side effects (p=0.03) was that stomatitis was more frequent and intense in the CT than in the IBR/CT group. Conclusions. Concurrent treatment with IBR and adjuvant chemotherapy appears feasible and safe, it does not increase acute surgical complications or chemotherapy side effects, and does not require any changes in dose intensity or the timing of inflation.
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  • 94
    ISSN: 1573-7217
    Keywords: breast cancer ; cell-mediated immunity ; lymphocyte blastogenesis assay ; prognostic indicators ; tumor-associated antigens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cell-mediated immune (CMI) responses to tumor-associated antigens (TAA) in the early postoperative period were examined for correlations with disease recurrence and survival in a 13-year-prospective study of 77 stage 1 and 2 breast cancer patients treated with modified radical or radical mastectomy alone. Among the 21 patients who had positive lymphoproliferative tests using patients' peripheral blood mononuclear cells and autologous TAA of breast cancer cells, only one died from metastatic disease (5%). Among the 56 patients who had a negative test, 23 died from metastatic disease (41%). This difference is statistically significant (p = 0.002) Three other risk factors including tumor size, nodal status and cell differentiation patterns were also analyzed. When these three clinical-pathologic criteria were analyzed individually, none reliably predicted disease recurrence and survival. Nodal status was the most predictive clinical-pathologic risk factor, but was not significant (p = 0.089). The results of this study demonstrate the detection of CMI responses against autologous TAA by lymphoproliferative assays identifies a sub-set of stage 1 and 2 breast cancer patients who are at minimal risk of developing metastatic disease. This testing also identifies immunologically unreactive patients who are at risk for disease recurrence.
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  • 95
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    Breast cancer research and treatment 60 (2000), S. 235-240 
    ISSN: 1573-7217
    Keywords: breast cancer ; cancer screening ; compression ; mammography ; pain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this study was to evaluate the pain experience of women during mammography for breast cancer screening. Possible associations with personal and medical history, sociodemographics and/or situational factors were studied. It was also investigated whether this pain influenced the intention to return for future breast cancer screening. In the Netherlands, women between 50–75 years are invited for screening every two years. A total of 1200 participants were asked to fill up a questionnaire. The response rate was 79.5% (n = 954), and 945 questionnaires contained adequate information for analyses. A total of 689 women (72.9%) described mammography as mild to severely painful. In this group, compared to the group that reported no pain, the following factors occurred significantly more often: sensitive breasts (P = 0.001), family history of breast diseases (P = 0.017), expected pain based on former mammography (P = 0.001), high education (P = 0.008), anxiety (P = 0.001), breast sensitivity in last three days (P = 0.001), insufficient attention of technologist (P = 0.001). Other factors like age, hormonal status, breast size and hormone use were not associated with the pain experienced. Thirty-two women (3.3%) indicated that they would not attend further screening, 25 (2.6%) reported that the pain might deter them, six women (0.6%) had other reasons, one woman (0.1%) was sure not to come because of severe pain. In conclusion, a large majority of women attending breast cancer screening describes mammography as painful (72.9%). Factors associated with pain were described. Relatively few women (2.7%) indicated that the pain might deter them from future mammography. Recommendations are given to reduce the pain experienced during screening mammography.
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  • 96
    ISSN: 1573-7217
    Keywords: axillary lymphnode metastasis ; breast cancer ; 111In-pentetreotide ; receptor autoradiography ; somatostatin receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We conducted a prospective analysis of somatostatin receptor scintigraphy using 111In radiolabeled pentetreotide, a somatostatin analog, in patients with breast cancer in the aim to visualize the primary tumor and axillary or parasternal metastatic extension because some malignant breast tumors express somatostatin receptors (SS-R) in 50%, approximately. An analysis of SS-R was performed by autoradiography. Patients and methods.Thirteen patients with clinically suspected breast tumors (T1, T2), and at least one palpable axillary node (N1) were included. In vivo planar scintigrams were acquired 1, 4, and 24 h after subcutaneous, then after intravenous injections (24 h delay between injections). Improved 111In-pentetreotide uptake in invaded nodes after subcutaneous injection was hypothesized. Ex vivo scintigrams of surgical specimens were also acquired immediately after tumor resection and axillary dissection. Pathological examination and receptor autoradiography were performed on all surgical specimens. Results.Among 11 pathologically proven malignant tumors (9 ductal and 2 lobular carcinomas), only four were scintigraphically visible although six expressed SS-R receptors in vitro. Among six pathologically proven malignant nodes, four expressed SS-R, including two visualized scintigraphically. Scintigrams acquired after subcutaneous injections were less sensitive than after intravenous injections. There were no false positive. False negatives occurred in cases with small tumors with low-density or heterogeneously distributed SS-R. There was no significant difference by histological type or prognostic factors. Conclusion.Somatostatin receptor scintigraphy does not appear to be sensitive enough to evaluate axillary node extension of breast cancer or even to confirm the presence of tumoral tissue, and this whatever the administration route for 111In-pentetreotide.
    Type of Medium: Electronic Resource
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  • 97
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 64 (2000), S. 241-251 
    ISSN: 1573-7217
    Keywords: breast cancer ; bilateral ; loss of heterozygosity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Women who develop bilateral breast cancer at an early age are likely to harbour germline mutations in breast cancer susceptibility genes. The aim of this study was to test for concordant genetic changes in left and right breast cancer of young women (age 〈50) with bilateral breast cancer that may suggest an inherited breast cancer predisposition. Microsatellite markers were used to test for loss of heterozygosity (LOH) in left and right tumours for 31 women with premenopausal bilateral breast cancer. Markers adjacent to or within candidate genes on 17p (p53), 17q (BRCA1), 13q (BRCA2), 11q (Ataxia Telangiectasia-ATM) and 3p (FHIT) were chosen. Mutational testing for BRCA1 and BRCA2 was performed for cases where blood was available. Concordant LOH in both left and right tumours was demonstrated for at least one of the markers tested in 16/31(54%) cases. Where allelic loss was demonstrated for both left and right breast cancer, the same allele was lost on each occasion. This may suggest a common mutational event. Four cases showed concordant loss of alleles in both left and right breast cancer at D17S791 (BRCA1). BRCA1 mutations were identified in two of these cases where blood was available. Four cases showed concordant LOH at D13S155 (BRCA2). Concordant LOH was further demonstrated in seven cases for D11S1778 (ATM) and four cases for D3S1300 (which maps to the FHIT gene), suggesting a possible role for these tumour suppressor genes in this subgroup of breast cancer patients. No concordant allelic loss was demonstrated for D17S786 suggesting that germline mutations in p53 are unlikely in such cases of bilateral breast cancer.
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  • 98
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 64 (2000), S. 287-296 
    ISSN: 1573-7217
    Keywords: breast cancer ; c-neu transgenic mice ; melatonin ; linolenic acid ; flaxseed oil ; IGF-1 concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Breast cancer is one of the most common cancers and is a leading cause of mortality in women. The TG.NK transgenic mouse line expresses the c-neu breast cancer oncogene under the control of a MMTV promoter and appears to be a useful animal model for evaluation of intervention strategies to delay/prevent breast cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have been shown to significantly delay the development of mammary cancer in the TG.NK model. Four-week-old hemizygous TG.NK female mice with MMTV/c-neu oncogene fed NTP-2000 diet were gavaged with 0.05–0.2 ml of flaxseed oil as the source of ω-3 rich PUFA, or melatonin at 50–200 mg/kg or a combination of 0.10 ml flaxseed oil and 50 mg/kg melatonin in a gavage volume of 0.2 ml per mouse with corn oil as the vehicle for 30 weeks. The time course of the mammary tumor incidence pattern was advanced by flaxseed oil compared to the control. At the high dose (0.2 ml) of flaxseed oil, when the ω-6: ω-3 PUFA ratio was closer to 1, there was some delay in the growth of mammary tumors. Melatonin delayed the appearance of palpable tumors and the growth of the tumors with a dose-related statistically significant negative trend for the incidence of tumors. The combination of flaxseed oil and melatonin caused a significant decrease in the number of tumors and tumor weight per mouse compared to the control and to flaxseed oil but not to melatonin alone. Flaxseed oil may delay the growth of mammary tumors if the ω-6:ω-3 PUFA ratio of fat consumed is closer to 1. Melatonin has the potential to markedly delay the appearance of palpable mammary tumors. Studies are in progress with the TG.NK mouse model to understand the histological and molecular changes associated with the dose-response pattern of mammary tumor incidence and growth after treatment with a broad range of doses of melatonin.
    Type of Medium: Electronic Resource
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  • 99
    ISSN: 1573-7217
    Keywords: adhesion ; breast cancer ; disintegrin ; integrins ; invasion ; metastasis ; angiogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We report the results of a multidisciplinary study on the inhibitory effect of a snake venom disintegrin, contortrostatin, a 13.5 kDa homodimeric protein isolated from Agkistrodon contortrix contortrix (southern copperhead) venom, on breast cancer progression. We demonstrate that contortrostatin binds to integrins and blocks the adhesion of human breast cancer cells (MDA-MB-435) to extracellular matrix (ECM) proteins including fibronectin and vitronectin, but it has no effect on adhesion of the cells to laminin and Matrigel. Contortrostatin also prevents invasion of MDA-MB-435 cells through an artificial Matrigel basement membrane. Daily local injection of contortrostatin (5 μg per mouse per day) into MDA-MB-435 tumor masses in an orthotopic xenograft nude mouse model inhibits growth of the tumor by 74% (p = 0.0164). More importantly, it reduces the number of pulmonary macro-metastasis of the breast cancer by 68% (p 〈 0.001), and micro-metastasis by 62.4% (p 〈 0.001). Contortrostatin is not cytotoxic to cancer cells, and does not inhibit proliferation of the breast cancer cells in vitro. However, contortrostatin inhibits angiogenesis induced by the breast cancer, as shown by immunohistochemical quantitation of the vascular endothelial cells in tumor tissue removed from the nude mice. We have identified αvβ3, an important integrin mediating cell motility and tumor invasion, as one of the binding sites of contortrostatin on MDA-MB-435 cells. We conclude that contortrostatin blocks αvβ3, and perhaps other integrins, and thus inhibits in vivo progression.
    Type of Medium: Electronic Resource
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  • 100
    ISSN: 1573-7217
    Keywords: Bcl-2 ; breast cancer ; chemosensitivity ; HDRA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2, bax and p53. The in vitro chemosensitivity of the 177 breast carcinomas was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), adriamycin (ADM), cisplatin (CDDP), and cyclophosphamide (CPA). The susceptibility of Bcl-2-negative tumors to all the drugs killing was significantly higher than that of Bcl-2-positive tumors. No relationship between Bax or p53 immunoreactivity and sensitivity for any of anticancer drugs studied was demonstrated. Immunohistochemical results regarding Bcl-2 are promising in the evaluation of the sensitivity of cancer cells to a series of anticancer drugs and might be therapeutically useful as an indicator of response to adjuvant chemotherapy for breast cancer.
    Type of Medium: Electronic Resource
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