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  • 2000-2004  (654)
  • General Chemistry  (378)
  • breast cancer  (140)
  • chemotherapy  (81)
  • Computational Chemistry and Molecular Modeling
  • Nuclear reactions
  • Rat
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  • 1
    Electronic Resource
    Electronic Resource
    ras p21 isoprenylation inhibition induces flat colon tumors in Wistar rats (2000)
    Springer
    Diseases of the colon & rectum 43 (2000), S. 70-75 
    Details
    ISSN: 1530-0358
    Keywords: Pravastatin ; ras p21 isoprenylation ; Colon carcinogenesis ; Flat colon tumor ; Azoxymethane ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The effect of pravastatin, an inhibitor ofras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associatedras p21 in colon tumors. CONCLUSIONS: These findings suggest that theras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02237247
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  • 2
    Electronic Resource
    Electronic Resource
    Development of the bones and synovial joints in the rat model of the VATER association (2000)
    Springer
    Journal of orthopaedic science 5 (2000), S. 390-396 
    Details
    ISSN: 1436-2023
    Keywords: Key words Adriamycin ; Rat ; Embryo ; VATER association ; Synovial joint ; Bones ; Limbs ; Vertebra ; Sirenomelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The adriamycin-induced rat model of the Vertebral, Anorectal, Tracheo-Esophageal, Radial and Renal (VATER) association produces a variety of vertebral, rib, and limb abnormalities. This study was designed to document accurately the nature of these abnormalities and to determine whether synovial joints are affected. Fetuses from pregnant Sprague Dawley rats that had received intraperitoneal injections of 1.75 mg/kg of adriamycin on days 6–9 or 10–13 of gestation were harvested. Double-stained skeletal preparations and histological sections were examined for vertebral, rib, and limb anomalies. The incidence of anomalies was high in the group treated on gestational days (GD) 6–9, while it was low in the GD 10–13 group. The length and thickness of the long bones were reduced, with bowing and reduction in their endochondral ossification. Sirenomelia occurred in the group treated on GD 6–9, and was often associated with a short tail and anal atresia. The joint cavities, and intra-articular structures such as menisci and the cruciate ligaments developed normally from the mesenchymal interzone. These data indicate that adriamycin inhibits skeletal growth and differentiation without any interference in the differentiation of the mesenchymal interzone, thus producing normal synovial joints.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007760050015
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  • 3
    Electronic Resource
    Electronic Resource
    Identification of High-Risk Breast Cancer Patients from Genetic Changes of Their Tumors (2000)
    Springer
    Surgery today 30 (2000), S. 516-522 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950070118
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  • 4
    Electronic Resource
    Electronic Resource
    Transcatheter therapy of gastric cancer metastatic to the liver: preliminary results (2000)
    Springer
    Journal of gastroenterology 35 (2000), S. 907-911 
    Details
    ISSN: 1435-5922
    Keywords: Key words: gastric cancer ; liver neoplasms ; secondary ; interventional radiology ; chemotherapy ; chemoembolization ; therapeutic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: Little is known about the effectiveness of transcatheter chemotherapy in liver metastases from gastric cancer. The aim of this study was to evaluate the initial results of hepatic artery infusion and oily chemoembolization in these liver secondaries. Courses of transcatheter arterial infusion with 5-fluorouracil/doxorubicin (12 patients) and oily chemoembolization with doxorubicin-in-iodized oil and gelatin sponge (12 patients) were performed in 24 patients with histologically proven unresectable gastric cancer liver metastases. A positive effect of treatment (partial response + stabilization) was seen in 92% of the patients after chemoinfusion and in 50% after chemoembolization. The 1- and 2-year actuarial survival rates were 92% and 53% for infusion vs 50% and 17% for chemoembolization, respectively (log-rank test, P = 0.0009). For patients who had already died, the mean survival was 19.2 months vs 9.5 months (Student's t-test, P 〈 0.05) with median survivals of 23 months vs 8 months, respectively. The results with arterial infusion were very close to those reported for liver resection. Transcatheter therapy appears to be useful for the palliation of unresectable liver metastases from gastric cancer. If regional chemotherapy is used, arterial infusion should be the first-choice treatment, with oily chemoembolization being reserved for patients who do not respond to infusion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005350070004
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  • 5
    Electronic Resource
    Electronic Resource
    Docetaxel (Taxotere®)–cisplatin (TC): An effective drug combination in gastric carcinoma (2000)
    Springer
    Annals of oncology 11 (2000), S. 301-306 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; docetaxel ; gastric cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:A multi-centric trial was performed to explore theclinical activity, in terms of response and toxicity (primary objectives),duration of response and survival (secondary objectives), of docetaxel withcisplatin in advanced gastric cancer (AGC). Patients and methods:Patients with measurable unresectable and/ormetastatic gastric carcinoma, performance status ≤1, normal hematological,hepatic and renal functions and not pretreated for advanced disease bychemotherapy received up to eight cycles of TC (docetaxel 85 mg/m2d1, cisplatin 75 mg/m2 d1) q3w. Dose escalation to 100mg/m2 was performed in five patients and was discontinued forexcessive toxicity. Results:Forty-eight patients were accrued. A median of 5cycles/patient was given. We observed 2 complete and 25 partial responses foran overall intent to treat response rate of 56% (95% CI:41%–71%). Twelve patients had stable disease for ≥9weeks (3 cycles). The median time to progression and overall survival were 6.6and 9 months, respectively. Grade ≥3 toxicities were neutropenia81%, anemia 32%, thrombocytopenia 4%, alopecia36%, fatigue 9%, mucositis 9%, diarrhea 6%,nausea/vomiting 4%, neurologic 2%, and one anaphylaxisprecluding treatment administration. We recorded nine episodes of non-fatalfebrile neutropenia in eight patients, two of them with docetaxel at 100mg/m2. There were no direct treatment-related deaths. Conclusions:TC is active in AGC with a high response rate in amulticentric trial. Despite its hematotoxicity, this regimen is well toleratedand can be recycled as originally planned in 78% of the cases. Theseresults may serve as basis for further developments of docetaxel containingregimens in this disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008342013224
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  • 6
    Electronic Resource
    Electronic Resource
    A phase I–II study of concomitant chemoradiotherapy with paclitaxel (one-hour infusion), 5-fluorouracil and hydroxyurea with granulocyte colony stimulating factor support for patients with poor prognosis head and neck cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 721-728 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; concomitant chemoradiotherapy ; head and neck cancer ; paclitaxel ; radiation ; reirradiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Concomitant chemoradiotherapy is an effectivetreatment modality for advanced head and neck cancer, but improved regimensare needed. We sought to define the toxicities, recommended phase II dose, andoutcome of a combination chemotherapy regimen with concomitanthyperfractionated radiotherapy in patients with poor prognosis cancers of thehead and neck, including those having received prior curative intentradiotherapy. Patients and methods:From 1995 until 1997, 54 patients weretreated, 25 of whom had received a prior full course of radiotherapy to thehead and neck. Patients were treated with 5-fluorouracil (5-FU) 600mg/m2/day continuous infusion × 5 days (days 1–5),hydroxyurea, 500 mg p.o. bid × 11 doses (days 1–6) and paclitaxel(60–150 mg/m2) by one-hour infusion on day 2 using a doseescalation strategy. Radiotherapy was given concomitantly on days 2–6,150 cGy bid. Each of 4–5 cycles was delivered every other week. Results:The MTD of paclitaxel was 100 mg/m2. Theregimen was feasible; radiotherapy was delivered at a median of 7300 cGy and83% of patients received ≥80% planned dose intensity.Hematological toxicity, with granulocyte colony stimulating factor, was verymild. Dose limiting toxicities were mucositis and dermatitis. Despite poorprognosis, two-year survival was 45%. Conclusions:The recommended phase II dose of this regimen is 5-FU600 mg/m2/day × 120 hours (days 1–5), hydroxyurea 500mg p.o. b.i.d. × 11 doses (days 1–6), paclitaxel 100mg/m2 over one hour on day 2, and radiotherapy 150 cGy b.i.d. days2–6. Concomitant chemotherapy and re-irradiation was feasible on thisprotocol and resulted in long-term survival in patients without other curativeintent options.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008324131519
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  • 7
    Electronic Resource
    Electronic Resource
    Spontaneous pneumothorax in malignancy: A case report and review of the literature (2000)
    Springer
    Annals of oncology 11 (2000), S. 887-889 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; lung metastases ; spontaneous pneumothorax
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Pneumothorax occurring in the absence of obvious lungdisease is defined as spontaneous pneumothorax. Spontaneous pneumothoraxoccurs in a variety of settings in patients with malignancies. Patients and methods:We present a case report of spontaneouspneumothorax in malignancy and review the literature. Results:No correlation was found between the occurrence ofpneumothorax with age, sex or smoking history. Pneumothorax occurred with avariety of primary tumors. However it was always associated with lungmetastases or lung involvement with tumor. In certain cases the metastaseswere detected after the occurrence of pneumothorax. Conclusions:The occurrence of pneumothorax in a patient withmalignancy should prompt a search for lung metastases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008323632078
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  • 8
    Electronic Resource
    Electronic Resource
    Paclitaxel and carboplatin in combination with gemcitabine: A phase I–II trial in patients with advanced non-small-cell lung cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1421-1426 
    Details
    ISSN: 1569-8041
    Keywords: carboplatin ; chemotherapy ; gemcitabine ; non-small-cell lung cancer ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The combination of paclitaxel (P) and carboplatin (C)is an effective treatment for advanced NSCLC. Gemcitabine (G) is an active newdrug. We planned a phase I study to find the maximum tolerated dose (MTD) ofthe PCG combination. A phase II study was subsequently conducted to evaluatethe activity and toxicity of PCG. Patients and methods:Forty-five patients entered the study.Twenty-eight had stage IIIA–B disease, 17 stage IV. In the phase Istudy, with a fixed dose of C at AUC = 6 on day 1, P was escalated usingincrements of 25 mg/m2 starting from 175 mg/m2 on day1 and G with increments of 200 mg/m2 starting from 800mg/m2 on day 1 and 8. Results:Fourteen patients entered the phase I study. The MTD wasreached at P 200 mg/m2, C AUC = 6 and G 1000 mg/m2.Neutropenic fever and grade 3 diarrhea were the dose limiting toxicities.Thirty-one patients were treated in the phase II study with P 175mg/m2, C AUC = 6 and G 1000 mg/m2. Response rate was57% (68% in stage III and 47% in stage IV).Myelosuppression was the main toxicity, with grade 3–4 leukopeniaoccurring in 35% of cases. Grade 3 anemia was observed in 24%of cases and grade 3–4 thrombocytopenia occurred in 34% ofpatients. Non-hematological toxicity was mild. Median survival and one-yearactuarial survival were 20.5 months and 74% for stage III and 11.5months and 47% for stage IV. Conclusions:PCG is a promising regimen for treating advancedNSCLC. A phase III study comparing PCG to paclitaxel plus carboplatin inadvanced NSCLC is ongoing. On the other hand, we are planning to introduce thePCG regimen in the treatment of stage II–III patients in the setting ofa multimodality treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026527004596
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  • 9
    Electronic Resource
    Electronic Resource
    Induction of adenocarcinoma containing myoepithelial cells in rat submandibular gland by 7,12-dimethylbenz(a)anthracene (2000)
    Springer
    Virchows Archiv 437 (2000), S. 314-324 
    Details
    ISSN: 1432-2307
    Keywords: Keywords 7 ; 12-dimethylbenz(a)anthracene ; Rat ; Submandibular gland ; Adenocarcinoma Myoepithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In an attempt to induce adenocarcinoma containing myoepithelial cells (MECs) in the rat submandibular gland, we injected 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in acetone into the glands of rat pups at the age of 10 days. In both male and female pups, the glands, including their developing terminal secretory units, contained far greater numbers of cells positive for proliferating cell nuclear antigen (PCNA) than did adult glands. A single administration of 1% DMBA (0.05 ml/130 g b.w.) did not produce adenocarcinoma, but did induce occasional sarcomas, such as rhabdomyosarcoma and fibrosarcoma, in 2 months. Most glands regenerated with minimal scar formation. Microscopically, these glands were atypical in that they contained increased numbers of PCNA-positive cells, underdeveloped granular ducts, and striated ducts surrounded by MECs positive for alpha smooth muscle actin (αSMA). Though these features were also observed in the regenerated glands after acetone injection, the number of PCNA-positive cells was relatively high in the glands of DMBA-treated females, especially in the terminal secretory unit. The second DMBA injection at 10 weeks of age produced adenocarcinoma made up of αSMA-positive MECs and keratin 19-positive duct cells. Such MEC-associated adenocarcinoma was induced in the glands of more than half the female but not the male animals. Replacement of either of the double DMBA treatments with acetone, or DMBA treatment, single or double, of adult glands did not produce adenocarcinoma, but did produce sarcoma and squamous cell carcinoma. These results suggest that (1) at least two genetic mutations are necessary for induction of adenocarcinoma with MECs in the rat submandibular gland, (2) the mutation is efficiently introduced to pup glands whose terminal secretory units exhibit extreme proliferative activity, and (3) the second mutation is difficult to introduce in male glands, whose proliferative activity is relatively low, and/or transformed cells need some female hormone after the mutation to propagate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280000223
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  • 10
    Electronic Resource
    Electronic Resource
    NCIC–CTG phase II study of gemcitabine in patients with malignant glioma (IND.94) (2000)
    Springer
    Annals of oncology 11 (2000), S. 315-318 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; gemcitabine ; malignant glioma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:We conducted a phase II multicentre study of gemcitabinein patients with anaplastic astrocytoma and glioblastoma multiforme at firstrelapse. Patients and methods:Patients with anaplastic astrocytoma orglioblastoma multiforme receiving a stable dose of steroids and ECOGperformance status ≤3 were eligible for this study at the time of firstrelapse. One adjuvant chemotherapy regimen was permissible. Patients receivedgemcitabine 1000 mg/m2 i.v. weekly × 3, repeated on afour-weekly cycle. Results:Of 20 patients enrolled, 15 were evaluable for response,19 for non-hematological toxicity and 18 for hematological toxicity. Sevenpatients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme(GBM). Age ranged from 28–71 years (median 50). Fifteen patientsdiscontinued therapy due to disease progression. The median number of cyclesadministered was 1 (range 1–11); only two patients received more thanthree cycles. Hematologic toxicity was acceptable and no grade 4 toxicity wasseen. One patient developed Pneumocystispneumonia and eventualpulmonary embolism; one died of gastric hemorrhage related to steroid therapy.No objective responses were seen. Nine patients had stable disease (medianduration 2.7 months, range 0.9–11.2). Conclusions:Gemcitabine given in this dose and schedule seemswell tolerated but is not active in patients with recurrent high-gradegliomas.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008336607135
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  • 11
    Electronic Resource
    Electronic Resource
    Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome (2000)
    Springer
    Annals of oncology 11 (2000), S. 307-313 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008340723974
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  • 12
    Electronic Resource
    Electronic Resource
    The contribution of molecular markers to the prediction of response in the treatment of breast cancer: A review of the literature on HER-2, p53and BCL-2 (2000)
    Springer
    Annals of oncology 11 (2000), S. 647-663 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008390429428
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  • 13
    Electronic Resource
    Electronic Resource
    Weekly administration of bendamustine: A phase I study in patients with advanced progressive solid tumours (2000)
    Springer
    Annals of oncology 11 (2000), S. 729-734 
    Details
    ISSN: 1569-8041
    Keywords: alkylating agents ; bendamustine ; chemotherapy ; phase I study ; solid tumours ; weekly chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The cytotoxic agent bendamustine combines apurine-like benzimidazol and alkylating nitrogen mustard group. The clinicallytolerated dose for single bolus bendamustine is 215 mg/m2, forfractionated therapy on four consecutive days 85 mg/m2. The maximumtolerated dose of a day 1 and 8 (q4w) 30 min infusion schedule was recentlyfound to be 160 mg/m2, mouth dryness and fatigue weredose-limiting. Our current phase I trial was designed to define therecommended dose of a new weekly short infusion schedule. Patients and methods:Patients with refractory malignant tumoursqualified for the trial after written informed consent was obtained.Bendamustine was given as a 30-min i.v. infusion weekly for up to eightconsecutive weeks. Results:Twelve patients (8 male, 4 female, median age 57.5 years,range 42–64) were enrolled in this trial. At the starting dose of 80mg/m2, two patients had dose-limiting toxicity (fatigue grade 3,mouth dryness grade 3, fever grade 4 Common Toxicity Criteria). Nodose-limiting events were observed in six patients treated at 60mg/m2. An intermediate dose level of 70 mg/m2 wasstudied in three younger, less heavily pre-treated patients, was welltolerated and not associated with dose-limiting events. Haematologicaltoxicity was mild except for grade 3–4 lymphocytopenia, occurring in 11of 12 patients. Bendamustine was found to induce long-lastingpanlymphocytopenia with predominant B-cell cytotoxicity. Conclusions:The maximum tolerated dose of weekly bendamustinegiven as a 30-min i.v. infusion is 80 mg/m2, mouth dryness, fatigueand fever are dose-limiting. The recommended dose for phase II trials is 60mg/m2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008309911008
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  • 14
    Electronic Resource
    Electronic Resource
    A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL (2000)
    Springer
    Annals of oncology 11 (2000), S. 691-695 
    Details
    ISSN: 1569-8041
    Keywords: anthracycline ; chemotherapy ; liposomal daunorubicin ; lymphoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Standard therapy for lymphoma consists of acyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP)combination regimen. Liposomal daunorubicin (DaunoXome®) is an alternativeto doxorubicin for patients with lymphoma because of its more favorable safetyprofile and potentially more selective uptake in lymphoma. The objectives ofthis study were to determine the maximum tolerated dose (MTD) of liposomaldaunorubucin with CVP (COP-X) and the tolerability of the regimen in patientswith indolent lymphoma. Patients and methods:Patients with low-grade andintermediate-grade lymphoma having adequate cardiac, hepatic, and renalfunction were enrolled. Patients received C 750 mg/m2, V 1.4mg/m2 (maximum 2.0 mg), and liposomal daunorubicin 50–100mg/m2 i.v. on day 1 and P 100 mg p.o. on days 1–5. MTD wasthe liposomal daunorubicin dose associated with 20% dose-limitingtoxicity (ANC 〈500/mm3 for 〉5 days or febrile neutropenia). Results:Twenty patients, median age 59 years, were treated. Theliposomal daunorubicin MTD combined with CVP was 70–80 mg/m2,depending on patient population. No significant non-hematologic toxicityoccurred. Response rate was 44% (2 complete and 5 partial responses). Conclusions:A liposomal daunorubicin dose of 80 mg/m2in the COP-X regimen was well tolerated with little non-hematologic toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008361914894
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  • 15
    Electronic Resource
    Electronic Resource
    Activity and toxicity of GI147211 in breast, colorectal and non-small-cell lung cancer patients: An EORTC–ECSG phase II clinical study (2000)
    Springer
    Annals of oncology 11 (2000), S. 793-797 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008373031714
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  • 16
    Electronic Resource
    Electronic Resource
    Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: A meta-analysis of published randomised trials (2000)
    Springer
    Annals of oncology 11 (2000), S. 837-843 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant ; chemotherapy ; gastric cancer ; meta-analysis ; randomised clinical trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Several studies have investigated the possible roleof the adjuvant chemotherapy after curative resection for gastric cancerfailing to show a clear indication; previous meta-analyses suggested smallsurvival benefit of adjuvant chemotherapy, but the statistical methods usedwere open to criticisms. Materials and methods:Randomised trials were identified by meansof Medline and CancerLit and by selecting references from relevant articles.Systematic review of all randomised clinical trials of adjuvant chemotherapyfor gastric cancer compared with surgery alone, published before January 2000,were considered. Pooling of data was performed using the fixed effect model.Death for any cause was the study endpoint. The hazard ratio and its95% confidence intervals (95% CI), derived according to themethod of Parmar, were the statistics chosen for summarising the relativebenefit of chemotherapyversuscontrol. Results:Overall 20 articles (21 comparisons) were considered foranalysis. Three studies used single agent chemotherapy, seven combination of5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU withoutanthracyclines. Information on 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82,95% CI: 0.75–0.89, P 〈 0.001). Association ofAnthracyclines to 5-FU did not show a statistically significant improvementwhen compared with the effect of the other regimens. Conclusions:Chemotherapy produces a small survival benefit inpatients with curatively resected gastric cancer. However, taking into accountthe limitations of literature based meta-analyses, adjuvant chemotherapy isstill to be considered as an investigational approach.
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    URL: http://dx.doi.org/10.1023/A:1008377101672
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  • 17
    Electronic Resource
    Electronic Resource
    Chromosome aberrations after etoposide containing cisplatin-based chemotherapy for malignant germ-cell tumours (2000)
    Springer
    Annals of oncology 11 (2000), S. 897-898 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; chromosome aberrations ; malignant germ-cell tumours
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008311532043
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  • 18
    Electronic Resource
    Electronic Resource
    An Analysis of Unicellular Mass Transfer Using a Microfabricated Experimental Technique (2000)
    Springer
    Biomedical microdevices 2 (2000), S. 305-316 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1009959323022
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  • 19
    Electronic Resource
    Electronic Resource
    Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients (2000)
    Springer
    Annals of oncology 11 (2000), S. 1301-1307 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; drug interaction ; in vitroassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Chemotherapy using multi-drug regimens is consideredmore active than single-agent therapy. This may be due to synergisticinteractions or, simply, a higher probability of administering an activeagent. We investigated in vitrothe type of drug interactions in arecognized regimen in relationship to tumour type and drug sensitivity. Patients and methods: The possibility of synergistic and additiveinteractions between individual cytotoxic drugs was investigated for thecomponent drugs of the established FEC regimen, i.e., 5-fluorouracil,epirubicin and cyclophosphamide, in 243 patient tumour samples representingvarious drug sensitivity using the non-clonogenic fluorometric microculturecytotoxicity assay. Results: Using a cell survival of ≤50% as a limit fordrug activity and sample sensitivity, the overall response rates to the mostactive single drug (Dmax) and the combination were 56% and64%, respectively, with a distribution among diagnoses similar to thatin the clinic. For 86% of the samples there was concordance withrespect to judgement of activity using either Dmax or thecombination. For samples being sensitive to at least one single drug,95% were also sensitive to the combination whereas for samples withinsignificant Dmax effect, only 2% were sensitive to thecombination. In samples with modest Dmax effects, i.e., cellsurvival in the range 〉50%–≤80%, 45%responded to the combination. The effect of the combination was generally wellpredicted from the Dmax effect. Conclusions:The superior antitumour effect of drug combinationscompared with single drugs may be due to the higher chance of selecting anactive agent. However, for intermediately sensitive tumours, additionalinteraction effects of a combination may be of clinical significance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008332816407
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  • 20
    Electronic Resource
    Electronic Resource
    A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 613-616 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; ovarian cancer ; second-line
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Gemcitabine is active in patients with otherwiseresistant or refractory ovarian cancer. As the drug is well tolerated, studiesusing gemcitabine combined with other antineoplastic agents are needed. Theaim of the study was to determine the maximum tolerated dose (MTD) ofepirubicin combined with gemcitabine, with and without support of G-CSF. Patients and methods:Patients with platinum-resistant orrefractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800mg/m2 day 1 and 8; 200 mg/m2 escalation per level) andepirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2escalation per level) were given every 21 days for four to six cycles. G-CSF(filgrastim 5 µg/kg/die) was given in case of grade 4 neutropenia(levels without support) or from day 9 up to leukocyte count〉10,000/mm3 after nadir (levels with support). Cohorts of threepatients were enrolled at each level, and another three patients were planned,if one dose-limiting toxicity (DLT) was registered. MTD was determined firstwithout and then with G-CSF. Results:Four levels were studied (G 800 + E 60; G 1000 + E 60;G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and threepatients enrolled, respectively. DLT (grade 4 febrile neutropenia) wasobserved in two patients at level 3. Thus, G1000 + E 60 mg/m2 wasthe MTD without G-CSF. The addition of prophylactic G-CSF did not allow afurther increase of the dose and grade 4 thrombocytopenia was the DLT at level4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in fourpatients. Among the 13 patients with measurable or evaluable disease, 3partial responses were observed for an overall response rate of 23.1%. Conclusions:The combination of gemcitabine 1000 mg/m2(day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasibletherapy. Grade 4 neutropenia is frequent and G-CSF support is often required.With prophylactic support of G-CSF, the DLT is thrombocytopenia.
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    URL: http://dx.doi.org/10.1023/A:1008344528791
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  • 21
    Electronic Resource
    Electronic Resource
    Comparative study of clinical, pathological and biological characteristics of symptomatic versus asymptomatic breast cancers (2000)
    Springer
    Annals of oncology 11 (2000), S. 581-586 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1008320317114
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  • 22
    Electronic Resource
    Electronic Resource
    Combined 4-hydroxy-ifosfamide and vinorelbine treatment in established and primary human breast cell cultures (2000)
    Springer
    Annals of oncology 11 (2000), S. 587-594 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008340902093
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  • 23
    Electronic Resource
    Electronic Resource
    Delayed adjuvant tamoxifen: Ten-year results of a collaborative randomized controlled trial in early breast cancer (TAM-02 trial) (2000)
    Springer
    Annals of oncology 11 (2000), S. 515-519 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1008321415065
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  • 24
    Electronic Resource
    Electronic Resource
    Primary cerebral lymphomas: Unsolved issues regarding first-line treatment, follow-up, late neurological toxicity and treatment of relapses (2000)
    Springer
    Annals of oncology 11 (2000), S. 39-44 
    Details
    ISSN: 1569-8041
    Keywords: brain tumor ; chemotherapy ; encephalopathy ; late neurological toxicity ; leucoencephalopathy ; primary cerebral lymphoma ; radiochemotherapy ; systematic follow-up
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Primary cerebral non-Hodgkin's lymphomas (NHL) inimmunocompetent patients (PCL) are located exclusively in the central nervoussystem, the eye, or meninges. Clinical management of these patients remainscontroversial. Patients and methods:Clinical characteristics of the patients andparameters influencing their outcome as of December 1998 were investigated andregistered in a database of 226 patients treated in the French Federation ofCancer Centers between 1980 and 1995. Results:Most PCL are diffuse large-cell NHL with a B phenotype.The incidence of PCL has been steadily increasing over the past 20 years insome but not all countries. The overall survival of primary cerebral lymphoma(PCL) patients in the published series, a median of 12–16 months and afive-year survival of 5%–20%, is poor. Several series havenow reported long-term survivals of more than 10 years and PCL may thereforebe a curable tumor in some patients. The optimal treatment of PCL is notknown. Complete resection of the tumor does not improve outcome andmultidisciplinary approaches combining chemotherapy and radiotherapy are nowcommonly used, although the superiority of combination over radiotherapy- orchemotherapy-alone has never been demonstrated in a phase III trial. Theoptimal chemotherapy regimen, the dose and even the usefulness of brainradiotherapy after chemotherapy are therefore still matters of debate.Recently, several authors have reported a relatively high incidence of lateneurological sequelae after PCL treatment. Conclusions:The optimal treatment of PCL patients remains to bedefined. Large cooperative international phase III trials are now required todefine and improve the optimal treatment of PCL and reduce its sequelae.
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    URL: http://dx.doi.org/10.1023/A:1008364612406
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  • 25
    Electronic Resource
    Electronic Resource
    Treatment of Hodgkin's disease: Results and current concepts of the German Hodgkin's Lymphoma Study Group (2000)
    Springer
    Annals of oncology 11 (2000), S. 81-85 
    Details
    ISSN: 1569-8041
    Keywords: ABVD ; BEACOPP ; chemotherapy ; clinical trials ; COPP ; dose intensification ; Hodgkin's disease ; radiotherapy ; risk factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Treatment strategies in Hodgkin's disease (HD) arechanging fundamentally over the last decades. Both radiotherapy andcombination chemotherapy are effective treatment modalities. However, theoptimal choice of treatment or combinations of treatment is still debated fordifferent prognostic groups. Patients and methods:The German Hodgkin's Lymphoma Study Group(GHSG) initiated randomized clinical trials since 1978. Over the past 20years, more than 6000 patients with HD in all stages were randomized, treatedand followed by the GHSG. Patients are now being recruited from more than 300clinical centers. Results:As a consequence of different clinical trials, it is nowthe policy of the GHSG to tailor treatment to the individual risk of patients,giving favorable patients less intensive and less toxic therapy thanunfavorable patients. The treatment for early and intermediate stage HDbecomes quite similar with few cycles of polychemotherapy followed by involvedfield irradiation. In advanced stage HD, the introduction of dose intensifiedchemotherapy (BEACOPP), has improved treatment results and thus willsubstitute the MOPP or ABVD regimens. Conclusions:Although most of the patients with HD will be curedby modern treatment stategies, several questions are still subjects of ongoingclinical trials: 1) which chemotherapy regimen in which quantity will be thebest with respect to efficacy and toxicity and 2) which dose and field sizeof radiotherapy is adequate within the combined modality.
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    URL: http://dx.doi.org/10.1023/A:1008317426152
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  • 26
    Electronic Resource
    Electronic Resource
    Phase II study of the multitargeted antifolate LY231514 (ALIMTA™, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 101-103 
    Details
    ISSN: 1569-8041
    Keywords: antifolate ; chemotherapy ; pancreatic cancer ; thymidylate synthase inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:To determine the safety and activity of LY231514(ALIMTA™, MTA, pemetrexed disodium, Eli Lilly and Co.,Indianapolis, IN) in chemotherapy-naïve patients with advanced pancreaticcancer. Patients and methods:Patients with unresectable or metastaticpancreatic cancer received LY231514 600 mg/m2 as a 10–minuteinfusion every three weeks. Results:Forty-two patients were enrolled in this phase II trial.The median age was 60.3 (range 37–77) years; 79% had metastaticdisease. Neutropenia was common (40% of patients ≥ grade 3) butinfectious complications were rare. Significant anemia or thrombocytopeniaoccurred in 〈20% of patients. Non-hematologic toxicities includedgrade 2 or 3 skin reaction which was ameliorated by dexamethasone. Elevationsof bilirubin or transaminases were infrequent (〈25% of patients) anddid not require dose reductions or treatment delays. Thirty-five patientsreceived two cycles of therapy and were evaluable for response. One complete(duration 16.2 months) and one partial (duration 6.9 months) were observedresulting in an objective response rate of 5.7% for evaluable patients.In addition, 17 patients (40%) had stable disease that lasted ≥6months in 5 patients. The median survival was 6.5 months, with 28% ofpatients alive at one year. Conclusions:LY231514 is a well-tolerated agent with minimalobjective antitumor activity in pancreatic cancer. The median and one yearsurvival times, which may be important indicators in phase II trials of newagents, are of interest. Combination trials of LY231514 in pancreatic cancerare planned.
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    URL: http://dx.doi.org/10.1023/A:1008305205159
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  • 27
    Electronic Resource
    Electronic Resource
    Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1349-1351 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008347226743
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  • 28
    Electronic Resource
    Electronic Resource
    A phase II trial of gemcitabine in combination with 5-fluorouracil (24-hour) and folinic acid in patients with chemonaive advanced pancreatic cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1267-1272 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; 5-FU ; folinic acid ; gemcitabine ; Gemzar® ; pancreas cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Gemcitabine (Gemzar®) and 5-fluorouracil (5-FU)plus folinic acid (FA) both have proven activity in the treatment of patientswith advanced pancreatic cancer. The present study was initiated toinvestigate the efficacy of gemcitabine in combination with 5-FU–FA. Patients and methods:Thirty-eight patients, median age 60 years(range 34–70) with inoperable, stage IV, pancreatic cancer were enrolledinto the study and treated on an outpatient basis. All except one patientreceived at least one cycle of treatment with gemcitabine (1000mg/m2), followed by FA (200 mg/m2) and 5-FU (750mg/m2) administered as a 24-hour continuous infusion on days 1, 8,15 and 22 of a 42-day schedule. No patient had received prior chemotherapy orradiotherapy. All 38 patients were assessed for efficacy, toxicity and timeto progressive disease. Results:Two patients (5%), achieved a partial response andthirty-four patients (89%) achieved stable disease. There were twoearly deaths (≤4 weeks). The median time to progression was 7.1 months(range 0.4–18.1+; 95% confidence interval (95% CI):5.3–7.9 months). Three patients had a progression-free interval ofgreater than 12 months and 12 of 38 patients (32%) survived longer than12 months. The median overall survival was 9.3 months (range 0.5–26.5;95% CI: 7.3–13.0 months). The incidence of grade 3 and 4toxicities was low. Conclusions:The combination of gemcitabine and 5-FU–FA isactive and well tolerated and seems to offer an improvement inprogression-free interval over both gemcitabine monotherapy and 5-FU–FAtherapy.
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    URL: http://dx.doi.org/10.1023/A:1008364018881
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  • 29
    Electronic Resource
    Electronic Resource
    ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1545-1550 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1008313310474
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  • 30
    Electronic Resource
    Electronic Resource
    Hepatic arterial 5-fluorouracil in patients with liver metastases of colorectal cancer: Single-centre experience in 145 patients (2000)
    Springer
    Annals of oncology 11 (2000), S. 1563-1570 
    Details
    ISSN: 1569-8041
    Keywords: 5-fluorouracil ; arterial access device ; chemotherapy ; colorectal cancer ; hepatic arterial chemotherapy ; liver metastases ; port-a-cath
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Hepatic arterial chemotherapy for liver metastases ofcolorectal cancer is still under discussion. Mainly because of the technicalcomplications of this mode of treatment and the lack of a survival benefit inrandomized studies. We performed an analysis of hepatic arterial5-fluorouracil (5-FU) chemotherapy in 145 consecutive patients treated at asingle institution. Patients and methods:One hundred forty-five patients withinoperable liver metastases from colorectal cancer were included. 5-FU, 1000mg/m2/day continuous infusion for five days every three weeks, wasdelivered in the hepatic artery by percutaneous catheter or arterial accessdevice. Results:The response rate was 34% for all patients,40% in patients with extrahepatic disease, and 15% in patientswith i.v. 5-FU-based pretreatment. TTP and OS for all patients were 7.5 and14.3 months, respectively. In patients with extrahepatic disease or i.v.5-FU-based pretreatment, OS was significantly shorter compared to patientswithout extrahepatic disease or 5-FU-based pretreatment (9.7 vs. 19.3 monthsand 10.1 vs. 17.4 months, respectively). forty-seven percent of patientsstopped treatment because of a complication. Complications most often seen inpatients with arterial ports were hepatic artery thrombosis (48%) anddislocation of the catheter (22%). Conclusions:The results of our analysis are in line with previousphase III studies. Extrahepatic disease and i.v. 5-FU-based pretreatment wereprognostic for reduced OS. The complication rate of hepatic arterial deliverywas worrisome, although, no negative impact on survival could be established.There is a strong need for improvement of hepatic arterial delivery methodsbefore further evaluation of hepatic arterial 5-FU will be worthwhile.
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    URL: http://dx.doi.org/10.1023/A:1008369520179
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    Electronic Resource
    High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol (2000)
    Springer
    Annals of oncology 11 (2000), S. 1585-1590 
    Details
    ISSN: 1569-8041
    Keywords: autologous stem-cell transplantation ; chemotherapy ; follicular lymphoma ; progression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Among the 566 patients with follicular lymphomas (FL)included in the GELF 86 prospective trials from October 1986 to September1995, 372 with progressive/relapsing disease were analyzed retrospectively toidentify prognostic factors at first relapse. Patients and methods:For progressive FL, patients received mono-(22%) or polychemotherapy (78%) followed by high-dose therapy(HDT) with ASCT for 83 patients (22%). The median time toprogression from initial treatment was 23 months (range 3–102 months)and 24% of documented patients (52 of 217) had histologicaltransformation (HT). Salvage therapy produced an overall response in64% of patients and the five-year survival from progression was42%. Results:For patients who underwent HDT with ASCT compared tostandard treatment, five-year freedom from second failure was at 42%vs. 16% (P = 0.0001) and five-year survival was58% vs. 38% (P = 0.0005), respectively. Thebenefit of HDT and ASCT remained if we consider only patients less than 65years (five-year survival at 60% vs. 40%; P =0.001). Multivariate analysis of parameters significant according tounivariate analysis found that no ASCT at first progression, age at relapse〉50 years, progression on-therapy were adversely significant onsurvival. Conclusions:HDT with ASCT compared to standard treatmentprolonged remission and survival after first progression of FL patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008399623564
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  • 32
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    Electronic Resource
    Cost-effectiveness of second-line treatment with irinotecan or infusional 5-fluorouracil in metastatic colorectal cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 157-161 
    Details
    ISSN: 1569-8041
    Keywords: 5-fluorouracil ; chemotherapy ; colorectal cancer ; cost/effectiveness analysis ; irinotecan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:It has been shown that irinotecan is superior toinfusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancerafter 5-FU failure. In a recent trial, median survival was 10.8 months forpatients treated with irinotecan, compared to 8.5 months in patients receivinginfusional 5-FU. Considering the statistically significant but clinicallyrelatively small advantage of irinotecan over 5-FU, cost effectiveness shouldalso be part of treatment decision. Purpose:To relate the costs of each management approach tooverall survival in patients with metastatic colorectal cancer. Patients and methods:The healthcare costs and medical benefits(treatment-added survival) of second-line chemotherapy in patients (infusional5-FU: 129, irinotecan: 127) were compared. Data on overall survival were drawnfrom a multicenter randomised trial that compared infusional 5-FU (continuousinfusion, AIO, or LV5-FU2 regimens) to irinotecan alone. Costs were derivedfrom the accounting system in two university hospitals in Paris, France. Results:The range in total healthcare costs was 14,135 to 12,192US$ patient between management approaches, with irinotecan chemotherapycosting most and 5-FU-continuous infusion least. If survival was included asa treatment benefit, the cost-effectiveness ratio of irinotecan over 5-FUranged from 9,344 to 10,137 US$ per year of added survival. Conclusions:The least expensive management for metastaticcolorectal was 5-FU infusion but the additional cost of irinotecan wasbalanced by the added months of survival, with a cost-effectiveness ratioclose to that of other cancer treatments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008358411251
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  • 33
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    Electronic Resource
    Phase II trial of gemcitabine in patients with previously untreated metastatic cancer of the esophagus or gastroesophageal junction (2000)
    Springer
    Annals of oncology 11 (2000), S. 1161-1164 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; esophageal cancer ; gemcitabine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:There were approximately 12,500 cases of esophageal carcinoma diagnosed in the US in 1992 and 12,200 deaths. The impact of chemotherapy on patients with metastatic disease is marginal with a median survival of only five months. Gemcitabine (LY188011,2,2,–difluorodeoxycytidine: dFdC), an analog of cytosine arabinoside (ara-C), is a pyrimidine antimetabolite. Gemcitabine has shown interesting clinical activity in initial phase II clinical trials in a variety of malignancies, including the aerodigestive malignancies, squamous-cell carcinoma of the head/neck and both non-small-cell and small-cell lung cancer. Patients and methods:A total of 21 patients with chemotherapy-naïve metastatic esophageal carcinoma were entered. Nineteen patients were evaluable for toxicity and seventeen patients were evaluable for response. Gemcitabine was administered intravenously at 1250 mg/m2 over 30–60 minutes on days 1, 8, and 15 followed by 1 week of rest. This four-week schedule defined a cycle of treatment. Patients may have received a maximum of six cycles. Results:Gemcitabine was well tolerated with minimal non-hematologic toxicity and grade 3–4 anemia, granulocytopenia, and thrombocytopenia occurring in 10.5%, 21%, and 0% of patients, respectively. No responses were seen in the seventeen evaluable patients. Conclusions:At the dose and schedule studied it would appear that gemcitabine has no activity in patients with chemotherapy-naïve esophageal carcinoma.
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    URL: http://dx.doi.org/10.1023/A:1008369718242
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  • 34
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    Electronic Resource
    Dose-finding study of oral idarubicin and cyclophosphamide in first-line treatment of elderly patients with metastatic breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 229-230 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cyclophosphamide ; elderly ; idarubicin ; oral chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008384820279
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  • 35
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    Electronic Resource
    A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 169-175 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1008345432342
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  • 36
    Electronic Resource
    Electronic Resource
    Myocardial enzyme activities in plasma after whole-heart irradiation in rats (2000)
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 27-32 
    Details
    ISSN: 1432-1335
    Keywords: Key words Heart irradiation ; Plasma enzyme levels ; Myocardial enzyme levels ; Rat ; AbbreviationsCK creatine kinase ; LDH lactate de-hydrogenase ; AST aspartate aminotransferase ; ALT alanine aminotransferase ; α-HBDHα-hydroxybutyrate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and α-hydroxybutyrate dehydrogenase (α-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and α-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.
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    URL: http://dx.doi.org/10.1007/PL00008461
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  • 37
    Electronic Resource
    Electronic Resource
    Decreased expression of vascular endothelial growth factor in glomeruli of puromycin aminonucleoside nephrosis (2000)
    Springer
    Clinical and experimental nephrology 4 (2000), S. 29-33 
    Details
    ISSN: 1437-7799
    Keywords: Key words VEGF ; Glomeruli ; Ribonuclease protection assay ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Vascular endothelial growth factor (VEGF) is a selective endothelial growth factor which potently enhances microvascular permeability. In the kidney, VEGF mRNA is known to be highly expressed in visceral epithelial cells in glomeruli. However, the physiological role of VEGF in glomerular function and its involvement in the pathogenesis of proteinuria are not clear. The present studies were designed to determine whether altered expression of VEGF mRNA was observed in the course of puromycin aminonucleoside (PAN) nephrosis in rats (a model of human minimal change nephrosis). Methods. The message level of VEGF in isolated glomeruli of PAN nephrosis rats was measured using a ribonuclease protection assay. Results. VEGF expression began to decrease 4 days after PAN injection and could not be detected in the nephrotic stage of PAN nephrosis (on days 8 and 16). In the remission of stage of PAN nephrosis (on day 28), mRNA was restored to the control level. Conclusions. According to our results, a functional defect in the VEGF expression of visceral epithelial cells was observed in PAN nephrosis. VEGF could be a functional marker of visceral epithelial cells, and the loss of normal expression of VEGF after damage to visceral epithelial cells could affect glomerular endothelial cell function in PAN nephrosis.
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    URL: http://dx.doi.org/10.1007/s101570050058
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  • 38
    Electronic Resource
    Electronic Resource
    Apoptosis in murine duodenum during embryonic development (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 485-487 
    Details
    ISSN: 1437-9813
    Keywords: Key words Duodenum ; Apoptosis ; Fetus ; Rat ; Duodenal atresia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Duodenum is thought to go through a solid-core stage followed by recanalization during its development. This study investigates the role of apoptosis in normal duodenal development, especially during widening of the lumen, and hence, the possible role of apoptosis in duodenal atresia (DA). Twenty-four time-mated Sprague-Dawley rats were killed from day 13 to day 20 of gestation. Duodenums of 3 fetuses were chosen randomly from each rat and processed. Apoptosis was determined by the terminal deoxytransferase-mediated biotin dUTP nick-end labeling (TUNEL) technique (ApopTag). Apoptosis count and cross-sectional areas were measured with an image analyzer (MetaMorph). The number of apoptotic cells per unit area duodenum peaked on day 15 for the mucosal/submucosal layer and on day 14 for the muscular/mesenchymal layer. The maximal number of apoptotic cells per cross-section of duodenum was between 7 and 8. The cross-sectional areas of the duodenal wall and lumen increased exponentially between day 17 and day 19 while duodenal-wall thickness remained relatively constant throughout duodenal development. The localization, timing, and intensity of apoptosis do not suggest that apoptosis is responsible for the widening of the duodenal lumen; enlargement of the lumen is related to the increase in duodenal circumference. Apoptosis thus may not be involved in the pathogenesis of DA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003830000408
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  • 39
    Electronic Resource
    Electronic Resource
    Organ-specific distribution of major histocompatibility antigens in rats (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 285-292 
    Details
    ISSN: 1437-9813
    Keywords: Key words Major histocompatibility complex (MHC) ; Rat ; Immunohistochemistry ; Distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study systematically investigated the expression and distribution of the major histocompatibility complex (MHC) classes I and II in the rat. About 150 native tissue probes from eight adult Lewis rats were taken, representative for most organs, tissues, and the vascular system. MHC expression was analyzed by two monoclonal antibodies (mAb) generated against the non-polymorphic determinants of rat MHC class I (Ox-18) and class II (Ox-6). Immunoreactivities were compared to those of different endothelial (HIS52, TLD-3A12, Ox-43, REHA-1 antigen), histiocytic (ED1, ED2), B-cell (RLN-9D3), and T-cell (MRC Ox-52) markers. A nonspecific mAb (MR12/53) served as a negative control. Pretested concentrations on various tissues and the alkaline phosphatase-anti-alkaline phosphatase technique allowed semiquantitative evaluation of serial cryostat tissue sections. MHC class I expression was detected on most immunocompetent cells. Endothelial cells were stained heterogeneously along the vascular system and the organ-specific microcirculation. Furthermore, some organs showed staining of parenchymal cells. MHC class II was found on all immunocompetent cells positive for the B-cell marker and about 15% of cells positive for the histiocytic markers. Besides the well-known expression of MHC class II in the outer zone of the renal proximal tubule, further organ-specific cell forms were found positive. In conclusion, the present study outlines tissue-specific distribution of MHC I/II and implies that each organ carries a variable immunologic burden that needs to be considered for any transplantation model.
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    URL: http://dx.doi.org/10.1007/s003830050746
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  • 40
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    Electronic Resource
    Proliferation, zonal maturation, and steroid production of fetal adrenal transplants in adrenalectomized rats (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 293-296 
    Details
    ISSN: 1437-9813
    Keywords: Key words Fetal transplantation ; Proliferation ; Adrenal glands ; Addisonian crisis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study investigated the histologic maturation, proliferative capacity, and steroid production of fetal adrenal transplants (Tx) in adrenalectomized rats. A pair of fetal adrenal glands (18–20 days of gestation) was transplanted into the omentum of syngeneic Lewis rats (n=45). Four weeks later, in 5 animals the grafts were excised for morphologic evaluation. Proliferation was investigated by immunohistochemical staining for KI-67 protein and quantified by the proliferation index (PI = positive cells/100 counts). All other hosts (Tx; n = 40) underwent bilateral adrenalectomy (AE) to induce Addisonian crisis. Postoperatively, survival and concentrations of potassium, sodium, aldosterone, and corticosterone were recorded for 6 months. These data were compared to controls (C = only AE; n = 30) and a sham group (S; n = 10). At the end of the study period all surviving hosts were killed for histologic examination of grafts. At 4 weeks post-Tx the adrenal grafts demonstrated a distinct zona glomerulosa and frequent proliferation with a PI of 0.084, comparable to normal control (0.092). Following AE survival was significantly prolonged in Tx (86% vs 12% of C, P 〈 0.05). Control animals developed severe hyponatremia and hyperkalemia, whereas in Tx only transient signs of Addisonian crisis were recorded. Levels of aldosterone dropped within 7 days in the Tx and C groups, but returned to normal for Tx within 8 weeks. Corticosterone levels of Tx animals fell to 25% within week, but steadily increased to 70% by the end of the study. At 6 months, grafts revealed a mature adrenocortical structure with little proliferative activity, which was comparable to controls. In a syngeneic rat model fetal adrenal transplants thus mature and proliferate to provide sufficient steroid production for adrenalectomized hosts.
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    URL: http://dx.doi.org/10.1007/s003830050747
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  • 41
    Electronic Resource
    Electronic Resource
    Antenatal dexamethasone administration inhibits smooth-muscle-cell DNA synthesis in pulmonary-arterial media in nitrofen-induced congenital diaphragmatic hernia in rats (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 414-416 
    Details
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Hypoplastic lung ; Bromodeoxyuridine (BrdU) ; Antenatal glucocorticoids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to investigate the effect of antenatal glucocorticoid therapy on smooth-muscle-cell (SMC) DNA synthesis in the pulmonary arteries (PA) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model following nitrofen administration on day 9.5 of gestation. Antenatal dexamethasone (DEX) was given intraperitoneally on days 18.5 and 19.5 of gestation. Bromodeoxyuridine (BrdU) was injected via a jugular vein into the dam 1 h before the fetuses were killed by cesarean section at term. The fetuses were divided into three groups: group I (n = 10): normal controls; group II (n = 10): nitrofen-induced CDH; group III (n = 10): nitrofen-induced CDH with antenatal DEX treatment. Immunostaining of the lungs with anti-BrdU antibody was obtained by a standard avidin-biotin complex method. The number of immunopositive cells in the PA media and adventitia were counted using an image analyzer and analyzed statistically. The number of BrdU-immunopositive cells in the media was significantly increased in group II (16.83 ± 3.01) compared to groups I (9.16 ± 2.20) and III (6.83 ± 1.70) (P 〈 0.01). There was no significant difference between groups I and III. The number of BrdU-immunopositive cells in the adventitia was not significantly different between the three groups. Antenatal DEX treatment inhibits SMC DNA synthesis in PA media in CDH lungs. This may be a possible mechanism by which antenatal DEX prevents structural PA changes in nitrofen-induced CDH in rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003839900336
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  • 42
    Electronic Resource
    Electronic Resource
    Long-term small bowel allograft function induced by short-term FK 506 application is associated with split tolerance (2000)
    Springer
    Transplant international 13 (2000), S. S532 
    Details
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Split tolerance ; FK 506 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0–5 in the rejection model and from days 0–9 in the long-term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term ( 〉 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely ( 〉 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050396
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  • 43
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    Electronic Resource
    Heart valve dysfunction resulting from cellular rejection in a novel heterotopic transplantation rat model (2000)
    Springer
    Transplant international 13 (2000), S. S528 
    Details
    ISSN: 1432-2277
    Keywords: Key words Implantation model ; Aortic valves ; Valve dysfunction ; Rejection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Structural failure of heart valve allografts may be related to technical factors or immunological reactions. To circumvent nonimmunological factors a new rat implantation model was developed to study whether alloreactivity results in histopathological changes and valve dysfunction. Syngeneic (WAG-WAG, DA-DA) and allogeneic (WAG-BN, WAG-DA) transplantation was carried out using this new technique, and the function of explanted valves was assessed 21 days later by retrograde comptence testing. Additionally, grafts were examined using standard histological and immunohistochemical techniques. There was no leakage during retrograde injection in nine of tem syngeneic and two of ten allogeneic grafts. Microscopically, syngeneic valves appeared normal without fibrosis or intimal thickening, although CD8+ lymphocytes and macrophages were found in necrotic myocardial rim and adventitia. In contrast, allogeneic valves were deformed and noncellular, with extensive infiltration of CD4+, CD8+ and CD68+ cells in adventitia and media. Absence of fibrosis and intimal thickening in syngeneic transplanted valves indicated circumvention of nonimmunological factors. Allogeneic valve transplantation induces cellular infiltration in the graft with subsequent graft failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050395
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  • 44
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    Electronic Resource
    Hypoxia-reoxygenation differentially stimulates stress-activated protein kinases in primary-cultured rat hepatocytes (2000)
    Springer
    Transplant international 13 (2000), S. S597 
    Details
    ISSN: 1432-2277
    Keywords: Key words Hypoxia-reoxygenation ; JNK1/SAPK1 ; Rat ; Hepatocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Organ injury after ischemia and reperfusion (I/R) remains one of the most important limiting factors in liver surgery and transplantation. Oxygen-free radical (OFR) generation is considered a major cause of this damage. JNK1/SAPK1, a member of MAPK family, regulates cell adaptation to stressful conditions. The aim of this study was to determine if hypoxia-reoxygenation (H/R) can activate JNK1/SAPK1 and if OFR are involved in this activation. Primary cultured rat hepatocytes isolated from other liver cells and blood flow were submitted to warm and cold H/R phases mimicking surgical and transplant conditions. JNK1/SAPK1 was activated by both warm and cold H/R. Deferoxamine (1 mM), di-phenyleneiodonium (50 μM) and N-acetylcysteine (10 mM) significantly inhibited this kinase activation.
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    URL: http://dx.doi.org/10.1007/s001470050410
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  • 45
    Electronic Resource
    Electronic Resource
    Real-time monitoring of nitric oxide in ischemia-reperfusion rat kidney (2000)
    Springer
    Urological research 28 (2000), S. 141-146 
    Details
    ISSN: 1434-0879
    Keywords: Key words Kidney ; Nitric oxide ; Ischemia-reperfusion injury ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study we attempted to clarify the release of nitric oxide (NO) and its role in the ischemia-reperfusion rat kidney. After right nephrectomy, male Wistar rats were divided into four groups: one sham operated and three groups who underwent ischemia (30 min) and reperfusion of the left renal artery. Thirty minutes prior to ischemia-reperfusion, two groups were injected intraperitoneally with 10 and 30 mg/kg of NG-nitro-l-arginine methylester (L-NAME). Real-time monitoring of blood flow and NO release in the rat kidney was measured with a laser Doppler flowmeter and an NO-selective electrode, respectively. Serum creatinine and blood urea nitrogen (BUN) levels were measured 1 and 7 days after the induction of ischemia-reperfusion. Clamping of the renal artery decreased blood flow to 1–5% of the basal level measured before clamping. After removal of the clip, the blood flow of the 30 mg/kg L-NAME rats was significantly lower than that of the controls. Immediately following the clipping of the renal artery, NO release rapidly increased. After removing the clip, NO release immediately returned to three-quarters of the basal level. Serum creatinine and BUN levels of the ischemia-reperfusion rats were slightly but not significantly higher and those of 30 mg L-NAME rats were significantly higher than those of the control or ischemia-reperfusion rats 1 day and 7 days after ischemia-reperfusion. Our data suggest that NO acts as a cytoprotective agent in ischemia-reperfusion injury of the rat kidney.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002400050153
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  • 46
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    Electronic Resource
    Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats (2000)
    Springer
    Urological research 28 (2000), S. 75-81 
    Details
    ISSN: 1434-0879
    Keywords: Key words Castration ; Epidermal growth factor ; Insulin-like growth factor I ; Prostate ; Testosterone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated Wistar rats were treated with growth factors (EGF 35 μg/rat per day; IGF-I 350 μg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P 〈 0.05), whereas treatment with IGF-I did not affect the prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration. Compared with testosterone, the effects of EGF treatment on the prostate involution were moderate, and the effects of EGF were not related to cellular proliferation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002400050141
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  • 47
    Electronic Resource
    Electronic Resource
    Effect of aging on bladder function and the response to outlet obstruction in female rats (2000)
    Springer
    Urological research 28 (2000), S. 33-37 
    Details
    ISSN: 1434-0879
    Keywords: Key words Bladder ; Rat ; Aging ; Obstruction ; Cystometrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bladder dysfunction in the aging population is a significant problem. However the concomitant presence of other diseases in many patients can make it difficult to distinguish between changes in bladder function and other influences. The present study was designed to study, in aging rats, bladder function and the effect of partial bladder outlet obstruction (BOO) on bladder function. Cystometrics were performed in awake, female Fischer 344 rats of four age groups (6, 12, 18 and 24 months) following subcutaneous implantation of a mediport catheter. Cystometric evaluations were carried out in control rats or those subject to three weeks of BOO. Bladder compliance significantly decreased with aging, which reflected an increase in threshold pressure without changes in bladder capacity. Partial BOO caused development of severe bladder instability. Following BOO, bladder capacity and compliance were significantly increased in all age groups. Threshold pressure was lower in obstructed animals, except for 6-month rats. Younger animals were able to generate a higher contraction pressure to compensate for the BOO, whereas older animals did not. Using an awake model of cystometric measurement, we have demonstrated that aging, by itself can affect bladder function. Furthermore, aged animals respond differently to BOO than younger animals. These results demonstrate that both aging and disease can contribute to bladder dysfunction, and suggest that treatment of bladder dysfunction may require a combination of therapies targeted to multiple etiologies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002400050007
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  • 48
    Electronic Resource
    Electronic Resource
    Morphological analysis of peripheral nerve regenerated by means of vein grafts filled with fresh skeletal muscle (2000)
    Springer
    Anatomy and embryology 201 (2000), S. 475-482 
    Details
    ISSN: 1432-0568
    Keywords: Key words Nerve repair ; Nerve fiber regeneration ; Sciatic nerve ; Muscle-vein-combined graft ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Clinical data have shown that a vein segment filled with fresh skeletal muscle can be considered a good autologous grafting conduit for the repair of peripheral nerve lesions. In this study, the long-term morphological organization of rat sciatic nerve fibers regenerated along a muscle-vein-combined graft conduit is further analysed by light and electron microscopy. Regenerated nerve fibers were organized into fascicles of various sizes that were clearly delimited by perineurial-like shells made by long and thin cytoplasmic processes of perineurial-like bipolar cells and by densely packed collagen fibrils. Grafted skeletal muscle fibers were still detectable among nerve fiber fascicles. However, in spite of the persistence of skeletal muscle along the graft, regenerated nerve fibers showed a good morphological pattern of regeneration, providing further evidence that the muscle-vein-combined grafting technique represents an effective surgical alternative to the classical fresh nerve autograft for the repair of peripheral nerve defects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004290050334
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  • 49
    Electronic Resource
    Electronic Resource
    Immunocytochemical distribution of the GABAB receptor splice variants GABAB R1a and R1b in the rat CNS and dorsal root ganglia (2000)
    Springer
    Anatomy and embryology 201 (2000), S. 1-13 
    Details
    ISSN: 1432-0568
    Keywords: Key words GABAB receptor ; CNS ; Dorsal root ganglia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The anatomical distribution of the GABAB receptor (GBR) splice variants GBR1a and 1b in the CNS has not previously been studied. In the present study, distribution of the splice variants was mapped using immunohistochemistry. Polyclonal antibodies against splice variant unique epitopes were raised in rabbits. Affinity purified antibodies were used according to routine immunohistochemical procedures in sections from the rat CNS or dorsal root ganglia (DRG). The staining intensity was high in the cerebral cortex but lower in basal ganglia and the hippocampus. In the cerebellum, there was a marked difference in the distribution of GBR1a- and 1b-like immunoreactivity (LI). GBR1a-LI was preferentially localised in the granule cell layer whilst GBR1b-LI was mostly found in Purkinje cells and in the molecular layer. Cell bodies of the deep cerebellar nuclei stained for the GBR1a antibody while terminals surrounding the cell bodies were strongly labelled with the GBR1b antibody. A similar pre- vs postsynaptic pattern was seen in several nuclei ventral or caudal to the cerebellum (e.g. the cochlear nucleus, the facial nucleus, the spinal cord) but not in regions rostral to the cerebellum. In the spinal cord, strong labelling for both antibodies was seen in the dorsal horn. The GBR1b but not the GBR1a antibody stained tanycytes in the epithelium of the 3rd ventricle and in the central canal at the brain stem level. DRG neurons were positive for both the GBR1a and 1b antibody, but the former stained the cells much more intensely. Satellite cells were labelled with the GBR1b antibody. The most important aspect of these findings is that in some nuclei, GBR1b may mediate inhibition of transmitter release while in the same regions, GBR1a may mediate postsynaptic inhibition. Further, the observations support previous findings that GBR1b is the predominant splice variant in Purkinje cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008224
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  • 50
    Electronic Resource
    Electronic Resource
    NK1, NK2 and NK3 tachykinin receptor localization and tachykinin distribution in the ileum of the mouse (2000)
    Springer
    Anatomy and embryology 202 (2000), S. 247-255 
    Details
    ISSN: 1432-0568
    Keywords: Key words Enteric neurons ; Interstitial cells of Cajal ; Smooth muscle cells ; Guinea-pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tachykinin receptors NK1r, NK2r and NK3r bind tachykinins with different affinities and share pharmacological and molecular differences among animal species. NK1r, NK2r, NK3r and tachykinin (SP/NKA) distribution was studied by immunohistochemistry in the ileum of mouse since no data are available for this species. The results were then compared to those obtained in the rat and guinea pig either by us or by others to ascertain interspecies similarities and/or differences. NK1r- and NK3r-immunoreactivity (IR) were detected in neurons and NK1r-IR in the interstitial cells of Cajal at the deep muscular plexus. At variance with rat and guinea pig, NK1r-IR was also found in the myoid cells of the villi, while NK2r-IR was never detected in nerve varicosities. This latter datum suggests that the NK2r does not play a presynaptic role in the mouse. Unexpectedly, a high NK2r-IR and the presence of NK3r-IR were observed at the inner portion of the circular muscle layer in the mouse as well as in the rat and guinea pig, demonstrating a subregional distribution of these receptors. Tachykinin distribution did not show noticeable species-related differences. The present findings show species-related differences in the tachykinin receptor distribution that might be related to a different tachykinin controlof intestinal motility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004290000106
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  • 51
    Electronic Resource
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    Systemic hypothermia following spinal cord compression injury in the rat: an immunohistochemical study on MAP 2 with special reference to dendrite changes (2000)
    Springer
    Acta neuropathologica 100 (2000), S. 546-552 
    Details
    ISSN: 1432-0533
    Keywords: Key words Hypothermia ; Immunohistochemistry ; Microtubule-associated protein 2 (MAP2) ; Rat ; Spinal cord injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Systemic hypothermia has been shown to exert neuroprotective effects in experimental ischemic CNS models caused by vascular occlusions. The present study addresses the question as to whether systemic hypothermia has similar neuroprotective qualities following severe spinal cord compression trauma using microtubule-associated protein 2 (MAP2) immunohistochemistry combined with the avidin-biotin-peroxidase complex method as marker to identify neuronal and dendritic lesions. Fifteen rats were randomized into three equally sized groups. One group sustained thoracic laminectomy, the others severe spinal cord compression trauma of the T8-9 segment. The control group contained laminectomized animals submitted to a hypothermic procedure in which the esophageal temperature was reduced from 38 °C to 30 °C. The two trauma groups were either submitted to the same hypothermic procedure or kept normothermic during the corresponding time. All animals were sacrificed 24 h following the surgical procedure. The MAP2 immunostaining in the normothermic trauma group indicated marked reductions in MAP2 antigen in the cranial and caudal peri-injury zones (T7 and T10, respectively). This reduction was much less pronounced in the hypothermic trauma group. In fact, the MAP2 antigen was present in almost equally sized areas in both the hypothermic groups independent of previous laminectomy alone or the addition of trauma. Our study thus indicates that hypothermia has a neuroprotective effect on dendrites of rat spinal cords subjected to compression trauma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010000206
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  • 52
    Electronic Resource
    Electronic Resource
    Changes of Fas and Fas ligand immunoreactivity after compression trauma to rat spinal cord (2000)
    Springer
    Acta neuropathologica 100 (2000), S. 75-81 
    Details
    ISSN: 1432-0533
    Keywords: Key words Fas ; Fas ligand ; Rat ; Spinal cord ; Trauma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This immunohistochemical study evaluated Fas and Fas ligand (FasL) in the rat nervous system and their changes in the spinal cord subjected to compression. Normal spinal cord showed a low level of Fas and FasL immunoreactivity in the white matter except in the corticospinal tracts. Fas and FasL immunoreactivity seemed to be located in axons and their myelin sheaths. Other regions of the nervous system did not show immunoreactivity to Fas and FasL. Moderate and severe compression injury of the spinal cord resulted in a reduction of Fas and FasL immunoreactivity in the white matter of injured T8–9 segments at 4 h and a complete loss at 1 day after trauma. This was seen even in the remaining white matter. In contrast, increased immunoreactivity to Fas and FasL was present in the cranial T7, caudal T10 (moderate injury) and T12 (severe injury) segments at day 4 with most intense staining were seen at day 9 after trauma. Increased Fas and FasL immunoreactivity may have pathophysiological implications for the development of secondary injuries after trauma to the spinal cord. Fas-FasL interactions may for instance be involved in apoptosis of oligodendrocytes which occurs as a delayed phenomenon after trauma to the spinal cord. The integrity of myelin sheaths may in this way be jeopardized by apoptosis of oligodendrocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010051195
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  • 53
    Electronic Resource
    Electronic Resource
    Maximum tolerated doses of methotrexate and 7-hydroxy-methotrexate in a model of acute toxicity in rats (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 69-73 
    Details
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxymethotrexate ; Methotrexate ; Maximum tolerated dose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD50 for reasons of animal welfare. Methods: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8–11.3 g/kg MTX and 0.1–1.2 g/kg 7-OH-MTX. Results: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. Conclusions: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800000111
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  • 54
    Electronic Resource
    Electronic Resource
    A polymorphism of the rat T-cell receptor β-chain variable gene 13 (BV13S1) correlates with the frequency of BV13S1-positive CD4 cells (2000)
    Springer
    Immunogenetics 51 (2000), S. 296-305 
    Details
    ISSN: 1432-1211
    Keywords: Key words Vβ13 ; CD4/CD8 ratio ; Rat ; Tcrb ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Three rat BV13S1 alleles (T-cell receptor β-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW×WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW×BN)×BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002510050623
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  • 55
    Electronic Resource
    Electronic Resource
    Constitutive NF-κB activity is modulated via neuron-astroglia interaction (2000)
    Springer
    Experimental brain research 130 (2000), S. 100-104 
    Details
    ISSN: 1432-1106
    Keywords: Key words NF-κB ; p65 ; Hippocampal neurons ; Glia ; Astrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  NF-κB is found in many neuronal cell types in different states of activity. This study aimed to define which conditions induce constitutive NF-κB activity in cultured hippocampal neurons using activity-specific antibody staining. In co-culture with astroglia, hippocampal neurons were devoid of activated NF-κB. In these co-cultures, NF-κB could not be activated via kainate or glutamate. In contrast, separating neurons from the glial compartment resulted in a time-dependent increase of activated neuronal NF-κB. In this line, activation of NF-κB by kainate or glutamate is very effective in freshly separated cultures, but inhibited when the cultures are reassembled after stimulation. These findings suggests that a neuronal-glial interaction may regulate gene expression via NF-κB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002210050011
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  • 56
    Electronic Resource
    Electronic Resource
    Localization of endothelin receptors in bleomycin-induced pulmonary fibrosis in the rat (2000)
    Springer
    Histochemistry and cell biology 122 (2000), S. 507-517 
    Details
    ISSN: 1432-119X
    Keywords: Endothelin-A receptor ; Endothelin-B receptor ; Rat ; Pulmonary fibrosis ; Immunohistochemistry ; Quantitative PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: AbstractPulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s00418-004-0708-7
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  • 57
    Electronic Resource
    Electronic Resource
    Resistance to growth hormone and insulin-like growth factor-I in acidotic rats (2000)
    Springer
    Pediatric nephrology 14 (2000), S. 720-725 
    Details
    ISSN: 1432-198X
    Keywords: Key words Metabolic acidosis ; Growth ; Growth hormone ; Insulin-like growth factor-I ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Growth impairment induced by chronic metabolic acidosis is associated with an abnormal growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To examine the potentially beneficial effects of IGF-I on acidosis-induced growth impairment and the influence of GH and IGF-I treatment on the GH/IGF-I axis, three groups of acidotic young rats (untreated, AC, n=12; treated with recombinant human GH, GH, n=8; treated with recombinant human IGF-I, IGF-I, n=8) were studied, and compared with nonacidotic rats fed ad libitum (C, n=9)) or pair-fed with the AC group (PF, n=12). After 14 days of acidosis and 7 days of treatment, growth rate, hepatic abundance of 4.7-kilobase (kb) and 1.2-kb GH receptor transcripts and 7.5-kb and 1.8- to 0.8-kb IGF-I transcripts, serum GH-binding protein (GHBP), and IGF-I concentrations (mean±SEM) were analyzed. Significant decreases of 4.7-kb GH receptor [26±2 vs. 49±6 arbitrary densitometry units (ADU)] and 7.5 kb IGF-I (41±3 vs. 104±10 ADU) transcripts and low serum GHBP (25±1 vs. 32±1 ng/ml) and IGF-I (279±50 vs. 366±6 nmol/l) levels were found in the AC compared with the C rats. The majority of these alterations were also observed in PF rats. Compared with acidotic untreated rats, GH and IGF-I therapy produced no improvement in growth rate. GH treatment normalized the levels of IGF-I mRNA, aggravated the acidosis-related inhibition of the GH receptor gene, and did not modify the serum levels of GHBP and IGF-I. In contrast, IGF-I administration depressed the hepatic expression of all GH and IGF-I transcripts and normalized serum IGF-I concentrations. Our results confirm that sustained metabolic acidosis alters the GH/IGF-I axis, in part because of associated malnutrition, and induced growth retardation that is resistant to GH therapy. Our study also shows that administration of IGF-I does not accelerate the growth of acidotic rats, suggesting a peripheral mechanism, at the level of target tissues, is responsible for the resistance to the growth-promoting actions of GH and IGF-I.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00013425
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  • 58
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    Electronic Resource
    Apoptosis parallels ceramide content in the developing rat kidney (2000)
    Springer
    Pediatric nephrology 15 (2000), S. 188-191 
    Details
    ISSN: 1432-198X
    Keywords: Key words Apoptosis ; Ceramide ; Development ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ceramide is emerging as an important hydrophobic sphingolipid involved in cell differentiation and apoptosis. Since apoptosis plays a significant role in cellular remodeling during renal morphogenesis, we measured ceramide content and apoptosis in the fetal (18 days gestation), neonatal (3, 7, and 14 days postnatal), and adult rat kidney. In addition, to determine whether developmental changes in ceramide content are tissue-specific, we compared renal ceramide content with that in lung and liver. Ceramide was measured by the diacylglycerol kinase assay, and apoptosis was determined by the TUNEL technique. Renal ceramide content fell over 100-fold from the fetus to the 7th postnatal day. Renal apoptosis paralleled ceramide content, with a greater than 300-fold decrease in apoptosis from fetal to adult life. Ceramide content of the lung and liver was significantly less than that of the kidney, and changed less with maturation. We conclude that maturational changes in ceramide content are tissue-specific, and that the high rate of apoptosis in the developing kidney may be related to the elevated ceramide content.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004670000444
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  • 59
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    Electronic Resource
    Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex (2000)
    Springer
    Psychopharmacology 151 (2000), S. 166-174 
    Details
    ISSN: 1432-2072
    Keywords: Keywords Novelty ; Context ; Environment ; Stress ; 6-OHDA ; Rotational behavior ; Striatum ; Nucleus accumbens shell ; Caudate ; Amphetamine ; Dopamine ; Glutamate ; Aspartate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900359
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  • 60
    Electronic Resource
    Electronic Resource
    Human interferon-α increases immobility in the forced swimming test in rats (2000)
    Springer
    Psychopharmacology 148 (2000), S. 106-110 
    Details
    ISSN: 1432-2072
    Keywords: Key words Interferon ; Depression ; Forced swimming test ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Objectives: We examined the immobility of the forced swimming test induced in an animal model by human interferon (IFN), which has often been reported to induce depression in clinical use. Methods: In the present study, we examined the effects of human IFNs on results of the forced swimming test in rats. Results: Single intravenous (IV) administration of human IFN-α (6×104 IU/kg), but not of human IFN-β or -γ, significantly increased immobility time in the forced swimming test in rats. Repeated administration of human IFN-α (6×103 IU/kg) also significantly increased the immobility time. On the other hand, none of the rat IFNs (rat IFN-α, -β and -γ, 6×104 IU/kg, IV) changed the immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity of rats. Conclusions: These findings suggest that human IFN-α has a greater potential for inducing increase of the immobility in the rat forced swimming test than human IFN-β and -γ, and that the effect of human IFN-α might not be mediated through IFN-α/β receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050031
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  • 61
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    Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the habituation of novelty-induced hypoalgesia in the rat (2000)
    Springer
    Psychopharmacology 148 (2000), S. 99-105 
    Details
    ISSN: 1432-2072
    Keywords: Key words Opiate receptor ; Antinociception ; Habituation ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. Objectives: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. Methods: In experiments 1–3, different groups of male, Wistar rats (275–300 g) were administered vehicle, 0.5, 1.0 or 2.0-nmol doses of the µ-selective antagonist Cys2-Tyr3-Orn5-Pen7-amide (CTOP), the δ-receptor selective antagonist naltrindole, or the κ-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5°C), once a day for eight consecutive days. Results: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. Conclusions: These results support the involvement of the µ and δ, but not the κ, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050030
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    Acute exposure to saccharin reduces morphine analgesia in the rat: evidence for involvement of N-methyl-d-aspartate and peripheral opioid receptors (2000)
    Springer
    Psychopharmacology 149 (2000), S. 56-62 
    Details
    ISSN: 1432-2072
    Keywords: Key words Morphine ; Opioid receptor ; NMDA ; Tolerance ; Rat ; Tail flick
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug’s peripheral effect, while learned tolerance involves activation of N-methyl-d-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. Methods: Six experiments used the rat’s tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the non-competitive NMDA receptor antagonist MK-801 on this modulation of analgesia. Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment 1a), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900337
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    Opiate withdrawal-induced place aversion lasts for up to 16 weeks (2000)
    Springer
    Psychopharmacology 149 (2000), S. 115-120 
    Details
    ISSN: 1432-2072
    Keywords: Key words Opiate ; Withdrawal ; Place aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown. Objectives: The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal. Methods: Morphine-dependent rats were tested in a three-chamber place- aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 µg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests). Results: A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points. Conclusions: In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900358
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    Role of dopamine in prepulse inhibition of acoustic startle (2000)
    Springer
    Psychopharmacology 149 (2000), S. 181-188 
    Details
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Sensorimotor gating ; Schizophrenia ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Objective: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. Results: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. Conclusions: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000369
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    Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat (2000)
    Springer
    Psychopharmacology 149 (2000), S. 366-376 
    Details
    ISSN: 1432-2072
    Keywords: Key words Prefrontal cortex ; Dopamine ; Anxiety ; Drug discrimination ; Pentylenetetrazol ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. Objectives: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. Conclusions: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ, suggesting a role for it in anxiety.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000390
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    In vivo estimates of efficacy at 5-HT1A receptors: effects of EEDQ on the ability of agonists to produce lower-lip retraction in rats (2000)
    Springer
    Psychopharmacology 149 (2000), S. 377-387 
    Details
    ISSN: 1432-2072
    Keywords: Key words 5-HT1A agonist ; Intrinsic activity ; Efficacy ; Irreversible antagonism ; Lower-lip retraction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. Objectives: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 〉 8-OH-DPAT 〉 buspirone 〉 ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose–response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone 〈 buspirone ≈ 8-OH-DPAT 〈 S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000374
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    Repeated dose (28 days) oral toxicity study of flutamide in rats, based on the draft protocol for the `Enhanced OECD Test Guideline 407' for screening for endocrine-disrupting chemicals (2000)
    Springer
    Archives of toxicology 74 (2000), S. 127-132 
    Details
    ISSN: 1432-0738
    Keywords: Key words Flutamide ; Androgen antagonist ; Rat ; Enhanced OECD Test Guideline 407 ; Endocrine disrupters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In association with the international validation project to establish a test protocol for the `Enhanced OECD Test Guideline 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting of 10 males and 10 females, and administered flutamide once daily by oral gavage at doses of 0 (control), 0.25, 1 and 4 mg/kg body weight/day. Male rats were killed 1 day after the 28th administration. Female rats were killed on the day they entered the diestrus stage in the estrous cycle following the last treatment. Male rats receiving flutamide at dose levels of 1 and 4 mg/kg showed lobular atrophy of the mammary gland and a decrease in epididymal weight. In addition, 4 mg/kg flutamide-treated males exhibited raised serum testosterone and estradiol levels and decreased weight of the accessory sex glands. In females, a slight prolongation of the estrous cycle was also observed in the 4 mg/kg flutamide-treated group. No dose-related changes could be detected by haematology, serum biochemistry and sperm analysis. Thus, among the parameters tested in the present experimental system, the weight of endocrine-linked organs and their histopathological assessment, serum hormone levels, and estrous cycle stage allowed the detection of endocrine-related effects of flutamide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050664
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    Changes in serum α2u-globulin levels in male rats given diethylstilbestrol and applicability to a screening test for endocrine-disrupting chemicals (2000)
    Springer
    Archives of toxicology 74 (2000), S. 48-53 
    Details
    ISSN: 1432-0738
    Keywords: Key wordsα2u-Globulin ; Diethylstilbestrol ; Endocrine disrupter ; Rat ; Screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract α2u-Globulin (AUG) is a major rat urinary protein, which has a molecular weight of 16 kDa (kidney type) or 19 kDa (native type). The biosynthesis of this protein is under multi-hormonal regulation. In this study, we investigated changes in serum AUG level and their association with changes in the reproductive organs of male rats after the administration of the estrogenic chemical, diethylstilbestrol (DES) at doses ranging from 0.01 mg/kg per day to 100 mg/kg per day by gavage for 14 days. Our aim was to establish basic data for the development of a new screening method for endocrine disrupting chemicals based on serum AUG levels. DES treatment decreased the weight of testes in a dose-dependent manner; and was accompanied by atrophic histopathological changes in testes. Testis weights were significantly decreased by the group given 1 mg/kg per day DES; however, histopathological abnormalities were found in the group given 0.1 mg/kg per day DES. In four of five animals in the group given 1 mg/kg per day there was no significant decrease in testis weight and only a slight or moderate degeneration of the pachytene spermatocytes. Despite these findings, serum AUG levels in this group decreased markedly, while the serum AUG level markedly decreased even in the animals with no histopathological change in the 1 mg/kg per day or 0.1 mg/kg per day groups with no histopathological change also showed decreased serum AUG level. These results suggest that the serum AUG level may be a sensitive parameter for detecting the activity of estrogenic chemicals in intact male rats. Although a uterotropic assay has been proposed for immature female or ovariectomized female rats and is currently undergoing validation studies internationally, there is no screening method for estrogenic chemicals in intact male animals. More data on AUG changes by treatment with other estrogenic chemicals are needed in order to determine the sensitivity and specificity of this response to estrogens. Nonetheless, an AUG-based screening test for estrogenic chemicals may be useful owing to its applicability to conventional toxicity studies and an apparently higher sensitivity of this parameter compared to organ weight change or histology of testis in intact male rats and applicability to conventional toxicity studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050651
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    The T-type calcium channel blocker mibefradil reduced interstitial and perivascular fibrosis and improved hemodynamic parameters in myocardial infarction-induced cardiac failure in rats (2000)
    Springer
    Virchows Archiv 436 (2000), S. 147-157 
    Details
    ISSN: 1432-2307
    Keywords: Key words T-type calcium channel blockade ; Mibefradil ; Myocardial infarction ; Cardiac remodeling ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dtmax were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dtmax were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008215
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    Sex differences in the discriminative stimulus effects of m-chlorophenylpiperazine and ethanol withdrawal (2000)
    Springer
    Psychopharmacology 149 (2000), S. 170-175 
    Details
    ISSN: 1432-2072
    Keywords: Key words  m-Chlorophenylpiperazine ; Drug discrimination ; Ethanol withdrawal ; Anxiety ; 17β-estradiol ; Sex difference ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. Objectives: This study examined sex differences in the anxiogenic stimu-li induced by a serotonin (5-HT)1b/2 agonist, meta- chlorophenylpiperazine (mCPP), prior to ethanol and during EW. Methods: Gonadectomized or sham-operated adult male and female rats and 17β-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0–1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. Results: Fewer sham female and β-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and β-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. Conclusions: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and β-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900353
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    The dynamic infusion test in rats (2000)
    Springer
    Child's nervous system 16 (2000), S. 451-456 
    Details
    ISSN: 1433-0350
    Keywords: Keywords Intracranial pressure ; CSF dynamics ; Infusion test ; Rat ; H-Tx rat ; Outflow resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Although the hydrocephalic H-Tx rat is a widely used model, data on the cerebrospinal fluid (CSF) dynamics in hydrocephalic rats are rare or – as the pressure volume index (PVI) – not available. We used hydrocephalic and nonhydrocephalic H-Tx rats, a stock with a high percentage of inherited hydrocephalus, for the evaluation of such data. In addition, a new, simple mathematical algorithm (”dynamic infusion test”), which has not formerly been used in animal experiments, was used as a pathophysiological model of CSF dynamics. Compared with classical methods for evaluation of these data, the dynamic infusion test gives a deeper insight into the relation between ICP and CSF dynamics. It was found that the resistance to outflow (ROF) in hydrocephalic rats was at least twice that in nonhydrocephalic rats. The PVI measured was similar in hydrocephalic and nonhydrocephalic animals, but clearly higher than the values reported in the literature. This may be attributable to the fact that the classically used bolus test, in contrast to the ”dynamic infusion test”, is representative only for the CSF compartment which is directly exposed to the bolus application.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00007290
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    Paclitaxel plus vinorelbine: An active regimen in metastatic breast cancer patients with prior anthracycline exposure (2000)
    Springer
    Annals of oncology 11 (2000), S. 85-89 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008374425246
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    Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy (2000)
    Springer
    Annals of oncology 11 (2000), S. 1289-1294 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008375016038
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    Breast cancer in women ≤35 years: Review of 1002 cases from a single institution (2000)
    Springer
    Annals of oncology 11 (2000), S. 1255-1262 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1008391401404
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  • 75
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    Infusional ECarboF in patients with advanced breast cancer: A very active and well-tolerated out-patient regimen (2000)
    Springer
    Annals of oncology 11 (2000), S. 1557-1561 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008378220547
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  • 76
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    Doxorubicin-based adjuvant chemotherapy in elderly breast cancer patients: The M.D. Anderson experience, with long-term follow-up (2000)
    Springer
    Annals of oncology 11 (2000), S. 1597-1601 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008315312795
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  • 77
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    Intra-arterial chemotherapy for unresectable pancreatic cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 569-573 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; intra-arterial ; liver metastasis ; unresectable pancreatic cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:A phase II trial of a new intra-arterial chemotherapyregimen for unresectable pancreatic cancer (UPC). Patients and methods:Ninety-six patients with UPC were treatedwith intra-arterial chemotherapy at three-weekly intervals. The schedule usedwas FLEC: 5-fluorouracil 1000 mg/m2, folinic acid 100mg/m2, carboplatin 300 mg/m2; epirubicin 60mg/m2. Results:The overall response rates by CT-scan evaluation were:15% partial response (PR), 44% stable disease (SD), 17%progressive disease (PD). The overall median survival was 9.9 months, and 10.6and 6.8 for UICC stage III and IV, respectively. Pain reduction occurred in42% of patients. A weight gain 〉7% from baseline occurred in8% of patients. A total of 341 courses of FLEC were administered. Grade3–4 hematological toxicity was seen in 25% of patients;ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; andgrade 3 alopecia in 16%. One sudden death, a pre-infarction angina, anda transitory ischemic attack were observed. The only complication related tothe angiographic procedure was an intimal dissection of the iliac artery. Conclusions:The intra-arterial FLEC regimen was well toleratedand active. It requires only one day of hospitalization. Efficacy could onlybe assessed in a randomized study against a gemcitabine containing regimen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008335331516
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  • 78
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    Ifosfamide plus oral etoposide salvage chemotherapy for platinum-resistant paclitaxel-pretreated ovarian cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 607-612 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; combination ; etoposide ; ifosfamide ; ovarian cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The prognosis of platinum resistant ovarian cancer isvery poor and the treatment of choice has not been clearly defined. Patients and methods:We conducted a phase II study with thecombination of ifosfamide i.v. at 2.25 g/m2 (days 1, 2) andetoposide per os at 100 mg daily (days 1–10) every four weeks. To beeligible for the study patients had to be resistant to platinum and paclitaxelpretreated. Results:Forty-one patients entered the study. The median intervalfrom the previous chemotherapy was 3.9 months. The median number of previouschemotherapeutic regimens was 2. Severe toxicities included neutropenia(41% of patients), leukopenia (29%) and thrombocytopenia(13%). Thirty-five patients are assessable for response. Nine patientsresponded (22% of the eligible, 26% of the assessable), four ofthemdemonstrated complete response to chemotherapy (10% and 12%,respectively), while three patients demonstrated stabilization of theirprogressive disease. After a median follow-up of 18 months, time toprogression is 3 months (range 0.9–14.4), duration of response is 9months (2.5–11) and median survival is 13 months (2.5–37.4+). Conclusions:The combination of ifosfamide with oral etoposideappears to have significant but manageable toxicity and encouraging efficacyin platinum resistant ovarian cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008327412571
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  • 79
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    Recurrent squamous-cell carcinoma of the head and neck: Overview of current therapy and future prospects (2000)
    Springer
    Annals of oncology 11 (2000), S. 11-16 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; gene therapy ; head and neck cancer ; immunotherapy ; radiotherapy ; recurrent ; surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Locoregional recurrence is the most common cause of failure after head andneck cancer surgery. It is a disease which causes significant morbidityespecially on speech and swallowing. There are many different treatmentsavailable including surgery, reirradiation and chemotherapy. However, none ofthese have produced any significant survival benefit. Because of this, therehas been considerable interest in the development of new biological therapiessuch as gene therapy and immunotherapy for this disease. The objectives ofthis article are to provide an overview of the currently available therapiesfor recurrent head and neck cancer including gene therapy and immunotherapy.Prevention of recurrent disease by the detection and treatment of minimalresidual disease is also discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008330026617
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  • 80
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    A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma (2000)
    Springer
    Annals of oncology 11 (2000), S. 113-114 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; hepatocellular carcinoma ; liposomal doxorubicin ; phase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Pegylated liposomal doxorubicin has an enhancedefficacy and reduced toxicity compared with free doxorubicin. The efficacy andtoxicity of pegylated liposomal doxorubicin was investigated in patients withhepatocellular carcinoma. Patients and methods:Patients with histologically confirmed,locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index〉60% were included in this prospective single-arm study. Exclusioncriteria were liver cirrhosis stage Child–Pugh C, previous chemotherapy,or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of30 mg/m2 every three weeks until progression of disease. Afterinclusion of five patients the dose could be escalated to 40 mg/m2in absence of toxicity grade 3 and 4. Results:Sixteen patients were evaluable for response. Noobjective response was achieved. The median survival time was 140 days(95% confidence interval: 126–154 days). Treatment toxicitiesgrade ≥3 comprised increased liver enzymes in patients with preexistinggrade 1 or 2 elevation (n = 6), hematologic toxicity (n =5), and hypersensitivity (n = 2). Conclusions:Pegylated liposomal doxorubicin is not effective fortreatment of advanced hepatocellular carcinoma. The favorable toxicity profilewas confirmed even in patients with underlying liver disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008386822906
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  • 81
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    A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil®) in controlling hot flashes in breast cancer survivors (2000)
    Springer
    Annals of oncology 11 (2000), S. 17-22 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008382706068
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  • 82
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    Socio-economic deprivation and stage of disease at presentation in women with breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 105-107 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008385321476
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  • 83
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    A phase I–II study of gemcitabine and paclitaxel in advanced non-small-cell lung cancer patients (2000)
    Springer
    Annals of oncology 11 (2000), S. 109-112 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; gemcitabine ; non-small-cell lung cancer ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thirty patients with chemotherapy-naïve advanced non-small-cell lungcancer (NSCLC) were given escalating doses of paclitaxel (150, 175, 200mg/m2) on day 1 in three consecutive cycles, together with a fixeddose of gemcitabine 1000 mg/m2 on days 1 and 8; cycles wererepeated every three weeks. The dose escalation of paclitaxel was feasible inthe majority of patients. Subsequently, 30 other NSCLC patients received adose of 200 mg/m2 paclitaxel with gemcitabine 1000 mg/m2in a phase II study. The major side effect was mild myelosuppression. Aresponse rate of 24% was achieved in 49 fully evaluable patients. Thisregimen proved to be safe and easy to administer on an out-patient setting,and constitutes now one of the arms of the current EORTC randomized study foradvanced NSCLC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008321000887
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  • 84
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    Patient participation in medical decision-making: A French study in adjuvant radio-chemotherapy for early breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 39-45 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008390027720
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  • 85
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    Acute hematologic toxicity and practicability of dose-intensified BEACOPP chemotherapy for advanced stage Hodgkin's disease (2000)
    Springer
    Annals of oncology 11 (2000), S. 1105-1114 
    Details
    ISSN: 1569-8041
    Keywords: BEACOPP ; chemotherapy ; dose intensification ; hematotoxicity ; Hodgkin's disease ; practicability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Evidence is recently accumulating that the novelBEACOPP (bleomycin (B), etoposide (E), adriamycin (A), cyclophosphamide (C),vincristine (O), procarbazine (P), prednisone (P)) chemotherapy is a highlyeffective treatment for advanced stage Hodgkin's disease. Two dose variantsof BEACOPP are currently tested in a phase III randomized multicenter trialof the GHSG. To enable more extensive testing of BEACOPP we characterized itspracticability regarding schedule adherence, acute hematotoxicity and need forsupportive treatment. Patients and methods:Data of 858 patients (6592 therapy cycles)from 184 participating institutions were evaluated. Planned total drug dosesof the baseline variant (arm 1) were 80, 2400, 200, 5200, 11.2, 5600 and 4480mg/m2 for B, E, A, C, O, P and P, respectively. Compared to arm 1,the doses of E, A and C in the dose-intensified variant (arm 2) were escalatedby factor 2.0, 1.4, 1.92, respectively, using G-CSF assistance. Stepwise dosereductions were specified in case of dose-limiting toxicities. Both variantsare given in eight three-weekly courses. Results:Median dose adherence (dose actually given relative toplanned arm 1 dose) in arm 1 was 1.0 for all drugs. Relative dose escalationof E, A, and C actually maintained in arm 2 was 1.83, 1.37 and 1.77 (medians),respectively, and 70% of patients maintained elevated dose levelsthroughout the entire treatment. Dose-limiting toxicities occurred in25% of cycles in arm 2, most frequently due to leukocytopenia andthrombocytopenia. Time courses of leukocytes in arm 2 showed more severe butnot more prolonged leukocytopenia compared with arm 1. WHO grades 3–4infections were documented in 2.1% (arm 1) and 3.1% (arm 2) ofall cycles. Erythrocytes were transfused in 6% (arm 1) and 28%(arm 2), platelets in 〈1% (arm 1) and 6% (arm 2) of allcycles. Conclusions:Both BEACOPP schemes are practicable in a largemulticenter setting. Despite increased hematotoxicity, moderate doseescalation is safe for the majority of the patients with G-CSF assistance andstandard supportive treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008301225839
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  • 86
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    Radiation myositis: The possible role of gemcitabine (2000)
    Springer
    Annals of oncology 11 (2000), S. 1615-1616 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; gemcitabine ; radiotherapy ; radiation myositis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008353224251
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  • 87
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    A phase II trial of docetaxel in platinum pre-treated patients with advanced epithelial ovarian cancer: A Japanese Cooperative Study (2000)
    Springer
    Annals of oncology 11 (2000), S. 1531-1537 
    Details
    ISSN: 1569-8041
    Keywords: advanced ovarian cancer ; chemotherapy ; docetaxel ; phase II trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:This phase II study was conducted to evaluate theefficacy and toxicity of docetaxel in Japanese patients with advanced ovariancancer. Patients and methods:Docetaxel was administered at a dose of 70mg/m2 intravenously to patients with platinum pre-treated advancedovarian cancer. Treatment was repeated every three weeks. No routinecorticosteroid premedication was given. Results:Ninety patients with advanced ovarian cancer were enteredand sixty were assessable for response. The overall response rate was28% in the assessable patients (95% confidence interval(95% CI): 17.5%–41.4%). CA125 responses were seenin 8 (24%) of 34 assessable patients for CA125 criteria. The 36platinum-refractory patients had a response rate of 25% compared with33% in the platinum-sensitive patients. The predominant toxicity wasneutropenia, with 86% of the patients experiencing grade 3 or 4.Hypersensitivity reactions occurred in 37% of the patients and were notlife threatening. Edema was mild and infrequent. Conclusion:Docetaxel at 70 mg/m2 demonstratedeffectiveness as a treatment of both platinum-sensitive andplatinum-refractory ovarian cancer patients, with a low incidence of severehypersensitivity reactions and edema.
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    URL: http://dx.doi.org/10.1023/A:1008337103708
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  • 88
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    Is `one cycle every three or four weeks' obsolete? A critical review of dose-dense chemotherapy in solid neoplasms (2000)
    Springer
    Annals of oncology 11 (2000), S. 133-149 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; dose ; dose-density ; dose-intensity ; high-dose chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Shortening the interval between cycles is one meansof increasing the dose intensity of chemotherapy, and can be supported bybiological and mathematical rationales. Our objective was to assess theclinical relevance of the rapid repetition of regimens (so-called `dose-densechemotherapy') in various solid neoplasms. Design:The medical literature was reviewed in accord withMulrow's recommendations. Randomised studies comparing frequently-repeatedchemotherapy to standard regimens as well as open studies are described andcritically examined. Results:Dose-dense regimens were widely found to be feasible. In small-cell lung cancer, survival of patients receiving dose-denseregimens was better than that of patients treated by standard chemotherapy inthree trials, two of which reached significance, when these intensive regimensallowed better dose intensity. In poor-prognosis germ-cell tumors, a dose-dense regimen was not betterthan standard therapy, perhaps because of an excessively high toxicity-relateddeath rate. However, recent phase II studies have provided encouragingresults. In early breast cancer, the one published randomized study in the adjuvantsetting showed only a trend towards better disease-free survival innode-positive women receiving a weekly-repeated regimen. Two randomized trialsfailed to show any benefit in the neoadjuvant setting with a dose-denseregimen. No evidence of a benefit was provided in metastatic breast cancer. In advanced colorectal cancer, evidence of an improvement in survival withweekly or bi-weekly 5-FU–leucovorin compared to a classic monthlyschedule has recently been shown in two randomized trials, and dose-denseregimens are recognized as standard therapy in many countries. Phase II studies of dose-dense regimens have also shown high response ratesand long survival in many neoplasms, including Ewing's sarcoma, gestationaltrophoblastic disease, ovarian carcinoma and gastric cancer. Conclusions:A considerable amount of experience has been gainedwith frequently-repeated regimens. A few randomized trials have demonstrateda benefit for survival on standard chemotherapy in small-cell lung cancer andadvanced colorectal cancer. However, this benefit appears to be weak. Thecombination of dose-dense chemotherapy regimens with new anti-cancerstrategies based on our insights into the mechanisms of oncogenesis is achallenge on the eve of the millennium.
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    URL: http://dx.doi.org/10.1023/A:1008344014518
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  • 89
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    Thyroid carcinosarcoma, a rare and aggressive histotype: A case report (2000)
    Springer
    Annals of oncology 11 (2000), S. 1497-1499 
    Details
    ISSN: 1569-8041
    Keywords: carcinosarcoma ; chemotherapy ; thyroid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thyroid carcinosarcoma is a rare and aggressive thyroid tumor. Histologicalexamination of a tumor showed the characteristic of epithelial carcinoma andmesenchymal differentiation. We retrospectively analyzed the course of thepatient and reviewed the literature in which only 19 other cases aredescribed. Carcinosarcoma of the thyroid is a very aggressive tumor with aclinical course similar to anaplastic thyroid carcinoma. Survival is veryshort despite aggressive multimodal treatment.
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    URL: http://dx.doi.org/10.1023/A:1026538410510
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  • 90
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    Acute myeloid leukemia and lung cancer occurring in a chronic lymphocytic leukemia patient treated with fludarabine and autologous peripheral blood stem-cell transplantation (2000)
    Springer
    Annals of oncology 11 (2000), S. 1493-1495 
    Details
    ISSN: 1569-8041
    Keywords: acute myeloid leukemia ; chemotherapy ; chronic lymphocytic leukemia ; immunosuppression ; second neoplasms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An increased incidence of different malignancies associated to chroniclymphocytic leukemia (CLL) has been reported. The association of CLL and acuteleukemia is a rare event described in 〈1% of CLL, the type of acuteleukemia being either from the lymphoid or more often from the myeloidlineage. The coexistence of acute myeloid leukemia (AML) and CLL in the samepatient has been occasionally reported. Most of these cases have beenassociated with the administration of chemotherapy or radioterapy for CLL,suggesting that the former may be a secondary leukemia. On the other hand, CLLcould precede, but could also be diagnosed at the same, or delayed time asAML, suggesting the presence of other leukemogenic factors. We describe theexceptional development of AML and lung cancer in a patient with previouslydiagnosed CLL in minimal residual disease status after fludarabine treatmentfollowed by autologous peripheral blood stem-cell transplantation.
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    URL: http://dx.doi.org/10.1023/A:1026505632679
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  • 91
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    Phase II EORTC trial with 5-fluorouracil, cisplatin and interferon-α as second-line treatment of advanced transitional cell cancer of the urothelial tract (2000)
    Springer
    Annals of oncology 11 (2000), S. 1391-1394 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; interferon ; transitionall-cell carcinoma ; urothelial tract
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Based on the favorable results of the combination5-fluorouracil (5-FU), cisplatin and interferon-α as second-line treatmentin advanced metastatic transitional-cell carcinoma of the urothelial tract aconfirmatory study was executed in a multicenter setting. Patients and methods:In this open label phase II study 43patients failing adequate previous chemotherapy were treated with IFN-α2b5 MU/m2 subcutaneously for 5 consecutive days starting on day 1 and22 simultaneous with 5-FU 500 mg/m2 daily as a continuous infusion.In between the same dose of IFN-α2b was given 3 times weekly with CDDP 25mg/m2 on days 1, 8, 15 and 22. This cycle was repeated every sixweeks. Results:In 40 eligible patients 5 PR were seen (12.5%;95% confidence interval (95% CI):4.1%–26.8%). The major toxicity was hematological. Twotoxic deaths were seen due to gastro-intestinal hemorrhage. Conclusions:In view of these results this combination can not berecommended as second line treatment for metastatic transitional-cellcarcinoma of the urothelial tract.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026589120989
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  • 92
    Electronic Resource
    Electronic Resource
    Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan (2000)
    Springer
    Annals of oncology 11 (2000), S. 1539-1544 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008383804811
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  • 93
    Electronic Resource
    Electronic Resource
    Metastatic secretory breast cancer. Non-responsiveness to chemotherapy: Case report and review of the literature (2000)
    Springer
    Annals of oncology 11 (2000), S. 1343-1347 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; Her2/neu ; indolent ; malignant ; palliative care ; secretory breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Secretory carcinoma of the breast is a rare and indolent tumour originallydescribed in children but occurring equally in the adult population. Theprincipal management problems following primary surgical treatment are localrecurrence and axillary lymph node metastases. Distant metastases areextremely rare. We present the case of a 27-year-old woman with pulmonary metastases froma secretory breast cancer treated by mastectomy and axillary lymph nodedissection 12 years previously. There was no response to chemotherapy; however, the patient remained aliveand active two years from presentation with metastatic disease and one yearfrom cessation of all cytotoxic chemotherapy. She eventually died ofrespiratory failure two and a half years after presentation. To our knowledge, this is only the fourth reported case of distantmetastases from secretory breast cancer and the second reported case in whichcurrent active chemotherapy has been used. We review the literature anddiscuss the apparent chemoresistance of this tumour including the lack ofmembrane staining for Her2/neu. In the absence of any proven effective chemotherapy we believe that symptomcontrol becomes the focus of management and offers patients with metastaticsecretory breast cancer the greatest chance of a functional and good qualityexistence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008387800525
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  • 94
    Electronic Resource
    Electronic Resource
    Front-line treatment of advanced breast cancer with docetaxel and epirubicin: A multicenter phase II study (2000)
    Springer
    Annals of oncology 11 (2000), S. 1249-1254 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008351310818
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  • 95
    Electronic Resource
    Electronic Resource
    p53 determination alongside classical prognostic factors in node-negative breast cancer: An evaluation at more than 10-year follow-up (2000)
    Springer
    Annals of oncology 11 (2000), S. 393-397 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008359722254
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  • 96
    Electronic Resource
    Electronic Resource
    A comparison of methods currently used in clinical practice to estimate familial breast cancer risks (2000)
    Springer
    Annals of oncology 11 (2000), S. 451-454 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008396129543
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  • 97
    Electronic Resource
    Electronic Resource
    A phase I trial of docetaxel and gemcitabine in patients with advanced cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 421-426 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; docetaxel ; gemcitabine ; non-small-cell lung cancer ; phase I trials ; taxanes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Docetaxel and gemcitabine are active in a broad rangeof malignancies. The objective of this phase I trial was to determine themaximally tolerated doses of the combination of docetaxel and gemcitabine. Patients and methods:Patients with advanced cancer, WHOperformance status 0–2, who had received up to one prior chemotherapyregimen were treated with gemcitabine on days 1 and 8 and docetaxel on day 8repeated every 21 days. Prophylactic ciprofloxacin was commenced on day 11 ofeach cycle and continued until the neutrophil count reached 1.0 ×109/l. G-CSF was not administered. Dose levels studied weredocetaxel/gemcitabine: 60/800, 60/1000, 75/1000, 75/1200, 85/1200 and 100/1200mg/m2. Results:Thirty-nine patients were entered and all were assessablefor toxicity. The highest administered dose level was 100 mg/m2docetaxel and 1200 mg/m2 gemcitabine with dose limiting toxicitiesof febrile neutropenia, grade 4 neutropenia ≥7 days, grade 4thrombocytopenia, grade 3 stomatitis and/or grade 3 fatigue in three out ofsix patients. Treatment was well tolerated (40 cycles) in the 10 patientstreated at the recommended dose level (85/1200) with only a single episode offebrile neutropenia and grade 3 or 4 non-hematologic toxicity was infrequent.There was no significant pulmonary toxicity. Responses were seen in a rangeof malignancies including non-small-cell lung cancer. Conclusions:The recommended dose level of 85 mg/m2docetaxel and 1200 mg/m2 gemcitabine has a favourable toxicityprofile and is suitable for further investigation in phase II trials. Thisnon-platinum containing regimen warrants further investigation as a potentialalternative to platinum containing regimens in non-small-cell lung cancer andother malignancies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008384326701
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  • 98
    Electronic Resource
    Electronic Resource
    Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study (2000)
    Springer
    Annals of oncology 11 (2000), S. 495-496 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008348704373
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  • 99
    Electronic Resource
    Electronic Resource
    Phase I study with weekly cisplatin–paclitaxel and concurrent radiotherapy in patients with carcinoma of the cervix uteri (2000)
    Springer
    Annals of oncology 11 (2000), S. 455-459 
    Details
    ISSN: 1569-8041
    Keywords: cervical cancer ; chemotherapy ; phase I ; radiotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background.Cisplatin and paclitaxel are active in cervical cancerand both are able to potentiate the effects of radiotherapy. In this study weevaluated the maximum-tolerated dose (MTD) of paclitaxel in combination witha fixed dose of cisplatin when given weekly concurrently with pelvicradiotherapy to patients with carcinoma of the cervix uteri. Patients and methods:Eighteen patients with cervical cancer wereenrolled in this study. Cisplatin (30 mg/m2) and paclitaxel(starting dose 40 mg/m2; 5 mg/m2 escalation per level)were given on day 1 of radiotherapy and then weekly for six times.Radiotherapy was given to the pelvis with a four-field box technique for fivedays each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of threepatients were enrolled at each level and three further patients were includedif one or two dose-limiting severe adverse events (SAE) were recorded. SAE wasdefined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomitingand alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (〉1week) neutropenia or thrombocytopenia. Results:Four levels were studied (paclitaxel 40, 45, 50, 55mg/m2) with three, five, four and six patients enrolled,respectively. The MTD of paclitaxel was found at 50 mg/m2/wk andcisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity.Thirteen patients were evaluable for response: seven complete and five partialresponses were obtained with an overall response rate of 92.3%. Conclusions:The MTD of paclitaxel is 50 mg/m2/wk whenassociated to cisplatin 30 mg/m2/wk and concurrent pelvicradiotherapy. Diarrhea is the dose limiting side effect. Preliminary datasuggest that concurrent chemoradiotherapy with paclitaxel and cisplatin couldbe a very active treatment for patients with locally advanced carcinoma of thecervix.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008379922120
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  • 100
    Electronic Resource
    Electronic Resource
    Psychosocial predictors of survival: Metastatic breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 469-474 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008396330433
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