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  • 1
    ISSN: 1432-0843
    Schlagwort(e): Etoposide ; Pharmacology ; Breast cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m2, peak plasma concentration 5.6±2.5 μg/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R 2=0.77). All patients who had a day 1 AUC〉2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R 2=98.9%). The equation AUCpr=−0.376+0.631×C4h+0.336×C6h was validated on the test set with a relative mean predictive error of −0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.
    Materialart: Digitale Medien
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  • 2
    ISSN: 1432-0843
    Schlagwort(e): Key words Etoposide ; Pharmacology ; Breast cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean±SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m2, peak plasma concentration 5.6± 2.5 μg/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R 2=0.77). All patients who had a day 1 AUC 〉2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R 2=98.9%). The equation AUCpr=−0.376+ 0.631×C4h+0.336×C6h was validated on the test set with a relative mean predictive error of −0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.
    Materialart: Digitale Medien
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  • 3
    Digitale Medien
    Digitale Medien
    Springer
    Annals of surgical oncology 5 (1998), S. 719-723 
    ISSN: 1534-4681
    Schlagwort(e): Breast cancer ; AJCC staging ; Re-excision
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: The current AJCC protocol for breast cancer staging does not include additional tumor found at the time of re-excision in the calculation of tumor size. We hypothesize that the AJCC protocol may result in understaging and undertreatment of breast cancer patients who have additional tumor found at re-excision. Methods: In a retrospective chart review of breast cancer patients, patients with tumor present at re-excision for positive margins were placed in group 1 (n=72); patients with no tumor present at re-excision, or who underwent a single, negative margin procedure were placed in group 2 (n=147). Results: Patients in group 1 had a higher risk of nodal metastases when compared to patients in group 2. Mean tumor size did not differ significantly between the subgroups. Positive re-excision was strongly associated with lymph node metastases on multivariate analysis after correction for age, grade, stage, and lymphatic invasion (odds ratio=3.13, 95% CI=1.58 6.18,P=.0011). Conclusions: Current AJCC guidelines may result in undertreatment of breast cancer patients with positive re-excisions. The presence of additional tumor at the time of re-excision should be considered when determining the need for systemic therapy, and may be relevant in determining T stage.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1534-4681
    Schlagwort(e): Ductal carcinoma in situ ; Breast cancer ; Lumpectomy ; Mastectomy ; Adjuvant radiation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Current mammographic technology has resulted in increased detection of ductal carcinoma in situ (DCIS). It is necessary to assess which patients presenting with DCIS are good candidates for breast conservation and which of these patients should receive adjuvant radiation. Methods: We accrued clinical data for 124 patients with a primary diagnosis of DCIS from 1979 through 1994. Primary therapy was a mastectomy for 18 patients, and a lumpectomy for 106 patients. Only 18 of the latter group of patients received adjuvant radiotherapy. For the 88 lumpectomy-alone patients (median follow-up, 5.2 years), we evaluated the effects of clinical (age and initial presentation) and pathologic (nuclear grade, architecture, parenchymal involvement, calcifications, and measured margins) factors on recurrence of DCIS or the development of invasive breast cancer. Results: Patients who underwent lumpectomy with or without adjuvant radiotherapy (median follow-up, 5.0 years) were significantly more likely to have recurrence of DCIS (P=.05) than those who underwent mastectomy (median follow-up, 6.7 years): 18% (19/106) versus 0% (0/18), respectively; lumpectomy-alone patients experienced a 19% (17/88) rate of DCIS recurrence. All recurrent DCIS was ipsilateral. For lumpectomy-alone patients, the factors associated with ipsilateral recurrence of DCIS were extent of involvement of the parenchyma (P=.01, for univariate;P=.07, for multivariate) and initial presentation (P=.05, for univariate;P=.07, for multivariate). Eleven lumpectomy-alone patients developed invasive breast cancer (6 ipsilateral, 5 contralateral); none of the 18 lumpectomy patients who received adjuvant radiation developed invasive disease. None of the factors investigated, including primary surgery and adjuvant radiotherapy, were associated with a significant effect on the development of invasive disease. Conclusions: Longer follow-up is required to determine if the benefits of either mastectomy or radiotherapy following lumpectomy persist. There is a suggestion that patients under 40 years of age or women who present with nipple discharge might be considered for either adjuvant radiotherapy following lumpectomy or a simple mastectomy.
    Materialart: Digitale Medien
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  • 5
    ISSN: 1534-4681
    Schlagwort(e): Breast cancer ; Local recurrence ; Lumpectomy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: The purpose was to determine the rate of local breast relapse in patients with breast cancer uniformly treated with partial mastectomy but without postoperative radiotherapy and without systemic adjuvant therapy. We also systematically examined the factors associated with local recurrence to determine whether a low-risk subgroup existed. Methods: A retrospective review of a prospectively followed (median, 8 years) cohort of 293 patients was performed. The end-point was ipsilateral local breast cancer recurrence. The patient's age, tumor size, nodal status, estrogen and progesterone receptor status, histology, and tumor and nuclear grade were studied, as were the presence and amount of carcinoma in situ and the presence of tumor emboli using univariate Kaplan-Meier and Cox step-wise multivariate analyses. Results: The overall local relapse rate was 26% (77 recurrences). Univariate factors significantly associated with decreased local relapse included older age, negative nodes, small tumor size, positive estrogen receptor status, and absence of tumor emboli. Significant multivariate variables were age, nodal status, estrogen receptor status, absence of comedo carcinoma in situ, and tumor emboli. A low-risk subgroup of 66 patients was defined with a 6% 10-year local recurrence rate. Conclusion: Important patient and tumor variables associated with local breast cancer relapse after breast-conserving surgery can define a low-risk subgroup.
    Materialart: Digitale Medien
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  • 6
    ISSN: 1534-4681
    Schlagwort(e): Breast cancer ; Disease-free survival ; Prognostic factors.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Invasive breast cancer is a frequently diagnosed disease that now comes with an ever expanding array of therapeutic management options. We assessed the effects of 20 prognostic factors in a multivariate context. Methods: We accrued clinical data for 156 consecutive patients with stage 1–3 primary invasive breast cancer who were diagnosed in 1989–1990 at the Henrietta Banting Breast Center, and followed to 1995. There is complete follow-up for 91% of patients (median follow-up of 4.9 years). The event of interest was distant recurrence (for distant disease-free survival, DFS). We used Cox and log-normal step-wise regression to assess the multivariate effects of the following factors on DFS: age, tumor size, nodal status, histology, tumor and nuclear grade, lymphovascular and perineural invasion (LVPI), ductal carcinoma-in-situ (DCIS) type, DCIS extent, DCIS at edge of tumor, ER and PgR, ERICA, adjuvant systemic therapy, ki67, S-phase, DNA index, neu oncogene, and pRb. Results: There was strong evidence against the Cox assumption of proportional hazards for nodal status, and nodal status was not in the Cox step-wise model. With step-wise log-normal regression, a large tumor size (P 〈 .001), positive nodes (P 5 .002), high nuclear grade (P 5 .01), presence of LVPI (P 5 .03), and infiltrating duct carcinoma not otherwise specified (P 5 .05) were associated with a reduction in DFS. Conclusions: For nodal status, there was strong evidence against the Cox assumption of proportional hazards, and it was not included in the Cox model although it was in the log-normal model. Only traditional factors were included in the step-wise models. Thus, this statistical management of prognostic markers in breast cancer appears to be very important.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1534-4681
    Schlagwort(e): Breast cancer ; Pregnancy ; Young age ; Cancer stage ; Survival
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: To evaluate the purported decreased survival of pregnancy-associated (PA) breast cancer, a previously described homogeneous cohort of women of childbearing age with primary operable cancer was studied. The current analysis was designed to (a) identify those patients among the cohort known to have PA cancer and (b) compare clinical factors, pathologic characteristics, stage at diagnosis, and survival statistics for PA and non-PA cancer subgroups. Methods: All patients ⩽30 years of age who underwent definitive operation between 1950 and 1989 at the Memorial Sloan-Kettering Cancer Center (MSKCC) for primary operable (stages 0-IIIA) breast adenocarcinoma were analyzed. Results:|Twenty-two of the 227 young women with primary operable breast cancer had PA cancer. Disease-related survival was decreased (p=0.004) in these 22 women compared with the remaining 205 patients with non-PA cancer. PA cancer patients were found to have larger tumors (p〈0.005), and a greater proportion had advanced staged (IIB or IIIA) cancers (p〈0.02). Among patients diagnosed with early invasive cancers (stages I or IIA), no difference (p=NS) in survival was observed comparing PA and non-PA subgroups (73% vs. 74% 10-year survival). Patients with stage IIIA cancer had shorter disease-free and overall survival when associated with pregnancy (0% vs. 35% 10-year survival). Conclusions: Women 30 years of age or younger with PA breast cancer have decreased survival compared with patients with non-PA cancer from the same cohort. Women with PA cancer have larger, more advanced cancers at the time of definitive surgery. Women with early staged PA cancers appear to have survival similar to that for women with early staged non-PA cancer.
    Materialart: Digitale Medien
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  • 8
    Digitale Medien
    Digitale Medien
    Springer
    Oxidation of metals 29 (1988), S. 23-43 
    ISSN: 1573-4889
    Schlagwort(e): Fe-Cr-Al ; aluminum oxide ; adherence ; sulfur
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Maschinenbau
    Notizen: Abstract Recently a new theory was proposed to explain the effect that reactive elements have on oxide adherence. Based on data obtained on Ni-Cr-Al-Y material, this theory stated that trace quantities of sulfur in the alloy degrade adherence by weakening the metal-Al2O3 bond. The work presented here extends this concept to Fe-Cr-Al alloys by examining Al2O3 adherence on foil samples with various bulk sulfur levels obtained using high-temperature vacuum anneals. Results show that long-time vacuum anneals dramatically increase the adherence of the subsequently grown aluminum oxide, concurrent with removal of sulfur from the matrix. This evidence shows that the Al2O3-metal bond is intrinsically strong without the presence of reactive elements such as Y or rare earths in the alloy. Sulfur in the alloy, and not void formation, was found responsible for oxide spalling. In addition, voids were eliminated by reducing the sulfur concentration near the oxide-metal interface.
    Materialart: Digitale Medien
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  • 9
    Digitale Medien
    Digitale Medien
    Springer
    Oxidation of metals 32 (1989), S. 337-355 
    ISSN: 1573-4889
    Schlagwort(e): Fe-Cr-Al ; aluminum oxide ; adherence ; sulfur ; reactive elements
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Maschinenbau
    Notizen: Abstract A recent theory, explaining the effect of reactive elements on oxide adherence, states that sulfur adversely affects adherence and that reactive elements improve adherence by tying up sulfur as refractory sulfides. This theory is supported by work presented here, which correlates adherence behavior of Fe-Cr-Al alloys containing group IIIB through VIB elements with the stability of the sulfides that these elements form. Results show that poor adherence is produced by elements that form sulfides less stable than Al2S3 (VB and VIB elements), while good adherence is produced by elements which form sulfides more stable than Al2S3 (IIIB and IVB elements). In addition, the relative stability of sulfides, oxides, nitrides, and carbides must be considered. For example, group-IIIB elements are effective at much lower concentrations than group-IVB elements, because they react preferentially with S while group IVB elements react with C, N, and O before S.
    Materialart: Digitale Medien
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  • 10
    ISSN: 1573-4889
    Schlagwort(e): Fe-Cr-Al ; oxidation ; air ; exhaust gas ; aluminum oxide ; oxide adherence ; reactive elements
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Maschinenbau
    Notizen: Abstract This work evaluated the adherence of oxide grown in air and synthetic exhaust gas on Fe-20Cr-5Al alloys containing strong sulfide-forming elements: Ca, Mg, Y, Ce, La, Ti, and Zr. Results support the theory that reactive elements provide good oxide adherence on alumina-forming materials primarily by tying up sulfur as stable Sulfides; however, other influences on adherence were found. Highly volatile elements, such as Ca and Mg, lose their sulfur-controlling ability by diffusing out of the matrix and into the growing oxide scale. Zirconium results in the growth of an extensive network of oxide pegs into the substrate which improves adherence. Titanium segregates to the alumina scale and acts as a sink for S in the matrix. In synthetic exhaust gas (N2+CO2+H2O), local oxide spalling was observed and was shown to be caused by H2O in the atmosphere. The added benefits of Ti and Zr, i.e., forming oxide pegs and sinks for S, improve adherence in this environment.
    Materialart: Digitale Medien
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