| 1. |
- Bergh, Jonas, et al.
(författare)
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Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer : A randomised trial
- 2000
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 356:9239, s. 1384-1391
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. Methods: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. Findings: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. Interpretation: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.
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| 2. |
- Amini, Rose-Marie, et al.
(författare)
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A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
- 2002
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 43:11, s. 2179-2189
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.
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| 6. |
- Henningsson, Anja, et al.
(författare)
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Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients
- 2003
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 39:8, s. 1105-1114
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.
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| 7. |
- Hovstadius, Peter, et al.
(författare)
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A Phase I Study of CHS 828 in Patients with Solid Tumor Malignancy
- 2002
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 8:9, s. 2843-2850
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1–5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 ± 1.3 h and half-life was 2.1 ± 0.52 h (mean ± SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.
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| 8. |
- Lampic, Claudia, et al.
(författare)
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Attainment and importance of life values among patients with primary breast cancer
- 2003
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Ingår i: Cancer Nursing. - : Lippincott Williams & Wilkins. - 0162-220X .- 1538-9804. ; 26, s. 295-
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Tidskriftsartikel (refereegranskat)abstract
- The main aims of this study were to investigate the extent to which women with recently diagnosed primary breast cancer (N = 29) and matched control subjects without cancer (N = 29) differ in perceived attainment and importance of life values and to study prospectively life value ratings during 1 year in a large group of recent attendees at mammography screening (N = 706). Life values were assessed by a study-specific version of a life value questionnaire, including ratings of the perceived attainment and importance of seven life value dimensions. Women with a recent diagnosis of primary breast cancer were found to attribute significantly more importance to positive relations than healthy controls. No other differences between these groups were found regarding the attainment or importance of life values. Perceptions of life values were found to vary as a function of age, marital or cohabitation status, and parenthood, and to be stable over a 9-month period in screening attendees. The implications of the current findings for the understanding of women's psychological adaptation to breast cancer are discussed.
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| 9. |
- Lampic, Claudia, et al.
(författare)
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Life values before versus after a breast cancer diagnosis
- 2002
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Ingår i: Research in Nursing & Health. - : John Wiley & Sons. - 0160-6891 .- 1098-240X. ; 25, s. 89-
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Tidskriftsartikel (refereegranskat)abstract
- The main aim of this study was to investigate whether women's life values change with a breast cancer diagnosis. In addition, associations between life values and anxiety/depression ratings were investigated. Life value changes were prospectively studied in 517 women recalled for further examination after attending mammographic screening, 38 of whom were diagnosed with primary breast cancer. Life values were assessed by a study-specific version of a life value questionnaire, including ratings of the perceived attainment and importance of seven life value dimensions. Three months after being recalled, women diagnosed with primary breast cancer reported a reduction of the attainment and the importance of Health. In addition, these women reported changes in the perceived importance of Responsibility and Involvement. High levels of anxiety and depression in particular were associated with large discrepancies between attainment and importance for some life values. This suggests that changes in the perceived importance of some life values may constitute one part of women's psychological adaptation to a breast cancer diagnosis.
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| 10. |
- Lindahl, Thomas, et al.
(författare)
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Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer.
- 2004
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 25:3, s. 375-80
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin E is one of the key regulators of the G(1)/S transition in the cell cycle. Overexpression of cyclin E has been observed in several malignancies and is associated with high proliferation, aberrant expression of other cell cycle regulators and chromosomal instability in vitro. To explore potential associations between cyclin E deregulation and inactivation of the p53 tumor suppressor gene in human breast cancer, we investigated the immunohistochemical expression of cyclin E in paraffin embedded breast cancers from 270 women with known p53 status by cDNA based sequencing of the p53 gene. The breast cancers were divided into three subgroups according to the percentage of cyclin E-positive cells. One hundred and seventy-one patients (63%) had low cyclin E, 72 (27%) medium and 27 (10%) had high cyclin E content. Fifty-six percent (15/27) of the breast cancers with high cyclin E had p53 gene mutations, compared with 14% (24/171) of those with low cyclin E content (P < 0.0001). In p53 mutated breast cancers high cyclin E content was associated with insertions, deletions and nonsense point mutations in the p53 tumor suppressor gene, whereas low cyclin E was linked to p53 missense point mutations. We also observed statistically significant associations between a high cyclin E content and aneuploidy, high S phase, larger tumor size, estrogen receptor negativity, presence of axillary node metastases and high tumor grade. High cyclin E content was associated with poor overall survival in univariate and multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.3-4.5). In summary, our findings demonstrate that overexpression of cyclin E is associated with an aggressive tumor phenotype and specific types of p53 mutations.
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| 11. |
- Lindman, Henrik, 1963-
(författare)
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Individually Tailored Toxicity-based Chemotherapy : Studies on Patients with Primary and Metastatic Breast Cancer
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect.Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases.Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases.In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.
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| 13. |
- Wengström, Yvonne, 1959-, et al.
(författare)
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Quantitative assessment of skin erythema due to radiotherapy : evaluation of different measurements
- 2004
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 72:2, s. 191-197
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Visual assessment is the most common clinical investigation of skin reactions in radiotherapy. Due to the unquantitative and subjective nature of this method additional non-invasive methods are needed for more accurate evaluation of the visible acute adverse skin reactions due to radiotherapy. The purpose of this study was to evaluate a new objective measure with regard to reliability and validity and compare it with an established objective measure and a visual assessment. Patients and methods: A sample of 53 consecutive patients commencing curative tangential radiation therapy to the breast parenchyma were included in the study. The skin area of the treated breast was divided into five sections and assessed individually at 0, 24 and 50 Gy. The RTOG scoring system was used for the visual assessment of the skin reactions. The first objective measure included reflectance spectrometry (DermaSpectrometer) measures at fixed points within the treatment area. For the second objective measure digital images (Camera) were taken with a system using a digital camera and software. The images were analyzed using the Adobe Photoshop 5.0 software program. Results: The results provided significant evidence of the test-retest reliability of the camera. The correlation between the objective measures proved to be significant as the treatment progressed. Conclusions: The results suggest that the camera may be used in a reliable and valid way to measure skin erythema due to radiotherapy. (C) 2004 Published by Elsevier Ireland Ltd.
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