| 1. |
- Aaltonen, Kirsimari, et al.
(författare)
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Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides
- 2006
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 94:11, s. 1697-1702
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.
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| 2. |
- Ahlin, Cecilia, et al.
(författare)
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Cyclin A is a proliferative marker with good prognostic value in node-negative breast cancer
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:9, s. 2501-2506
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Tidskriftsartikel (refereegranskat)abstract
- Background: Proliferative markers are not recommended as prognostic factors for clinical use in breast cancer due to lack of standardization in methodology. However, proliferation is driving several gene expression signatures emphasizing the need for a reliable proliferative marker IF or clinical use. Studies suggest that cyclin A is a prognostic marker with satisfying reproducibility. We investigated cyclin A as a prognostic marker in node-negative breast cancer using previously defined cutoff values. Patients and Methods: In a case-control study, we defined 190 women who died from breast cancer as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size <= 50 mm, no lymph node metastases and no adjuvant chemotherapy. Tumor tissues were immunostained for cyclin A using commercially available antibodies. Results: We found a statistically significant association between expression of cyclin A and breast cancer death in a univariate model: odds ratio for cyclin A(ave) 2.7 [95% confidence interval (CI), 1.7-4.3] and cyclin A(max) 3.4 (CI, 2.1-5.5). Corresponding odds ratio for Ki67 were Ki67(ave) 1.9 (CI, 1.2-3.1) and Ki67(max) 1.7 (CI, 1.1-2.7) and for grade 3.1 (CI, 1.8-5.1). Cyclin A was strongly correlated to Ki67 and grade why a model including all was not appropriate. Conclusions: Cyclin A is a prognostic factor for breast cancer death in node-negative patients using standardized methodology regarding scoring and cutoff values. Adding cyclin A as a proliferative marker to established clinicopathologic factors will improve the separation of low and high risk breast cancer.
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| 3. |
- Ahlin, Cecilia, et al.
(författare)
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Ki67 and cyclin A as prognostic factors in early breast cancer : What are the optimal cut-off values?
- 2007
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Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 51:4, s. 491-498
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To find the optimal cut-off values for cyclin A and Ki67 in early breast cancer tumours and to evaluate their prognostic values. METHODS AND RESULTS: Tissue microarray (TMA) slides were constructed from 570 T1-4 N0-1 M0 breast cancer tumours. The TMA slides were stained for cyclin A and Ki67 using immunohistochemistry with commercial antibodies. To investigate the optimal cut-off values for cyclin A, Ki67 average and maximum values the material was split into two parts at cut-offs defined by dividing it into deciles. For each cut-off value the relative risk (RR) for metastasis-free survival (MFS) and overall survival (OS) was calculated comparing patients with high versus low cyclin A or Ki67 expression. When using a cut-off value around the seventh decile, cyclin A and Ki67 score correlated with the highest RR ratio for MFS in the chemotherapy-naïve subgroup. Among patients having received adjuvant chemotherapy, no statistically significant differences in MFS or OS were found. CONCLUSIONS: The optimal cut-off value for cyclin A average is 8% and for cyclin A maximum value 11%; for Ki67 the corresponding values are 15% and 22%. Additional studies are needed to verify these results.
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| 4. |
- Ahlin, Cecilia, et al.
(författare)
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Aberrant expression of cyclin E in low-risk node negative breast cancer
- 2008
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 47:8, s. 1539-1545
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Tidskriftsartikel (refereegranskat)abstract
- Background. Cyclin E is a cell cycle regulatory protein which occurs in G1, peaks in late G1 and is degraded in early S-phase. Cyclin E overexpression appears to be an independent prognostic factor for overall survival in breast cancer. Material and Methods. Nuclear cyclin A is a reliable marker for S-and G2-phases. Consequently, aberrant expression of cyclin E can be detected by simultaneous immunostainings for cyclin A and cyclin E. Studies have shown that aberrant cyclin E might provide additional prognostic information compared to that of cyclin E alone. This study aimed to investigate cyclin E and aberrant cyclin E expression in low-risk node negative breast cancer. We compared women that died from their breast cancer (n=17) with women free from relapse>8 years after initial diagnosis (n=24). All women had stage I, low risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumour differentiation. Tumour samples were analysed regarding expression of cyclin A, cyclin E and double-stained tumour cells using immunoflourescence staining and digital microscopy. Results. No differences were seen regarding expression of cyclin E or aberrant cyclin E in cases compared to controls. Discussion. We conclude that neither cyclin E nor aberrant cyclin E is a prognostic factor in low-risk node negative breast cancer patients.
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| 5. |
- Ahlin, Cecilia, 1966-
(författare)
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Cyclin A and cyclin E as prognostic factors in early breast cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is one of the most common malignancies in women. Due to early detection and the use of screening programs approximately 60% of all new cases lack lymph node involvement. Today, a substantial proportion of these women will be offered adjuvant systemic chemotherapy. However, better proliferation markers are needed to predict patient outcome and to avoid overtreatment. Cyclin A, cyclin E and Ki-67 are all markers for proliferation and involved in the regulation of the cell cycle. Overexpression has been associated with disease recurrence in several studies, but the results have not been consistent. However, none of these studies has investigated aberrant expression of cyclin E (the expression of cyclin E during phases of the cell cycle other than late G1 and early S-phase). Studies have shown that aberrant cyclin E might provide additional prognostic information compared to cyclin E alone.The aims of this thesis were 1.to investigate the prognostic value of cyclin A, cyclin E and aberrant cyclin E in early breast cancer. 2.to validate the tissue microarray (TMA) technique for cyclin A and 3.to define the most optimal cut-off values for cyclin A and Ki-67.We found that the agreement of TMA and large section results was good with kappa values 0.62-0.75 and that the reproducibility of the two readers’ results was good or even very good, with kappa values 0.71 – 0.87. The optimal cut-off value for cyclin A average was 8% and for cyclin A maximum value 11%. The corresponding values for Ki-67 were 15 and 22%. Neither cyclin E nor aberrant cyclin E was a prognostic factor in low-risk node negative breast cancer patients. Finally, we conclude that cyclin A is a prognostic factor in node negative breast cancer (univariate analysis average value OR=2.9 95% CI 1.8-4.6; maximum value OR=3.7 95% CI 2.3-5.9).
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| 6. |
- Fjällskog, Marie-Louise H., et al.
(författare)
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Treatment with Combined Streptozotocin and Liposomal Doxorubicin in Metastatic Endocrine Pancreatic Tumors
- 2008
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 88:1, s. 53-8
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with combined streptozotocin and liposomal doxorubicin is safe and efficient in patients with endocrine pancreatic tumors (EPTs). No cardiac toxicity was reported. BACKGROUND: The combination of streptozotocin and doxorubicin has been shown to be superior to streptozotocin and fluorouracil in the treatment of metastatic EPTs. However, the risk of cardiac toxicity from anthracyclins hampers the usefulness of the drug combination. Liposomal doxorubicin has a lower frequency of cardiac adverse events compared to doxorubicin. We wanted to assess the efficacy and safety of combined streptozotocin and liposomal doxorubicin in patients with metastatic EPTs. METHODS: Thirty patients with metastatic EPTs were recruited from three medical centers in Norway and Sweden during a time period of 3 years. All patients had histopathologically confirmed diagnoses and bidimensionally measurable lesions. 30 mg/m(2) of liposomal doxorubicin was administered on day 1 of each cycle. During the first course, 1 g of streptozotocin was given on 5 consecutive days. Thereafter, 2 g of streptozotocin was given on day 1 only. Treatment was repeated every 3 weeks. RESULTS: Twelve of 30 patients (40%) achieved an objective radiological response with a median duration of 9 months. Stabilization of disease was achieved in 17 of 30 patients (57%) for a median duration of 11 months. Only one patient had progressive disease as best response. The 2-year progression-free survival was 18% and the 2-year overall survival was 72%. The treatment was well tolerated. None of the patients experienced cardiac toxicity. CONCLUSION: We conclude that combined streptozotocin and liposomal doxorubicin is a safe and efficient treatment for EPTs. The efficacy seems to be comparable to that of combined streptozotocin and doxorubicin, whereas the cardiac toxicity clearly favors using the liposomal drug combination. 2008 S. Karger AG, Basel.
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| 7. |
- Fjällskog, Marie-Louise, et al.
(författare)
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Treatment of endocrine pancreatic tumors
- 2005
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 44:4, s. 329-338
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine pancreatic tumors are rare with an incidence of 4 per million inhabitants. Most tumors are malignant except for insulinomas that usually are benign. They are slowly growing in the majority of cases but there are exceptions with rapidly progressing malignant carcinomas. Because of the rarity of these tumors large randomized trials are difficult to accomplish. However, most physicians treating these patients agree that surgery should be considered in all cases and that medical treatment with chemotherapy and biotherapy is well established for this group of patients.
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| 8. |
- Fjällskog, Marie-Louise, et al.
(författare)
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Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas
- 2007
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 46:6, s. 741-746
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor receptor (PDGFR) beta signaling is involved in autocrine growth stimulation of tumor cells, tumor angiogenesis and regulation of tumor interstitial fluid pressure. Development of PDGFR antagonists has further increased the interest for PDGFR as targets for anticancer treatments. Malignant endocrine pancreatic tumors (EPTs) express PDGFR beta both in stroma and on tumor cells. To investigate the role of PDGFR beta signaling in EPTs we compared PDGFR beta expression in normal endocrine pancreas to malignant EPTs and metastases. PDGFR beta expression was examined by immunohistochemistry using specific polyclonal antibodies in ten tissue samples from normal endocrine pancreas, 21 from primary EPTs and 19 from metastases. In eight patients we compared the expression in normal endocrine pancreas to the corresponding primary tumor and metastases, in two patients normal tissue to the primary tumor and in 11 patients primary tumors to the corresponding metastases. Six of ten tissues containing normal pancreas stained negative for PDGFR beta on endocrine cells, while seven of ten stained positive in the stroma. Eighteen of 21 (86%) primary tumors stained positive for PDGFR beta on tumor cells and all had positive stroma stainings. All 19 metastases stained positive for PDGFR beta on tumor cells and in evaluable stroma (n=16). We have found that PDGFR beta is more frequently expressed in primary EPTs and metastases as compared to normal endocrine pancreatic tissue. This is also true for PDGFR beta expression in the corresponding stroma. We suggest that new therapeutic options to inhibit the growth and spread of EPTs could include targeting of PDGFR beta.
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| 9. |
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| 10. |
- Welin, Staffan, et al.
(författare)
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Expression of tyrosine kinase receptors in malignant midgut carcinoid tumors
- 2006
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 84:1, s. 42-48
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Tidskriftsartikel (refereegranskat)abstract
- Background: The expression of certain tyrosine kinase receptors (TKR) has been shown to have a prognostic value in many tumor entities. In recent years, inhibitors and monoclonal antibodies directed towards these receptors have been developed. Several have shown antitumoral effects and have been tested in clinical trials. We wanted to investigate whether midgut carcinoid tumors express TKR and therefore would be suitable for clinical trials with TKR inhibitors (TKRI) or monoclonal antibodies. Material and Methods: Tumor tissue from 36 patients (24 women and 12 men) with a malignant midgut carcinoid tumor was obtained. The tissues were examined with immunohistochemistry, using polyclonal antibodies against platelet-derived growth factor receptor-α (PDGFRα), platelet-derived growth factor receptor-β (PDGFRβ), epidermal growth factor receptor (EGFR) and c-kit. Human BON1 cells were cultivated and stimulated with PDGF-BB. We also present a case report of a patient with a malignant midgut carcinoid tumor who had stabilization of tumor growth during treatment with imatinib. Results: Immunohistochemical staining for PDGFRα in tumor cells showed immunoreaction for the receptor in 13/34 (38%) for PDGFRβ in 29/33 (88%), and 24/33 (73%) were immunoreactive for EGFR. No tumor tissue showed immunoreaction for c-kit. In tumor stroma PDGFRα was expressed in 35%, PDGFRβ in 94% and EGFR in 9%. We show that human neuroendocrine tumor cells respond to PDGF, indicating that these tumors express functional PDGF receptors. Conclusion: Malignant midgut carcinoid tumors may express three of the four TKR tested in this investigation. Therefore, these tumors might be susceptible for treatment with TKRI or monoclonal antibodies and this should be further explored in clinical trials.
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