| 1. |
- Heikkinen, Katri, et al.
(author)
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RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability
- 2006
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In: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 27:8, s. 1593-1599
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Journal article (peer-reviewed)abstract
- The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P = 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G > A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxyterminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
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| 2. |
- Koskenvesa, Perttu, et al.
(author)
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Imatinib and pegylated IFN-alpha 2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response
- 2014
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In: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 92:5, s. 413-420
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Journal article (peer-reviewed)abstract
- Objectives Previous studies indicate that 40-50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-alpha 2b) and imatinib may increase the rate of successful discontinuation. Methods In this pilot study, we prospectively stopped imatinib from patients (n=12) who had achieved major molecular response (MMR) after >= 12months of treatment with either imatinib or imatinib+Peg-IFN-alpha 2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed. Results In the monotherapy group, 5/6 patients lost MMR within 4months. One patient remains to date in MR4.0 61months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4months while still receiving Peg-IFN-alpha 2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3months. One patient is still in sustained MR4.0 at 58months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells. Conclusions A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (<2yr) may allow for therapy discontinuation but this needs to be confirmed in larger prospective studies.
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| 3. |
- Olsson-Strömberg, Ulla, et al.
(author)
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Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph plus ALL receiving dasatinib
- 2010
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In: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 85:5, s. 399-404
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Journal article (peer-reviewed)abstract
- As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.
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| 4. |
- Porkka, Kimmo, et al.
(author)
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Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia
- 2008
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 112:4, s. 1005-12
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Journal article (peer-reviewed)abstract
- Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
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