| 1. |
- Ansari, Daniel, et al.
(författare)
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Protein deep sequencing applied to biobank samples from patients with pancreatic cancer.
- 2015
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 1432-1335 .- 0171-5216. ; 141:2, s. 369-380
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic cancer is commonly detected at advanced stages when the tumor is no longer amenable to surgical resection. Therefore, finding biomarkers for early stage disease is urgent. Here, we show that high-definition mass spectrometry (HDMS(E)) can be used to identify serum protein alterations associated with early stage pancreatic cancer.
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| 2. |
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| 3. |
- El Missiry, Mohamed, et al.
(författare)
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Assessment of bone marrow lymphocytic status during tyrosine kinase inhibitor therapy and its relation to therapy response in chronic myeloid leukaemia
- 2016
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 142:5, s. 1041-1050
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Tidskriftsartikel (refereegranskat)abstract
- Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p < 0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR-ABL1 < 10 % showed higher lymphocyte counts than patients with BCR-ABL1 > 10 % (23 vs. 17 %, p < 0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients. Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.
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| 4. |
- Garvin, Stina, 1977-, et al.
(författare)
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Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery
- 2018
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer. - 0171-5216 .- 1432-1335. ; 144:7, s. 1253-1263
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance. Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy gamma-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival. CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells. Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.
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| 5. |
- Göhler, Stella, et al.
(författare)
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Impact of functional germline variants and a deletion polymorphism in APOBEC3A and APOBEC3B on breast cancer risk and survival in a Swedish study population
- 2016
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer. - 0171-5216 .- 1432-1335. ; 142:1, s. 273-276
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The C -> T mutation signature caused by APOBEC family members contributes to the development of breast cancer (BC). Also overexpression of APOBEC3B and a similar to 29. 5-kb deletion polymorphism between APOBEC3A and APOBEC3B have been associated with increased BC risk. Methods: We investigated in a population-based study, with 782 Swedish BC cases and 1559 controls, associations between potentially functional germline variants in APOBEC3A or APOBEC3B gene and BC risk and survival. Additionally, we identified deletion polymorphism carriers and explored possible associations with BC. Results: No evidence of association between any germline variant, including the deletion polymorphism, and BC risk or survival was observed. Only APOBEC3A promoter polymorphism rs5757402 was associated with low stage (OR = 0.69, 95 % CI 0.50-0.96, dominant model). Conclusion: The reported association between the deletion polymorphism and BC risk was not confirmed in the Swedish population, nor did any genotyped germline variant show any association with BC risk or survival.
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| 6. |
- Karlsson, Elin, et al.
(författare)
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PTPN2 deficiency along with activation of nuclear Akt predict endocrine resistance in breast cancer
- 2019
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : SPRINGER. - 0171-5216 .- 1432-1335. ; 145:3, s. 599-607
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The protein tyrosine phosphatase, non-receptor type 2 (PTNP2) regulates receptor tyrosine kinase signalling, preventing downstream activation of intracellular pathways like the PI3K/Akt pathway. The gene encoding the protein is located on chromosome 18p11; the 18p region is commonly deleted in breast cancer. In this study, we aimed to evaluate PTPN2 protein expression in a large breast cancer cohort, its possible associations to PTPN2 gene copy loss, Akt activation, and the potential use as a clinical marker in breast cancer. Methods PTPN2 protein expression was analysed by immunohistochemistry in 664 node-negative breast tumours from patients enrolled in a randomised tamoxifen trial. DNA was available for 146 patients, PTPN2 gene copy number was determined by real-time PCR. Results PTPN2 gene loss was detected in 17.8% of the tumours. Low PTPN2 protein expression was associated with higher levels of nuclear-activated Akt (pAkt-n). Low PTPN2 as well as the combination variable low PTPN2/high pAkt-n could be used as predictive markers of poor tamoxifen response. Conclusion PTPN2 negatively regulates Akt signalling and loss of PTPN2 protein along with increased pAkt-n is a new potential clinical marker of endocrine treatment efficacy, which may allow for further tailored patient therapies.
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| 7. |
- Niinivirta, Marjut, et al.
(författare)
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Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib
- 2017
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 143:6, s. 961-970
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Tyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.Methods Cubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.Results Fifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS >3 months).Conclusions We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.
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| 8. |
- Rajala, Hanna L. M., et al.
(författare)
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Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia
- 2017
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : SPRINGER. - 0171-5216 .- 1432-1335. ; 143:8, s. 1543-1554
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.
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| 10. |
- Söderlund Leifler, Karin, 1979-, et al.
(författare)
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The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer
- 2015
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Publishing Company. - 0171-5216 .- 1432-1335. ; 141:5, s. 797-804
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A single-nucleotide polymorphism, RAD51 135G/C, in the untranslated region of the RAD51 gene has been found to elevate breast cancer risk among BRCA2 carriers. The purpose of this study was to investigate if this polymorphism is related to RAD51 protein expression, prognosis of early breast cancer and if it contributes to resistance to radiotherapy or cyclophosphamide/5-fluorouracil/methotrexate (CMF) chemotherapy.Methods: We genotyped 306 patients with early breast cancer, who were randomised to receive post-operative radiotherapy or CMF chemotherapy, for the RAD51 135G/C polymorphism. Expression of RAD51 protein was evaluated with immunohistochemistry.Results: The frequency of C-allele was 15.4% (including three C/C homozygotes). There was no correlation between genotype and protein expression pattern in tumours. Patients who were homozygous for the wildtype G/G genotype had a significant benefit of radiotherapy (RR=0.32, 95% C.I. 0.16-0.64, p=0.001). CMF chemotherapy significantly reduced the risk of distant recurrence during the first 20 years in patients who had the C-allele (RR=0.29, 95% C.I. 0.10-0.88, p=0.03), whereas patients who were G/G homozygotes had no benefit from chemotherapy over radiotherapy (RR=1.09, 95% C.I. 0.77-1.6, p=0.61). There was a significant interaction between chemotherapy and genotype (p=0.02). Genotype was not related to the rate of distant recurrence among patients treated with radiotherapy.Conclusion: Breast cancer patients who were homozygous for the wildtype G allele had a significant benefit of radiotherapy. The results suggest that the RAD51 135G/C polymorphism predicts the effect of CMF chemotherapy in early breast cancer.
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