| 1. |
- Karamanis, Georgios, et al.
(author)
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Cancer incidence and mortality patterns in women with anorexia nervosa
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 134:7, s. 1751-1757
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Journal article (peer-reviewed)abstract
- Caloric restriction in animals is an effective way to reduce carcinogenesis. Anorexia nervosa (AN) is considered a model of extreme caloric restriction in humans. The aim of our study was to assess cancer incidence and mortality in women with AN. A total of 6,009 women with at least one inpatient treatment for AN during the period 1973-2003 were included in the study. Standardized incidence ratios (SIR) and standardized mortality ratios (SMR) were calculated. Overall, there was no statistically significant difference in cancer incidence compared to women in the general population. At a statistically significant or borderline significant level, a higher incidence for lung cancer and cancer of lymphoid, hematopoietic and related tissue was observed along with a reduced breast cancer incidence. Women with AN had twice as high mortality from cancer in general, and more specifically from melanoma, cancers of genital organs and cancers of ill-defined, secondary and unspecified sites. The increased lung cancer incidence may be due to smoking habits among women with AN. The worse prognosis with higher mortality from melanoma, cancers of genital organs and cancers of ill-defined, secondary and unspecified sites may be explained by AN-specific attitudes toward seeking medical care, adherence to treatment or worse biological precondition due to starvation and cachexia.
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| 2. |
- Isaksson, Johan, et al.
(author)
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Predictors of long-term survival and recurrence patterns after definitive chemoradiotherapy in stage III NSCLC – a multicenter cohort study from Mid Sweden
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Other publication (other academic/artistic)abstract
- Background: Stage III NSCLC is heterogeneous but often recurs despite intensive treatment with curative intent. Clinical tools to predict the risk and pattern of recurrence and long-term survival in individual patients are largely lacking. Methods: NSCLC stage III patients (N=193) treated 2009-2018 with definitive, curatively intended chemoradiotherapy (CRT, 60Gy+) were retrospectively identified from three healthcare regions in Mid Sweden. Outcome variables included overall survival (OS), progression-free survival (PFS) and recurrence patterns. Results: Median follow-up of patients alive was 52 months. 1, 2 and 5-year OS was 80%, 63% and 34% with a mOS of 32 months. Pre-treatment serum inflammatory markers were associated with inferior OS, including leukocyte count > 10 (HR 1.58, 95% CI 1.08-2.31, p=0.018) and CRP > 5 (HR 1.81, 95% CI 1.16-2.83, p=0.009). CRP remained independently associated with OS in multivariable analysis, HR 1.67 (1.05-2.65, p=0.029). No other pre-treatment variable was significantly associated with OS. Progressive disease (PD) was documented in 65% of patients after a median time of 9.5 months, 96% within 3 years from CRT, and was typically either distant or locoregional (12% mixed). Distant PD developed earlier (6.3 months) than locoregional PD (11.5 months; p=0.052). N3 disease (OR 2.7, 95% CI 1.2-6.3,; p=0.022) and presence of driver mutations (OR 4.6, 95% CI 1.5-14.0; p=0.0076) increased the risk of distant PD, while ≥2 concurrent chemotherapy courses was protective of locoregional PD (OR 0.38, 9% CI 0.1-1.0; p=0.049). Brain metastases were the first indication of PD in 22 patients (12%) and were in all cases isolated without synchronous extracranial PD. A post-CRT 18F-FDG-PET SUVmax of ≥7 was associated with a shorter time to PD (HR 0.41, 95% CI 0.21-0.79, p=0.008). Conclusions: The study reinforces the prognostic role of systemic inflammation in stage III NSCLC and provides clinically useful indicators of relapse pattern as a basis for rational disease monitoring following CRT.
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| 3. |
- Sooman, Linda, et al.
(author)
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PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas
- 2014
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In: Tumor Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 35:5, s. 4479-4488
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Journal article (peer-reviewed)abstract
- The prognosis of high-grade glioma patients is poor, and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients, the epigenetic regulation of the expression of PTPN6, and the role of its expression in chemotherapy resistance in glioma-derived cells. PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6-overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite pyrosequencing, and demethylation of PTPN6 was done with decitabine treatment. The PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p = 0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increase resistance (p < 0.05) to the chemotherapeutic drugs bortezomib, cisplatin, and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis, or autophagy. Low PTPN6 promoter methylation correlated to protein expression, and the protein expression was increased upon demethylation in glioma-derived cells. PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients, and in glioma-derived cells, its expression is epigenetically regulated and influences the response to chemotherapy.
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| 4. |
- Sooman, Linda, et al.
(author)
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Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival
- 2013
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In: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 30:3, s. 638-
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Journal article (peer-reviewed)abstract
- The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.
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| 5. |
- Tsakonas, Georgios, et al.
(author)
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An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non-small-cell lung cancer
- 2020
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In: European Journal of Cancer. - : ELSEVIER SCI LTD. - 0959-8049 .- 1879-0852. ; 132, s. 24-34
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Journal article (peer-reviewed)abstract
- Background: Dissemination of non-small-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts.Methods: We identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter (R) PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software.Results: We compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours.Conclusions: We identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.
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| 6. |
- Tsakonas, Georgios
(author)
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Biomarkers for CNS metastasis in non-small cell lung cancer (NSCLC)
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Non-small cell lung cancer (NSCLC) comprises more than 75% of lung cancer cases and is usually diagnosed in advanced stages. Lung cancer is the leading cause of cancer death among all solid tumours and the second most common malignancy globally. The prognosis of NSCLC patients with brain metastases (BM) is poor with a median overall survival of 4–11 weeks in untreated patients and 4–15 months in treated patients. Approximately 45% of patients with non-oncogenic driven NSCLC and 70% of patients with EML4-ALK rearrangements or EGFR mutations will be diagnosed with BM during the course of the disease. The incidence of BM appears to be increasing mostly owing to improvements in diagnostic imaging and in survival associated with more effective systemic therapies. The main purpose of this thesis is to identify clinical and molecular biomarkers for BM of NSCLC, as well as to explore the molecular diversity between CNS metastases and primary NSCLC. Paper I was a single institution cohort study including brain metastasized lung cancer patients who received Whole Brain Radiotherapy (WBRT) at Karolinska University Hospital, Stockholm, Sweden. The aim of this trial was to find prognostic factors that can influence OS in lung cancer patients with BM treated with WBRT, in order to identify which patients will live long enough to experience the palliative benefit of WBRT, regarding disease control in the CNS. This study provided additional information on the selection of BM NSCLC patients who should receive WBRT by combining RPA and GRA prognostic indexes. In paper II we analysed a total of 43 tissue samples from NSCLC patients for systematic mRNA expression; 13 primary tumours and 30 brain metastases. The material was obtained from 25 patients, of which 13 underwent surgery of the primary tumour. The paired samples were 26 (13 patients with both available lung and brain tissue samples). A unique gene downregulation pattern in brain metastases compared with primary tumours was observed. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in the brain metastatic setting. In paper III the validity of Lung-molGPA index in an ALK-positive lung cancer cohort with BM (n= 44) was explored, and a new prognostic scoring system, the ALK-BPI score, which can be easily applicable in clinical practice was proposed. PS, sex and BM at diagnosis, were used as prognostic variables in ALK-BPI. The aim of paper IV - a retrospective cohort study consisting of 304 patients with surgically removed NSCLC- was to investigate whether high expression of NRF2 or TrxR1 in early stage NSCLC is predictive for relapse in CNS or other organs. High expression of NRF2 in cytokeratine positive cells in the whole tissue core compartment was correlated with higher risk for CNS relapse. This is to our knowledge the first study to report a predictive biomarker for CNS relapse in early stage NSCLC. In summary, this thesis expands the knowledge regarding the molecular diversity between CNS metastases and primary NSCLC, and proposes new clinical and molecular biomarkers for BM of NSCLC.
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| 7. |
- Tsakonas, Georgios, et al.
(author)
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c-MET as a biomarker in patients with surgically resected non-small cell lung cancer
- 2019
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In: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 133, s. 69-74
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Journal article (peer-reviewed)abstract
- Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet. Patients and methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored. Results: c-MET H-score >= 20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64 - 0.97). The prognostic effect of c-MET H-score >= 20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40 - 0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43 - 0.83). Conclusion: c-MET H-score >= 20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score >= 20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.
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| 8. |
- Tsakonas, Georgios, et al.
(author)
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High Density of NRF2 Expression in Malignant Cells Is Associated with Increased Risk of CNS Metastasis in Early-Stage NSCLC
- 2021
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In: Cancers. - : MDPI. - 2072-6694. ; 13:13
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Journal article (peer-reviewed)abstract
- Simple Summary We retrospectively analyzed 304 patients with surgically removed non-small cell lung cancer (NSCLC). Multiplex antibody staining of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was an independent prognostic factor, with an eightfold increase in odds regarding the risk of relapse in the central nervous system (CNS). This is the first study to report a tumor-cell-associated protein biomarker for CNS relapse in early-stage lung cancer and the first trial to report the correlation between NRF2 expression and risk of CNS relapse. The results of our study may have an impact on the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis. Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining of NRF2 and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was correlated with a higher risk of central nervous system (CNS) relapse OR = 7.36 (95% CI: 1.64-33.06). The multivariate analysis showed an OR = 8.00 (95% CI: 1.70-37.60) for CNS relapse in NRF2+/CK+ high-density cases. The density of TrxR1+/CK+ cells failed to show any statistically significant risk of relapse. The OS analyses for NRF2+/CK+ and TrxR1+/CK+ cell density failed to show any statistical significance. This is the first study to report a correlation between NRF2+/CK+ cell density and the risk of CNS relapse in early-stage NSCLC. The results of our study may impact the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis.
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| 9. |
- Tsakonas, Georgios, et al.
(author)
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Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature
- 2023
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:1
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Journal article (peer-reviewed)abstract
- Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.
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