| 1. |
- Ahlén Bergman, Emma, et al.
(författare)
-
Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients
- 2018
-
Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.
|
|
| 2. |
- Ahrné, Karin, et al.
(författare)
-
Rödlista över fjärilar Lepidoptera
- 2015
-
Ingår i: Rödlistade arter i Sverige 2015. - Uppsala : ArtDatabanken SLU. - 9789187853104 ; , s. 98-112
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
| 3. |
- Beilmann-Lehtonen, Ines, et al.
(författare)
-
The Relationship between the Tissue Expression of TLR2, TLR4, TLR5, and TLR7 and Systemic Inflammatory Responses in Colorectal Cancer Patients
- 2021
-
Ingår i: Oncology. - : S. Karger. - 0030-2414 .- 1423-0232. ; 99:12, s. 790-801
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally. CRC patients with elevated plasma C-reactive protein (CRP) levels exhibit compromised prognoses. Toll-like receptors (TLRs), activating the innate and adaptive immune systems, may contribute to pro- and antitumorigenic inflammatory responses. We aimed to identify a possible link between local and systemic inflammatory responses in CRC patients by investigating the association between tissue TLRs and plasma CRP.Methods: Tissue expressions of TLR2, TLR4, TLR5, and TLR7 were assessed using immunohistochemistry of tissue microarray slides from 549 CRC patients surgically treated between 1998 and 2005. Blood samples were drawn preoperatively, centrifuged, aliquoted, and stored at −80°C until analysis. Plasma CRP was determined through high-sensitivity time-resolved immunofluorometric assay. We investigated the association of TLRs to clinicopathologic variables, plasma CRP, and survival.Results: High TLR2 expression (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.41–0.85; p = 0.005), high TLR5 expression (HR 0.60; 95% CI 0.45–0.83; p = 0.002), positive TLR7 expression (HR 0.49; 95% CI 0.33–0.72; p < 0.001), and low CRP (HR 1.48; 95% CI 1.08–2.11; p = 0.017) were associated with a better prognosis. A high TLR2 immunoexpression was associated with a better prognosis among low-CRP patients (HR 0.53; 95% CI 0.35–0.80; p = 0.002), high TLR4 expression among high-CRP patients (HR 2.04; 95% CI 1.04–4.00; p = 0.038), high TLR5 expression among low-CRP patients (HR 0.059; 95% CI 0.37–0.92; p = 0.021), and positive TLR7 expression among low-CRP patients (HR 0.53; 95% CI 0.28–1.00; p = 0.049). In multivariate analyses, no biomarkers emerged as significant independent variables.Conclusions: High tissue TLR2, TLR5, and TLR7 levels were associated with a better prognosis. Among low-CRP patients, those with high TLR2, TLR5, and TLR7 immunoexpressions exhibited a better prognosis. Among high CRP patients, a high TLR4 immunoexpression was associated with a better prognosis.
|
|
| 4. |
- Edin, Sofia, et al.
(författare)
-
The Prognostic Importance of CD20+ B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets
- 2019
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20+ B lymphocytes along with infiltration of CD8+ cytotoxic T cells, FOXP3+ T regulatory cells, CD68+ macrophages and CD66b+ neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20+ B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20+ B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28-0.73, P = 0.001), which remained significant in multivariable analysis. CD20+ B lymphocytes were highly and positively associated with CD8+ T lymphocytes (P < 0.001), and part of the prognostic role was found to be a cooperative effect between these lymphocyte subsets. Our results support a favourable prognostic value of tumour-infiltrating CD20+ B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20+ B lymphocytes and CD8+ T lymphocytes is suggested.
|
|
| 5. |
- Fedirko, Veronika, et al.
(författare)
-
Pre-diagnostic anthropometry and survival after colorectal cancer diagnosis in Western European populations
- 2014
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:8, s. 1949-1960
-
Tidskriftsartikel (refereegranskat)abstract
- General and abdominal adiposity are associated with a high risk of developing colorectal cancer (CRC), but the role of these exposures on cancer survival has been less studied. The association between pre-diagnostic anthropometric characteristics and CRC-specific and all-cause death was examined among 3,924 men and women diagnosed with CRC between 1992 and 2009 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (FIRS) and corresponding 95% confidence intervals (as). Over a mean follow-up period of 49 months, 1,309 deaths occurred of which 1,043 (79.7%) were due to CRC. In multivariable analysis, prediagnostic BMI kg/m2 was associated with a high risk for CRC-specific (HR = 1.26, 95% CI = 1.04-1.52) and all-cause (HR = 1.32, 95% CI = 1.12-1.56) death relative to BMI <25 kg/m(2). Every 5 kg/m(2) increase in BMI was associated with a high risk for CRC-specific (HR = 1.10, 95% CI = 1.02-1.19) and all-cause death (HR = 1.12, 95% Cl = 1.05-1.20); and every 10 cm increase in waist circumference was associated with a high risk for CRC-specific (HR = 1.09, 95% Cl = 1.02-1.16) and allcause death (HR= 1.11, 95% CI= 1.05-1.18). Similar associations were observed for waist-to-hip and waist-to-height ratios. Height was not associated with CRC-specific or all-cause death. Associations tended to be stronger among men than in women. Possible interactions by age at diagnosis, cancer stage, tumour location, and hormone replacement therapy use among postmenopausal women were noted. Pre-diagnostic general and abdominal adiposity are associated with lower survival after CRC diagnosis.
|
|
| 6. |
- Gkekas, Ioannis, 1981-, et al.
(författare)
-
Colon cancer patients with mismatch repair deficiency are more likely to present as acute surgical cases
- 2021
-
Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 157, s. 1-9
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The effect of the genetic imprint on the emergency presentation of colon cancer remains unclear. The disparity between tumours evolving along different carcinogenetic pathways has not been studied systematically. This retrospective multicenter cohort study evaluates the association between mismatch repair status and the risk for acute surgery of colon cancer.Patients and methods: A retrospective multicenter cohort study including in total 870 patients from three different countries. Scandinavian cohort (Finland and Sweden), including a total of 412 patients operated between January 1, 1995 and December 31, 2010, was validated against a cohort from the Czech Republic, including a total of 458 patients, operated between January 1, 2018 and December 31, 2019. The proficiency or deficiency of mismatch repair was determined by immunohistochemistry. Primary outcome was the risk for acute colon cancer surgery given as the Odds Ratio (OR) in the univariable and multivariable analyses. Acute colon cancer surgery was defined as surgery performed during the same hospital admission as when the diagnosis of colon cancer was made.Results: Of the 870 patients (399 females [46%]) included in the analyses, median age at surgery was 69 [interquartile range, 61–76] years, deficient Mismatch Repair (dMMR) status was found in 190 patients (22%), and 179 patients (21%) underwent acute surgery during the same hospital admission as when the diagnosis of colon cancer was made. In the Scandinavian cohort, a significant association between dMMR status and acute surgery was seen in both the univariable (OR 1.82, 95% CI 1.11–3.02, P = 0.017) and the multivariable (OR = 2.21, 95% CI 1.28–3.95, P = 0.005) analyses. This was confirmed in the Czech validation cohort in both the univariable (OR = 1.94, 95% CI 1.09–3.26, P = 0.022) and the multivariable (OR = 1.77, 95% CI 1.15–3.18, P = 0.021) analyses.Conclusion: This multicenter study reveals a strong association between acute colon cancer surgery and dMMR tumour status.
|
|
| 7. |
- Gkekas, Ioannis, et al.
(författare)
-
Deficient mismatch repair as a prognostic marker in stage II colon cancer patients
- 2019
-
Ingår i: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 45:10, s. 1854-1861
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A number of reports have evaluated the relationship between deficient DNA mismatch repair (dMMR) and colorectal cancer prognosis. Unfortunately, the exact prognostic role of dMMR has not been clearly established due to contradictory results. This study aims to determine the prognostic impact of dMRR in stage II colon cancer patients only. The appropriate identification of high-risk stage II colon cancers is of paramount importance in the selection of patients who may benefit from adjuvant treatment after surgery.METHODS: Four hundred and fifty-two patients with curative resection of stage II colon cancer were included. Hospital records were used as data source, providing clinical, surgical, pathology, oncology and follow-up information for statistical analysis focusing on overall survival (OS) and time to progression (TTP). Mismatch repair status was determined by immunohistochemistry. Patient survival was followed-up for a mean of 77·35 months.RESULTS: dMMR was detected in 93 of 452 patients (20·6%). No impact on overall survival (Log-Rank, p = 0·583, 95% CI 0·76-1·67). However, the hazard ratio 0·50 for TTP was highly significant (Log-Rank, p = 0·012, 95% CI 0·28-0·87) in patients with dMMR compared with those with mismatch repair proficient tumours (pMMR).CONCLUSIONS: Patients with dMMR tumours have a lower risk for recurrence compared to those with pMMR tumours, but this finding did not correlate to better overall survival.
|
|
| 8. |
- Gkekas, Ioannis, et al.
(författare)
-
Microsatellite instability as a prognostic factor in stage II colon cancer patients : a meta-analysis of published literature
- 2017
-
Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 37:12, s. 6563-6574
-
Forskningsöversikt (refereegranskat)abstract
- BACKGROUND/AIM: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients.MATERIALS AND METHODS: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio (HR) according to the method of Peto.RESULTS: Analysis was performed on 19 studies including 5,998 patients. A 47.3% of patients received postoperative chemotherapy and included 52.8% males and 47.2% females. Eight studies included some rectal cancer patients although this cohort was not clearly defined in 3 of these. MSI observed in 20.8% (mean) of patients (median 19.9%). HR for overall survival (OS) of MSI vs. microsatellite stable (MSS) tumors for the entire population: 0.73 (95% confidence interval (CI)=0.33-1.65); HR for disease-free survival (DFS):0.60 (95%CI=0.27-1.32). No statistical significant difference was found when studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) were compared separately (MG vs. IHC: HR OS 0.45, 95%CI=0.10-2.05 vs. 0.95, 95%CI=0.57-1.58; HR DFS 0.51, 95%CI=0.14-1.85 vs. 0.67, 95%CI=0.26-1.70). However, numerically MSI determination with genotyping shows significantly lower hazard ratios for both DFS and OS. Separate analysis of studies describing colon cancer patients only showed HR OS 0.72 (95%CI=0.31-1.71); HR DFS 0.60 (95%CI=0.27-1.31).CONCLUSION: No significant relation was found between MSI status and OS or DFS. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended. New large scale high quality studies are needed to answer this question definitively, since currently analyzed studies vary considerably.
|
|
| 9. |
- Gkekas, Ioannis, 1981-
(författare)
-
Mismatch repair deficiency in colorectal cancer : prognosis and prediction for basic treatment strategies
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) remains a significant healthcare problem worldwide, being the third most common cancer and the fourth most frequent cause of cancer death. Environmental and dietary factors such as alcohol abuse, cigarette smoking, and genetic predisposition seem to constitute the main aetiologies.Two major distinct molecular genetic pathways have been recognised as models of transition from normal epithelium to adenoma and carcinoma. The first involves chromosomal instability (CIN) and the second involves microsatellite instability (MSI). The MSI pathway constitutes 2-4% of CRCs with a hereditary Mismatch Repair (MMR) defect (dMMR) and approximately 15% of sporadic MMR defects due to epigenetic silencing of the MutL homologue 1 (MLH1) promoter. Extracellular factors and spontaneous copy errors necessitate molecular systems to survey and repair human genetic information, and to protect it from chemical disruption. A complicated and entangled network of DNA damage response mechanisms, including multiple DNA repair pathways, damage tolerance processes, and cell cycle checkpoints safeguard genomic integrity. It has recently become apparent that key proteins contributing tocellular survival by taking part in DNA repair become executioners in the face of excess DNA damage. All prokaryotic and eukaryotic organisms have major DNA repair pathways. In each of these DNA repair pathways there are key proteins that have dual functions in DNA damage sensing/repair and apoptosis, taking advantage of the fact that DNA is a double helix with the same information present on both strands. Damages that affect one strand can easily be repaired by excision and replacement with newly synthesised DNA using the complementary strand as a template. MMR plays a critical role in the repair of errors that occur spontaneously during DNA replication, such as single base mismatches. dMMR increases the mutation frequency in an affected cell by approximately 1000 times, leading to MSI through the accumulation of short repetitive DNA sequences called microsatellites. Carcinogenesis in dMMR cases can present as hereditary cases (Lynch syndrome) due to germline mutation inin one of the main MMR genes – MLH1, MSH2, MSH6, and PMS2 or somatic/sporadic cases (epigenetic silencing or somatic inactivation of MLH1promoter. dMMR seems to have a favourable prognosis as these CRCs seems to be less prone to metastasising. This phenomenon is much more obvious for tumour stages II and III, while in advanced disease dMMR seems to lose its positive prognostic effect. Even if the underlying mechanism is not fully understood, some studies attribute the positive effect of dMMR tumours to their increased immunogenicity leading to a stronger more effective immune response. On the other hand, the predictive value of the dMMR mechanism isless well understood and has only gained attention in recent years. In general, dMMR seems to predict a poor response to 5-FU, the basis of gastrointestinal chemotherapy.The aims of this thesis were: 1. To review the latest publications on the role of MSI status as prognostic factor in stage II colon cancer (CC) patients (Study I); 2. To validate MMR status as a prognostic factor in patients with CC Stage II (Study II); 3. To verify MMR status as a predictive factor in relation to the administration of adjuvant chemotherapy in patients with stage II CC (Study III); 4. To investigate the potential role of MMR status as a risk factor for acute CC surgery (Study IV); and finally 5. To investigate the association between CRC with sporadic dMMR and non-colorectal malignancy (Study V).Study I, a meta-analysis reviewing recently published papers, revealed that MSI status in stage II CC patients does not seem to affect overall survival (OS)and disease-free survival (DFS). This lack of impact could be explained by selection bias and the extremely high proportion of patients receiving adjuvant chemotherapy in the studies included. This was the first meta-analysis specifically evaluating patients with colon cancer stage II. The optimal treatment algorithm for these patients remains unclear, and approximately 20% experience relapse and finally die from disseminated disease.Study II verified the prognostic role of MMR status in patients with stage II CC. Patients with a dMMR tumour have a significantly lower risk for cancer recurrence, a finding that is particularly important for CC treatment. This relationship does not correlate to a better OS since these patients are older and often die from other causes. Debate on the best postoperative strategy in stage II CC continues. What this study contributes is the idea that determination of MMR status can have prognostic value in these patients.Study III also verified the predictive role of MMR status in patients with stageII CC, only this time in relation to treatment with adjuvant chemotherapy. Patients with proficient MMR (pMMR) status receiving adjuvant chemotherapy have a significantly better OS than those not receiving adjuvant treatment. This relationship was not seen in patients with a dMMR tumour. Furthermore, patients with a pMMR tumour receiving adjuvant treatment have a significantly longer survival time after the first relapse compared to those not receiving adjuvant treatment.Study IV revealed the higher probability of dMMR tumours to present as a surgical emergency. Stage III and IV tumours were also associated with acute surgery. This association was significant regardless of the potential bias due toretrospective methodology and possible heterogeneity between the differentcohorts. Further research is required before our conclusions can be applied in clinical practice due to the multicomplex relationship and interactions between variables that influence the oncologic outcome of acute CC surgery.Study V revealed that patients with sporadic, non-hereditary dMMR CRC run a greater risk for having non-colorectal cancer prior to or after the diagnosis ofCRC. This implies that patients with a dMMR tumour should be screened for other non-colorectal cancer, more so than in the the general population.Conclusion: CRC continues to be a significant healthcare problem worldwide, and treatment algorithms for patients with different genomic backgrounds can vary significantly. This thesis supports the idea of using MMR status as a prognostic and predictive factor in everyday clinical practice, especially in stage II CC and acute cases.
|
|
| 10. |
- Gkekas, Ioannis, et al.
(författare)
-
Mismatch repair status predicts survival after adjuvant treatment in stage II colon cancer patients.
- 2020
-
Ingår i: Journal of Surgical Oncology. - : John Wiley & Sons. - 0022-4790 .- 1096-9098. ; 121:2, s. 392-401
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Stage II colon cancer is primarily a surgical disease. Only a still not well-defined subset of patients may benefit from postoperative adjuvant chemotherapy. The relationship between adjuvant chemotherapy and survival after relapse is furthermore still not definitely explored in this group of patients. A number of reports suggest some association between defective mismatch repair (dMMR) and colorectal cancer stage II prognosis, but due to contradictory results from existing studies, the exact predictive role is still not fully understood.METHODS: Retrospective multicenter study including 451 stage II colon cancer patients. The proficiency or deficiency of mismatch repair was tested using immunohistochemistry and analyzed in relationship to two survival outcomes: overall survival (OS) and postrelapse survival.RESULTS: Patients with dMMR (20.4%) derived no OS benefit from adjuvant chemotherapy (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.47-2.38; P = .897). Patients with proficient mismatch repair (pMMR) tumors receiving adjuvant chemotherapy had the significantly better OS in comparison to those not receiving chemotherapy (HR, 0.54; 95% CI, 0.35-0.82; P = .004). This relationship remained significant in multivariable analysis (HR, 0.42; 95% CI, 0.22-0.78; P = .007). Patients with pMMR relapsing after adjuvant treatment lived significantly longer than those relapsing without previous adjuvant treatment (HR, 0.55; 95% CI, 0.32-0.96; P = .033) and this result remained significant in the multivariable model (HR, 0.49; 95% CI, 0.26-0.93; P = .030).CONCLUSION: In stage II CC patients, adjuvant chemotherapy improves therapeutic outcomes only in patients with pMMR tumors. Survival after relapse in patients having received adjuvant chemotherapy is significantly longer for patients with pMMR. No survival benefit from adjuvant chemotherapy was seen among patients with dMMR tumors.
|
|
