| 1. |
- Andersson, Roland, et al.
(författare)
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Pancreatic cancer–the past, the present, and the future
- 2022
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 57:10, s. 1169-1177
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Forskningsöversikt (refereegranskat)abstract
- Background: Pancreatic cancer has been and still is associated with a very poor prognosis. This is due to a lack of major breakthroughs with respect to early diagnosis, prognostication, prediction, as well as novel, targeted therapies. The benefits of surgery and chemotherapy are evident, but the fact that only some 10% of all patients have early, localized disease highlights the unmet need for new early detection methods. An improved understanding of tumor biology and the development of molecular markers detectable both in the circulation and in cancer tissues may underlie the development of new tools for optimizing both diagnosis and treatment. Material and methods: Review of the literature. Results and conclusion: If we do not improve precision oncology for pancreatic ductal adenocarcinoma, the prognosis will still remain dismal and the” burden” on society will increase substantially.
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| 2. |
- Andersson, Roland, et al.
(författare)
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Surveillance after resection of pancreatic ductal adenocarcinoma : How to do it and what are the benefits?
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Ingår i: Scandinavian Journal of Surgery. - 1457-4969.
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Surveillance following resection with curative intent of pancreatic cancer varies widely, and supporting evidence is limited. Recurrence is although frequent, not at least during the first 2 years. Surveillance may be costly, but evidence on how this influences overall survival is not fully elucidated. Methods, Results: There are reports implying that signs of biological recurrence (increasing CA 19-9) precede radiologically demonstrated recurrence by months. Conclusions: The possibility of initiating salvage therapy earlier is discussed, potentially based on improved future biomarker panels.
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| 3. |
- Beilmann-Lehtonen, Ines, et al.
(författare)
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The Relationship between the Tissue Expression of TLR2, TLR4, TLR5, and TLR7 and Systemic Inflammatory Responses in Colorectal Cancer Patients
- 2021
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Ingår i: Oncology. - : S. Karger. - 0030-2414 .- 1423-0232. ; 99:12, s. 790-801
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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.
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| 4. |
- Bertonnier-Brouty, Ludivine, et al.
(författare)
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E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma
- 2024
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Ingår i: Cancer Medicine. - 2045-7634. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs.OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion.METHODS AND RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells.CONCLUSION: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
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| 5. |
- Edin, Sofia, et al.
(författare)
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The Prognostic Importance of CD20+ B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9:1
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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.
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| 6. |
- Gkekas, Ioannis, 1981-, et al.
(författare)
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Colon cancer patients with mismatch repair deficiency are more likely to present as acute surgical cases
- 2021
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 157, s. 1-9
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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.
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| 7. |
- Gkekas, Ioannis, 1981-, et al.
(författare)
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Sporadic deficient mismatch repair in colorectal cancer increases the risk for non-colorectal malignancy : a European multicenter cohort study
- 2024
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Ingår i: Journal of Surgical Oncology. - : John Wiley & Sons. - 0022-4790 .- 1096-9098. ; 129:7, s. 1295-1304
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status.Methods: A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex.Results: Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60–75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89–3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67–3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28–2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72–3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05–2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63–3.42, p = 0.005), respectively.Conclusion: In this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non-colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.
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| 8. |
- Gramolelli, Silvia, et al.
(författare)
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PROX1 is a transcriptional regulator of MMP14
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.
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| 9. |
- Gunnarsson, Ulf, et al.
(författare)
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Association between local immune cell infiltration, mismatch repair status and systemic inflammatory response in colorectal cancer
- 2020
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Ingår i: Journal of Translational Medicine. - : BioMed Central. - 1479-5876. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.METHODS: Complete clinical and long-term survival data were retrieved for 316 CRC patients operated at Helsinki University Hospital between the years 1998 and 2003. Tissue microarrays were prepared from surgical specimens and further processed and analyzed for local immune cell infiltration using multispectral imaging with a Vectra quantitative pathology imaging system and Inform software. Multiplex immunohistochemistry was applied using antibodies against CD66b, CD8, CD20, FoxP3, CD68 and pan-Cytokeratin. After exclusions, data on immune infiltration were available for 275 patients. Mismatch repair status was determined by immunohistochemistry.RESULTS: CRP was seen to be an independent predictor of cancer-specific survival but not overall survival in uni- and multivariable (HR 1.01 (1.00-1.02); p = 0.028) analyses of non-irradiated patients. There was no significant difference in CRP according to mismatch repair status, but all cases (n = 10) with CRP ≥ 75 mg/l had proficient mismatch repair (pMMR). There was a significant negative correlation between intratumor stromal infiltration by T-regulatory FOXP3+ cells and CRP (p = 0.006). There was significantly lower intratumor stromal infiltration by FOXP3+ cells (p = 0.043) in the right colon compared to the rectum, but no significant difference in CRP (p = 0.44). CRP was not a predictor of overall survival (HR 0.99, 95% CI 0.98-1.01) nor cancer-specific survival in irradiated patients (HR 0.94, 95% CI 0.94-1.02).CONCLUSIONS: There was a significant negative relationship between SIR, defined as an elevated CRP, and intratumor stromal infiltration by T-regulatory FOXP3+ cells. This and the fact that all cases with a CRP > 75 mg/l had pMMR suggests that SIR and dMMR are independent entities in CRC. Indeed, the general lack of difference in CRP between cases with dMMR and pMMR may be evidence of overlap in cases with a less pronounced SIR.
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| 10. |
- Heby, Margareta, et al.
(författare)
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Additive clinical impact of epidermal growth factor receptor and podocalyxin-like protein expression in pancreatic and periampullary adenocarcinomas
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The outcome of periampullary adenocarcinomas remains poor with few treatment options. Podocalyxin-like protein (PODXL) is an anti-adhesive protein, the high expression of which has been shown to confer a poor prognosis in numerous malignancies. A correlation and adverse prognostic synergy between PODXL and the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer. Here, we investigated whether this also applies to periampullary adenocarcinomas. We analyzed the immunohistochemical expression of PODXL and EGFR in tissue microarrays with tumors from two patient cohorts; (Cohort 1, n = 175) and (Cohort 2, n = 189). The effect of TGF-β-induced expression and siRNA-mediated knockdown of PODXL and EGFR, were investigated in pancreatic cancer cells (PANC-1) in vitro. We found a correlation between PODXL and EGFR in these cancers, and a synergistic adverse effect on survival. Furthermore, silencing PODXL in pancreatic cancer cells resulted in the down-regulation of EGFR, but not vice versa. Consequently, these findings suggest a functional link between PODXL and EGFR, and the potential combined utility as biomarkers possibly improving patient stratification. Further studies examining the mechanistic basis underlying these observations may open new avenues of targeted treatment options for subsets of patients affected by these particularly aggressive cancers.
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