| 1. |
- BORG, DAVID, et al.
(författare)
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Expression of IFITM1 as a prognostic biomarker in resected gastric and esophageal adenocarcinoma
- 2016
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Ingår i: Biomarker research. - : Springer Science and Business Media LLC. - 2050-7771. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is an increasing amount of reports on IFITM1 (interferon-inducible transmembrane protein 1) in various malignancies. The aim of this study was to examine the expression of IFITM1 and its prognostic significance in gastroesophageal adenocarcinoma.METHODS: Tissue samples were obtained from a consecutive cohort of 174 patients surgically treated between 2006 and 2010 for gastroesophageal (gastric, gastroesophageal junction and esophageal) adenocarcinoma, not subjected to neoadjuvant therapy. Expression of IFITM1 was examined using immunohistochemistry on tissue microarrays of primary tumors and paired samples of adjacent normal epithelium, intestinal metaplasia and lymph node metastases.RESULTS: Expression of IFITM1 was significantly elevated in primary tumors and lymph node metastases compared to adjacent normal epithelium and intestinal metaplasia, regardless of tumor location. Overexpression of IFITM1 was associated with M0-disease (no distant metastases). In gastric cancer IFITM1 expression was significantly associated with improved TTR (time to recurrence) in Kaplan-Meier analysis and Cox regression, both in the unadjusted analysis (HR 0.33, 95 % CI 0.12-0.88) and in the adjusted analysis (HR 0.32, 95 % CI 0.12-0.87) but there was no significant impact on OS (overall survival). In esophageal adenocarcinoma expression of IFITM1 had no impact on TTR or OS in Kaplan-Meier-analyses, but in the adjusted Cox regression IFITM1 expression had a negative impact on both TTR (HR 3.05, 95 % CI 1.09-8.53) and OS (HR 2.71, 95 % CI 1.11-6.67).CONCLUSIONS: IFITM1 was overexpressed in gastroesophageal adenocarcinoma and associated with M0-disease. In gastric cancer IFITM1 expression had a positive impact on TTR but in esophageal cancer it seemed to have an adverse impact on survival. The reason for the diverging prognostic impact of IFITM1 in esophageal and gastric cancer is unclear and warrants further studies.
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| 2. |
- Elebro, Jacob, et al.
(författare)
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Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma
- 2014
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 12, s. 289-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pancreatic cancer and other pancreaticobiliary type periampullary adenocarcinomas have a dismal prognosis even after resection and neoadjuvant chemotherapy. Intestinal type periampullary adenocarcinomas generally have a better prognosis, but little is known on optimal neoadjuvant and adjuvant treatment. New prognostic and treatment predictive biomarkers are needed for improved treatment stratification of patients with both types of periampullary adenocarcinoma. Expression of the Special AT-rich sequence-binding protein 1 (SATB1) has been demonstrated to confer a worse prognosis in several tumour types, whereas its close homologue SATB2 is a proposed diagnostic and favourable prognostic marker for colorectal cancer. The prognostic value of SATB1 and SATB2 expression in periampullary adenocarcinoma has not yet been described. Methods: Immunohistochemical expression of SATB1 and SATB2 was analysed in tissue microarrays with primary tumours and a subset of paired lymph node metastases from 175 patients operated with pancreaticoduodenectomy for periampullary adenocarcinoma. Kaplan-Meier and Cox regression analysis were applied to explore the impact of SATB1 and SATB2 expression on recurrence free survival (RFS) and overall survival (OS). Results: Positive expression of SATB1 was denoted in 16/106 primary pancreatobiliary type tumours and 11/65 metastases, and in 15/63 primary intestinal type tumours and 4/26 metastases, respectively. Expression of SATB1 was an independent predictor of a significantly shorter RFS and OS in pancreatobiliary type, but not in intestinal type adenocarcinomas. Moreover, SATB1 expression predicted an improved response to adjuvant chemotherapy in both tumour types. SATB2-expression was seen in 3/107 pancreatobiliary type primary tumours, and in 8/61 intestinal type primary tumours. The small number of cases with positive SATB2 expression did not allow for any firm conclusions on its prognostic value. Conclusions: These findings demonstrate the potential utility of SATB1 as a prognostic and predictive biomarker for chemotherapy response in both intestinal type and pancreatobiliary type periampullary adenocarcinomas, including pancreatic cancer.
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| 3. |
- Fristedt, Richard, et al.
(författare)
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Expression and prognostic significance of the polymeric immunoglobulin receptor in esophageal and gastric adenocarcinoma
- 2014
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 12, s. 83-
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The polymeric immunoglobulin receptor (PIGR) has been proposed to be a candidate prognostic biomarker in a few cancer forms, and one previous study reported that reduced PIGR expression signifies more aggressive tumours of the distal esophagus and gastroesophageal junction (GEJ). In the present study, we examined the expression, clinicopathological correlates and prognostic significance of PIGR expression in an extended cohort of adenocarcinoma of the upper gastrointestinal tract. Materials and methods: Immunohistochemical PIGR expression was examined in a consecutive cohort of patients with surgically resected, radio-chemonaive adenocarcinoma of the esophagus, GE-junction and stomach (n = 173), including paired samples of benign-appearing squamous epithelium (n = 51), gastric mucosa (n = 114), Barrett's esophagus (BE) or intestinal metaplasia (IM) (n = 57) and lymph node metastases (n = 75). Non-parametric tests were applied to explore associations between PIGR expression in primary tumours and clinicopathological characteristics. Classification and regression tree analysis was applied for selection of prognostic cut-off. The impact of PIGR expression on overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier analysis and hazard ratios (HR) calculated by adjusted and unadjusted Cox proportional hazards modelling. Results: PIGR expression was significantly higher in intestinal metaplasia (BE or gastric IM) compared to normal tissues and cancer (p < 0.001). Reduced PIGR expression in primary tumours was significantly associated with more advanced tumour stage (p = 0.002) and inversely associated with involved margins (p = 0.034). PIGR expression did not differ between primary tumours and lymph node metastases. There was no significant difference in PIGR expression between tumours with and without a background of intestinal metaplasia. High PIGR expression was an independent predictor of a prolonged OS (HR = 0.60, 95% CI 0.36-0.99) and RFS (HR = 0.49, 95% CI 0.27-0.90) in patients with radically resected (R0) primary tumours and of an improved RFS (HR = 0.32, 95% CI 0.15-0.69) in curatively treated patients with R0 resection/distant metastasis-free disease. Conclusion: High PIGR expression independently predicts a decreased risk of recurrence and an improved survival in patients with adenocarcinoma of the upper gastrointestinal tract. These findings are of potential clinical relevance and merit further validation.
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| 6. |
- Fristedt, Richard, et al.
(författare)
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Prognostic impact of tumour-associated B cells and plasma cells in oesophageal and gastric adenocarcinoma
- 2016
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Ingår i: Journal of Gastrointestinal Oncology. - : AME Publishing Company. - 2078-6891 .- 2219-679X. ; 7:6, s. 848-859
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Tidskriftsartikel (refereegranskat)abstract
- Background: While it is well established that the cell-mediated immune response plays an important role in cancer progression and spread, the role of the humoral immune response in this regard has been less studied. According to the existing literature, dense infiltration of B cells or plasma cells appears to correlate mainly with an improved prognosis in several types of cancer, but their prognostic impact in oesophageal and gastric cancer has not yet been described. Methods: Immunohistochemistry was applied on tissue microarrays (TMA) to assess the stromal density of B cells (CD20+) and plasma cells [CD138+ or immunoglobulin kappa C (IGKC+)] in chemo-/radiotherapy-naive tumours from a consecutive cohort of 174 patients with resected oesophageal or gastric adenocarcinoma. Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on overall survival (OS) and time to recurrence (TTR). Results: In curatively treated patients with oesophageal adenocarcinoma, high expression of IGKC was an independent predictor of a prolonged OS [hazard ratio (HR) 0.10; 95% confidence interval (CI), 0.02-0.57], and TTR (HR 0.15; 95% CI, 0.03-0.71). In curatively treated patients with gastric adenocarcinoma, high expression of IGKC independently predicted a prolonged OS (HR 0.46; 95 % CI, 0.24-0.87) and TTR (HR 0.46; 95% CI, 0.21-0.98). Expression of CD20 was not prognostic, and CD138 expression was only prognostic in unadjusted analysis of TTR in gastric cancer. Conclusions: These results demonstrate, for the first time, that abundant infiltration of IGKC+ plasma cells independently predicts a prolonged survival in both oesophageal and gastric cancer.
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| 7. |
- Fristedt, Richard
(författare)
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Prognostic role of the tumour microenvironment in esophago-gastric, pancreatic and periampullary adenocarcinoma: B cells and beyond
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer development depends on cells aquiring a skillset of limitless growth and finally invasive properties to allow for metastasis, as summarised by the six hallmarks of cancer. Recently four more hallmarks have been added: genomic instability, deregulating cellular metabolism, tumour-promoting inflammation and avoiding immune destruction. This thesis focuses on the latter two: immune system and cancer cell interactions. Oesophageal and gastric cancer present late and only 25% and 30%, respectively, will be subjected to curative treatment. Periampullary cancer includes: pancreatic cancer (PDA), biliary, ampullary and duodenal cancer. Periampullary cancer is often dichotomised into intestinal (I)-type and pancreatobiliary (PB)-type. Overall survival for PDA is 5%, whilst I-type periampullary cancer has a better prognosis.The aim of this thesis was to analyse the expression of the polymeric immunoglobulin receptor (pIgR), and the abundance of B cells and plasma cells in oesophago-gastric, pancreatic and periampullary adenocarcinoma, and to explore their potential prognostic and predictive value.To this end, two patient cohorts were used The first cohort encompassed 174 patients with surgically resected oesophago-gastric adenocarcinoma, who had not received neoadjuvant treatment. The second cohort encompassed 175 patients treated with pancreatoduodenectomy for pancreatic and periampullary adenocarcinoma. Tissue microarrays were constructed from primary tumours and selected metastases and immunohistochemistry (IHC) was applied with validated antibodies against pIgR, CD20+ B cells, CD138+ and IGKC+ plasma cells. Light microscopy and/or digital image analysis was used for detection. In addition, PIGR gene expression was assessed by quantitative polymerase chain reaction. High expression of pIgR, a transporter protein that transcytoses antibodies across epithelial cells to mucosal surfaces and has been associated with improved survival in many cancer types, was associated with a prolonged time to recurrence (TTR) and overall survival (OS) in oesophageal and gastric junction adenocarcinoma. Furthermore, reduced expression of pIgR was associated with decreased OS in I-type periampullary adenocarcinoma. In oesophageal and gastric adenocarcinoma, high density of IGKC+ plasma cells was associated with a prolonged TTR and OS. No association was seen for IGKC+ plasma cells in I-type or PB-type periampullary adenocarcinoma but a, high density of CD20+ B cells was associated with both a prolonged TTR and OS. In addition, there was a significant treatment interaction in relation to OS between high density of CD20+ B cells and adjuvant chemotherapy in patients with PB-type periampullary adenocarcinoma. In conclusion, high pIgR expression is associated with improved outcomes in oesophageal, GE junction and I-type periampullary adenocarcinoma. IGKC+ plasma cells are associated with a prolonged survival in esophageal and gastric adenocarcinoma. CD20+ B cells are associated with a prolonged survival in I-type and PB-type periampullary adenocarcinoma, and, possibly, with an improved response to adjuvant chemotherapy in PB-type tumours. The underlying mechanistic principles remain to be deciphered.
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| 8. |
- Fristedt, Richard, et al.
(författare)
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Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11, s. 112728-112728
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Tidskriftsartikel (refereegranskat)abstract
- The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p < 0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study.
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| 9. |
- Papadakos, Konstantinos S, et al.
(författare)
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The prognostic and potentially immunomodulatory role of cartilage oligomeric matrix protein in patients with gastric and esophageal adenocarcinoma
- 2024
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Ingår i: Cancer Immunology Immunotherapy. - 1432-0851. ; 73:5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment.METHODS: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm.RESULTS: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma.CONCLUSIONS: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.
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| 10. |
- Svensson, Maria C, et al.
(författare)
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The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:42, s. 72108-72126
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies have demonstrated a prognostic impact of tumor-infiltrating T lymphocytes and natural killer (NK) cells in esophageal and gastric adenocarcinoma, but whether these associations differ by the density of tumor-infiltrating immune cells of the B cell lineage remains largely unknown. Results: High infiltration of any T and NK lymphocytes investigated was in general associated with a favorable prognosis, but the strongest beneficial prognostic impact was seen in combination with high B lymphocyte infiltration. These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3(+), CD8(+) and FoxP3(+) with CD20(+) cells (p(interaction) = 0.012, 0.009 and 0.007, respectively) and for FoxP3(+) with IGKC(+) cells (p(interaction) = 0.034). In esophageal tumors, there was only a significant interaction for CD3(+) and CD20 (+) cells (p(interaction) = 0.028). Methods: Immunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3(+), CD8(+), FoxP3(+)) and NK cells (NKp46(+)) in chemoradiotherapy-naive tumors from a consecutive cohort of 174 patients with resected esophageal or gastric adenocarcinoma. The density of B lymphocytes (CD20(+)) and plasma cells (IGKC(+)) had been assessed previously. Kaplan-Meier analysis and Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS). Conclusions: These data support that the antitumoral effects of tumor-infiltrating T lymphocytes in esophageal and gastric adenocarcinoma may be largely dependent on a functional interplay between T and B lymphocytes or plasma cells.
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