| 1. |
- 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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| 2. |
- 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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| 3. |
- Jonsson, Liv, et al.
(författare)
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High RBM3 expression in prostate cancer independently predicts a reduced risk of biochemical recurrence and disease progression
- 2011
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Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 6, s. 91-
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Tidskriftsartikel (refereegranskat)abstract
- Background: High expression of the RNA-binding protein RBM3 has previously been found to be associated with good prognosis in breast cancer, ovarian cancer, malignant melanoma and colorectal cancer. The aim of this study was to examine the prognostic impact of immunohistochemical RBM3 expression in prostate cancer. Findings: Immunohistochemical RBM3 expression was examined in a tissue microarray with malignant and benign prostatic specimens from 88 patients treated with radical prostatectomy for localized disease. While rarely expressed in benign prostate gland epithelium, RBM3 was found to be up-regulated in prostate intraepithelial neoplasia and present in various fractions and intensities in invasive prostate cancer. High nuclear RBM3 expression was significantly associated with a prolonged time to biochemical recurrence (BCR) (HR 0.56, 95% CI: 0.34-0.93, p = 0.024) and clinical progression (HR 0.09, 95% CI: 0.01-0.71, p = 0.021). These associations remained significant in multivariate analysis, adjusted for preoperative PSA level in blood, pathological Gleason score and presence or absence of extracapsular extension, seminal vesicle invasion and positive surgical margin (HR 0.41, 95% CI: 0.19-0.89, p = 0.024 for BCR and HR 0.06, 95% CI: 0.01-0.50, p = 0.009 for clinical progression). Conclusion: Our results demonstrate that high nuclear expression of RBM3 in prostate cancer is associated with a prolonged time to disease progression and, thus, a potential biomarker of favourable prognosis. The value of RBM3 for prognostication, treatment stratification and follow-up of prostate cancer patients should be further validated in larger studies.
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| 4. |
- Jonsson, Liv, et al.
(författare)
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Low RBM3 protein expression correlates with tumour progression and poor prognosis in malignant melanoma : An analysis of 215 cases from the Malmo Diet and Cancer Study
- 2011
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 9, s. 114-
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously reported that expression of the RNA-and DNA-binding protein RBM3 is associated with a good prognosis in breast cancer and ovarian cancer. In this study, the prognostic value of immunohistochemical RBM3 expression was assessed in incident cases of malignant melanoma from a prospective population-based cohort study. Methods: Until Dec 31(st) 2008, 264 incident cases of primary invasive melanoma had been registered in the Malmo Diet and Cancer Study. Histopathological and clinical information was obtained for available cases and tissue microarrays (TMAs) constructed from 226 (85.6%) suitable paraffin-embedded tumours and 31 metastases. RBM3 expression was analysed by immunohistochemistry on the TMAs and a subset of full-face sections. Chi-square and Mann-Whitney U tests were used for comparison of RBM3 expression and relevant clinicopathological characteristics. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the relationship between RBM3 and recurrence free survival (RFS) and overall survival (OS). Results: RBM3 could be assessed in 215/226 (95.1%) of primary tumours and all metastases. Longitudinal analysis revealed that 16/31 (51.6%) of metastases lacked RBM3 expression, in contrast to the primary tumours in which RBM3 was absent in 3/215 (1.4%) cases and strongly expressed in 120/215 (55.8%) cases. Strong nuclear RBM3 expression in the primary tumour was significantly associated with favourable clinicopathological parameters; i. e. non-ulcerated tumours, lower depth of invasion, lower Clark level, less advanced clinical stage, low mitotic activity and non-nodular histological type, and a prolonged RFS (RR = 0.50; 95% CI = 0.27-0.91) and OS (RR = 0.36, 95% CI = 0.20-0.64). Multivariate analysis demonstrated that the beneficial prognostic value of RBM3 remained significant for OS (RR = 0.33; 95% CI = 0.18-0.61). Conclusions: In line with previous in vitro data, we here show that RBM3 is down-regulated in metastatic melanoma and high nuclear RBM3 expression in the primary tumour is an independent marker of a prolonged OS. The potential utility of RBM3 in treatment stratification of patients with melanoma should be pursued in future studies.
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| 5. |
- Nodin, Björn, et al.
(författare)
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High MCM3 expression is an independent biomarker of poor prognosis and correlates with reduced RBM3 expression in a prospective cohort of malignant melanoma
- 2012
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Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 7:1, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Malignant melanoma is the most lethal form of skin cancer with a variable clinical course even in patients with thin melanomas and localized disease. Despite increasing insights into melanoma biology, no prognostic biomarkers have yet been incorporated into clinical protocols. Reduced expression of the RNA binding motif protein 3 (RBM3) has been shown to correlate with tumour progression and poor prognosis in melanoma and several other cancer forms. In ovarian cancer, an inverse association was found between expression of RBM3 and the minichromosome maintenance 3 (MCM3) gene and protein. In melanoma, gene expression analysis and immunohistochemical validation has uncovered MCM3 as a putative prognostic biomarker. The aim of the present study was to examine the associations of MCM3 expression with clinical outcome and RBM3 expression in a prospective, population-based cohort of melanoma. Methods: Immunohistochemical MCM3 expression was examined in 224 incident cases of primary melanoma from the Malmo Diet and Cancer Study, previously analysed for RBM3 expression. Spearman's Rho and Chi-Square tests were used to explore correlations between MCM3 expression, clinicopathological factors, and expression of RBM3 and Ki67. Kaplan Meier analysis, the log rank test, and univariable and multivariable Cox proportional hazards modelling were used to assess the impact of MCM3 expression on disease-free survival (DFS) and melanoma-specific survival (MSS). Results: High MCM3 expression was significantly associated with unfavourable clinicopathological features and high Ki67 expression. A significant inverse correlation was seen between expression of MCM3 and RBM3 (p = 0.025). High MCM3 expression was associated with a reduced DFS (HR = 5.62) and MSS (HR = 6.03), and these associations remained significant in multivariable analysis, adjusted for all other factors (HR = 5.01 for DFS and HR = 4.96 for MSS). RBM3 expression remained an independent prognostic factor for MSS but not DFS in the multivariable model. Conclusions: These findings provide validation of the utility of MCM3 expression as an independent biomarker for prognostication of patients with primary melanoma. Moreover, the inverse association and prognostic impact of MCM3 and RBM3 expression indicate a possible interaction of these proteins in melanoma progression, the functional basis for which merits further study.
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| 6. |
- Fridberg, Marie, et al.
(författare)
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Modifying effect of gender on the prognostic value of clinicopathological factors and Ki67 expression in melanoma : a population-based cohort study
- 2012
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Ingår i: Biology of Sex Differences. - : Springer Science and Business Media LLC. - 2042-6410. ; 3, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Malignant melanoma is the most deadly form of skin cancer. Female sex is known to have a protective effect on incidence, tumour characteristics, and mortality from melanoma. However, the potentially modifying effect of sex on the prognostic significance of clinicopathological and investigative factors is generally not taken into consideration in biomarker studies. In this study, we compared the sex-specific distribution and prognostic value of established tumour characteristics and Ki67 expression in 255 cases of incident primary melanoma in a prospective, population-based cohort study.METHODS: The study included 255 incident cases of melanoma, 132 females and 123 males, in the Malmö Diet and Cancer Study. Tumours from 226 (88.6%) cases had been assembled in tissue microarrays. Clinicopathological factors and immunohistochemical Ki67 expression were assessed and correlated with disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier analysis, log rank test and univariable and multivariable Cox regression analyses, stratified for gender. Effect of gender on melanoma-specific survival (MSS) after first recurrence was also analysed.RESULTS: Women were significantly younger at diagnosis than men (p = 0.012). The most common tumour sites were the legs in women (37.5%) and the dorsal trunk in men (37.8%). Kaplan-Meier analysis revealed that tumour location had no prognostic impact in women, but in men, location to the frontal trunk was significantly associated with a reduced DFS compared with all other locations combined and location to the dorsal trunk was significantly associated with a prolonged OS. High Ki67 expression was significantly associated with a reduced DFS and OS in men but not in women, also when adjusted for other factors. In men, but not in women, ulceration was an independent prognostic factor for both DFS and OS. MSS after first local, regional or distant recurrence was significantly shorter for men than for women.CONCLUSIONS: The results from this study demonstrate that the prognostic value of tumour location, Ki67 expression and ulceration in melanoma differs according to gender. These findings need to be validated in future studies, as they may help improve prognostication in patients with melanoma. Moreover, our findings demonstrate that sex-stratified analyses add valuable information to biomarker studies.
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| 7. |
- Jonsson, L., et al.
(författare)
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High expression of RNA-binding motif protein 3 in esophageal and gastric adenocarcinoma correlates with intestinal metaplasia-associated tumours and independently predicts a reduced risk of recurrence and death
- 2014
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Ingår i: Biomarker Research. - : BioMed Central Ltd.. - 2050-7771. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: High nuclear expression of the RNA-binding motif protein 3 (RBM3) has previously been found to correlate with favourable clinicopathological characteristics and a prolonged survival in several cancer forms. Here, we examined the clinicopathological correlates and prognostic significance of RBM3 expression in tumours from a consecutive cohort of upper gastrointestinal adenocarcinoma.Material and methods: Immunohistochemical RBM3 expression was analysed in tissue microarrays with primary radiotherapy- and chemotherapy-naive adenocarcinoma of the esophagus, gastroesophageal junction and stomach (n = 173). In addition paired samples of normal squamous epithelium (n = 53), gastric mucosa (n = 117), Barrett's esophagus/gastric intestinal metaplasia (n = 61) and lymph node metastases (n = 71) were analysed. Kaplan-Meier analysis and Cox proportional hazards modelling was applied to assess the impact of RBM3 expression on overall survival (OS) and recurrence-free survival (RFS).Results: RBM3 expression was similar in primary tumours and lymph node metastases, but significantly higher in primary tumours and metastases arising in a background of intestinal metaplasia compared with cases without intestinal metaplasia (p < 0.001). RBM3 expression was significantly reduced in more advanced tumour stages (p = 0.006). Low RBM3 expression was significantly associated with a shorter OS in cases with radically resected (R0) tumours (HR 2.19, 95% CI 1.33-3.61, p = 0.002) and RFS in curatively treated patients with R0 resection/distant metastasis-free disease (HR = 3.21, 95% CI 1.64-6.30, p = 0.001). These associations remained significant in adjusted analysis (HR = 1.95, 95% CI 1.17-3.25, p = 0.010 for OS and HR = 3.02, 95% CI 1.45-6.29, p = 0.003 for RFS).Conclusion: High expression of RBM3 may signify a subset of upper gastrointestinal cancers arising in a background of intestinal metaplasia and independently predicts a reduced risk of recurrence and death in patients with these cancer forms. These findings are of potential clinical utility and merit further validation.
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| 8. |
- Toksvang, Linea Natalie, et al.
(författare)
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Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia : a NOPHO ALL2008 sub-study
- 2021
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer. - 0344-5704 .- 1432-0843. ; 88:5, s. 911-917
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. Methods We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. Results After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged >= 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. Conclusion Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.
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