| 1. |
- Andersson, Gustav, et al.
(författare)
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Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma
- 2019
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Ingår i: Biomarker research. - : Springer Science and Business Media LLC. - 2050-7771. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tamoxifen treatment has previously been reported to confer life-prolonging effects in patients with advanced pancreatic cancer, and most evidently so in women. None of these trials did however include biomarkers, and the relevance of female hormone signaling in pancreatic or other periampullary adenocarcinoma remains largely unexplored. The aim of this study was to examine the extent and potential clinical significance of estrogen receptor-α (ER) and progesterone receptor (PR) expression in pancreatic and other periampullary cancers. Methods: ER and PR expression was examined using immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, with long-term clinical follow-up. Non-parametric and Chi square tests were applied to examine the associations of stromal ER and PR expression with patient and tumor characteristics. Kaplan-Meier analysis and log rank test were applied to illustrate survival differences in relation to ER and PR expression. Cox regression proportional hazards models were applied to examine the associations between investigative factors and risk of death and recurrence, and to test for interactions between KRAS mutation status and hormone receptor expression in relation to survival. Results: Expression of both ER and PR was more frequent in the tumor-associated stroma than in the epithelium. A significant prognostic interaction, independent of tumor morphology, was found between stromal PR expression and KRAS mutation status in relation to both overall and recurrence-free survival (pinteraction = 0.026 and pinteraction = 0.005), in particular in women (pinteraction = 0.002 and pinteraction = 0.005). Specifically, stromal PR expression was associated with a prolonged survival in patients with KRAS-mutated tumors, whereas the opposite was seen for KRAS wild-type tumors. The prognostic value of ER positivity was limited to the subgroup of women with tumors of pancreatic origin. Conclusions: These results demonstrate that stromal PR rather than ER expression, together with KRAS mutation status, provides long-term prognostic information in patients with periampullary adenocarcinoma. Further study into the mechanistic basis for these observations may unveil important clues to the pathogenesis of these cancers and open up for the discovery of novel treatment options.
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| 2. |
- Ansari, Daniel, et al.
(författare)
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Single-institution experience with solid pseudopapillary neoplasm of the pancreas.
- 2011
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 46:12, s. 1492-1497
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare clinical entity. The objective of this study was to review a single institution's experience with this uncommon tumor, as well as review the literature. Material and Methods. Consecutive patients, who underwent surgery for a pathologically confirmed SPN between 1991 and 2010, were retrospectively reviewed. A PubMed search (January 1980-June 2011) was conducted to identify risk factors for death among SPN patients. Results. The institutional review identified 16 patients with SPN. Thirteen patients were female and three patients were male (median age 34 years). All patients underwent radical resection. Two patients had metastatic disease at the time of operation as evident by the presence of lymph node metastasis and gallbladder metastasis. One developed liver metastasis 4 months postoperatively and subsequently died. The other patient received adjuvant chemotherapy (gemcitabine and capecitabine), and 23 months after the initial operation, no tumor recurrence was detected and the patient is still alive. All other patients remain disease-free. Analysis of 29 fatalities reported in the English literature (including the present case) revealed several atypical features including male gender, old age, tumor size >5 cm, diffuse growth pattern, cellular or nuclear atypia, high mitotic rate, extensive necrosis, extrapancreatic invasion, metastasis and incomplete resection. Conclusions. SPN is not always indolent. Male patients and those with old age, atypical histopathology (large tumors, diffuse growth, cellular/nuclear atypia, mitotic activity, necrosis, invasion/metastasis) and incomplete resection may have a higher risk of recurrence and death, deserving particular attention.
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| 3. |
- Elebro, Jacob, et al.
(författare)
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Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1, 2 and 3 in Periampullary Adenocarcinoma
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumours with dismal prognosis, for which there is an urgent need to identify novel treatment strategies. The human epithelial growth factor receptors EGFR, HER2 and HER3 have been studied in several tumour types, and HER-targeting drugs have a beneficial effect on survival in selected types of cancer. However, these effects have not been evident in pancreatic cancer, and remain unexplored in other types of periampullary cancer. The prognostic impact of HER-expression in these cancers also remains unclear. The aim of this study was therefore to examine the expression and prognostic value of EGFR, HER2 and HER3 in periampullary cancer, with particular reference to histological subtype. To this end, protein expression of EGFR, HER2 and HER3, and HER2 gene amplification was assessed by immunohistochemistry and silver in situ hybridization, respectively, on tissue microarrays with tumours from 175 periampullary adenocarcinomas, with follow-up data on recurrence-free survival (RFS) and overall survival (OS) for up to 5 years. EGFR expression was similar in pancreatobiliary (PB) and intestinal (I) type tumours, but high HER2 and HER3 expression was significantly more common in I-type tumours. In PB-type cases receiving adjuvant gemcitabine, but not in untreated cases, high EGFR expression was significantly associated with a shorter OS and RFS, with a significant treatment interaction in relation to OS (pinteraction = 0.042). In I-type cases, high EGFR expression was associated with a shorter OS and RFS in univariable, but not in multivariable, analysis. High HER3 expression was associated with a prolonged RFS in univariable, but not in multivariable, analysis. Neither HER2 protein expression nor gene amplification was prognostic. The finding of a potential interaction between the expression of EGFR and response to adjuvant chemotherapy in PB-type tumours needs validation, and merits further study.
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| 4. |
- 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 .- 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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| 5. |
- Elebro, Jacob, et al.
(författare)
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Prognostic effect of hENT1, dCK and HuR expression by morphological type in periampullary adenocarcinoma, including pancreatic cancer.
- 2016
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Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 55:3, s. 96-286
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Tidskriftsartikel (refereegranskat)abstract
- Putative biomarkers of gemcitabine response have been extensively studied in pancreatic cancer, but less so in other types of periampullary adenocarcinoma. The most studied biomarker is human equilibrative nucleoside transporter 1 (hENT1), and the activating enzyme deoxycytidine kinase (dCK) has also been linked to treatment response. The RNA-binding protein human antigen R (HuR) has been demonstrated to confer increased dCK levels in vitro and to predict gemcitabine response in vivo. Here, we investigated the prognostic impact of hENT1, dCK and HuR in pancreatobiliary (PB) and intestinal (I) type periampullary cancers, respectively.
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| 6. |
- Elebro, Jacob
(författare)
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Prognostic factors in periampullary adenocarcinoma. A retrospective study over an 11 year period.
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Periampullary adenocarcinoma, including pancreatic cancer, has a poor prognosis that has not improved in the last decades. Therefore, in order to find more effective treatment regimens, it is necessary to gain more insight into the biology and clinical behaviour of these tumours. This thesis entails a thorough histopathological characterization of retrospectively collected tumours from a consecutive cohort of patients with resected periampullary adenocarcinoma, followed by tissue microarray-based immunohistochemical studies of eight candidate protein biomarkers. Tumours were classified as being of pancreatobiliary type (PB-type) or intestinal type (I-type), using histological criteria, and all biomarker analyses were performed in strata according to morphological type. In Paper I, histopathological studies showed that a standardized and meticulous protocol for assessment of the surgical specimens, as well as blind revisions of slides, had impact on the decision on tumour origin, the number of involved lymph nodes and involved margins. The biomarker studies in Paper II revealed that expression of the global gene regulator special AT-rich sequencebinding protein 1 (SATB1) was an independent factor of poor prognosis in PB-type tumours. SATB1 expression, however, also indicated a better response to adjuvant chemotherapy, in particular in I-type tumours. A closely related protein, SATB2, was found to be expressed in a few tumours only, making it difficult to draw any firm conclusions on its prognostic value. In Paper III, biomarker studies on proteins related togemcitabine metabolism revealed that a high ratio between cytoplasmic and nuclear expression of human protein R (HuR) indicated resistance to chemotherapy in PB-type tumours. In I-type tumours, high expression of human equilibrative nucleoside transporter 1 (hENT1) was a favourable prognostic factor and high expression of deoxycytidine kinase (dCK) indicated sensitivity to chemotherapy. In Paper IV, biomarker studies on the human epidermal growth factor receptors 1-3 (HER1-3) revealed a potential negative predictive effect of high EGFR (HER1) expression in relation to adjuvant chemotherapy in PB-type tumours. Six percent of I-type tumours had high expression of HER2, and gene amplification was confirmed in assessable cases. In I-type tumours, high expression of HER3 was a favourable prognostic factor, but not independent of other prognostic factors. Several of the potentially treatment predictive associations described in this thesis are novel, and may be of clinical interest if the results can be repeated in other cohorts and if the mechanistic basis is understood. The results presented here must be however be interpreted with caution, since the cohort is retrospective and many tests have been made.
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| 7. |
- Elebro, Jacob, et al.
(författare)
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Use of a standardized diagnostic approach improves the prognostic information of histopathologic factors in pancreatic and periampullary adenocarcinoma.
- 2014
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Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Variability in reported histopathology parameters in operated periampullary adenocarcinomas may affect the prognostic weight of the parameters. Standardized axial sectioning produces a higher incidence of involved margins and also seems to produce a lower relative incidence of pancreatic compared with distal bile duct origin and a higher incidence of involved lymph nodes, compared with non-standardized procedure. The aims of this study were to 1) assess how a previously not described standardized pathology procedure, with longitudinal sectioning along the distal bile duct, affects reported tumour origin, margin status and involved lymph nodes, compared with non-standardized procedure, 2) assess if re-evaluation of microscopic slides affects the prognostic value of margin status and 3) compare the results of this standardized procedure with reported results of other standardized and non-standardized procedures.
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| 8. |
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| 9. |
- 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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| 10. |
- Gremel, Gabriela, et al.
(författare)
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A systematic analysis of commonly used antibodies in cancer diagnostics
- 2014
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Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 64:2, s. 293-305
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Tidskriftsartikel (refereegranskat)abstract
- AimsImmunohistochemistry plays a pivotal role in cancer differential diagnostics. To identify the primary tumour from a metastasis specimen remains a significant challenge, despite the availability of an increasing number of antibodies. The aim of the present study was to provide evidence-based data on the diagnostic power of antibodies used frequently for clinical differential diagnostics. Methods and resultsA tissue microarray cohort comprising 940 tumour samples, of which 502 were metastatic lesions, representing tumours from 18 different organs and four non-localized cancer types, was analysed using immunohistochemistry with 27 well-established antibodies used in clinical differential diagnostics. Few antibodies, e.g. prostate-specific antigen and thyroglobulin, showed a cancer type-related sensitivity and specificity of more than 95%. A majority of the antibodies showed a low degree of sensitivity and specificity for defined cancer types. Combinations of antibodies provided limited added value for differential diagnostics of cancer types. ConclusionsThe results from analysing 27 diagnostic antibodies on consecutive sections of 940 defined tumours provide a unique repository of data that can empower a more optimal use of clinical immunohistochemistry. Our results highlight the benefit of immunohistochemistry and the unmet need for novel markers to improve differential diagnostics of cancer.
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