BackgroundSeveral 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.ResultsHigh 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 (pinteraction =0.012, 0.009 and 0.007, respectively) and for FoxP3+ with IGKC+ cells (pinteraction =0.034). In esophageal tumors, there was only a significant interaction for CD3+ and CD20 + cells (pinteraction =0.028).MethodsImmunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3+, CD8+, FoxP3+) and NK cells (NKp46+) in chemoradiotherapy-naïve 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).ConclusionsThese 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.

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.

IntroductionThe 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 methodsImmunohistochemical 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.ResultsPIGR 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.ConclusionHigh 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.

BackgroundPancreatic 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.MethodsImmunohistochemical 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).ResultsPositive 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0289-8) contains supplementary material, which is available to authorized users.

BackgroundThere 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.MethodsTissue 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.ResultsExpression 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).ConclusionsIFITM1 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40364-016-0064-5) contains supplementary material, which is available to authorized users.

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.

Introduction: The polymeric immunoglobulin receptor (PIGR) is a member of the immunoglobulin superfamily and key component of the mucosal immune system that mediates epithelial transcytosis of polymeric immunoglobulins. High PIGR expression has been reported to correlate with a less aggressive tumor phenotype and favorable prognosis in e.g. gastro-esophageal, colon, urinary bladder and ovarian cancer, and with a greater metastatic potential and poor prognosis in hepatitis B-derived hepatocellular carcinoma, PIGR has recently been demonstrated to be up-regulated in pancreatic cancer cells upon exposure to stromal cells in vitro, but its expression and prognostic significance in human pancreatic cancer has not yet been reported. The aim of the present study was therefore to examine the longitudinal expression and prognostic significance of PIGR in a large consecutive series of pancreatic and periampullary adenocarcinoma. Material and Methods: The study cohort encompasses a consecutive series of 175 patients surgically treated by means of pancreaticoduodenectomy for pancreatic and periampullary adenocarcinomas in the University hospitals of Malmö and Lund, Sweden, from January 1, 2001 to December 31, 2011. Tissue microarrays were constructed from all primary tumors (n =175) and paired lymph node metastases from 105 cases. PIGR was expressed in the cytoplasm and both the staining intensity and fraction of positive cells was denoted. For statistical purposes, a multiplier of the fraction and intensity of staining was applied. Mann Whitney U test was applied for analysis of PIGR expression in relation to clinicopathological characteristics. Classification and regression tree analysis was used for selection of prognostic cut-off. The impact of PIGR expression on 5-year overall survival (OS) and hazard ratios (HR) was calculated by adjusted and unadjusted Cox proportional hazards modeling. Results: PIGR expression could be evaluated in 172/175 (98.3%) of the primary tumors and in 96/105 (91.4%) lymph node metastases. High PIGR expression was significantly associated with more well differentiated tumors (p=&lt;0.001), and inversely associated with perineural growth (p=0.016), lymphatic invasion (p=0.010), vascular invasion (p=0.027) and infiltration of the peripancreatic fat (p=0.024). PIGR expression was significantly down regulated in lymph node metastases as compared to primary tumors (p=0.018). High PIGR expression was significantly associated with a prolonged 5-year survival (unadjusted HR 0.21, 95% CI 0.09-0.48, p=&lt;0.001) and this association remained significant after adjustment for T-stage, N-stage, tumor size, tumor grade, perineural growth, invasion in lymphatic vessels, invasion in blood vessels, growth in peripancreatic fat, involved margins, age and sex (HR 0.27, 95% CI 0.12-0.63, p=0.002). Conclusion: The results from this study demonstrate, for the first time, that high PIGR expression is associated with a more favorable tumor phenotype and is an independent marker of improved prognosis in pancreatic and periampullary cancer. The observed down regulation of PIGR expression in lymph node metastases as compared with primary tumors further supports a tumor suppressing role for PIGR in these cancers. These findings are of potential clinical relevance and warrant confirmation in additional patient cohorts. In addition, elucidating the mechanistic basis for the role of PIGR in tumor progression, with particular reference to the interplay of tumor cells and stroma, remains an intriguing challenge for future functional work. Citation Format: Richard Fristedt, Jacob Elebro, Alexander Gaber, Björn Nodin, Mathias Uhlén, Karin Jirström. High expression of PIGR is an independent favorable prognostic factor in pancreatic and periampullary adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B30.

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