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Background: Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) are proteins that belong to the IGF axis, which is involved in glucose and lipid metabolism and may as well promote carcinogenesis., Goals: The aim of this study was to evaluate the serum concentration levels of IGF-1 and IGFBP-2 in patients with newly diagnosed pancreatic adenocarcinoma (PDAC) to verify their possible role in the diagnosis of the disease., Study: The study included 69 patients with PDAC and 20 healthy controls. The concentrations of IGF-1 and IGFBP-2 were estimated by means of ELISA. The study protocol was approved by the Bioethics Committee at the Medical University of Lodz in Poland., Results: PDAC patients compared with controls have a significantly lower mean serum IGF-1 level (45.83±30.03 vs. 70.66±60.57 ng/mL; P<0.0001). In contrast, in PDAC patients, the mean IGFBP-2 level was significantly higher compared with the control group (225.06±86.37 vs. 51.92±29.40 ng/mL; P<0.0001). The results show that, at the 0.01 sensitivity level, the IGF-1/IGFBP-2 ratio <0.85 points indicates PDAC presence. At this level of sensitivity, the test has a specificity of 0.097 (α=0.01; β=0.097; IGF-1/IGFBP-2≤0.85)., Conclusions: Our results show that IGF-1 to IGFBP-2 ratio ≤0.85 may be a powerful PDAC indicator. Further studies in this area in a larger patient group are necessary to confirm our findings.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. Several cytokines, such as activin A and myostatin, ligands of the transforming growth factor-β superfamily, have been shown to influence the pathogenesis of muscle wasting and tumor progression. The aim of our study was to assess the clinical significance of these cytokines in patients with different stages of PDAC. The study included 93 patients: 73 with newly diagnosed PDAC and 20 healthy volunteers as the control group. PDAC patients included 42 diagnosed with non-metastatic pancreatic cancer (stage I - III) and 31 patients with metastatic cancer (stage IV). The peripheral venous blood samples were collected from each patients at the time of cancer diagnosis and plasma concentrations of activin A and myostatin have been measured with an enzyme-linked immunoassay. Forty five patients (61.6%) presented weight loss > 5%, including 24 (57.1%) with stage I - II and 21 (67.7%) with metastatic PDAC (P > 0.05). Plasma levels of activing A were significantly higher in metastatic PDAC patients compared with stage I - III PDAC patients and control group (P < 0.01). The relationship between higher activin A levels and weight loss was also observed (P < 0.05). On the other hand, myostatin was not associated with weight loss in analysed group of patients. In conclusion, the current study demonstrates that high activin A plasma levels at the time of PDAC diagnosis is associated with unintentional weight loss and may be an useful biomarker for identifying patients with metastatic disease. However, further prospective studies are needed to fully explore the clinical significance of myostatin in pathogenesis of progressive weight loss in PDAC patients.

Introduction: Barrett's esophagus (BE), which develops as a result of gastroesophageal reflux disease, is a preneoplastic condition for esophageal adenocarcinoma (EAC). A new hypothesis suggests that cancer is a disease of stem cells, however, their expression and pathways in BE - EAC sequence are not fully elucidated yet., Aims: We used a panel of putative cancer stem cells markers to identify stem cells in consecutive steps of BE-related cancer progression., Methods: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded blocks from 58 patients with normal cardiac mucosa (n=5), BE (n=14), early EAC (pT1) from mucosal resection (n=17) and advanced EAC (pT1-T4) from postoperative specimens (n=22). Expression of the CD133, CD44, Musashi-1 and EpCAM was analyzed using respective monoclonal antibodies., Results: All markers showed a heterogeneous expression pattern, mainly at the base of the crypts of Barrett's epithelium and EAC, with positive stromal cells in metaplastic and dysplastic lesions. Immuno-expression of EpCAM, CD44 and CD133 in cardiac mucosa was significantly lower (mean immunoreactivity score (IRS)=1.2; 0.0; 0.4; respectively) compared to their expression in Barrett's metaplasia (mean IRS=4.3; 0.14; 0.7; respectively), in early adenocarcinoma (mean IRS=4.4; 0.29; 1.3; respectively) and in advanced adenocarcinoma (mean IRS=6.6; 0.7; 2.7; respectively) (p<0.05). On the contrary, Musashi-1 expression was higher in BE and early ADC compared to GM and advanced ADC (NS)., Conclusion: Our results suggest that the stem cells could be present in premalignant lesions. EpCAM, CD44 and CD133 expression could be candidate markers for BE progression, whereas Musashi-1 may be a marker of the small intestinal features of Barrett's mucosa., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Background/aims: Esophageal adenocarcinoma (ADC) incidence has been increasing dramatically in the past 3 decades despite the surveillance programs in patients with Barrett’s esophagus (BE). Therefore, markers of early neoplastic progression are required to predict of cancer risk in BE patients. The aim of this study was to investigate the frequency of Her2/neu amplification in different stages during Barrett’s-related carcinogenesis., Methodology: Her2/neu amplification analysis in 39 patients with gastroesophageal reflux disease (GERD), in 34 with BE, in 11 with dysplasia and 13 with ADC were performed with PCR., Results: Her2/neu amplification was detected in 8% (3/39) GERD patients, 15% (5/34) with BE, 41% (7/17) with dysplasia and in 54% (7/13) with ADC. We observed an increasing trend in the frequency of Her2/neu alteration between BE-carcinogenesis stages (p=0.001). This finding was confirmed in the logistic regression analysis showing gradient in odds ratios between BE (2.07; 95% CI: 0.46-9.39), dysplasia (8.4; 95% CI: 1-83-38.53) and ADC (14.0; 95% CI: 2.81-69.69) compared to GERD; it was even higher after adjustment for age and gender., Conclusions: Her2/neu alterations may occur early and increasingly during Barrett’s malignant progression. We suggest that it may be useful to stratify the risk of adenocarcinoma in patients with Barrett’s esophagus.

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Vascular endothelial growth factor (VEGF) is necessary for microvasculature development and important for growth and spread of pancreatic tumors. Functional polymorphism of VEGF gene at position C-460T and G+405C may influence VEGF serum level. VEGF gene polymorphisms at position C-460T and G+405C were evaluated in 85 patients with pancreatic adenocarcinoma (PA), 72 - with chronic pancreatitis (CP) and 50 healthy volunteers. VEGF genotypes were studied in DNA isolated from blood samples and serum VEGF concentrations were measured. We found an increased frequency of the homozygous +405C/C VEGF genotype in patients with PA (55.3%) compared with CP (25%) and control group (16%; p<0.01). In contrast, the distribution of genotype and allele frequencies of the -460C/T polymorphism in the PA patients did not differ from those in CP and control groups. Serum levels of VEGF were significantly higher in PA patients (mean level: 441 ± 37.2 pg/ml) compared with CP patients (217 ± 13.6 pg/ml; p<0.001) and control group (137 ± 7.7 pg/ml; p<0.001). No relationship between VEGF serum levels and VEGF gene polymorphisms have been found. Our findings suggest that +405C/C VEGF genotype may contribute to pancreatic carcinogenesis. VEGF serum levels, although elevated in PA patients, are not associated with analysed VEGF polymorphisms.

Background: Neopterin and tissue polypeptide-specific antigen (TPS) have been suggested to be useful in differential diagnosis between pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The aim of our study was to compare the clinical usefulness of CA19-9, neopterin and TPS serum levels in patients with PA and CP., Methods: The study included 85 patients with PA, 72 with CP and 50 healthy controls. The serum concentrations of neopterin, TPS and CA19-9 were measured (DRG International, USA). The associations of the analyzed markers and clinical data at diagnosis have been evaluated., Results: Serum levels of neopterin, TPS and CA19-9 were higher in PA patients compared to CP (p < 0.001). TPS and CA19-9 levels were also elevated in patients with CP compared to the control group (p < 0.001). In contrast, there was no difference between neopterin serum levels in CP patients and the control group (p > 0.05). Neopterin showed the best sensitivity and specificity (91.8 and 87.5%) in PA diagnosis compared to CA19-9 (respectively 83.5 and 75%) and TPS (75.3 and 65.3%)., Conclusion: Our results indicate that neopterin may be potentially useful in differential diagnosis between PA and CP. Assessment of TPS probably adds no significant information to that obtained with CA19-9 and neopterin. and IAP., (Copyright © 2011 S. Karger AG, Basel.)

The aim of our study was to assess the clinical significance of -174G/C Il-6 gene polymorphism and Il-6 serum level in patients with pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The study included 41 with pancreatic adenocarcinoma, 56 with chronic pancreatitis, and 50 healthy volunteers, hospitalized between 2003 and 2006. Il-6 serum levels were measured with an enzyme-linked immunoassay and Il-6 gene polymorphism was studied in DNA isolated from peripheral blood. In PA and CP patients Il-6 serum levels were significantly higher than in the control group (P < 0.01). The levels of Il-6 in the patients with tumor size >or=3.5 cm were higher than that in patients with smaller tumors (P < 0.01). The elevated Il-6 levels were also correlated with the presence of liver metastases (P < 0.01). Mean Il-6 serum level was significantly higher in patients homozygous G/G for -174 Il-6 gene compared with patients with at least one C allele. Our findings indicate that -174G/C Il-6 gene polymorphism influences circulating Il-6 levels. Increased Il-6 serum levels may be correlated with tumor size and the presence of liver metastases in patients with pancreatic adenocarcinoma.

Several biochemical pathways can lead to cancer cachexia, one of which involves the elevation of the cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interferon gamma (INF-gamma). It was suggested that TNF-alpha and INF-gamma genes polymorphisms may influence these cytokines serum levels, but published data are still controversial. The aim of our study was to assess the clinical significance of -308G/A TNF-alpha and +874A/T INF-gamma genes polymorphisms as well as TNF-alpha and INF-gamma serum levels in pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP) as regards to healthy volunteers. We studied 41 patients with pancreatic adenocarcinoma, 56 with chronic pancreatitis and 50 healthy volunteers. Peripheral venous blood samples were obtained from all patients for TNF-alpha and INF-gamma serum concentrations measurement. After DNA isolation TNF-alpha and INF-gamma genes polymorphisms have been studied using restriction fragment length polymorphism (RFLP) analysis. Plasma levels of TNF-alpha were significantly higher in PA patients (32.7 pg/ml) compared with CP patients (3.2 pg/ ml) and control group (<1.6 pg/ml; p<0.01). Similarly, plasma levels of INF-gamma in PA patients (12.7 pg/ml) were higher from those in CP and control group (<7.1 pg/ml; p<0.01). In contrast, there were no differences between CP patients and healthy volunteers in INF-gamma levels. We observed a trend toward a correlation between weight loss in PA patients and TNF-alpha serum level (p=0.02). The TNF-alpha and INF-gamma genotype distribution were similar in patients with PA, CP and control group. We have not observed any association between TNF-alpha and INF-gamma serum levels and their genes polymorphisms. Our results suggest that elevated TNF-alpha serum level may have clinical significance in the development of cachexia in PA patients. -308G/A TNF-alpha and +874A/T INF-gamma genes polymorphisms probably do not play important role in pancreatic diseases. Key words: pancreatic adenocarcinoma, tumor necrosis factor alpha, interferon gamma, cytokines, polymorphism.

Despite scientific efforts and significant progress in understanding the basic cellular event in pancreatic adenocarcinoma (PA), survival rates have not changed much during the last 20 years. Prognosis in pancreatic cancer remains unsatisfactory due to its late clinical presentation, low surgical resectability rates, and resistance to chemotherapy. Novel therapeutic strategies are needed in order to improve the prognosis of patients with PA. Improvement of our knowledge of the molecular biology of pancreatic cancer may have important clinical implications in pancreatic cancer risk assessment, early diagnosis, and management. In human pancreatic cancer, a specific sequence of oncogene and tumor suppressor gene alterations is observed, including K-ras, HER-2/neu, p16, p53, and DPC4. The prevalence of these genetic alterations rises with increasing severity of dysplasia of the ductal mucosal lesions. Drugs that target these molecular abnormalities hold great promise for PA treatment in the near future. The focus of this review is to evaluate the gene mutations in pancreatic cancer, with emphasis on those studies that are most important to the clinical practice. Our review also summarizes current aspects of PA treatment and the differential diagnosis of pancreatic cancer and chronic pancreatitis.

Background/aims: Pancreatic adenocarcinoma (PA) has a very poor prognosis. In patients suffering from chronic pancreatitis (CP) the risk for the PA development is higher than in the general population. The purpose of the study was to compare the prevalence of p53 mutations in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases., Methodology: We examined 49 patients who underwent Whipple resection or distal pancreatectomy for pancreatic adenocarcinoma (26 subjects) or chronic pancreatitis (23 subjects). DNA from pancreatic tissue was analyzed for p53 mutations with PCR/SSCP methods., Results: The p53 gene mutation has been shown in 16 (61.5%) of the PA patients (9 in exon 5 and 7 in exon 7) and in 2 (8.6%) of CP patients (1 in exon 5 and 1 in exon 8; p < 0.001). There was a significant correlation between p53 mutation and G3 tumor differentiation (p < 0.01). Overall median survival in patients with PA was 8.5 months. No relationship between presence of p53 mutation and survival time in PA patients has been observed., Conclusions: The specificity of p53 mutation for pancreatic cancer is very high. Our results indicate that p53 gene mutation may provide an additional tool in differential diagnosis of CP and PC.

Background: The differentiation of chronic pancreatitis (CP) from pancreatic adenocarcinoma (PA) remains the great challenge for clinicians. The purpose of this study was to compare the prevalence of K-ras and c-erbB-2 mutations in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases., Methods: The study included 49 patients who underwent Whipple resection or distal pancreatectomy for pancreatic adenocarcinoma (26 subjects) or chronic pancreatitis (23 subjects). DNA from pancreatic tissue was analyzed for K-ras codon 12 and c-erbB-2 mutations with PCR amplifications., Results: The K-ras gene mutation has been shown in 20 (76.9%) PA cases and in 8 (34.8%) CP cases (p<0.01). Prevalence of c-erbB-2 amplification in patients with PA was 17 (65.3%), which was not different from CP, 16 (56.5%) (p=0.58). There was a significant correlation between K-ras mutation and lymph node metastases (p=0.025) as well as between K-ras mutation and G3 tumor differentiation (p=0.037). Overall median survival in patients with PA was 9.5 mo. There was no relationship between presence of K-ras (p=0.58) or c-erbB-2 (p=0.17) mutation and survival time in PA patients., Conclusion: Those results may indicate that both K-ras and c-erbB-2 play a role in pancreatic carcinogenesis, however only K-ras may provide an additional tool in differential diagnosis of CP and PC.

Background: The differentiation of chronic pancreatitis (CP) from pancreatic adenocarcinoma (PA) remains a great challenge. The purpose of the study was to compare the prevalence of p16 and K-ras mutation in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases., Methods: The study included 44 patients who underwent Whipple resection or distal pancreatectomy for PA (23 subjects) or CP (21 subjects). DNA from pancreatic tissue was analysed for K-ras mutation (codon 12) and p16 mutations with PCR amplifications., Results: The K-ras gene mutation has been shown in 17 (73,9%) cases with pancreatic adenocarcinoma which was significantly more often than in chronic pancreatitis - 9 (42,8%) (p<0,01). Prevalence of p16 mutations in patients with PA was 18 (78,3%) and with CP - 7 (33,3%) (p<0,01). K-ras and p16 mutations together have been observed in 16 (69,6%) cases in patients with PC and only in 3 (14,3%) - with CP (p<0,01). No statistically significant association between K-ras or p16 mutations and tumor size, sex or patient age has been observed., Conclusion: It is suggested that simultaneous measurement of K-ras and p16 mutations may provide an additional tool in differential diagnosis of chronic pancreatitis and pancreatic adenocarcinoma.

Background/aims: Tyrosine kinase and a number of growth factors, especially EGF and TGF-alpha are known to stimulate proliferation in much of the gastrointestinal tract, including colon. In humans increased colonic mucosal proliferative activity has been observed in numerous premalignant lesions including adenomatous polyps and ulcerative colitis. The aim of the present study was to determine the differences of proliferative patterns in patients with adenomatous polyps, ulcerative colitis and colonic adenocarcinoma as reflected by rectal mucosa tyrosine kinase, EGF receptor tyrosine kinase and PCNA and to evaluate the role of tyr-k in colonic mucosal cell proliferation during carcinogenic process., Materials and Methods: The study population comprised 40 patients, aged 17-74 years (mean 57), in which 10 patients had adenomatous polyps, 10-ulcerative colitis in remission phase, 10- colon adenocarcinoma and 10 healthy controls. After informed consent 6-8 rectal mucosal biopsy specimen were obtained at 10 cm from the anal verge at the beginning of the colonoscopy examination and at least 10 cm away from any macroscopic mucosal changes., Results: Mean PCNA labeling indices in patients with colon adenocarcinoma, adenomatous polyps, ulcerative colitis ulcerosa and healthy controls were respectively: 27.6% +/- 5.75; 12.18% +/- 6.76; 10.9% +/- 5.34 and 1.5% +/- 0.97. PCNA labeling index in rectal mucosa of patients with adenomatous polyps, ulcerative colitis and colon cancer was significantly higher (p < 0.01) than in the control group. An upward expansion of the proliferative compartment was also observed in patients with premalignant and malignant colon conditions as regards to the control group. Total tyrosine kinase activity in the rectal mucosa of patients with polyps was elevated by 219%, with ulcerative colitis by 224% and with colorectal carcinoma by 600% as regards to the control group. EGF receptor tyrosine kinase was increased in colonic mucosa by 35.2% in patients with adenomatous polyps, by 40.6% in patients with ulcerative colitis and by 123% in patients with colon cancer., Conclusions: Increased values of this enzyme in the above mentioned group of patients may suggest that tyrosine phosphorylation represents an early sign of colonic mucosa susceptibility for cancer development. We conclude, that overall an EGF receptor-associated tyrosine kinase plays an important role in the development of hyperproliferative state of the colonic mucosa and colon carcinogenesis.