Levels of retinol and retinoic acid in pancreatic cancer, type-2 diabetes and chronic pancreatitis.

AIMS: Retinoids participate in multiple key processes in the human body e.g., vision, cell differentiation and embryonic development. There is growing evidence of the relationship between retinol, its active metabolite- all-trans retinoic acid (ATRA) - and several pancreatic disorders. Although low levels of ATRA in pancreatic ductal adenocarcinoma (PDAC) tissue have been reported, data on serum levels of ATRA in PDAC is still limited. The aim of our work was to determine serum concentrations of retinol and ATRA in patients with PDAC, type-2 diabetes mellitus (T2DM), chronic pancreatitis (CHP) and healthy controls. METHODS: High performance liquid chromatography with UV detection (HPLC) was used to measure serum levels of retinol and ATRA in 246 patients with different stages of PDAC, T2DM, CHP and healthy controls. RESULTS: We found a significant decrease in the retinol concentration in PDAC (0.44+/-0.18 mg/L) compared to T2DM (0.65+/-0.19 mg/L, P<0.001), CHP (0.60+/-0.18 mg/L, P< 0.001) and healthy controls (0.61+/-0.15 mg/L, P<0.001), significant decrease of ATRA levels in PDAC (1.14+/-0.49 ug/L) compared to T2DM (1.37+/-0.56 ug/L, P<0.001) and healthy controls(1.43+/-0.55 ug/L, P<0.001). Differences between early stages (I+II) of PDAC and non-carcinoma groups were not significant. We describe correlations between retinol, prealbumin and transferrin, and correlation of ATRA and IGFBP-2. CONCLUSION: Significant decrease in retinol and ATRA levels in PDAC compared to T2DM, healthy individuals and/or CHP supports existing evidence of the role of retinoids in PDAC. However, neither ATRA nor retinol are suitable for detection of early PDAC. Correlation of ATRA levels and IGFBP-2 provides new information about a possible IGF and retinol relationship.

Novel biochemical markers for non-invasive detection of pancreatic cancer.

To identify non-invasive biomarkers of non-metastatic pancreatic cancer (PC), the blood from 186 patients (PC n=28; DM-diabetes mellitus n=60; ChP-chronic pancreatitis n=47; healthy controls n=51) was analyzed for 58 candidate biomarkers. Their effectiveness to identify PC was compared with CA19-9. Panel defined by Random-forest (RF) analysis (CA19-9, AAT, IGFBP2, albumin, ALP, Reg3A, HSP27) outperforms CA19-9 in discrimination of PC from DM (AUC 0.92 vs. 0.82). Panel (S100A11, CA72-4, AAT, CA19-9, CB, MMP-7, S100P-s, Reg3A) is better in discrimination PC from ChP than CA19-9 (AUC 0.90 vs. 0.75). Panel (MMP-7, Reg3A, sICAM1, OPG, CB, ferritin) is better in discrimination PC from healthy controls than CA19-9 (AUC 0.89 vs. 0.78). Panel (CA19-9, S100P-pl, AAT, albumin, adiponectin, IGF-1, MMP7, S100A11) identifies PC among other groups better than CA19-9 (AUC 0.91 vs. 0.80). Panel defined by logistic regression analysis (prealbumin, IGFBP-2, DJ-1, MIC-1, CA72-4) discriminates PC from DM worse than CA19-9 (AUC 0.80 vs. 0.82). Panel (IGF-1, S100A11, Reg1alfa) outperforms CA19-9 in discrimination PC from ChP (AUC 0.76 vs. 0.75). Panel (IGF-2, S100A11, Reg3A) outperforms CA19-9 in discrimination PC from healthy controls (AUC 0.95 vs. 0.78). Panel (albumin, AAT, S100P-serum, CRP, CA19-9, TFF1, MMP-7) outperforms CA19-9 in identification PC among other groups (AUC 0.89 vs. 0.8). The combination of biomarkers identifies PC better than CA19-9 in most cases. S100A11, Reg3A, DJ-1 were to our knowledge identified for the first time as possible serum biomarkers of PC.

Osteopontin as a discriminating marker for pancreatic cancer and chronic pancreatitis.

INTRODUCTION: We analyzed concentrations of osteopontin (OPN) in patients with pancreatic ductal adenocarcinoma (PDAC) in order to determine firstly whether it is useful to distinguish between PDAC patients and those with chronic non-hereditary pancreatitis (CP) and type 2 diabetes mellitus (T2DM), and secondly whether OPN concentrations depend on the PDAC stage. METHODS: Groups consisting of 64 patients with PDAC, 71 with CP, 67 with T2DM and 48 healthy controls (CON) were enrolled in the study. Controls were compared with regard to levels of OPN, oxidative stress markers, conventional tumor markers and other biochemical parameters. RESULTS: Levels of OPN were higher in patients with PDAC compared with CP patients (P< 0.001), T2DM (P< 0.001) and CON (P< 0.001). There were increased OPN levels in CP patients in comparison with T2DM (P< 0.001) and CON (P< 0.001). Patients with PDAC in stage IV had higher OPN levels than PDAC patients in stage III (P< 0.01). There was no difference in OPN levels of PDAC patients in stage III compared to patients in stage II. CONCLUSION: Our pilot study demonstrates the usefulness of estimating OPN levels to differentiate between pancreatic cancer and chronic pancreatitis. Higher OPN levels over 102 ng/ml could be a potential diagnostic biomarker for pancreatic cancer.

Chronic pancreatitis and the composition of plasma phosphatidylcholine fatty acids.

Chronic pancreatitis (CP) is an irreversible inflammatory disorder characterized by the destruction of both exocrine and endocrine tissue. There is growing evidence that dysregulation of fatty acid (FA) metabolism is connected with many diseases; however, there are few data concerning FA composition in CP. Therefore, we analyzed FA profiles in plasma phosphatidylcholines in 96 patients with CP and in 108 control subjects (CON). The patients with CP had, in comparison with CON, increased sum of monounsaturated FA (ΣMUFA) and decreased content of polyunsaturated FA (PUFA) in both n-6 and n-3 families. Moreover, CP patients had increased indexes for delta-9, delta-6 desaturases, and fall in activity of delta-5 desaturase. Increased ratio of 16:1n-7/18:2n-6 (marker of essential n-6 FA deficiency), was more prevalent among CP patients. These changes implicated decreased fat intake, including n-3 as well as n-6 PUFA, and intrinsic changes in FA metabolism due to the alteration of delta desaturase activities.

[Preventing colorectal cancer]. / Prevence kolorektálního karcinomu.

Colorectal cancer is one the most frequently diagnosed cancer at the presence. The mortality can be reduced by early investigations. Screening tests are able to detect both early adenomatous polyps and cancers soon (immunochemical tests, colonoscopy and other methods virtual colonoscopy etc.).

Premalignant and malignant lesions of the heterotopic pancreas in the esophagus: a case report and review of the literature.

Heterotopic pancreas is a congenital pathology of the gastrointestinal tract, particularly rare in the esophagus. Both symptomatology and findings during preoperative examinations are non-specific and therefore do not often lead to an accurate diagnosis, which is usually revealed only by histopathological assessment of a resected specimen. We report an unusual case of a patient suffering from severe dysphagia caused by heterotopic pancreas in the distal esophagus with chronic inflammation and foci of premalignant changes. This article also reviews 14 adult cases of heterotopic pancreas in the esophagus previously reported in the literature, with the aim of determining the clinical features of this disease and possible complications including rare premalignant lesions and malignant transformation. Especially with regard to those complications, we suggest that both symptomatic and incidentally found asymptomatic lesions should be resected.

Antioxidant status and oxidative stress markers in pancreatic cancer and chronic pancreatitis.

OBJECTIVES: Oxidative stress has been implicated in the pathogenesis of chronic pancreatitis (CP) and pancreatic cancer (PC). The study aim was to assess the oxidative stress markers and antioxidant defense system in patients with CP and those with PC. METHODS: Activities of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (GPX1), glutathione reductase (GR), arylesterase (PON1-A) and lactonase (PON1-L) activities of paraoxonase 1 (PON1) and concentrations of reduced glutathione, conjugated dienes in low-density lipoprotein (CD/LDL) and oxidized LDL (ox-LDL/LDL) were assessed in 50 PC and 50 CP patients and 50 age and sex-matched controls. RESULTS: Comparison of PC and CP groups to controls found the following changes: glutathione peroxidase 1 (GPX1) (-20.2%, -25.5%; P < 0.001), glutathione reductase (GR) (-9.5%, -11.9%; P < 0.05), SOD1 (+22.9%; P < 0.01), CAT (-10.6%; P < 0.05), PON1-A (-34.3%, -16.0%; P < 0.001), PON1-L (-44.2%; -17.0%; P < 0.01), conjugated dienes in LDL (CD/LDL) (+20%, +33.3%; P < 0.05) and ox-LDL/LDL (+42.2%, +14.4%; P < 0.05). The patients with PC had changed activities and levels of SOD1 (+24.2%), CAT (-10.4); P < 0.01), PON1-A (-21.7%), PON1-L (-32.9%), and ox-LDL/LDL (+24.3%); (all P < 0.01) compared with the patients with CP. CONCLUSIONS: Reduced antioxidant defense system capacity and increased markers of oxidative stress were found in PC and CP. PON1-L and CAT activities, along with ox-LDL/LDL levels, were the independent factors differentiating the patients with PC from the patients with CP.

Plasma fatty acid composition in patients with pancreatic cancer: correlations to clinical parameters.

Pancreatic cancer (PC) ranks as the fourth cause of cancer-related deaths in the Czech Republic. Evidence exists that deregulation of fatty acid (FA) metabolism is connected with some malignancies; therefore, we decided to analyze FA profile in plasma lipid classes in patients with PC with relation to tumor staging, nutritional status, and survival. The study included 84 patients (47 males, 37 females) with PC and 68 controls (36 males, 32 females). FA patterns were analyzed in plasma lipid classes by gas-chromatography. We observed increased proportion of total monounsaturated FA (MUFA) in PC group in all plasma lipid classes. These changes were connected with increased Δ9-desaturase (SCD1) and Δ5-desaturase indices. Correlations of dihomo-γ-linolenic acid (DHGLA) with these variables were opposite. Longer survival of patients was connected with higher content of EPA, DHA, and with lower SCD1 index, respectively. Plasma phospholipid proportions of α-linolenic acid, DHGLA, EPA, and n-3 polyunsaturated fatty acids displayed negative trend with tumor staging. Plasma lipid FA pattern in PC patients resulted from decreased dietary fat intake and increased de novo synthesis of FA with transformation into MUFA. Changes in FA profile implicated some pathophysiological mechanisms responsible for disturbed FA metabolism in PC and importance of appropriate nutritional support.

Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study.

Prognosis of patients with pancreas cancer is very poor. The aim of the study was to test the significance of laboratory parameters in the prognosis of patients with pancreas cancer. The studied group included 57 patients (31 men, 26 women, mean age 65 ± 9 years). Blood was collected at the time of diagnosis of pancreas cancer and basic laboratory parameters, including nutritional and inflammatory markers and tumour markers were measured. Patients were followed up until death (median survival 147 days). Ferritin, iron, albumin, prealbumin, cholinesterase, haemoglobin, C-reactive protein, alkaline phosphatase and carcinoembryonic antigen were significant for patients' prognosis in univariate analysis while CA 19-9, bilirubin, liver, pancreas and kidney tests and lipids were not. Multivariate Cox regression demonstrated ferritin, iron and albumin as independent mortality predictors (RR (95%CI), per standard deviation: ferritin 1.497(1.215-2.241), p = 0.002; albumin, 0.716(0.521-0.977), p = 0.035; iron, 0.678(0.504-0.915), p = 0.010). Iron correlated significantly with albumin (r = 0.397, p = 0.002) but neither iron nor albumin correlated with ferritin. Patients who survived 100 days had significantly lower ferritin (median 239 µg/l vs. non-survivors 435 µg/l, p = 0.014), significantly higher albumin but the difference in serum iron was not quite significant. ROC analysis for ferritin revealed AUC for 100 days survival of 0.710, p = 0.007 (and 0.725, p = 0.004 for 200 days survival). AUC for albumin for 100 days survival was not significant (p = 0.073). This study points out ferritin as an independent mortality predictor in patients with pancreas cancer. High serum levels of ferritin at the time of diagnosis of pancreas cancer indicate bad prognosis of the patient.

[Current status of pancreatic cancer diagnosis]. / Soucasný stav diagnostiky karcinomu pankreatu.

Pancreatic cancer still remains one of the tumors with the worst prognosis. The five-year survival rate ranges between 0.4 to 2 per cent. In most cases the tumor is diagnosed at an advanced stage, which does not allow a radical surgical treatment. Currently, the diagnosis of pancreatic cancer is based on dynamically developing imaging methods that allow detecting even small lesions. The basic testing method is the contrast computed tomography which is, in most cases, linked up to the endoscopic ultrasonography. In most patients results of the cytopathological and histological examinations are obtained before surgical or oncological therapy. The decisive factor for further therapeutic approach is the tumor staging. Despite the apparent progress in diagnostic techniques, the early diagnosis of pancreatic cancer remains unsatisfactory.

[Our experience with pancreatic cancer and its relation to diabetes mellitus]. / Karcinom pankreatu--nase zkusenosti se vztahem k diabetes mellitus.

BACKGROUND: Despite the introduction of new imaging methods, the prognosis of pancreatic carcinoma (PC) remains hopeless. Therefore, there has been exerted much effort to elucidate the risk factor enabling the diagnosis of PC in the "preclinical state". At the time of PC diagnosis, more than 30% of patients suffer from diabetes mellitus, much more often than in the rest of the population. It is not clear whether DM is a risk factor for PC onset or DM appears secondary to the destruction of the gland by the tumor progression or by the effect of unknown factors produced by the cancer cells. METHODS AND RESULTS: We enrolled 204 individuals into the study, 69 of them were controls, 70 patients had type 2 diabetes mellitus and 65 cases had newly diagnosed PC. The patients with PC had in 68% of cases disturbed glucose homeostasis and significantly higher values of insulin resistance index (HOMA-IR) in comparison with the control group. The presence of glucose homeostasis disturbances does not influence tumor staging and localization. CONCLUSIONS: Results of our pilot study confirmed the so far unsatisfactory state of PC diagnostics (majority of cases fall to stages III and IV) and corroborated the close relation to DM. The early markers for the risk of pancreatic carcinoma development should be searched among the factors participating in the regulation of the glucose homeostasis and insulin sensitivity.

Soluble receptor for advanced glycation end-products (sRAGE) and polymorphisms of RAGE and glyoxalase I genes in patients with pancreas cancer.

OBJECTIVES: The receptor for advanced glycation end-products (RAGE) takes part in the pathogenesis of many diseases, including diabetes mellitus and cancer. AGE-precursors are detoxified by glyoxalase (GLO). sRAGE, soluble RAGE, is an inhibitor of pathological effects mediated via RAGE. The aim was to study sRAGE and polymorphisms of RAGE (AGER) and GLO genes in patients with pancreas cancer (PC). DESIGN AND METHODS: The studied group consisted of 51 patients with PC (34 with impaired glucose tolerance-IGT, 17 without IGT), 34 type 2 DM and 154 controls. For genetic analysis, the number of patients was increased to 170. Serum sRAGE was measured by ELISA and all polymorphisms (RAGE -429T/C, -374T/A, 2184A/G, Gly82Ser and GLO A419C) were determined by PCR-RFLP and confirmed by sequencing. RESULTS: Soluble RAGE is decreased in patients with PC compared to patients with DM and controls (975+/-532 vs. 1416+/-868 vs. 1723+/-643pg/mL, p<0.001). Patients with PC and IGT have lower sRAGE levels compared to patients with PC without IGT (886+/-470 vs. 1153+/-616pg/mL, p<0.05). No relationship of sRAGE to the stage was found. We did not show any difference in allelic and genotype frequencies in all RAGE and GLO polymorphisms among the studied groups. CONCLUSION: This is the first study demonstrating decreased sRAGE in patients with pancreas cancer. Its levels are even lower than in diabetics and are lowest in patients with PC and IGT. Our study supports the role of glucose metabolism disorder in cancerogenesis. Further studies are clearly warranted, especially with respect to potential preventive and therapeutic implications.

Spontaneous bacterial peritonitis in the Czech Republic: prevalence and aetiology.

The aim of the study was to determine the prevalence and detailed data concerning the incidence of spontaneous bacterial peritonitis in the Czech Republic. Ninety-nine patients with liver cirrhosis and ascites were examined. Spontaneous bacterial peritonitis was diagnosed in 35 patients (35.4%). It was revealed more often in patients with alcoholic aetiology of cirrhosis whose anamnesis involved sub-febrile or febrile states and the deterioration of ascites. Elevated serum leucocyte counts and increased levels of C-reactive protein can contribute to the diagnosis. A low level of total protein and albumin in ascites predisposes to the increase of this infection. The reduction of the platelet count in a set of patients with spontaneous bacterial peritonitis indicates the influence of portal hypertension in the aetiology of the disease.