Serum Metabolite Biomarkers for Pancreatic Tumors: Neuroendocrine and Pancreatic Ductal Adenocarcinomas-A Preliminary Study.

BACKGROUND: Pancreatic cancer is the most common pancreatic solid malignancy with an aggressive clinical course and low survival rate. There are a limited number of reliable prognostic biomarkers and a need to understand the pathogenesis of pancreatic tumors; neuroendocrine (PNET) and pancreatic ductal adenocarcinomas (PDAC) encouraged us to analyze the serum metabolome of pancreatic tumors and disturbances in the metabolism of PDAC and PNET. METHODS: Using the AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) with liquid chromatography-mass spectrometry (LC-MS), we identified changes in metabolite profiles and disrupted metabolic pathways serum of NET and PDAC patients. RESULTS: The concentration of six metabolites showed statistically significant differences between the control group and PDAC patients (p.adj < 0.05). Glutamine (Gln), acetylcarnitine (C2), and citrulline (Cit) presented a lower concentration in the serum of PDAC patients, while phosphatidylcholine aa C32:0 (PC aa C32:0), sphingomyelin C26:1 (SM C26:1), and glutamic acid (Glu) achieved higher concentrations compared to serum samples from healthy individuals. Five of the tested metabolites: C2 (FC = 8.67), and serotonin (FC = 2.68) reached higher concentration values in the PNET serum samples compared to PDAC, while phosphatidylcholine aa C34:1 (PC aa C34:1) (FC = -1.46 (0.68)) had a higher concentration in the PDAC samples. The area under the curves (AUC) of the receiver operating characteristic (ROC) curves presented diagnostic power to discriminate pancreatic tumor patients, which were highest for acylcarnitines: C2 with AUC = 0.93, serotonin with AUC = 0.85, and PC aa C34:1 with AUC = 0.86. CONCLUSIONS: The observations presented provide better insight into the metabolism of pancreatic tumors, and improve the diagnosis and classification of tumors. Serum-circulating metabolites can be easily monitored without invasive procedures and show the present clinical patients' condition, helping with pharmacological treatment or dietary strategies.

Endoscopic findings in the upper gastrointestinal tract in patients with Crohn's disease are common, highly specific, and associated with chronic gastritis.

Crohn's disease (CD) may affect the entire gastrointestinal tract including its upper part. However, this aspect is poorly addressed in scientific literature and considered a rare finding. Here we aimed to prospectively investigate the prevalence, characteristics and clinical significance of upper gastrointestinal tract involvement in patients with CD, with particular focus on stomach bamboo joint-like appearance (BJA), Helicobacter pylori status and presence of microscopic changes. 375 prospectively recruited patients were included. In CD patients the prevalence of gastric and duodenal, but not esophageal, mucosal lesions, such as gastric mucosal inflammation, duodenal edema, ulcerations, and duodenal bulb deformation was significantly higher (at least p < 0.01 for all). Similar results were found when only H. pylori negative individuals were analyzed. Moreover, BJA of the stomach and in case of H. pylori negative patients also duodenal bulb deformation were detected exclusively in CD patients. Presence of BJA lesion was not significantly associated with neither duration of the disease nor use/history of biologic treatment. Despite absence of H. pylori infection microscopic features of chronic gastritis were found in almost all (93.5%) patients, and in 31% of controls (p < 0.00001). Our analysis outlines that upper gastrointestinal tract involvement in CD is a very common event and frequently manifests with a highly specific BJA lesion. Furthermore, our study reveals that in almost all CD patients features of H. pylori negative gastritis are present.

Impact of Selected Serum Factors on Metastatic Potential of Gastric Cancer Cells.

(1) Background: stromal-derived factor-1 (SDF-1/CXCL12), hepatocyte and vascular-endothelial growth factors (HGF and VEGF) have been shown to facilitate cell motility, proliferation and promote local tumor progression and metastatic spread. Recent research shows the important role of these cytokines in gastric cancer (GC) progression. (2) Methods: 21 gastric cancer patients and 19 healthy controls were included in the study. SDF-1, HGF and VEGF levels were evaluated in sera by ELISA. Patients and control sera were used to stimulate CRL-1739 GC cell line, and chemotaxis, adhesion and proliferation potential were assessed. (3) Results: Concentrations of SDF-1, HGF and VEGF were significantly higher in patients than in controls. Chemotaxis and adhesion assays revealed a significant response of GC cells to patients' serum. Furthermore, significant relationships were seen between chemotactic/adhesion response and tumor stage. Serum from intestinal early GC patients produced significantly stronger chemotactic response when compared to patients with metastatic spread. In turn, serum from patients with distal metastases significantly increased the adhesion of GC cells when compared to sera from the patients with no distal metastases. We also observed that HGF strongly stimulated the proliferation of CRL-1739 cells. (4) Conclusions: We observed that the sera from GC patients, but also SDF-1, HGF and VEGF used alone, have a strong pro-metastatic effect on CRL-1739 cells. We also demonstrated that the concentration of these cytokines is specifically elevated in the sera of patients in an early stage of malignancy. Our results indicate that SDF-1, HGF and VEGF are very important molecules involved in gastric cancer progression.

Lipoxins and Resolvins in Patients With Pancreatic Cancer: A Preliminary Report.

Eicosanoids are bioactive lipids derived from arachidonic acid, which have emerged as key regulators of a wide variety of pathophysiological processes in recent times and are implicated as mediators of gastrointestinal cancer. In this study, we investigated the systemic levels of lipoxygenase (LOX)-derived lipoxin A4 and B4, together with resolvin D1 and D2 in patients with pancreatic adenocarcinoma (n = 68), as well as in healthy individuals (n = 32). Systemic concentrations of the aforementioned immunoresolvents were measured using an enzyme-linked immunosorbent assay (ELISA). In this study, we observed that compared with concentrations in healthy individuals, the peripheral concentrations of the aforementioned eicosanoids were significantly elevated (2- to 10-fold) in patients with pancreatic cancer (in all cases p<0.00001). No significant association was observed between eicosanoid levels and the TNM clinical staging. Furthermore, we observed no significant differences in concentrations of the analyzed bioactive lipids between patients diagnosed with early-stage (TNM stage I-II) and more advanced disease (TNM stage III-IV). Receiver operating characteristic (ROC) curve analysis of each aforementioned immunoresolvent showed area under the curve values ranging between 0.79 and 1.00. Sensitivity, specificity, as well as positive and negative predictive values of the eicosanoids involved in the detection/differentiation of pancreatic adenocarcinoma ranged between 56.8% and 100%. In summary, our research is the first study that provides clinical evidence to support a systemic imbalance in LOX-derived lipoxins and resolvins as the mechanism underlying the pathogenesis of pancreatic adenocarcinoma. This phenomenon occurs regardless of the clinical TNM stage of the disease. Furthermore, our study is the first to preliminarily highlight the role of peripheral levels of immunoresolvents, particularly resolvin D1, as potential novel biomarkers of pancreatic cancer in humans.

Cerebral venous sinus thrombosis in a young patient with ulcerative colitis: A case report.

RATIONALE: Cerebral venous sinus thrombosis (CVST) represents one of the most alarming forms of hemostatic abnormalities that may occur in patients with inflammatory bowel diseases (IBDs). PATIENT CONCERNS: Here we report a case of a 25-year-old male with ulcerative colitis, who developed such thromboembolic complication during flare of the disease. CVST in our patient was clinically manifested by headache and nausea. DIAGNOSIS: Angio-magnetic resonance imaging scan of the head revealed segments of contrast filling defects/absence indicating right dural venous sinus thrombosis of the transverse sinus. INTERVENTION: Immediate treatment with low-molecular-weight heparin has been introduced and led to full remission of symptoms and total recanalization of the thrombotic cerebral regions. OUTCOMES: Currently (over 2 years after diagnosis) the patient is in remission of the disease, and no further thromboembolic complications have been observed. LESSONS: Our case study highlights the clinical difficulties and challenges associated with diagnosis and treatment of CVST, as well as presents the current state of knowledge about this complication among patients with IBDs. Physicians taking care of IBD patients should be aware of this alarming hemostatic abnormality.

Hydroxyeicosatetraenoic acids in patients with pancreatic cancer: a preliminary report.

Previous experimental reports have demonstrated that lipoxygenase (LOX) derivatives of arachidonic acid (AA), such as hydroxyeicosatetraenoic acids (HETEs), may be of significance in the pathogenesis of pancreatic cancer. However, these observations have not been confirmed in clinical studies. In the current study, we comprehensively evaluated the systemic levels of selected LOX-derived HETEs such as 5-, 12- and 15-HETE in patients with pancreatic adenocarcinoma (n=36), chronic pancreatitis (n=39), and in healthy individuals (n=35). Compared to healthy individuals, patients with pancreatic adenocarcinoma showed 3-8-fold higher levels of 5-, 12- and 15-HETE (at least P<0.003). Similar results were observed in patients with chronic pancreatitis, who had elevated concentrations of all examined HETE acids compared to healthy volunteers (in all cases at least P<0.03). Interestingly, the levels of the examined HETEs were not significantly associated with the TNM stage of pancreatic cancer in our patients. Finally, analyses of receiver operating characteristic curves demonstrated that all HETEs examined had relatively low area under the curve values for discriminating pancreatic adenocarcinoma from non-cancerous conditions (0.49-0.61; P>0.05 in each case). Our study provides first preliminary clinical evidence for the significance of the examined HETEs in the clinical pathogenesis of pancreatic cancer and other pancreatic diseases in humans. Moreover, our data demonstrate that the HETEs examined here do not show sufficient clinical potential to be used as independent (bio)markers for differentiating pancreatic adenocarcinoma from other non-cancerous conditions in humans.

Expression of Cancer Testis Antigens in Colorectal Cancer: New Prognostic and Therapeutic Implications.

Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study. We selected a panel of 18 CTAs that were previously detected in CRC as well as some new gene candidates, and their expression was detected at the mRNA level by employing RQ-PCR. Additionally, we evaluated CTA expression in three colon cancer cell lines (CL-188, HTB-39, and HTB-37) after exposure to the DNA methylation-modifying drug 5-azacytidine. Results. We report that 6 out of 18 (33%) CTAs tested (MAGEA3, OIP5, TTK, PLU1, DKKL1, and FBXO39) were significantly (p < 0.05) overexpressed in tumor tissue compared with healthy colon samples isolated from the same patients. Conclusions. Moreover, we found that MAGEA3, PLU-1, and DKKL expression positively correlated with disease progression, evaluated according to the Dukes staging system. Finally, 5-azacytidine exposure significantly upregulated expression of CTAs on CRC cells, which indicates that this demethylation agent could be employed therapeutically to enhance the immune response against tumor cells.

[The restoration of hand functions after irreparable injury of the radial nerve].

Introduction: The aim of our study was to evaluate the methods used and results achieved for the restoration of function of the hands in patients with irreparable injury to the radial nerve. Materials and methods: We studied the type and number of methods used for the restoration of mobility function of the hands by tendon transfer of active muscle to affected muscle. Moreover, we implemented rehabilitation treatment in patients with irreparable injury to the radial nerve. Descriptions of the treatment were presented in 6 scientific reports published between 1996 and 2015. The available literature presents the results of the treatment of 129 patients with irreparable injury to the radial nerve. Results: The restoration activities of patients' hand function was most frequently done by tendon transfer, i.e. the pronator teres muscle on the extensor carpi radialis brevis in 100 (72.5%) patients, the palmaris longus muscle on the extensor pollicis longus in 88 (68.2%) patients, and the flexor carpii ulnaris muscle on the extensor digitorum communis in 99 (76.7%) patients. During the pre- and postoperative period rehabilitation treatment played a crucial role in the restoration of patients' hand functions. Conclusion: All patients regained a complete or almost complete extension of the wrist and fingers. The strength of the hands was generally satisfactory. The dexterity of the hands in the majority of the studied patients was very good or good.

An Attempt to Evaluate Selected Aspects of "Bone-Fat Axis" Function in Healthy Individuals and Patients With Pancreatic Cancer.

Recently, much attention has been paid to a potential biochemical cross-talk between the metabolism of the adipose tissue (AT) and bone (marrow), termed "bone-fat axis." We hypothesized that selected substances, participating in this "dialog," are associated with body mass and peripheral trafficking of bone marrow-derived stem cells (BMSCs) in both healthy individuals and patients with obesity-associated malignancies such as pancreatic adenocarcinoma.We performed an analysis of the systemic levels of selected substances involved in the regulation of bone (marrow) homeostasis (parathormone, calcitonin, osteopontin, osteonectin, stem cell factor [SCF], and fibroblast growth factor-23) in 35 generally healthy volunteers and 35 patients with pancreatic cancer. Results were correlated with the absolute number of circulating BMSCs and body mass values. Additionally, subcutaneous and visceral/omental AT levels of the aforementioned molecules were analyzed in lean and overweight/obese individuals.Intensified steady-state trafficking of only Lin-CD45 + CD133 + hematopoietic stem/progenitor cells was observed in overweight/obese individuals and this was associated with BMI values and elevated levels of both osteonectin and SCF, which also correlated with BMI. In comparison to healthy individuals, patients with cancer had significantly higher osteopontin levels and lower values of both osteonectin and osteonectin/osteopontin ratio. While no significant correlation was observed between BMI and the number of circulating BMSCs in patients with cancer, peripheral trafficking of CD34 + KDR + CD31 + CD45-endothelial progenitor cells and CD105 + STRO-1 + CD45-mesenchymal stem cells was associated with the osteonectin/osteopontin ratio, which also correlated with BMI (r = 0.52; P < 0.05). AT levels of the examined substances were similar to those measured in the plasma, except for osteonectin, which was about 10 times lower.Our study highlights the potential role of osteonectin, osteopontin, and SCF as communication signals between the bone (marrow) and AT in both healthy individuals and patients with pancreatic cancer. We postulate that these molecules may be overlooked biochemical players linking body mass and BMSCs with obesity-associated cancer development and/or progression in humans.

Selected cytokines in patients with pancreatic cancer: a preliminary report.

BACKGROUND/AIMS: Recent experimental studies have suggested that various cytokines may be important players in the development and progression of pancreatic cancer. However, these findings have not yet been verified in a clinical setting. METHODS: In this study, we examined the levels of a broad panel of cytokines, including interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, IL-17, and IL-23, as well as tumor necrosis factor alpha (TNFα) and granulocyte-colony stimulating factor (G-CSF) in patients with pancreatic adenocarcinoma (n=43), other pancreatic malignancies (neuroendocrine [n=10] and solid pseudopapillary tumors [n=3]), and healthy individuals (n=41). RESULTS: We found that there were higher levels of IL-6, IL-8, IL-10 and TNFα in patients with pancreatic cancer compared to healthy controls (for all, at least p<0.03). Cancer patients had lower IL-23 concentrations than healthy individuals and patients diagnosed with other types of malignancies (for both, p=0.002). Levels of IL-6, IL-8, IL-10, and IL-23 were significantly associated with the direct number of circulating bone marrow (BM)-derived mesenchymal or very small embryonic/epiblast-like stem cells (SCs) in patients with pancreatic cancer. Moreover, our study identified a potential ability of IL-6, IL-8, IL-10, IL-23, and TNFα levels to enable discrimination of pancreatic cancer from other pancreatic tumors and diseases, including acute and chronic pancreatitis and post-pancreatitis cysts (with sensitivity and specificity ranging between 70%-82%). CONCLUSIONS: Our study i) supports the significance of selected cytokines in the clinical presentation of pancreatic cancer, ii) highlights numerous associations between selected interleukins and intensified BMSCs trafficking in patients with pancreatic cancer, and iii) preliminarily characterizes the diagnostic potential of several cytokines as potential novel clinical markers of pancreatic cancer in humans.

Selected hemostatic parameters in patients with pancreatic tumors.

INTRODUCTION: Recent experimental studies have suggested that various coagulation-related molecules may be important players in the development and progression of pancreatic cancer. However, these findings have not yet been verified in a clinical setting. METHODS: In this study, we comprehensively examined the levels of multiple hemostatic substances, including prothrombin, antithrombin, plasminogen, thrombin-anti-thrombin (TAT) and plasmin-anti-plasmin (PAP) complexes, as well as, soluble CD40 (sCD40) in patients diagnosed with pancreatic cancer (n = 37) or other tumors (neuroendocrine neoplasms - NEN [n = 7] or solid pseudopapillary tumors-SPT [n = 3]), and healthy individuals (n = 31). RESULTS: We found significantly higher anti-thrombin, PAP and sCD40 levels in patients with pancreatic cancer compared to healthy controls and patients diagnosed with other types of pancreatic tumors (for all, at least p < 0.05). Cancer patients had lower plasminogen concentrations than individuals from the other analyzed groups (for both, p < 0.05). None of the examined coagulation-related parameters was significantly associated with neither systemic sCD40 concentrations nor clinical staging of malignancy. Levels of analyzed molecules were comparable between pancreatic cancer patients presenting with early and advanced disease. Moreover, our study identified a potential diagnostic value of prothrombin/TAT and anti-thrombin/TAT coefficients in detection of pancreatic cancer in humans. However, both of these were inferior to currently used marker-CA19.9. CONCLUSIONS: Subclinical hemostatic alterations (mainly in plasmin-related molecules) i) appear as soon as during the earliest stages of the pancreatic adenocarcinoma development in humans, ii) do not seem to alter within progression of the disease nor are associated with clinical staging, iii) are not observed in patients with other types of pancreatic tumors, as well as, iv) do not seem to be associated with elevated sCD40 concentrations in pancreatic cancer patients. Moreover, examined thrombin- and plasmin-related substances do not appear to possess a sufficient diagnostic value to serve as makers of pancreatic adenocarcinoma in humans.