High VEGF serum values are associated with locoregional spread of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascularized neoplasms, capable of synthethisizing VEGF-A, a key mediator of angiogenesis. In pancreatic neuroendocrine tumors (pNETs) VEGF expression is higher in benign and low-grade tumors and associated with good prognosis (neuroendocrine paradox) while the VEGF role in gastrointestinal NETs (GI-NETs) is still unclear. In this study, we examined the VEGF-1154A/G polymorphism in 145 GEP-NET patients and 150 controls. Next, we measured VEGF serum levels and VEGF tumor protein expression, comparing it with Ki67 and tumor grade. Patients' VEGF serum levels were compared with VEGF -1145A/G genotypes and metastatic status as well as with chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA) in case of GI-NET patients. In this study GEP-NET patients had elevated VEGF serum values when compared to healthy controls (p = 0.0013). VEGF-1145G allele correlated with higher VEGF serum levels (p = 0.002). Patients with metastatic tumors had higher VEGF serum values when compared to patients without metastases (p = 0.033), and highest levels were observed in case of lymph node metastases (p = 0.008). VEGF-1145G allele was more frequent in non-functional GI-NET patients than in healthy controls (p = 0.041). CgA was superior to VEGF in tumor detection, while VEGF was superior to 5-HIAA. A correlation was observed between VEGF immunohistochemical staining and Ki-67 (p = 0.028). Tumours with weaker VEGF protein expression were more aggressive than tumours with stronger VEGF expression, confirming a "neuroendocrine paradox" in GI-NETs. Our results suggest the role of VEGF in GI-NETs locoregional spread.

Interleukin 1ß gene single-nucleotide polymorphisms and susceptibility to pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with not fully understood etiology. Interleukin 1ß (IL1ß) plays an important role in pancreatic pathology, especially carcinogenesis, but its role in pNET development remains unknown. The aim of this study was to analyze the association between IL1ß polymorphisms and susceptibility to pNETs. IL1ß -511 C/T and +3954 C/T single-nucleotide polymorphisms (SNPs) were analyzed by real-time polymerase chain reaction-SNP analysis. IL1ß serum values in pNET patients were also determined. Association between high-expression C/T -511 IL1ß genotype and susceptibility to pNET (p=0.042) was found, especially with functional pNET (p=0.014), where it was associated with the T allele (p=0.016). Combination of genotype analyses confirmed carriers of -511/+3954 CTCT to be at risk of developing functional pNETs (p=0.006) and carriers of -511/+3954 CTCC at risk of developing nonfunctional pNETs (p=0.019). IL1ß serum levels of all patients were below the limit of detection. Our results suggest IL1ß involvement in pNET development, and we also found association between the IL1ß -511 SNP and susceptibility to pNET, especially functional pNETs. Nonfunctional pNETs seem to have inferior prognosis when compared with functional pNETs. It is possible that they differ in tumor microenvironment and that nonfunctional tumors share similarities with adenocarcinoma. We believe that our findings will contribute to understanding of the etiology and possible novel prognostic markers for pNETs when future studies investigating the serum and tumor tissue IL1ß levels are done.

IL-2 -330 T/G SNP and serum values-potential new tumor markers in neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NETs).

Cytokines participate in tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Single nucleotide polymorphisms (SNPs) in cytokine genes influence expression of proteins and are evaluated in cancer susceptibility. The aim of this study was to evaluate IL-2 -330 T/G SNP and susceptibility to GEP-NETs, and analyze the correlation between G-allele and IL-2 serum values in GEP-NET patients. Moreover we assessed the value of IL-2 as a tumor serum marker. IL-2 -330 T/G SNP was examined in 101 patients and 150 healthy volunteers and IL-2 serum levels in patients and 20 controls. Patients' IL-2 serum levels were compared to IL-2 -330 T/G genotypes and tumor functional status and finally with known markers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA). There was a significant difference in genotype distribution of the IL-2 -330 polymorphisms between GEP-NET and control group (p = 0.0006) as well as in the frequency of G-allele (p = 0.010). G-allele correlated with higher IL-2 serum levels (p = 0.028) and elevated in all patients, being highest in patients with functional tumors (p = 0.039). Compared to CgA and 5-HIAA, IL-2 was more specific in detecting GEP-NET patients (p < 0.0001 and p < 0.0001, respectively). Our results indicate importance of IL-2 in GEP-NET development and biochemical diagnosis.

IL-6-174 C/G polymorphism in the gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

IL-6 is a pleiotropic cytokine with still controversial role in tumorigenesis of different cancer types. Its promoter SNP-174 C/G is associated with increased IL-6 transcription and in some tumor types with elevated IL-6 serum levels. The role of IL-6 polymorphisms and IL-6 serum values and their correlation in the gastroenteropancreatic neuroendocrine tumors is lacking. We investigated for the first time frequencies of IL-6-174 genotypes in 80 GEP-NET patients and 162 age- and sex-matched healthy controls, serum values of IL-6 in GEP-NET patients and their correlation with IL-6-174 genotypes. To analyze IL6-174 C/G polymorphism PCR-NlaIII RFLP method was used, and serum levels were measured on Immulite analyzer by enzymatic solid-phase chemiluminescent immunometric method. Serum IL-6 values were elevated (>5.9 pg/ml) in 36.8% GEP-NET patients. Differences in genotypes distribution between patients and healthy controls as well as between patients with gastrointestinal and pancreatic neuroendocrine tumors (PETs) and functioning and nonfunctioning PETs were tested by chi(2) test and Fisher's Exact test. Analysis of variance (ANOVA with proc GLM in SAS/Stat) was performed for the group comparison. Level of significance was alpha=0.05. Patients with nonfunctioning PETs had only high expression IL-6-174 CG and GG genotypes and according to genotypes differed significantly (p=0.0289) from functioning PETs. High serum IL-6 values in all GEP-NET patients correlated significantly with GG IL-6-174 genotype (p=0.0139). Nonfunctioning PET patients had significantly (p=0.000777) higher IL-6 serum values in comparison to patients with functioning PETs and gastrointestinal NETs. Serum IL-6 values correlated significantly with IL-6-174 genotypes in nonfunctioning PETs and gastrointestinal NETs (p<0.05), but not in functioning PETs.

Plasma interleukin-8 as a potential predictor of mortality in adult patients with severe traumatic brain injury.

Because of complex pathophysiology and severe consequences, traumatic brain injuries (TBI) are an important medical problem. Pathophysiology of TBI includes local and systemic stress response, in which interleukin-8 (IL-8) is considered as a key mediator of neuroinflammation. However, prognostic relevance of IL-8 measurement in adult patients with severe TBI is not certain. Therefore, IL-8 was determined in blood samples from central venous and jugular bulb catheter and in cerebrospinal fluid of twenty patients with isolated TBI at admission to Intensive Care Unit. None of the patients had history of stroke, dementia, autoimmune diseases, acute infection or medication with anti-inflammatory drugs. Ten patients died due to traumatic brain injury, while the other ten recovered well. While there was no significant difference of IL-8 levels in cerebrospinal fluid between survivors and nonsurvivors, central venous plasma level of IL-8 was significantly lower in survivors (71.00 +/- 14.17 pg/ml), than in nonsurvivors (111.26 +/- 16.9 pg/ml). Receiver Operating Characteristic (ROC) analysis revealed significant prognostic value for IL-8 in the blood as well as for the age of patients, Glasgow Coma Scale (GCS) and Acute Physiologic and Chronic Health Evaluation (APACHE II). These findings suggest that the central venous plasma values of IL-8 at admission might be an early predictive marker in patients with severe TBI, comparative to standard clinical prognostic markers such as APACHE II and GCS.

Clinical and neurohumoral response to posture, physical exercise, and ascites treatment in Child-Pugh C liver cirrhosis: randomized prospective trial.

AIM: To assess clinical and neurohumoral response to posture, physical exercise, and ascites treatment in patients with Child-Pugh C liver cirrhosis and tense ascites. METHOD: Fifty patients with Child-Pugh C liver cirrhosis and tense ascites were randomly allocated into 5 groups. Thirty patients were treated with paracentesis of 6 L of acites paralleled by plasma volume expansion with 200 mL of 20% low sodium albumin (10 patients), 600 mL fresh frozen plasma (10 patients), or 900 mL solution of synthetic gelatine (10 patients), ie, doses with comparable oncotic power, and bed rest for 24 h before and after the procedure. They were compared with 10 patients treated with paracentesis of 6 L of ascites without plasma volume expansion and no bed rest, and 10 patients treated with 40 mg of furosemide IV daily and no bed rest. Mean arterial pressure, heart rate, body weight loss, urine flow rate, creatinine clearance, plasma renin activity, plasma aldosterone concentration, and plasma atrial natriuretic peptide (ANP) were measured before the procedure and 6 hours, 2, 3, and 6 days after the procedure. RESULTS: Diuretic treatment and paracentesis of 6 L of ascites without plasma volume expansion and no bed rest 24 h before and after the procedure were associated with significant hypotension (p<0.01) during 6 days of the trial, tachycardia (p<0.01) on day 1 and 2 (p=0.012), lower total body weight loss (p=0.007), increase in plasma renin activity 6 hours after the beginning of the study (p=0.025) and on day 6 (p=0.024), increase in plasma aldosterone concentration on day 6 (p=0.030), no significant change in plasma ANP levels, and decrease in creatinine clearance on day 6 (p=0.046). Albumin was superior to the other plasma expanders. Comparison between groups treated with plasma volume expansion did not show significant differences in measured parameters at any time during the study. The differences were found in the amount of needed volume of each substitute, daily sodium balance on day 1 of the trial, increase in plasma aldosterone concentration in bed rest-paracentesis-polygeline group on day 6, and the increase in plasma ANP on day 1 (p=0.077), which was proportional to the amount of infused volume. CONCLUSION: Therapeutic paracentesis of 6 L of ascites, bed rest 24 h before and after the procedure, and intravenous substitution of volume with albumin, fresh frozen plasma, and solution of synthetic gelatine were safe, rapid, and effective treatments, provided that intravascular volume was substituted simultaneously.