New insights into the role of chronic inflammation and cytokines in the etiopathogenesis of gastroenteropancreatic neuroendocrine tumors.

Although previously considered rare, recent epidemiological studies have revealed that the incidence (3.6/100,000) and prevalence (35/100,000) of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased over the past few decades. Despite the progress in the understanding of GEP-NET molecular biology, there is still little advance in the early diagnosis due to lack of specific tumor markers. As the tumors are mostly detected in their late stage, they are not well controlled by either biotherapy or conventional chemotherapy, and thus represent a significant clinical issue. Chronic inflammation has been implicated in the development of GEP-NETs. This review presents recent findings that link pro-inflammatory cytokines to the molecular basis of GEP-NET tumorigenesis, leading to a more personalized approach to disease management and therapy.

Analysis of polymorphisms in EGF, EGFR and HER2 genes in pancreatic neuroendocrine tumors (PNETs).

OBJECTIVES: Pancreatic neuroendocrine tumors (NETs) are rare and account for about 7% of all cancers occurring in the pancreas. The epidermal growth factor family of receptors and their ligands play an important role in the growth and progression of tumors but their role in PNET development remains unknown. We hypothesized that functional single nucleotide polymorphisms (SNPs) in the EGF, EGFR, and HER2 genes might affect individual susceptibility to PNETs development and invasion like it was shown for various other tumors. METHODS: We genotyped 68 patients with unresectable PNETs and 300 controls to evaluate the association between EGF, EGFR, and HER2 polymorphisms and susceptibility to PNETs and presence of metastases. RESULTS: Genotype analysis of three SNPs EGF +61A/G (rs4444903), EGFR +1562 G/A (rs11543848), and HER2 +1963 A/G (rs1136201) showed that carriers of EGFR +1562 AG genotype and AA/AG EGF +61/HER2 +1963 genotype combination are at risk of developing PNET. Furthermore, EGFR +1562 AA genotype could be associated with the susceptibility to insulinoma development. CONCLUSIONS: Our results suggest involvement of EGFR signaling pathway in etiology of PNET development.

Position of intragastric balloons in global initiative for obesity treatment.

Obesity is chronic disease with multiple health consequences and among the most severe health problems worldwide. According to public health records around 65% of population in Croatia are overweight and 20% obese. National physicians chamber with support of Health and Social Welfare Ministry gave recommendations on diagnosing and treating of obesity in form of national consensus. Treatment of obesity is complex and enrolls multiple clinical specialties. Change of life style, strenuous physical activity and pharmacotherapy are part of conservative treatments. Patients are treated more efficiently by minimally invasive endoscopic procedures or bariatric surgery depending on starting body mass index score. Implantation of intragastric balloons is conceptually simple method of obesity treatment. Modern devices as Bio-Enterics intragastric balloons (BIB), (Inamed Health, USA) are gaining wide popularity among both patients and physicians. BIB intragastric offers the best gains with individuals ranging BMI from 35 to 40. Efficiency has relative timeline dependance from 85% at 6 months to 24% at 36 months. BIB offers substantial ameliorative influence on obesity comorbidities, particularly cardiovascular risk. Treatment with BIB is also efficient but transient treatment modality in morbidly and superobese individuals to reduce preoperative risks of general and bariatric surgery. Obesity treatment with BIB is well tolerated and safe, offering better quality of life. Nevertheless, due to relative poor results of conservative obesity treatments on long-term follow up further investigations defining new clinical parameters for solving treatment resistance. In order to provide resourcefully individualized approach modern perspectives are focused on endocrine constitutes of obesity. Hormonal effects of BIB treatment in compare to bariatric surgery are potentially interesting for the prospect studies.

[Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic neuroendocrine tumors]. / Postupnik za dijagnostiku, lijecenje i pracenje oboljelih od neuroendokrinih tumora gusterace.

Pancreatic neuroendocrine tumors (PETs) are increasingly recognized. In order to assure an optimal treatment of patients and to propose an efficient diagnostic algorithm we were prompted to organize meetings, with participating experts, specialists in different fields of expertise. The idea for the meetings was to try to give a standardized approach, which would in future help in stratification of PET patients. Results of meetings are given in a form of Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic neuroendocrine tumors.

Inflammation-related cytokines and their roles in gastroenteropancreatic neuroendocrine neoplasms.

Proinflammatory counterworks are important at different stages of tumor development, particularly during invasion and metastasis. Immune cells and their signal molecules can influence all stages of tumor progression, as well as therapeutic intervention. Proinflammatory cytokines are known triggers of growth in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we explored the immunohistochemical expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), IL-2, and IL-6 in tissues from 43 GEP-NEN patients with tumors of gastric, duodenal, ileal, appendiceal, and colonic origin. The immunohistochemical expression of TNF-α was increased in tumor groups with high proliferation rates (Ki-67; p = 0.034), as well as in those with higher tumor grades (p = 0.05). Moreover, the immunohistochemical expression of TNF-α positively correlated with death outcomes (p = 0.016). Expression of IL-6, IL-1ß, and IL-2 displayed similar immunohistochemical expression patterns regardless of Ki-67, although the expression between the ILs differed. Most GEP-NENs had high levels of IL-6 and lower levels of IL-1ß and IL-2. Although further comprehensive studies are required for a complete understanding of activated mechanisms in proinflammatory protumoral microenvironment of GEP-NENs, TNF-α is a potential marker in the prognosis of those tumors.

[Recommendations of Croatian societies on treatment of macrovascular and microvascular complications in patients with metabolic syndrome and diabetes type 2--treatment of residual risk]. / Preporuke Hrvatskih strucnih drustava o lijecenju makrovaskularnih i mikrovaskularnih komplikacija u bolesnika s metabolickim sindromom i secernom bolesti tipa 2--lijecenje preostalog kardiovaskularno [corrected] rizika.

Quite a number of studies have shown that despite achieving targets for total and LDL cholesterol, blood pressure and glycemia according to the guidelines, many patients remain at high residual risk for cardiovascular diseases (CVD), both macrovascular and microvascular. This is particularly true for patients with established CVD, type 2 diabetes, obesity and/or metabolic syndrome who have very often atherogenic dyslipidemia characterized by decreased plasma concentrations of HDL cholesterol and increased triglycerides. To address this issue a working group of experts has been established to produce this document in order to recommend therapeutic interventions for reducing this residual risk. This document has been endorsed by relevant Croatian scientific and professional societies (Croatian atherosclerosis socitey, Croatian hypertension society, Croatian cardiac society, Croatian diabetes society, Croatian endocrinology society, Croatian obesity society, Croatian internal medicine society and Croatian society for clinical pharmacology).

Could diabetic retinopathy be an autoimmune disease?

Diabetic retinopathy is a common and progressive complication of diabetes mellitus. It is characterized by the loss of pericytes, hypertrophy of basement membrane, microaneurysms formation, increased vascular permeability, capillary occlusions, neovascularisation and fibrovascular proliferation. The pathogenesis of diabetic retinopathy is still insufficiently understood, although some reports have implicated the role of the immune system. We hypothesize that, according to some current data diabetic retinopathy could also be considered as an autoimmune disease. The finding of antipericyte and antiendothelial cell autoantibodies in the circulation of diabetic patients strongly suggests that some autoimmune activity has been involved in the early pathophysiology of diabetic retinopathy. There is even more evidence that implicates the presence of autoimmune mechanisms in the proliferative stage of this disease: elevated levels of tumor necrosis factor-alpha, interleukin-8 and soluble interleukin-2 receptor in the serum of diabetic patients, increased vitreous concentration of the interleukin-6 and interleukin-8 in patients with proliferative retinopathy. Furthermore, preretinal membranes in diabetic patients contain deposits of immunoglobulins, activated complement components, monocytes, T and B lymphocytes, fibroblastes and lymphokynes. In diabetic patients human leukocyte antigen DR and DQ expression on the retinal vascular endothelial cells as well as on pigment and nonpigment epithelial cells was found. These antigens are normally restricted to immunocompetent cells and play an important regulatory role in the immune response. Their aberrant expression has been found on nonlymphoid cells in various autoimmune diseases whilst abnormal expression of DR and DQ antigens at sites where they do not normally exist would result in autoimmunity by converting the target cell into a functional antigen-presenting cell. In conclusion, although the pathogenesis of diabetic retinopathy is not completely understood it is known that the immune system is certainly involved in its development. However, there is increasing evidence of the presence of some autoimmune processes in the early stages of diabetic retinopathy and particularly in its proliferative phases. Consequently, diabetic retinopathy could also be considered as an autoimmune disease.

A single-centre experience with octreotide in the treatment of different hypersecretory syndromes in patients with functional gastroenteropancreatic neuroendocrine tumors.

The aim of this research was to assess the clinical and biochemical efficacy of the octreotide in the treatment of patients with various functional gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The study included 14 patients treated with octreotide for 6 months. They were diagnosed with VIPoma, glucagonoma, gastrinoma, medullary thyroid carcinoma (solitary and as a part of MEN-II syndrome), pancreatic carcinoids (solitary and as a part of multiple endocrine neoplasia type-1 syndrome-MEN-1 syndrome) and midgut carcinoids. The patients presented with Verner-Morrison, glucagonoma, Zollinger Ellison and carcinoid syndrome respectively. All had a metastatic disease at the time of diagnosis and a positive octreoscan finding. Initially elevated chromogranin A (CgA) levels were detected in 11 (78.6%) and elevated 5-hydroxyindolacetic acid (5-HIAA) levels in 8 (57.1%) patients. Symptomatic efficacy assessments were made by diarrhea reductions during treatment course, and laboratory efficacy was assessed through changes in 5-HIAA and CgA levels. Assessments were made initially and following 6 months of therapy. Median urinary 5-HIAA and the number of stools decreased significantly (p = 0.016 and p = 0.009 respectively, p < 0.05) while CgA levels had the decreasing tendency but not statistically significant (p = 0.14). There was a positive correlation between the 5-HIAA reduction and the decrease in stool number at baseline and during treatment course (p < 0.05). No correlation was observed between 5-HIAA and CgA levels and also there was no correlation between CgA reduction and symptomatic improvement. The results prove octreotide to be effective in reducing symptoms and biochemical markers associated with hypersecretory syndromes of GEP-NETs.

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.

Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy.

Obesity is a medical condition caused by accumulated excess body fat with negative impact on patients' health, including decreased life expectancy. It has become a major health problem in most developed and developing countries, since the worldwide prevalence of obesity nearly doubled during the last 30 years. Consequently, novel treatments focusing on obesity are being investigated. Potential targets include several pathophysiological mechanisms involved in appetite control affecting multiple organ systems, like adipose tissue; some cell types in the stomach and gut; pancreas; thyroid gland; several hypothalamic areas; and centers located in the brainstem. One of the most important orexigenic neuropeptides is ghrelin, which is produced and secreted primarily by ghrelin cells located in the stomach and duodenum. In humans, plasma ghrelin levels rise when the stomach is empty and fall shortly after meal ingestion. In fat tissue, ghrelin increases fat storage. In the brain, it exerts its orexigenic action through activation of NPY/AgRP neurons in the arcuate nucleus. From the pharmacological point of view, it seems that opposing ghrelin activity could be used as a therapeutic principle in treating obesity. The principal idea of antiobesity drugs is to augment anorexigenic and lipolytic signaling, or to block orexigenic and lipogenic mediators. Recent studies have shown that therapeutic vaccines could be a new approach in the development of antiobesity medications. A vaccine should provoke an immune response to a specific causal factor for a particular disease. Several types of anti-ghrelin vaccines have been developed so far, with significant immune response in terms of rising anti-ghrelin antibodies. However, in the only clinical trial performed yet, the results were disappointing, showing no additional weight loss in the study group. Until now, several studies have demonstrated the "proof of concept", but more studies are required to develop prophylactic and therapeutic vaccines to prevent and/or cure obesity.

Endocrinology and immunology of obesity, obesity vaccines.

The amount of body fat is precisely regulated in the overall process of energy homeostasis. Multiple organ systems participate in the regulatory process. Key regulatory signals reach the brain from the blood and control food intake and energy expenditure. The hypothalamus region integrates neurohormonal signaling from gut and adipose tissue. Morbid obesity is also associated with low grade systemic inflammation and immune activation. It can be at least in part regarded as an inflammatory disease. The anti-ghrelin vaccine decreases food intake, decreases hypothalamic orexigenic signals and increases energy expenditure and therefore might become an alternative treatment tool.

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.

Obesity treatment using a Bioenterics intragastric balloon (BIB)--preliminary Croatian results.

AIM OF STUDY: This study aims to assess the effectiveness, tolerance, safety, and patient satisfaction of obesity treatments using the Bioenterics intragastric balloon (BIB). METHODS: Prospective controlled trial of 33 obese patients who were treated with the BIB from March 2008 to March 2009 and who completed the 6 months treatment. Patients were selected on the basis of workup by a multidisciplinary team. The 33 obese patients (26 females, seven males) had a median age of 35 years (range 20-58). Their median baseline body weight (BW) was 114 kg (range 89-197) and their median body mass index (BMI) was 41.4 kg/m(2) (range 31.2-60.8). RESULTS: Average weight reduction was 14 kg (range 2-37), loss total weight 10.1% (range 1.4-23.1), control BMI 35.6 kg/m(2) (range 29.4-50.3), delta BMI 4.5 (range 0.6-13.1), percentage excess weight loss 29.2 (range 2.8-53.6), and percent of excess BMI loss 29.3 (range 2.7-67.4). In one female patient the BIB was removed early due to intolerance. During the first week, minor side effects were noticed: nausea/vomiting occurred in 21 patients (63.6%), and abdominal cramps in 15 (45.5%). There was one balloon deflation and one impaction in the stomach. Those incidents were both successfully treated endoscopically. Patients had no major complications from mucosal lesions and no need for surgical interventions. All intragastric balloons were successfully removed endoscopically. Patients' treatment satisfaction correlated with the degree of BW loss (p = 0.0138). CONCLUSION: BIB treatment in our setting showed the best results for individuals with BMI from 35 to 40 kg/m(2). Our preliminary results showed that BIB is safe, well tolerated with minor side effects, and alters quality of life for the better. The complication rate was negligible, due to the detailed pretreatment examinations and follow-up.

Morbidly obese are ghrelin and leptin hyporesponders with lesser intragastric balloon treatment efficiency : ghrelin and leptin changes in relation to obesity treatment.

BACKGROUND: Ghrelin and leptin recently emerged as the most influential neuroendocrine factors in the pathophysiology of obesity. The said peptides act in reciprocity and are responsible for regulation of appetite and energy metabolism. Intragastric balloons acquired worldwide popularity for obesity treatment. However, the roles of ghrelin and leptin in intragastric balloon treatment were still not systematically studied. METHODS: A prospective single-center study included 43 Caucasians treated with BioEnterics intragastric balloon, with age range of 18-60, and divided to non-morbid (body mass index cutoff 40 kg/m(2)) or morbid type of obesity, with 12 months follow-up. Serum hormonal samples were taken from fasting patients and kept frozen until analyses. RESULTS: Significant differences were observed in anthropometrics and there were no differences between genders or comorbidities. The baseline weight for non-morbid vs. morbid was 104 kg (90-135) vs. 128.5 kg (104-197). Weight loss was statistically different between the studied groups during the study course with a median control weight at 6 months of 92 kg (72-121) vs. 107 kg (84-163), p < 0.001. Treatment was successful for 18 (94.7%) vs. 16 (66.7%) patients, p = 0.026. Ghrelin varied from 333.3 to 3,416.8 pg/ml and leptin from 1.7 to 61.2 ng/ml, with a statistically significant time-dependent relationship. A significant difference (p = 0.04) with emphasized ghrelin peak was found in the 3rd month of treatment for non-morbidly obese subjects. CONCLUSIONS: The importance of ghrelin and leptin in treatment-induced changes was reaffirmed. Ghrelin hyper-response in non-morbidly obese subjects characterized greater short-term treatment efficiency and landmarked an inclination to weight regain. The results suggest a potential pattern of individualization between obese patients according to body mass index towards intragastric balloon or bariatric surgery. Further studies are needed in order to get better insights in the pathophysiologic mechanisms of obesity.

Hormones and aging.

Since the 19th century, there have been sporadic attempts to attribute the changes of aging to one or another endocrine deficit and efforts to reverse these changes by various replacement therapies. This search for a hormonal 'fountain of youth' continues today.

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.

Metabolic control in type 2 diabetes is associated with sulfonylurea receptor-1 (SUR-1) but not with KCNJ11 polymorphisms.

BACKGROUND AND AIMS: Sulfonylureas are hypoglycemic agents used for promotion of insulin secretion in type 2 diabetics (T2D). They bind to sulfonylurea receptor-1 (SUR-1), which is a functional subunit of the ATP-sensitive potassium channel (K(ATP)). The other component of the potassium channel is Kir6.2, encoded by gene KCNJ11. Polymorphisms in these genes may lead to modulated response to sulfonylurea therapy. The aim of this study was to determine a relationship between SUR-1 [exon 16 (-3C/T), exon 31 (Arg1273Arg; AGG-->AGA) and exon 33 (S1369A)] and KCNJ11 (E23K) polymorphisms and the following parameters of metabolic control in T2D: fasting plasma glucose (FPG), postprandial glucose (PPG) and HbA1c in Caucasian T2D of European origin. METHODS: A total of 228 unrelated patients with T2D on sulfonylurea therapy were included in the study. Genotyping of all polymorphisms was performed by PCR-RFLP method. Biochemical parameters were determined using standard laboratory methods. RESULTS: There was no difference in FPG and PPG concentration in any of the genotype subgroups. However, diabetics with wild-type C/C genotype of the SUR-1 exon 16 polymorphism had significantly lower HbA1c concentration compared to the patients with variant T/T genotype [6.9 (6.2-7.7) mmol/L vs. 8.1 (6.7-8.8) mmol/L; p=0.009]. Also, patients with wild-type G/G genotype of the SUR-1 exon 31 polymorphism had significantly higher HbA1c concentration compared to the patients with variant A/A genotype [7.8 (6.9-8.8) mmol/L vs. 6.3 (5.7-6.8) mmol/L; p<0.001]. CONCLUSIONS: SUR-1 exon 16 and exon 31 polymorphisms are significantly associated with HbA1c concentration.

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.

TNF-alpha promoter single nucleotide polymorphisms in gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) secrete biogenic amines, hormones and growth factors, tumor necrosis factor-alpha (TNF-alpha) being one of them. As the expression of TNF-alpha is mostly regulated at the transcriptional level, its promoter polymorphisms have been intensively studied as a potential determinant of TNF-alpha production and cancer susceptibility. We have analyzed for the first time the potential association between -238, -308, -857 and -1031 TNF-alpha promoter polymorphisms and GEP-NETs. The study included 65 individuals diagnosed with GEP-NET and 154 healthy age- and sex-matched controls. Although most of the patients had solitary GEP-NETs, 6 were diagnosed with GEP-NET as a part of multiple endocrine neoplasia type 1 and 1 as a part of neurofibromatosis type 1. The C allele at the -1031 position was more frequent in GEP-NET patients (p < 0.0005), suggesting its possible role in GEP-NET development. The significant difference between foregut and midgut GEP-NET patients was observed in the -308 high expression genotypes and -308A allele (high expression) which tend to occur more frequently in the foregut GEP-NETs (p = 0.0392 and p = 0.0350, respectively). When functional and nonfunctional pancreatic endocrine tumors were compared, there were no significant differences in the researched TNF-alpha SNPs. The results suggest the putative role of TNF-alpha -1031 polymorphism in the development of GEP-NET.

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.