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Background There are very few data in the current literature regarding the short- and long-term outcome of surgery for pediatric pancreatic tumors (PPT). No data are available on the impact of pancreatic surgery on the children's growth. Methods This is a retrospective cohort study on a consecutive series of pediatric/adolescent patients who underwent pediatric surgery at Karolinska University Hospital from January 2005 to July 2017. Results Overall 14 pancreatic operations were performed in 13 patients. The median age was 11.4 years (range 3–15). Six pancreaticoduodenectomies (42.8%), 5 distal pancreatectomies (35.7%), and 3 enucleations (21.5%) were performed. The final histology revealed a solid pseudopapillary tumor in 9 cases (69.2%), neuroblastoma in 1 (7.7%), ganglioneuroma in 1 (7.7%), pancreatoblastoma in 1 (7.7%), and insulinoma in 1 (7.7%). Overall, 3 patients developed post-operative complications (23%). There was no peri-operative mortality. All patients are alive after a median follow-up time of 80 months. Exocrine insufficiency was detected post-operatively in 4 patients (30.7%) Endocrine insufficiency requiring insulin treatment developed in one patient (7.7%). No significant impact on growth was detected in any of the patients after pancreatic resection. Conclusions In our series, surgery performed for PPTs seems to be safe and effective. The effect of pancreatic surgery on children's growth does not seem to be significant.

Objective: To evaluate whether upregulation of liver and muscle uncoupling protein 2 (UCP-2) is an acute phenomenon in obstructive jaundice and associated with secondary metabolic effects. Methods: Male Sprague-Dawley rats were divided into four groups bile duct ligated (BDL) and sham-operated pair-fed (PF), ad libitum fed (AL), and controls BDL. PF. and AL rats were further divided into subgroups according to the interval postoperatively when they were reanesthetized and sampled for tissue and blood 2, 4, and 8 d, respectively Bilirubin, liver enzymes. glucose, free fatty acids, and insulin in blood plasma were analyzed Liver and muscle tissue were sampled for UCP-2 and adenosine triphosphate analysis. Results: The BDL rats showed an increase of the liver UCP-2 expression compared with PF and AL rats (P < 0 05) 4 d postoperatively. Liver adenosine triphosphate in BDL rats showed a decrease compared with sham-operated controls at all intervals < 0 05) Plasma glucose concentration in BDL rats was decreased compared with the other groups. Free fatty acids showed an initial increase 2 d postoperatively compared with sham-operated controls and PF and AL rats (P < 0 05) at the corresponding time point Conclusion: Obstructive jaundice is associated with an early upregulation of liver UCP-2. reduced liver adenosine triphosphate content, and decreased plasma glucose concentration, supporting the hypothesis that obstructive Jaundice results in impaired energy homeostasis in the liver. which might cause decreased glucose output and hypoglycemia as a consequence (C) 2010 Elsevier Inc. All flats reserved (Less)

A 7-year-old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160,000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C-peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5- and 27-months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C-peptide levels were 0.67 +/- 0.07 and 3.36 +/- 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet-bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long-term clinically significant metabolic control.

After pancreaticoduodenectomy (PD) patients may be deficient in essential micronutrients. This study was designed to determine if this is a consequence of surgery.Long-term survivors (6 months) of PD for peri-ampullary neoplasia and healthy controls (patients' spouse/partner) were enrolled in the study. Specific clinical parameters were recorded, serum micronutrient levels were measured and subjects completed 7-day food diaries.Thirty-seven patients were studied, 25 with paired controls. All were well nourished, as defined by body mass index and food diary analysis. Patients with paired controls were representative of all patients studied. Patients had raised transferrin (median 2.60 vs. 2.16 g/l, p = 0.001) and low ferritin levels (34.9 vs. 119.0 g/l, p0.001) indicating relative iron deficiency. Patients also demonstrated lower levels of the anti-oxidants selenium (0.77 vs. 0.93 micromol/l, p0.001) and vitamin E (23.2 vs. 35.7 micromol/l, p0.001) with 57% of patients having frank selenium deficiencies. Patients had lower levels of vitamin D than controls (15.7 vs. 19.6 micromol/l, p = 0.001) and 30% of patients had a raised parathyroid hormone level, suggesting compensatory mechanisms operate to maintain normocalcaemia.Long-term survivors of PD are relatively deficient in several micronutrients compared to non-operated controls taking the same diet. We recommend that micronutrient status should be regularly checked in these patients and treated where necessary.

Intratumoral hypoxia and paracrine insulin stimulate the expression of hypoxia inducible factor-1alpha (HIF-1alpha) in pancreatic cancer cells. In the present studies, we investigated whether insulin-induced HIF-1alpha expression is a prerequisite for insulin to induce other trophic effects in MiaPaCa2 human pancreatic cancer cells and whether inhibition of HIF-1alpha expression would decrease tumor glycolysis and improve host energy homeostasis. We found that hypoxia was a prerequisite for induction of HIF-1alpha mRNA expression by insulin in MiaPaCa2 cells. Under hypoxic conditions, insulin stimulated glycolysis, cell proliferation, and the secretion of vascular endothelial growth factor in regular MiaPaCa2 cells but not in a MiaPaCa2 variant (si-MiaPaCa2) that expressed specific short interfering RNA for HIF-1alpha and therefore lacked HIF-1alpha protein. This suggests that HIF-1alpha expression is required for insulin to induce other trophic effects. When si-MiaPaCa2 cells were transplanted into the pancreas of athymic mice, they were less tumorigenic and expressed less hexokinase than regular MiaPaCa2 cells. Body weight gain was attenuated in mice hosting tumors composed of regular MiaPaCa2 but not si-MiaPaCa2 cells. These results suggest that an interaction between insulin and HIF-1alpha helps sustain pancreatic cancer cells and disturbs host energy homeostasis.

A dysregulated immune response has been suggested to be important for the pathogenesis of chronic pancreatitis (CP). Formation of immunological memory is based on the differentiation of naive T lymphocytes to memory T lymphocytes after exposure to antigens and specific cytokines. The aim of this study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with CP for different T lymphocyte subsets including naive and memory T cells.PBMCs from 9 patients who had undergone pancreatic resection due to CP, 9 CP patients who had not been resected and 9 healthy controls were analyzed by flow cytometry.Patients with CP had a skewed distribution of T lymphocytes, with an increased level of CCR7+/CD45RA- central memory T lymphocytes compared to healthy controls. Nonresected CP patients and subjects who had undergone pancreatic resection due to CP had similar levels of central memory T lymphocytes.Our results indicate that the dysregulation of the immune system in chronic pancreatitis seems to persist even after removal of large parts of the local inflammatory site. We suggest that the increase of central memory T lymphocytes may be important for maintaining the inflammatory process in chronic pancreatitis.

This experiment investigated the influence of age on prefrontal acetylcholine (ACh) release and Fos response in the hypothalamic paraventricular nucleus and the nucleus tractus solitarius (NTS) of rats following isoflurane anesthesia. It is known that isoflurane decreases acetylcholine release in most brain regions. In the present study, we found that the level of prefrontal acetylcholine was significantly lower in 28-month-old rats (14% of baseline) than in 3-month-old rats (38% of baseline) during 2 h of isoflurane anesthesia (P < 0.05). The old rat group showed significantly greater Fos induction in the paraventricular nucleus compared to the young adult rat group (P < 0.05), indicating that the old rats were subjected to stress. No difference in Fos response was noted in the nucleus tractus solitarius. The old rats displayed a significant increase in feeding behavior during the 3-h recovery period (P < 0.05), but there was no difference in overall acetylcholine levels. Taken together, these findings suggest that isoflurane anesthesia influences old rats more profoundly than young adult rats with regard to reductions in acetylcholine release and stress responses. This may have implications for understanding the development of postoperative delirium in aged patients.

Tumor necrosis factor alpha (TNF-alpha) appears to play a role in the cachexia and diabetes seen in patients with cancers. However, increased TNF-alpha is seen in some, but not all, of the cancer patients.The mRNA transcripts of TNF-alpha and its receptors (TNF-RI and TNF-RII) were quantified in blood cells of pancreatic cancer patients, using competitive quantitative reverse transcriptase-polymerase chain reaction. Plasma TNF-alpha was also quantified in these patients by enzyme-linked immunosorbent assay. Control blood came from healthy subjects.The TNF-alpha mRNA transcripts (per microgram of total RNA) were increased in pancreatic cancer patients (6.8 +/- 2.1 x 10(6), n = 10), compared to control (1.2 +/- 0.2 x 10(6), n = 9, p0.05). After the tumour was removed, the TNF-alpha mRNA transcripts were reduced to a level (2.1 +/- 0.8 x 10(6)) similar to the control. In the cancer patients, no significant changes were found in TNF-RI and TNF-RII gene transcription, compared to the controls.The expression of the TNF-alpha gene is upregulated in patients with pancreatic cancer and normalized after the pancreatic tumor is removed. These results are consistent with the concept that TNF-alpha is involved in metabolic disorders associated with pancreatic cancer.

Metabolic stress after surgery is associated with peripheral insulin resistance. Recent studies have suggested that preoperative glucose can ameliorate postoperative decreases in insulin-stimulated glucose disposal. In the present experiments, we used a bowel-resection model of surgical trauma to test the hypothesis that elevations of serum insulin induced by preoperative oral glucose or ad libitum feeding affects postoperative insulin-stimulated glucose uptake in skeletal muscle. Insulin-stimulated glucose transport was measured in vitro in soleus muscles after surgical trauma in fasted rats given oral glucose or water before surgery. Insulin-stimulated glucose transport was also assessed in vitro in fasted or fed traumatized rats and non-traumatized control animals. In addition, stress hormones (glucagon, corticosterone, and adrenaline) were measured before and after surgical trauma in fasted rats and rats fed ad libitum. In vitro skeletal-muscle insulin sensitivity and responsiveness were reduced postoperatively in fasted animals that received oral glucose loads before bowel resections and in rats fed ad libitum or fasted before surgery versus non-traumatized rats (all P < 0.05). Stress-hormone concentrations after trauma did not differ between fed and fasted animals. In the current study, insulin sensitivity and responsiveness were reduced in isolated skeletal muscles after bowel resection, but neither preoperative glucose supplementation nor free intake of mixed nutrients ameliorated the development of postoperative insulin resistance.

Islet amyloid polypeptide (IAPP or amylin) potently reduces food intake in rats at or near physiological concentrations. Although the mechanisms of action of IAPP are not understood, the brain is a suggested site. Changes in hypothalamic and striatal neurotransmission have been reported following acute systemic administration of a pharmacological concentration of IAPP. In the current study, we evaluated the effects of chronic administration of low doses of IAPP on satiety-related neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat. Doses of 0, 5 and 25 pmol IAPP/kg-min were administered subcutaneously for 2 or 5 days. Food intake was reduced by 27 and 44% (both P0.001) for the 5 and 25 pmol/kg-min groups, respectively, in the 2-day experiment and was decreased by 14% (P0.01) and 24% (P0.001), respectively, in the 5-day experiment. Body weight was significantly decreased in a dose-dependent fashion. In the 2-day experiment, norepinephrine increased in the hypothalamus in the 5 pmol IAPP/kg-min group, and neurotensin increased in the hippocampus in the 25 pmol/kg-min rats (both P0.05). In the 5-day, 5 pmol/kg-min rats, 5-hydroxyindoleacetic acid (5-HIAA) increased in the hypothalmus and cholecystokinin (CCK) increased in the striatum (both P0.05). In the 5-day, 25 pmol/kg-min group, neuropeptide Y (NPY) increased in the hypothalamus (P0.01) and CCK increased in the hypothalmus and striatum (both P0.05). The present study confirms that IAPP is a potent anorectic peptide at low doses and suggests that IAPP not only affects classical neurotransmitters in the brain but also alters concentrations of neuropeptides known to be involved in food intake.

Introduction: Enteral feeding has been reported to increase intestinal mucosa proliferation after resection. Dietary components influence the intestinal adaptive response. The purpose of this study was to evaluate the effect of ornithine- (OKG) or arginine-ketoglutarate (AKG) bolus supplementation on intestinal postresectional adaptation in the rat. Methods: Male Wistar rats underwent 65% small-bowel resection and received either OKG 3 g/kg/day, isonitrogenous AKG or saline by gavage once daily. The animals had free access to rat chow. Sampling was done 10 days after resection. Fed animals without surgery or specific treatment served as controls. Results: Mucosal wet weight, DNA, RNA, protein content and sucrose activity of the mucosa, as well as villus height were significantly increased in all resected animals compared to controls. No significant differences in body weight or intestinal adaptation could be found between the three dietary groups. Conclusion: Postoperative enteral bolus feeding supplemented with OKG or AKG did not significantly enhance the adaptation of the remnant small bowel 10 days after massive intestinal resection when rats had free access to rat chow. © 2000 Elsevier Science Inc.

The kinetic properties of recombinant human mitochondrial deoxyguanosine kinase (dGK, EC 2.7.1.113) for 2′-deoxyguanosine and the clinically important nucleoside analogs 2-chloro-2′-deoxyadenosine (CdA), 9-β -D-arabinofuranosylguanine (araG) and 2′,2′,-difluorodeoxyguanosine (dFdG) were determined. The Michaelis–Menten kinetic parameters, comparing ATP and UTP as phosphate donors, demonstrated a marked increase in phosphorylation efficiency ( V max K m ) with UTP in comparison with ATP for both CdA and araG. The difluoro analog dFdG was an efficient substrate for recombinant dGK with an apparent K m of 16 μM with ATP as phosphate donor. We compared the kinetic properties of dGK with those of the related enzyme deoxycytidine kinase (dCK, EC 2.7.1.74). Although the purines 2′-deoxyguanosine (dGuo) and 2′-deoxyadenosine are substrates for both dGK and dCK, only CdA among the purine nucleoside analogs tested was an efficient substrate for both dCK and dGK. In competition with dGuo, the most efficient analog for phosphorylation by dGK was araG, as indicated by a lower K i value than for CdA and dFdG. Of the purine analogs tested as substrates for dCK, only CdA could compete with 2′-deoxycytidine (dCyd). No inhibition of dCK-mediated dCyd phosphorylation was found by either araG or dFdG. In crude cell extract of HeLa and Capan 2 cells, the major CdA phosphorylation was contributed by dCK, while most araG phosphorylation was a result of dGK activity. Our study with pure recombinant enzymes confirms that dGK is mainly responsible for araG and dFdG phosphorylation, whereas dCK is the most important enzyme for activation of CdA and 2′,2′-difluorodeoxycytidine (dFdC).

The cytotoxic anti-cancer purine nucleoside analogs 2-chloro-2'-deoxyadenosine (CdA), 9-beta-D-arabinofuranosylguanine (araG), and 2',2'-difluorodeoxyguanosine (dFdG) are phosphorylated by human mitochondrial deoxyguanosine kinase (dGK) in vitro. We overexpressed dGK as a fusion protein to the green fluorescent protein in the human pancreatic cancer cell lines PanC-1 and MIA PaCa-2 to determine the importance of dGK-mediated nucleoside analog phosphorylation. The transfected cells showed mitochondrial fluorescence patterns, and the mitochondrial locations of endogenous and overexpressed dGK were verified by Western blot analysis of cell extracts with polyclonal anti-dGK antibodies. The increase of dGK activity in the overexpressing cells was approximately 4-fold. These cell lines exhibited increased sensitivity to CdA, araG, and dFdG as compared with the untransfected parent cell lines. This is, to our knowledge, the first demonstration of a correlation between the activity of a mitochondrial deoxyribonucleoside kinase and the cytotoxicity of nucleoside analogs. Our data imply that the dGK activity is rate-limiting for the efficacy of nucleoside analogs in the cell lines investigated.

Background & Aims: Patients with pancreatic adenocarcinoma have a high incidence of diabetes, profound insulin resistance, and high circulating amylin concentrations. It was hypothesized that pancreatic cancer cells produce a factor that stimulates islets to secrete amylin but not insulin. Methods: Amylin and insulin secretion were measured after coculture of pancreatic cancer cells with β cells (BRIN-BD11). The factor responsible was characterized by exposing β cells to cancer cell–conditioned medium. Results: Coculture with pancreatic (PANC-1 HPAF, and MiaPaCa2) but not colonic cancer cells (Colo 320) significantly increased amylin secretion but did not change insulin output. This effect was both time and cell number dependent. Coculture with PANC-1 or HPAF cells significantly decreased intracellular amylin, but not insulin, content. PANC-1 or HPAF cell–conditioned medium also increased amylin secretion and decreased intracellular amylin content. The factor responsible was extracted under both neutral and acidic conditions, was heat labile, and had a molecular weight of 1500. Conclusions: A soluble factor from pancreatic cancer cells selectively stimulates amylin secretion from islet cells, explaining the excessive amylin secretion found in pancreatic cancer. Because elevation of amylin concentration is an early feature of pancreatic cancer, characterization and measurement of the tumor-derived amylin-releasing factor might be valuable in the early detection of this disease. GASTROENTEROLOGY 1998;114:130-138

Raw soya diet in the hamster had short-term trophic effects on the pancreas, causing significant increases in pancreatic weight, DNA, RNA, and protein. These changes appear to be mediated by cholecystokinin (CCK) because the increases were blocked by infusion of the CCKA receptor antagonist, MK329. Raw soya diet significantly increased plasma levels of CCK in both the short-term and long-term studies. However, raw soya did not potentiate pancreatic cancer in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Infusion of MK329 during the initiation period of carcinogenesis did not change tumor incidence or yield, suggesting that endogenous CCK does not influence tumor induction during the initiation period in the hamster.

Diabetes in patients with pancreatic cancer occurs in 70% to 80% of the patients and is characterized by high plasma levels of insulin. In type II diabetes that is not associated with pancreatic cancer, peripheral insulin resistance and impaired muscle glycogen synthesis are major pathogenic factors. We investigated peripheral insulin sensitivity in patients with pancreatic cancer before and after tumor removal. The effects of pancreatic tumor extracts on glycogen synthesis in skeletal muscle in vitro and the tumor content of pancreatic islet hormones were also investigated. Marked peripheral insulin resistance was found in the patients with pancreatic cancer and was more pronounced in the diabetic patients than in the nondiabetic patients. Insulin sensitivity was not correlated with weight loss, tumor size, or bilirubin levels but improved after surgery. Tumor extracts from diabetic patients with pancreatic cancer caused a marked reduction of glycogen synthesis in skeletal muscle in vitro . All tumors contained islet hormones but not in concentrations sufficient to explain the effect on glycogen synthesis. These findings indicate that a diabetogenic factor associated with pancreatic adenocarcinomas could be involved in the development of the profound peripheral insulin resistance and thereby could contribute to the high incidence of diabetes observed in patients with pancreatic cancer.