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Our objective was to study whether islet amyloid polypeptide (IAPP) produces satiety by an endocrine mechanism. We used a rat model to determine whether postprandial plasma levels of IAPP are comparable to those required to inhibit feeding when IAPP is administered by continuous intravenous infusion. Food intake in rats with aortic catheters increased plasma IAPP levels from a fasting level of 10.8 ± 0.5 pM to a peak level of 19.0 ± 1.0 pM at 2.2 ± 0.5 h. In rats with jugular vein and aortic catheters, the threshold intravenous dose for IAPP suppression of feeding was between 1 and 3 pmol ⋅ kg−1 ⋅ min−1. The 3 pmol ⋅ kg−1 ⋅ min−1dose decreased 4-h intake by ∼25% by decreasing meal frequency rather than meal size. This dose increased plasma IAPP by ∼24 pM. These results suggest that postprandial plasma levels of IAPP are not quite sufficient to independently produce satiety.

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 development of front-line endoscopic technology has introduced new opportunities during endoscopic retrograde cholangiopancreatography (ERCP) to single-handedly allow direct inspection of detailed structures of the biliary and even the pancreatic duct. This paper presents a new flexible technology delivered with an outer diameter of 0.9 mm giving an image transmission of 6000 pixels. We report on a case where direct inspection of an alleged duct defect, of potential pathogenetic significance, was considered essential in order to substantiate the subsequent clinical management.

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.

Luminal nutrients and growth factors regulate postresectional intestinal growth. The interplay between glutamine and regulatory gastrointestinal peptides is not known.The effects of intestinal resection on tissue and plasma concentrations of peptides were studied in 60 Sprague-Dawley rats divided into resected, transected, or unoperated groups. Subgroups were fed either a glutamine-free or a glutamine-supplemented diet for 7 days. Epidermal growth factor, transforming growth factor-alpha, insulin-like growth factors (IGF) I and II, peptide YY (PYY), and enteroglucagon were analyzed in intestinal mucosa and in portal plasma by radioimmunoassay.No glutamine-specific effects were seen. The mucosal content of IGF-II (P0.01) and the portal levels of enteroglucagon and PYY (P0.05-0.01) increased after intestinal resection.The increase in PYY and enteroglucagon in portal blood supports a hormonal role in the postresectional adaptation. The increase in IGF II in the ileal mucosa, without changes in plasma, implies autocrine or paracrine growth stimulation at this stage after resection.

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

Islet amyloid polypeptide (IAPP) is a 37-amino acid polypeptide coproduced with insulin in the beta-cells of the pancreatic islets. The physiological effects of IAPP have not been established. Although effects on glucose metabolism are seen only at pharmacological doses both in vitro and in vivo, effects on food intake have been shown at near-physiological concentrations. The aim of the present study was to investigate the effects of similar elevations of circulating plasma IAPP levels on glucose metabolism in rats and to evaluate the function of a novel aortic catheterization technique. In a cross-over design, two sets of experiments in which conscious unrestrained rats received chronic IAPP infusions at 0 and 2 or 0 and 7 pmol/kg min were performed. Peripheral glucose disposal was determined by means of the hyperinsulinemic euglycemic clamp technique. Chronic elevations of circulating IAPP at concentrations that reduced food intake [43.5 +/- 6.2 g (control) vs. 35.7 +/- 8.2 g (IAPP; P0.01) and 34.0 +/- 2.2 g (control) vs. 28.8 +/- 1.4 g (IAPP; P = 0.07) for the 7 and 2 pmol/kg x min experiments, respectively] had no effect on the glucose metabolic rate [GMR; 18.5 +/- 0.6 mmol/kg x h (control) vs. 18.7 +/- 0.9 mmol/kg x h (IAPP) and 14.4 +/- 0.7 mmol/kg x h (control) vs. 15.6 +/- 0.7 mmol/kg x h (IAPP) for the 7 and 2 pmol/kg x min experiments, respectively]. Thus, effects on glucose metabolism are unlikely to explain the anorectic effect of IAPP.

The diabetes or impaired glucose tolerance that occurs in most patients with pancreatic cancer is characterized by profound insulin resistance. Recent evidence suggests that the diabetes may result from the presence of the tumor rather than being a predisposing factor to development of the malignancy. Some islet hormones have been shown to exhibit diabetogenic effects. To investigate the potential role of these hormones in the diabetic state associated with pancreatic cancer, we measured islet hormones during fasting in pancreatic cancer patients (n = 30), patients with other malignancies (n = 43), and healthy controls (n = 25). Preoperative pancreatic cancer patients were classified as normal glucose tolerance (NGTT), impaired glucose tolerance (IGTT), non-insulin-requiring diabetes (NIRD), and insulin-requiring diabetes (IRD). Nine pancreatic cancer patients were studied after tumor removal by subtotal pancreatectomy. Some preoperative pancreatic cancer patients (n = 19), postoperative patients (n = 9), and controls (n = 8) were also studied during hyperglycemia and following glucagon injection. Fasting plasma C-peptide was elevated in NIRD pancreatic cancer patients compared to controls. Fasting levels of islet amyloid polypeptide (IAPP), glucagon, and somatostatin were elevated in NIRD and IRD patients. IAPP and glucagon, but not somatostatin, normalized following subtotal pancreatectomy. During hyperglycemia, increases in C-peptide and IAPP were seen only in controls and in NGTT and postoperative pancreatic cancer patients. After glucagon infusion, IAPP levels increased in controls and nondiabetic cancer patients; C-peptide levels increased in controls, nondiabetic patients, and NIRD. Responses of C-peptide and IAPP to glucagon normalized after pancreatectomy. During hyperglycemia, glucagon levels fell in all groups except IGTT patients and a decrease in somatostatin concentrations was seen in controls.

The cosecretion of insulin and islet amyloid polypeptide (IAPP) is altered when isolated rat pancreatic islets are incubated in culture media conditioned by human pancreatic cancer cells.Pancreatic cancer is usually associated with impaired glucose tolerance. This study investigates the tumor-derived influence on beta-cell secretion of pancreatic islets.Four conditioned media were prepared from two human pancreatic cancer cell lines (Panc-1 and HPAF), a hamster pancreatic cancer cell line (PC-1), and a fibroblast cell line (Ag1523). Isolated rat pancreatic islets were incubated first in the conditioned media or nonconditioned control medium for 24 h, then in the same kind of media containing 100 microM carbamylcholine for 90 min. Insulin and IAPP secretion were measured by radioimmunoassay.Islets in media conditioned by Panc-1 and HPAF cells demonstrated dissociation of insulin and IAPP secretion. During 24-h incubation, the dissociation was expressed as selectively decreased insulin secretion. With addition of 100 microM carbamylcholine, the dissociation was expressed as normal secretion of insulin and hypersecretion of IAPP. As a result, the IAPP/insulin molar ratios were increased in both groups during both time periods. The islets in PC-1 and Ag1523 media did not show any significant changes in insulin and IAPP secretion.

Pancreatic cancer patients frequently show hyperglycemia, but it is uncertain whether hyperglycemia stimulates pancreatic cancer cells. We have investigated whether excess glucose induces hypoxia-inducible factor-1α (HIF-1α) and stimulates glucose metabolism and cell migration in pancreatic cancer cells. We studied wild-type (wt) MiaPaCa2 pancreatic cancer cells and a MiaPaCa2 subline (namely si-MiaPaCa2) that had HIF-1α-specific small interfering RNA. Wt-MiaPaCa2 cells are known to be HIF-1α-positive in hypoxia and HIF-1α-negative in normoxia, whereas si-MiaPaCa2 cells are devoid of HIF-1α in both normoxia and hypoxia. We incubated these cells with different amounts of glucose and determined HIF-1α mRNA and protein by real-time polymerase chain reaction and western blotting. We determined glucose consumption, lactate production and intracellular hexokinase-II and ATP to assess glucose metabolisms and determined pyruvate dehydrogenase kinase-1, reactive oxygen species and fumarate to assess mitochondrial activities. Further, we studied cell migration using a Boyden chamber. Excess glucose (16.7−22.2mM) increased HIF-1α in hypoxic wt-MiaPaCa2 cells. HIF-1α expression increased ATP contents and inhibited mitochondrial activities. Extracellular glucose and hypoxia stimulated glucose metabolisms independent of HIF-1α. Excess glucose stimulated the migration of wt- and si-MiaPaCa2 cells in both normoxia and hypoxia. Thus, glucose stimulated cell migration independent of HIF-1α. Nevertheless, hypoxic wt-MiaPaCa2 cells showed greater migrating ability than their si-MiaPaCa2 counterparts. We conclude that (1) excess glucose increases HIF-1α and ATP in hypoxic wt-MiaPaCa2 cells, (2) extracellular glucose and hypoxia regulate glucose metabolisms independent of HIF-1α and (3) glucose stimulates cell migration by mechanisms that are both dependent on HIF-1α and independent of it.

Islet amyloid polypeptide (IAPP), also called amylin, is a hormonal peptide produced by the islet beta-cells of the pancreas. Because the peptide is co-stored and co-released with insulin, attention has been focused on IAPP's ability to interfere with glucose metabolism. However, IAPP also has other effects, such as a reduction of food intake.In this study we investigated the dose-response effect of acute systemic administration of rat and human IAPP on food intake, and the cumulative effect of chronically increased circulating IAPP concentrations on food intake and body weight in the rat.All doses of rat IAPP investigated acutely inhibited food intake. The lowest infusion rate of 8 pmol/kg/min caused an 28% inhibition of the food intake at 2 h (p0.05). No effect of human IAPP was observed. Chronic administration of rat IAPP via an osmotic minipump during a 6-day period caused prolonged inhibitory effects on food intake and reduced body weight. During the first 3 days of infusion the food intake of the IAPP group was only 44% of the food intake of the control group (p0.001). The body weight of the IAPP group had fallen 18.6 +/- 2.7 g by day 3, in contrast to a small increase in the control group (4.0 +/- 3.1 g; p0.001). The reduction in food intake was sustained throughout the last 3 days of study (IAPP, 16.7 +/- 1.1 g/day; control, 20.6 +/- 1.5; p0.05). Similarly, the body weight still differed at the end of day 6 and, compared with day 0, was -8.7 +/- 3.7 g for the IAPP group and +10.9 +/- 4.8 for the control group (p0.01).These findings show that chronic increase of circulating IAPP levels can cause a marked reduction in both food intake and body weight and, together with the reduced food intake seen after acute administration of the peptide, indicates the possibility of IAPP functioning as a satiety factor.

The use of artificial nutrition remains controversial for cancer patients in palliative care, and its prevalence is largely unknown. We therefore conducted a national study to investigate the prevalence, indications for, and perceived benefit of enteral/parenteral nutrition and intravenous glucose in this patient group. A cross-sectional study was performed within the palliative care research network in Sweden (PANIS), using a web-based survey with 24 questions on demographics, prescribed nutritional treatment, estimated survival and benefit from treatment. Data was received from 32 palliative care units throughout the country, representing 1083 patients with gastrointestinal and gynecological malignancies being the most common diagnoses. Thirteen percent of the patients received enteral/parenteral nutrition or intravenous glucose. Parenteral nutrition (PN) was significantly more common in home care units serving the urban Stockholm region (11%) than in other parts of the country (4%). Weight and appetite loss were the predominant indications for PN, with this treatment deemed beneficial for 75% of the palliative patients. Data show that there was great variation in PN use within the country. PN was predominately initiated when patients had weight and appetite loss but still had oral intake, indicating a use of PN that extends beyond the traditional use for patients with obstruction/semi obstruction.

Rendezvous intraoperative endoscopic retrograde cholangiography (RV-IOERC), also called guidewire-facilitated IOERC, is one of the single-stage options available for managing common bile duct stones (CBDS) during laparoscopic cholecystectomy. The objective of this study is to investigate procedure-related complications in IOERC patients and stone clearance. All patients who underwent IOERC between January 2000 and December 2009 were identified from the local registry of Karolinska University Hospital in Huddinge. Medical charts and ERC reports were studied, and descriptive statistics were obtained. Outcomes were procedure-related complications, especially post-ERCP pancreatitis (PEP), stone clearance, and mortality. 307 patients were identified. In 264 of the patients, the rendezvous cannulation technique was successful (86 %); in the remaining 43 patients, conventional cannulation technique was necessary. In total, PEP occurred in seven patients (2.28 %). One of the PEP patients was in the rendezvous cannulated group (0.37 %), whereas six patients developed PEP in the nonrendezvous group (13.95 %, p

Background. For many tumors, therapeutic options are sparse beyond the guidelines, especially for pancreatic cancer. At the same time, more and more biomarkers are known, informing about or supporting treatment decisions. Finally, tumor DNA analysis with next generation sequencing (NGS) is quickly becoming a routine test, at least for tumors. However, to analyse the vast amount of data and provide concrete, evidence-based treatment recommendations has been a challenge. Methods. Applying NGS in a quality controlled set-up together with the newly developed evidence-based software tool EngineusGUIDETM (CE-marked). Results. During the time from Oct 2013 until Oct 2015, 87 patients were analysed with EngineusGUIDE. In 7 cases, more than one tumor was investigated. NGS was performed (WXS = 48; panel/paired = 16, panel = 23). Sequencing could be performed in all but one patient (Whole Exome; bone metastasis). Sequencing quality was insufficient for analysis in 3 cases (paired panel), sequencing revealed insufficient tumor content in the sample for one patient (Whole Exome) leaving 82 patients. The indication was: Pancreatic Neoplasms = 21 cases; Colorectal Neoplasms = 12; Breast Neoplasms = 5; CUP = 6; NSCLC = 3; 2 cases each for Bronchial Neoplasms, Adenoid Cystic Carcinoma, Common Bile Duct Neoplasms, Glioblastoma, Multiple Myeloma, Prostatic Neoplasms and 1 case each for Adenocarcinoma, Duodenal Neoplasms, Endometrial Neoplasms, Hemangiosarcoma, Hypopharyngeal Neoplasms, Leukemia (Lymphocytic, Chronic, B-Cell), Liposarcoma, Liver Neoplasms, Lung Neoplasms, B-Cell Lymphoma, Mantle-Cell Lymphoma, Meningioma, Oropharyngeal Neoplasms, Ovarian Neoplasms, Paranasal Sinus Neoplasms, Parathyroid Neoplasms, Sarcoma, Sigmoid Neoplasms, Squamous Cell Neoplasms, Stomach Neoplasms, Thyroid Neoplasms, Urinary Bladder Neoplasms, Uveal melanoma. In 67/82 patients, druggable targets (response biomarkers) could be identified (range 0-8; median 2). In 45/82 patients (range 0-5; median 1) biomarkers indicated lack of efficacy (e.g. KRAS mutation in CRC). In 65/82 patients, biomarkers indicated increased toxicity (range 0-7; median 2), in 19/82 patients FDA-approved biomarkers for toxicity were detected (28 biomarkers). Of the positive biomarkers, 40 biomarkers in 26 patients indicated drugs approved in the indication, 75 biomarkers in 45 patients indicated approved drugs, and 58 biomarkers in 39 patients indicated experimental drugs (pre-clinical and phase I - III). Six patients have already received drugs recommended by EngineusGUIDE. In 11 patients, toxicity markers may explain observed toxicity during previous treatment. We are currently collecting the outcome parameters of EngineusGUIDE recommendations. Citation Format: Matthias Löhr, Katrin Stecker, Caroline Huelsewig, Sandra Morandell, Isin Ertongur, Sarah Luke-Glaser, Anna Laib, Linnéa Malgerud, Carlos Fernández Moro, Masoud Karimi, Johan Permert, Rainer Heuchel, Johan Lindberg, Valtteri Wirta, Alexander Picker, Marco Del Chiaro, Stephan L. Haas, Caroline S. Verbek, Lars Engstrand, Jens Siveke, David Jackson, Henrik Grönberg, Dirk Jäger, Stephan Brock. An evidence-based software tool for personalized cancer medicine to recommend therapeutic options and avoid toxicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3165.

The current study used islet amyloid polypeptide (IAPP) knockout mice (KO mice) to investigate the physiological role of IAPP in the regulation of food intake (FI).FI and body weight were measured in KO and wild-type (WT) mice for 27 weeks. In an additional short-term experiment, IAPP (25 pmol·kg(-1)min(-1)) was infused subcutaneously for 3 days in KO and WT mice, and FI, meal pattern, and body weight were analyzed.In the long-term experiment, no significant differences in body weight were seen between WT and KO mice at any point. FI, meal number, and meal size did not differ significantly between the groups in any of the five selected weeks that were studied. In the short-term experiment, FI decreased significantly during IAPP infusion in both WT and KO groups. FI was significantly lower in the KO mice compared with WT on days 1 and 2 (p0.05 and p0.01, respectively).The data showing no differences in FI and body weight were seen between KO and WT mice, indicating that FI can be controlled in the absence of IAPP. The more marked anorectic effect seen in the KO mice during IAPP infusion suggests that IAPP receptors and/or IAPP post-receptor signaling pathways are up-regulated in mice lacking endogenous IAPP.

Objective: To investigate the potential of a series of growth factors which may be involved in liver regeneration. Design: The concentrations of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and insulin-like growth factor I (IGF-I) were measured in plasma and liver tissue 48h after liver resection or sham operation combined with malnutrition. Methods: Forty-four rats were randomized to either semistarvation or ordinary food intake; half of each group was partially hepatectomized, and the other half underwent a sham operation and served as controls. Growth factors were measured by radioimmunoassay. Results: Plasma EGF levels were increased following semistarvation and were also increased in plasma and liver tissue after 48 h of liver regeneration

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.

Nine human exocrine pancreatic adenocarcinomas were examined by serial sectioning and double- and triple-labeled immunohistochemical techniques with antibodies against chromogranin A, insulin, islet amyloid polypeptide, glucagon, somatostatin, pancreatic polypeptide, serotonin, pancreastatin, and neuron-specific enolase. The results were correlated with the stage of the disease, histologic characteristics of the tumors, and survival of the patients. Cells immunoreactive with most or all of the antibodies were found in all nine cases. Abnormal co-location of some hormones in the same cell and the lack of normal co-location of other hormones were found. Endocrine cells also were identified in the invasive regions of the cancer, including perineural spaces. Abnormality in the production and release of the peptide was indicated not only in the endocrine cells of exocrine cancer, but also in the islets near the cancer. Patients whose cancer contained many endocrine cells seemed to survive longer than those with tumors containing fewer endocrine cells. The overall data suggested that the observed abnormalities may contribute to the impaired glucose tolerance found in six of these patients.

The mechanism by which high-fat diet potentiates pancreatic cancer is not known, but trophic hormones may be involved. In preliminary growth studies, hamsters fed a high fat diet (17.5% lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P < 0.01) in pancreatic weight compared to controls on low fat diet (2.5% lard, 2.5% corn oil). A significant increase was also seen at 28 days. Similar increases were seen in pancreatic DNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05) at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were 2.5 fold higher in the animals fed high fat (P < 0.01). Infusion of the CCK antagonist MK329 (25 nmol/kg/h) completely abolished the increase in pancreatic weight, pancreatic DNA and pancreatic RNA. The effect of CCK receptor blockade during the initiation period of carcinogenesis was investigated in hamsters fed the same diets used in the growth studies. One hundred animals received a single injection of N-nitrosobis(2-oxopropyl)amine, (BOP, 20 mg/kg). Half of the hamsters in each diet group received a 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 days before carcinogen administration. At the time of death, 55 weeks after carcinogen administration, non-fasting plasma CCK levels were 31% higher in the high fat fed hamsters than in the low fat fed animals (P < 0.01). The high-fat diet group had a 3-fold increase in total cancer incidence and a 5-fold increase in advanced lesions (adenocarcinomas). Tumor incidence and yield were not changed in either diet group by CCK-receptor blockade during the initiation period. Cholecystokinin appears to mediate the short-term trophic effect that high-fat feeding has on the pancreas. However, potentiation of pancreatic cancer by high-fat diet in the hamster cancer model does not appear to be influenced by endogenous cholecystokinin at the time of tumor induction.

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.

In this study, we investigated whether the anti-inflammatory drug PP56 (alpha-trinositol) may improve cancer-induced metabolic disorders. We implanted human MiaPaCa2 pancreatic cancer cells in the pancreas of 14 athymic mice for 12 weeks, using six intact littermates as normal controls. During the 12 weeks, seven tumor-cell recipients were treated with PP56 by daily injection (PPT mice). The tumor-cell recipients that were otherwise untreated were used as tumor controls (TC mice). Impaired glucose tolerance and decreased body weight gain were seen in TC but not PPT mice. When an enzyme for fatty acid beta-oxidation namely medium-chain acyl-CoA dehydrogenase (MCAD) was determined in tumor grafts; tumors from PPT mice showed more MCAD than those from TC mice. This suggests that PP56 stimulated fatty acid beta-oxidation in MiaPaCa2 cells in vivo. In keeping with this notion, PPT mice had decreased plasma free fatty acids. In vitro, we demonstrated that MiaPaCa2 cells consumed more fatty acids in the presence of PP56. In another experiment, we infused PP56 or vehicle in normal mice and found that PP56 decreased circulating glucose in the animals. We also showed that PP56 increased glucose transport in L6 skeletal muscle cells in vitro. In conclusion, PP56 increases the turnover of circulating nutrients such as glucose and helps maintain energy homeostasis in mice with pancreatic cancer.

Background Ischemia-reperfusion injury is a major concern with portal triad clamping (PTC) in liver surgery. Microdialysis allows continuous intraoperative monitoring of tissue metabolism in the liver. Our aim was to evaluate the feasibility of microdialysis as a tool to assess the intrahepatic metabolic effects of PTC in patients undergoing liver resection. Methods Eleven patients who underwent liver resection were subjected to intrahepatic microdialysis. Dialysis fluid samples were collected before, during, and after a 20-min period of PTC. Glucose, lactate, pyruvate (markers of ischemia), and glycerol (marker of cell membrane damage) were analyzed and the lactate/pyruvate ratio was calculated. Results During PTC, intrahepatic glucose, lactate, and glycerol increased from 9.1 ± 2.2 to 14.5 ± 2.4mM, from 2.2 ± 0.3 to 5.8 ± 0.5mM, and from 63 ± 14 to 142 ± 28 μM, respectively. Pyruvate was unchanged, resulting in an increased lactate/pyruvate ratio (from 39 ± 10 to 104 ± 32). During initial reperfusion, glucose further increased to 16.4 ± 2.9mM. Pyruvate increased after reperfusion (from 93 ± 18 to 138 ± 23 μM), while lactate was stable, resulting in a normalized lactate/pyruvate ratio. Glycerol continued to increase during initial reperfusion. Conclusions PTC was associated with considerable intrahepatic metabolic alterations with anaerobic metabolism, increased glycogenolysis, and cellular membrane damage resulting in increased levels of glucose, lactate, glycerol, and lactate/pyruvate ratio. Microdialysis is easy to use and allows continuous monitoring of intrahepatic metabolism during liver surgery.

The purpose of this study was to evaluate the accuracy of diffusion-weighted imaging (DWI) in diagnosis of pancreas cancer, to compare DWI with a conventional comprehensive MRI (MRI-c) and to analyse apparent diffusion coefficient (ADC) values of lesions. Thirty-six patients with pancreatic lesions (12 malignant and 24 benign) and 39 patients without lesions were included. MRI-c and DWI (free breathing, b values 0 and 500 s/mm(2)) were performed prospectively and consecutively in a 1.5-T system. The analysis was retrospectively performed blinded by two radiologists in consensus. The sensitivity, specificity, accuracy, and positive and negative predictive values of DWI and MRI-c were 92, 97, 96, 85, 98% and 100, 97, 97, 86, 100%, respectively. Mean ADC values of malignant lesions were significantly lower than those of benign lesions. DWI has a similar accuracy to MRI-c in diagnosis of pancreas cancer.

In this study, we investigated whether increased dietary fat influences established pancreatic cancer cells. MiaPaCa2 human pancreatic cancer cells were grown orthotopically in athymic mice fed normal diet (ND) or high-fat diet (HF). In the resulting tumors, medium-chain acyl-coenzyme A dehydrogenase (MCAD, a regulator of fatty acid beta-oxidation) and Cu/Zn-superoxide dismutase (an antioxidant enzyme) were determined using Western blotting. The MCAD messenger RNA (mRNA) was determined by real-time polymerase chain reaction. Intracellular lipid droplets, proliferating cells (Ki67 positive), and apoptotic cells were stained in tumor sections. The HF tumors were heavier than the ND tumors (1.60 +/- 0.08 vs 1.13 +/- 0.10 g, P < .01, 6 tumors per group). The MCAD and Cu/Zn-superoxide dismutase proteins and the MCAD mRNA were increased in HF tumors compared with those seen in ND tumors. The HF tumors contained extensive central necrosis, which was surrounded with apoptotic and proliferating cells. The HF tumors also showed numerous lipid droplets. In the ND tumors, necrosis was uncommon, apoptotic cells were sporadic, and lipid droplets were few. In follow-up experiments, MiaPaCa2 cells were incubated in vitro in the presence or absence of fatty acids (oleic and linoleic acids). The fatty acid exposure increased lipid droplets, cell proliferation, and MCAD mRNA expression in MiaPaCa2 cells. In conclusion, increased dietary fat stimulates lipid metabolism and cell turnover in MiaPaCa2 human pancreatic cancer cells.

The stress response to surgery is characterized by activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, and by an inflammatory response and hyperglycemia. The aim of the present study was to investigate if preoperative corticosterone could reduce the postoperative systemic stress response, without aggravating hyperglycemia or interfering with activation of the hypothalamic-pituitary-adrenal axis, in a standardized rat model of surgical trauma. We used a standardized experimental model of intestinal resection in the rat. Exogenous corticosterone (8 mg/kg body weight) or vehicle was administered 2 hours before surgery; and postoperative plasma concentrations of interleukin-6, interleukin-10, adrenaline, noradrenaline, glucose, and insulin were determined. Exogenous corticosterone decreased preoperative plasma adrenaline but did not change plasma glucose or insulin levels. Moreover, corticosterone reduced postoperative plasma interleukin-6, catecholamines, and glucose (all P < .001-.05) without any effect on the plasma corticosterone concentration compared with vehicle-treated controls. A preoperative 2-hour exposure of physiologic poststress corticosterone concentrations not only suppressed plasma IL-6 levels but also inhibited surgery-induced adrenaline release and suppressed plasma glucose levels. We hypothesize that glucocorticoids attenuated the inflammatory response in injured tissues that reduced afferent input into brain areas regulating the neuroendocrine response.

Massive hemorrhage results in hypovolemia and hypotension that activate the sympathetic-adrenal-system, the hypothalamic-pituitary-adrenal axis, and induce metabolic changes such as hyperglycemia. Blood loss during surgery, however, is rapidly compensated by intravenous fluids to minimize negative impact on circulation. The aim of this study was to develop an experimental model for studies of the stress response and metabolic alterations seen after major abdominal surgery by combining intestinal resection with compensated non-hypotensive blood loss.Intestinal resection in the rat was combined blood loss (7% and 16% of total blood volume) with subsequent fluid replacement (2 x volume of saline + hydroxyethyl starch, 50:50) to investigate the effects on blood pressure, plasma adrenaline, noradrenaline (0-2 h postoperatively), glucose, insulin, corticosterone, and hematocrit (0-24 h postoperatively).Surgical trauma alone or in combination with blood loss and fluid replacement did not decrease mean arterial blood pressure (MAP) compared with anesthetized controls. Plasma levels of catecholamines were unchanged during the period of blood loss. After surgery and blood loss, plasma glucose showed a blood loss volume-dependent increase up to 12 h postoperatively compared to surgery alone (P0.001-0.05). Plasma corticosterone increased after surgery alone and in combination with blood loss but the changes were not dependent on the magnitude of blood loss.Surgical trauma combined with compensated non-hypotensive blood loss induced persistent volume-dependent hyperglycemia that did not depend on changes in plasma corticosterone and, in the early postoperative phase, MAP and catecholamines. Our data indicate that blood loss per se, without causing hypotension or acute elevations in catecholamines, can induce marked postoperative hyperglycemia. The experimental model presented in this report will be a useful tool to further elucidate mechanisms underlying the changes in glucose metabolism seen after surgical injury.

Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death–inducing DNA fragmentation factor-α–like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P < 0.05) and correlated with elevated levels of FAs and reported weight loss (P < 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P < 0.01), decreased glucose oxidation by 40% (P < 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P < 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P < 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs. [Cancer Res 2008;68(22):9247–54]

In vivo activated T lymphocytes exhibit altered expression of insulin-like growth factor-1 receptor (IGF-1R) compared to the naive T lymphocyte pool. The objective of this study was to investigate the expression of IGF-1R RNA in CD4 and CD8 positive cells after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with and without GVHD. For this purpose we isolated RNA from CD4 and CD8 positive cells, sorted with immunomagnetic beads. We used real-time PCR for RNA quantification. We demonstrate a significantly decreased expression of IGF-1R RNA in both CD4 and CD8 positive cells up to 12 months after HSCT. We could not demonstrate a correlation between the IGF-1R RNA expression and T cell activating processes like GVHD, expansion of CD4 or CD8 populations or virus infections.

Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although 'proof-of-principle' has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.

In the subdiaphragmatic vagal deafferentation procedure (SDA), the afferent fibers of the vagus are surgically severed unilaterally where they enter the brain stem. The technique includes a subdiaphragmal truncal vagotomy performed on the contralateral side. This procedure has been used to study the control of food intake, but it has not been used previously to investigate the role of vagal afferent fibers in the control of gastric emptying (GE). The current experiment studied the effect of SDA on the inhibition of GE by islet amyloid polypeptide (IAPP or amylin) and cholecystokinin (CCK) in awake, unrestrained rats with gastric cannulas. The experimental group underwent subdiaphragmatic vagal deafferentation; the control group had sham operations. All rats received 20-min intravenous infusions of IAPP (1, 3, 9, 27, and 81 pmol/kg/min), CCK (3, 30 and 90 pmol/kg/min), and normal saline in random order. Gastric emptying of saline was measured by the phenol red method during the last 5 min of each infusion period. CCK dose-dependently inhibited gastric emptying in both the control and SDA animals. The inhibition of GE by CCK was significantly attenuated by SDA (p0.01). IAPP also inhibited gastric emptying dose-dependently, but the difference between the SDA and control groups was not significant. The current experiment, which used a different methodology than previous studies, provides support for the hypothesis that the inhibition of gastric emptying by CCK, but not by IAPP, is mediated partly by afferent vagal fibers.

Islet amyloid polypeptide (IAPP) is postulated to act as a hormonal signal from the pancreas to the brain to inhibit food intake and reduce adipose energy reserves. The present study compared the effects of chronic peripheral and chronic central administration of IAPP on food intake and meal pattern in rats. IAPP was administered subcutaneously (SC) for 7 days at doses of 0, 0.25, 2.5 and 25 pmol kg −1 min −1 using an osmotic minipump or administered centrally at doses of 0, 0.025, 0.25 and 2.5 pmol kg −1 min −1 using an osmotic minipump connected to an intracerebroventricular (ICV) catheter inserted into the third ventricle. Both SC and ICV infusion decreased total food intake dose-dependently. The minimal effective dose was 2.5 pmol IAPP kg −1 min −1 for SC administration and 0.25 pmol kg −1 min −1 for ICV infusion. The decrease in food intake produced by infusion of IAPP was mainly due to decreased meal size, although a significant decrease in meal number also occurred at the highest SC and ICV doses. SC administration produced a larger, more persistent decrease in food intake during the light period than in the dark period, while ICV infusion caused a larger, more persistent decrease during the dark period. The 10-fold difference in minimal effective doses indicates that ICV-administered IAPP acted primarily in the brain to inhibit food intake. The difference between the effects of IAPP on meal pattern with the two methods of administration suggests that IAPP does not act on the same target(s) when administered centrally as it does when it is administered peripherally.

He Z, Wang F, Kumagai-Braesch M, Permert J, Holgersson J. Long-term gene expression and metabolic control exerted by lentivirus-transduced pancreatic islets. Xenotransplantation 2006; 13: 195–203. © Blackwell Munksgaard, 2006 Abstract: Background: Genetic modification of non-human islets before transplantation may provide means by which they can escape immunity and, thus, be used in a human host. To accomplish this, efficient gene transfer methods are needed. Lentiviral vectors are transgene vehicles capable of stably transducing a variety of primary, post-mitotic cells including islets. Methods: We investigated whether lentiviral transduction impaired rat pancreatic islet function long term. Following transduction, the gross morphology, viability and in vitro functionality of islets were evaluated by microscopy, adenylate nucleotide and insulin secretion assays, respectively. Further, in vivo functionality of transduced islets was assessed by transplanting the islets under the kidney capsule of diabetic nude mice. Results: All transduced islets contained green fluorescent protein (GFP)-positive cells. In single cell suspensions prepared from transduced islets, 33±8% (n=3) of dispersed islet cells were GFP-positive. The ADP/ATP ratio was 0.07±0.01 for transduced islets and 0.06±0.01 for controls (normal range

group meets at six 3-day meetings. These takes place at the different universities where the mentors are working. To the fi rst course, which started in August 1999, participants were recruited from the Nordic and Baltic countries, to the second and 3rd courses participants from several northern European countries, including Germany, Switzerland, UK, France, and the Czech republic, were invited. Along with pancreatological education and leadership training the participants also plan and carry through scientifi c projects in network-based groups of 5–6 persons, guided by two mentors. This implies brain-storming for research ideas (fi rst meeting), implement ideas to research protocols, apply for ethical approval and funding, realise the projects and write a manuscript suitable for submission. The scientifi c projects also runs between the meetings and the aim is to fi nish the different projects during the two and a half years. This has, however, not always been possible. Some of the groups have thus continued and fi nished their projects outside the timeframe of the six meetings but still within the Pancreas 2000 network. This far, 13 different projects have been initiated and of these 5 have been accepted or published [1–5] and 4 have been, or will soon be, submitted [6–9] . One study of risk factors, predictors and course in ERCP-induced acute pancreatitis is ongoing and three of the initiated projects will probably not be completed. During the last decades the number of active scientists within pancreatology has decreased in Europe and the age of the active scientists has increased. To guarantee the future of clinical pancreatology and pancreatic research, the educational program ‘Pancreas 2000’ started in August 1999. This is a new concept for continuous collaboration between the university (Karolinska Institutet) and the pharmacological industry (Solvay Pharmaceuticals) with the purpose of creating an international network of physicians/scientists interested in pancreatology and thus to contribute to a positive development of European pancreatology. This is a true collaboration, scientifi c as well as economic, as the program is sponsored partly by the respective departments of the participants and partly by the industry. The program is designed to stimulate development in especially three areas: pancreatology, scientifi c thinking and group leadership. The program, of which the 3rd course now is running, has recruited 22–25 young physicians/scientists to each course. They work together with 10 senior pancreatologists, the mentors. The mentors are actively contributing to the lectures and discussions and, furthermore, to every meeting special guests (world leading pancreatologists) are also invited to give lectures. Associated to the program is one leadership expert, who participates in every meeting, and a statistician. One program runs over two and a half years during which the Published online: August 18, 2005

Release of glycerol and free fatty acids (FFA) was investigated in human skeletal muscle strips. In the basal state, glycerol and FFA were released at almost equimolar rates (0.3 nmol/ng tissue.90 min). A nonselective beta-adrenoceptor agonist, isoprenaline, caused a concentration-dependent stimulation of glycerol release, whereas FFA release was unaffected. Basal and isoprenaline-induced glycerol release correlated positively with the age of the donors (r = 0.5, P0.005) but not with their body mass index (Por = 0.4). Biochemical experiments with hormone-sensitive lipase (HSL) showed that most enzyme activity was both in the cytosol and mitochondrial fraction and that it constituted the common long and active form of the protein. Electron microscopy studies in rat skeletal muscle using labeled highly specific HSL antibodies verified the cytosolic location of HSL and, furthermore, indicated an accumulation of HSL-adjoining mitochondria. These results suggest that FFA produced in myocytes during catecholamine-induced lipolysis are retained by the muscle and, therefore by inference, reused. It is conceivable that efficient hydrolysis of acylglycerol by HSL located in the cytosol as well as near the mitochondria may facilitate mitochondrial FFA oxidation. In addition, muscle lipolysis activity increases during aging and may be independent of total body fat.

Hemorrhage from the pancreatic duct, i.e. hemosuccus pancreaticus (HP), is a rare cause of gastrointestinal bleeding. This potentially life-threatening complication of chronic pancreatitis may pose a significant diagnostic and therapeutic dilemma, especially in patients with silent forms of the disease.We report a case of a 64-year-old man with no history or symptoms but positive findings of chronic calcifying pancreatitis at computed tomography (CT) scan.The patient presented with repeated episodes of gastrointestinal bleeding requiring transfusion and did not, until later in the disease, develop hyperamylasemia and epigastric pain. Repeated endoscopies could not reveal the source of bleeding. The radiological diagnosis and successful transcatheter embolization of a small splenic pseudoaneurysm were performed during an interval when the patient was asymptomatic and showed no signs of bleeding.We suggest that when HP is suspected, a contrast-enhanced CT angiography with reconstruction of the arteries should be performed regardless of whether the patient shows signs of active bleeding or not.

Islet amyloid polypeptide (IAPP) reduces food intake and body weight in laboratory animals. In addition, IAPP appears to regulate nutrient metabolism. In the present studies, we investigated the effect of chronic IAPP treatment on different aspects of energy homeostasis.IAPP was infused (25 pmol/kg/min) from subcutaneous osmotic pumps for 2-7 days. Rats in 2 saline-infused control groups were fed ad libitum (AF) or pair-fed (PF) against the IAPP-treated rats.As expected, the IAPP infusion reduced food intake and body weight gain. In addition, the IAPP treatment decreased the epididymal fat pad (vs. PF rats, p0.05) and lowered circulating levels of triglycerides (vs. PF rats, p0.05), free fatty acids (vs. PF rats, p0.05), leptin (vs. both AF and PF rats, p0.05) and insulin (vs. AF rats, p0.05). In contrast, glucose and protein metabolism in the IAPP-treated rats was largely unchanged, as shown in results regarding serum glucose, glucose transport in skeletal muscle, blood urea nitrogen, and glycogen and protein content in the liver and in skeletal muscle.In summary, chronic IAPP exposure led to a changed lipid metabolism, which was characterized by decreased adiposity, hypolipidemia and hypoleptinemia, and to unchanged glucose and protein homeostasis. These results were similar to those seen in rodents during chronic exposure to another satiety/adiposity regulator, leptin. In conclusion, chronically administered IAPP plays a role as a satiety and adiposity signal in rats, and helps regulate energy homeostasis.

Background & aim : Little is known about the perspectives that patients with advanced cancer and their family members have concerning nutritional problems and nutritional support. The aim of this study was to investigate their experiences of the nutritional situation prior to introduction of home parenteral nutrition (HPN) in order to understand factors contributing to the decision to accept HPN. Methods : Semi-structured interviews were conducted with 13 patients with advanced cancer who had received HPN and 11 family members. The constant comparative method was used for data analysis. Results : Patients and family members described the nutritional situation prior to HPN as a source of worry and often desperation. Patients reported wanting and trying to eat, but being unable to do so. Family members experienced powerlessness and frustration, as they could not enable the patient to eat. A lack of attention to nutritional problems by the hospital staff was described. The offer of HPN came when patients and family no longer felt able to solve the nutritional problems within the family. Conclusion : The desperate and chaotic nutritional situation in the family led to willingness to accept HPN. Because of the severity of the problems, HPN was viewed as a positive alternative.

SUMMARY The objective of this study was to investigate if oligoclonality of the Ig repertoire post-haematopoietic stem cell transplantation (HSCT) is restricted to memory B lymphocytes or if it is a general property among B lymphocytes. As a measure of B lymphocyte repertoire diversity, we have analysed size distribution of polymerase chain reaction (PCR) amplified Ig H complementarity determining region 3 (CDR3) in naive and memory B lymphocytes isolated from patients before HSCT and at 3, 6 and 12 months after HSCT as well as from healthy controls. We demonstrate a limited variation of the IgH CDR3 repertoire in the memory B lymphocyte population compared to the naive B cell population. This difference was significant at 3 and 6 months post-HSCT. Compared to healthy controls there is a significant restriction of the memory B lymphocyte repertoire at 3 months after HSCT, but not of the naive B lymphocyte repertoire. Twelve months after HSCT, the IgH CDR3 repertoire in both memory and naive B lymphocytes are as diverse as in healthy controls. Thus, our findings suggest a role for memory B cells in the restriction of the oligoclonal B cell repertoire observed early after HSCT, which may be of importance when considering reimmunization of transplanted patients.

Chronic pancreatitis has an incidence of 3-8 new cases per 100,000 inhabitants and year. Alcohol is the most common cause. It is, however, not an independent risk factor but rather a co-factor. Smoking and genetic predisposition are increasingly regarded as causative factors. The diagnosis is today based mainly on history and findings at imaging tests. Pain treatment starts with NSAID-medication with or without paracetamol. Oral pancreatic enzyme therapy for pain should be tested early in the course. Endoscopic stent insertion into the main pancreatic duct can be used in selected cases. Operation is not recommended until other less invasive methods have been tested but should ideally be performed before addiction to opiates occurs. Oral enzyme supplementation is effective in the majority of cases with malnutrition. Most patients with chronic pancreatitis and diabetes need insulin treatment. Interdisciplinary specialist treatment teams should be established and take responsibility for diagnosis, assessment and interventional procedures (e.g. endoscopy, surgery). Due to the low incidence of the disease 3-4 such teams/centres seem appropriate in our country to allow a critical patient load.

Objective Enteral feeding in the early postoperative phase may improve gut integrity and reduce infectious complications after trauma and surgery. The aim of the current study was to evaluate the feasibility of α-ketoglutarate enrichment of enteral feeding and the effect on protein metabolism after major surgery. Methods Patients undergoing elective abdominal surgery were randomly allocated to receive a standard whole-protein–based enteral nutrition solution ( n = 9) or an isonitrogenous, isocaloric solution enriched with α-ketoglutarate ( n = 11) for 5 d postoperatively. The nutritional goals by day 4 were 25 kcal and 0.17 g of nitrogen, respectively, per kilogram of body weight every 24 h. Standard blood analysis, including prealbumin and C-peptide, was performed preoperatively and on days 1, 3, and 6. Urine was collected daily for nitrogen and 3-methylhistidine analyses. Results Due to restricted tolerance to enteral feeding, the nitrogen delivery reached only 0.10 g of nitrogen per kilogram of body weight. Transthyretin decreased by 25% in both groups, and albumin decreased significantly in the enriched group compared with the standard nutrition. There were no significant differences in nitrogen balance, excretion of 3-methylhistidine, or clinical outcome between groups. Conclusions Enrichment of a whole-protein–based formula with α-ketoglutarate did not improve protein metabolism or decrease muscle catabolism after major abdominal surgery.

Background: In malignant diseases, circulating amino acid profiles correlate with organ sites of malignancy. Direct effects of malignant cells on the extracellular amino acid profile are still uncertain. Methods: Free amino acids were measured in serum-free culture media (RPMI-1640) conditioned by two human pancreatic cancer cell lines (Panc-1 and HPAF), a hamster pancreatic cancer cell line (PC-1), a human epidermoid carcinoma cell line (A-431), and a human fibroblastic cell line (Ag-1523). Non-conditioned RPMI-1640 medium was used as control. Results: Amino acid profiles were changed in all the conditioned media, caused by a decrease or increase in the original amino acids and by the appearance of amino acids that were not present in non-conditioned medium. Media conditioned by two human pancreatic cancer cell lines showed similar amino acid profiles, which were characterized by a decrease in glutamine, cysteine and serine, increase in glycine, proline and glutamic acid and appearance of ornithine and alanine. Conclusion: Culture media show changed amino acid profiles following incubation with cell lines of pancreatic or non-pancreatic origins. Different human pancreatic cancer cell lines cause similar changes in amino acid profiles of media.

The incidence of pancreatic cancer has fallen during the last ten years in Sweden. Early signs and symptoms of the disease are still undiscovered and when diagnosis is made the disease is incurable in most patients. Transabdominal ultrasonography is the first-line imaging test followed by spiral computed tomography (CT) and magnetic resonance imaging (MRI) if required for definite diagnosis. Spiral CT is also the imaging test of choice for assessment of resectability of the tumor. Surgical removal of the tumor is the only chance of cure. Markedly improved hospital mortality after pancreaticoduodenectomy is reported and an association between hospital volume and outcome of the operation has been established. Longterm survival after attempted curative resection continues to be dismal, however. Adjuvant treatment should not be given outside clinical studies. Palliative treatment has improved thanks to progress in the field of endoscopy, interventional radiology and in management of pain and nutrition. Palliative chemotherapy should only be given selectively outside clinical studies. Radiotherapy has no proven effects on survival. Special pancreatic cancer treatment teams with catchment areas of 2-4 million inhabitants are recommended by international authorities.

A majority of patients with pancreatic cancer have obstructive jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with significant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditure and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown.Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro.The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemic and hypoinsulinemic but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats.Experimental obstructive jaundice in the rat is associated with increased liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulated liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreatic cancer patients.

This report by The Swedish Council on Technology Assessment in Health Care (SBU) reviews, classifies, and grades the scientific literature on cancer chemotherapy in some major tumour types, describes the practice of chemotherapy in Sweden, compares practice with scientific knowledge, and analyses the costs and cost-effectiveness of chemotherapy. The report is intended primarily for decision-makers at various levels, both practitioners and administrators. It is also of interest for the medical profession. The extensive body of scientific literature was reviewed according to strict criteria that reflected the scientific weight of the literature. Sixteen experts representing different disciplines (oncology, surgery, internal medicine, health economy and quality of life research) participated in the literature review. Each section was discussed within the project group and was reviewed by at least one, but usually two international researchers. Additional input was provided by national experts representing different scientific disciplines. For the final evaluation to be as close to the objective truth as possible, a concerted effort was made to guarantee objectivity and thorough assessment of current knowledge about the effects of chemotherapy on the selected cancers. The tumour types selected for this assessment include firstly those types where three investigations had shown an increased use of chemotherapy in Sweden during the latest decade. These were non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, colorectal cancer and urinary bladder cancer. Secondly, the two tumour types comprising the greatest number of patients treated with chemotherapy in Sweden, breast cancer and haematological malignancies, were included. Among the haematological malignancies, the most prevalent ones, acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), aggressive non-Hodgkin's lymphoma (NHL) of the large B-cell type and indolent NHL of follicular type were evaluated. These constitute about 75%, of all haematological malignancies. Thirdly, ovarian cancer was included since chemotherapy has been extensively used and since, at the time of the planning of this overview, a group of very expensive drugs, the taxanes, had preliminarily shown promising results. A wealth of scientific literature has been published on cancer therapy. The review presented in this report is limited to scientific studies judged to be important for evaluating chemotherapy efficacy. Assessments of the content and quality of these studies, and a critical summary of the results in all stages of the selected tumours, have never before been attempted in this way. However, similar comprehensive overviews of certain stages of the tumours have previously been made. These overviews were also critically evaluated. Totally 1,496 studies involving 558,743 patients were reviewed. The survey of practice of chemotherapy use involved all departments of surgery, urology, gynaecology, internal medicine including haematologic units, pulmonary medicine and general and gynaecologic oncology at 16 hospitals in two health care regions in Sweden, covering 39% of the Swedish population. During the 4 weeks of the survey, all patients with the diagnoses concerned who received chemotherapy were registered. The study included 1,590 patients. The working group's general conclusions are summarised in the following points: The literature on the effects of chemotherapy is extensive. Chemotherapy has a well-documented role in the curative and palliative treatment of patients with several types of cancer. The use of chemotherapy is of utmost importance for the possibility of cure in certain tumour types. In other tumours, chemotherapy increases the possibility of cure when added to local and regional treatments, particularly surgery. In the instances of no possibility of cure, chemotherapy may to a variable extent improve both patient survival and well-being. In Sweden chemotherapy is largely used in accordance with that documented in the scientific literature. The extent of both over- and under-treatment seems to be limited but cannot be excluded at the individual patient level. The literature-based knowledge is scientifically of lower quality in the most chemotherapy sensitive tumours than in tumours showing more limited sensitivity. In the more sensitive tumours, positive effects on a symptomatic stage and survival were seen several decades ago. In those days, clinical treatment studies did not fulfil the current high quality requirements. Small life-prolonging effects of chemotherapy are sometimes very well documented in large, high quality scientific studies. Some of these s

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40:155-65). The conclusions of this overview in pancreatic cancer are based on 10 randomised studies with, and 18 randomised studies without, an untreated control group. Altogether, 4,028 patients were included in the phase III studies. Furthermore, 32 phase II studies or retrospective analyses including 1,404 patients have been evaluated. The conclusions reached can be summarized into the following points: There is no convincing evidence that pancreatic cancer patients benefit from adjuvant chemotherapy treatment, with or without concomitant radiotherapy. Adjuvant chemotherapy in patients with pancreatic cancer should thus not be used routinely. In locally advanced/metastatic pancreatic cancer, six randomised trials comparing combination chemotherapy with an untreated control group were retrieved. In three trials, two of which were performed recently, chemotherapy provided statistically significant prolongation in median survival in the range of three to nine months. The three other trials, all reported in the early 80s, essentially showed no difference in survival between the treatment groups. In the locally advanced/metastatic setting there are also several randomised trials comparing various chemotherapy regimens. Except for an improvement in median survival of one to two months from gemcitabine compared with 5-FU, no differences were observed. There is no convincing evidence that a large fraction of pancreatic cancer patients will benefit from palliative chemotherapy. The few open-design studies that have explored the influence on symptom relief/quality of life indicate that between 20-35% of the patients get clinical benefit, but usually short-lived. Recently performed randomised studies, all using adequate methodology, indicate that the beneficial effects observed in advanced pancreatic cancer are similar to those of accepted therapy in other cancer types. However, due to the limited positive effects, palliative chemotherapy in pancreatic cancer can only be recommended selectively and should preferably be used within controlled clinical trials exploring new treatment combinations or concepts.