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In animal models of cachexia, alterations in the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway have been demonstrated in atrophying skeletal muscles. Therefore, we assessed the activity of proteins in this pathway in muscle and liver biopsies from 16 patients undergoing pancreatectomy for suspect of carcinoma. Patients were divided in a non-cachectic or cachectic group according to their weight loss before operation. Extracts of skeletal muscle and liver tissue from eight cachectic patients with pancreas carcinoma and eight non-cachectic patients were analysed by Western blotting using pan- and phospho-specific antibodies directed against eight important signal transduction proteins of the PI3-K/Akt pathway. Muscle samples from cachectic patients revealed significantly decreased levels of myosin heavy chain (-45%) and actin (-18%) in comparison to non-cachectic samples. Akt protein level was decreased by -55%. The abundance and/or phosphorylation of the transcription factors Foxo1 and Foxo3a were reduced by up to fourfold in muscle biopsies from cachectic patients. Various decreases of the phosphorylated forms of the protein kinases mTOR (-82%) and p70S6K (-39%) were found. In contrast to skeletal muscle, cachexia is associated with a significant increase in phosphorylated Akt level in the liver samples with a general activation of the PI3-K/Akt cascade. Our study demonstrates a cachexia-associated loss of Akt-dependent signalling in human skeletal muscle with decreased activity of regulators of protein synthesis and a disinhibition of protein degradation.

BACKGROUND Lamps and Mac-2-BP are ligands of galectin-3, and they were suggested to influence tumor proliferation and metastasis formation. The authors studied the expression of Lamp-1, Lamp-2, and Mac-2-BP in pancreatic carcinoma and evaluated their influence on patient prognosis. METHODS Northern blot analysis, in situ hybridization, and immunohistochemistry were performed in 12 normal and 28 pancreatic carcinoma tissue samples and in pancreatic carcinoma cell lines. The molecular findings in the tumor samples were correlated with the prognosis and histopathologic tumor characteristics. In addition, in Lamp-1 transfected CAPAN-1 pancreatic carcinoma cells, cell proliferation was analyzed. RESULTS Lamp-1, Lamp-2, and Mac-2-BP were overexpressed in 61% (1.6-fold increase, not significant), 71% (3.0-fold increase, P < 0.01), and 93% (5.6-fold increase, P < 0.01) of the pancreatic carcinoma samples. Lamp-1 and Lamp-2 immunoreactivity was present at the luminal side of the ductal carcinoma cells whereas Mac-2-BP immunoreactivity was diffusely spread over the whole cytoplasm and the nucleolus of ductal carcinoma cells. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited high Lamp-1 mRNA expression lived significantly longer (median, 17 months) after tumor resection than patients whose tumors exhibited low to moderate Lamp-1 mRNA levels (median, 8 months; P < 0.02). No relation between Lamp-2 and Mac-2-BP mRNA expression and any of the histopathologic parameters was found. Lamp-1 transfected CAPAN-1 cells showed decreased cell growth compared with the nontransfected cells. CONCLUSIONS Lamp-1 might influence local tumor progression rather than the formation of tumor metastasis in pancreatic carcinoma, whereas Mac-2-BP and Lamp-2 seem to have little influence on these parameters in pancreatic carcinoma. Cancer 2002;94:228–39. © 2002 American Cancer Society.

BackgroundMortality due to severe or necrotizing acute pancreatitis most often results from multiorgan dysfunction syndrome (MODS) occurring either early (within the first 14 days) or 2 weeks or more after the onset of symptoms due to septic complications. The aim of this study was to analyse the course of the disease in patients who died from severe acute pancreatitis.MethodsBetween January 1994 and August 2000 details of 263 consecutive patients with acute pancreatitis were entered prospectively into a database. All patients were treated in an intermediate or intensive care unit.ResultsThe overall mortality rate was 4 per cent (ten of 263 patients). The mortality rate was 9 per cent (ten of 106) in patients with necrotizing disease. No patient died within the first 2 weeks of disease onset. The median day of death was 91 (range 15–209). Six patients died from septic MODS. Ranson score, Acute Physiology and Chronic Health Evaluation (APACHE) II score during the first week of disease, pre-existing co-morbidity, body mass index, infection and extent of necrosis were significantly associated with death (P < 0·01 for all parameters). However, only infection of the necrotic pancreas was an independent risk factor in the multivariate analysis.ConclusionEarly deaths in patients with severe acute pancreatitis are rare, mainly as a result of modern intensive care treatment. Nine of the ten deaths occurred more than 3 weeks after disease onset. Infection of pancreatic necrosis was the main risk factor for death.

PURPOSE: Papilla of Vater cancer has a much better prognosis than pancreatic cancer. It is not known whether this is the result of differences in the tumor biology of the two malignancies. Because metastasis formation is a critical step in tumor progression and a negative prognostic factor, we compared the expression of nm23-H1 and KAI1, two metastasis-suppressing genes, in papilla of Vater cancer and pancreatic cancer. PATIENTS AND METHODS: Analysis was performed in nine normal human papilla of Vater samples, 27 papilla of Vater cancers, 16 normal pancreatic samples, and 29 pancreatic cancers. Expression of nm23-H1 and KAI1 was analyzed by Northern blot analysis and in situ hybridization. In addition, immunohistochemistry was performed to localize the respective proteins. RESULTS: There was no difference in nm23-H1 and KAI1 mRNA expression levels in normal versus cancerous papilla of Vater samples. In contrast, nm23-H1 and KAI1 RNA expression was upregulated in early tumor stages of pancreatic cancer and reduced in advanced tumor stages. When expression of nm23-H1 and KAI1 RNA was analyzed by use of in situ hybridization, normal epithelial cells of the papilla of Vater exhibited mRNA staining intensity similar to that of papilla of Vater cancer cells. Similar levels of nm23-H1 and KAI1 immunoreactivity also were observed in these samples. In contrast, early stage pancreatic cancer samples exhibited stronger nm23-H1 and KAI1 immunoreactivity than normal controls. Furthermore, early pancreatic cancer stages exhibited higher KAI1 and nm23-H1 immunostaining than advanced tumor stages. CONCLUSION: Differences in the expression patterns of the two tumor suppressor genes nm23-H1 and KAI1 may contribute to the different prognoses of papilla of Vater cancer and pancreatic cancer. Our findings support the hypothesis that biologic differences rather than earlier diagnosis influence the different outcomes of these two tumor entities.

Primary endocrine neoplasms of the biliary tract are exceedingly rare. We report on a 60-year-old man with diarrhea, vomiting and gastroesophageal reflux disease, with a primary gastrinoma of the common hepatic duct. The tumor was positive for a variety of immunohistochemical markers. Postoperatively the patient’s symptoms disappeared and in the follow-up the patient was symptom free. To our knowledge, this is the first case in the literature of a primary gastrinoma in the common hepatic duct. The fact that the common hepatic duct is not located within the gastrinoma triangle made the diagnosis difficult and the distinct localization made the surgical treatment demanding.

Objectives: Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by vancomycin-resistant enterococci. Resistance to linezolid has been associated with a G2576U mutation in domain V of the 23S rRNA. Patient and methods: We present clinical details and susceptibility data from multiple Enterococcus faecium strains isolated from a liver transplant patient over 13 months. MICs of linezolid, vancomycin and quinupristin/dalfopristin were determined using Etest. Molecular typing was performed by pulsedfield gel electrophoresis. Domain V of the 23S rRNA gene in the vancomycin-resistant Enterococcus faecium was amplified. Linezolid concentrations were analysed by HPLC. Results: We report the emergence of resistance to linezolid in a vancomycin-resistant Enterococcus faecium during linezolid treatment. After discontinuation of the linezolid therapy, the isolate reverted to susceptibility. However, after re-administration of linezolid the vancomycin-resistant Enterococcus faecium became resistant to linezolid again. The isolates that were resistant to linezolid had a G2576T mutation in their 23S rDNA. Conclusion: We describe a clinical case that shows the shift of a vancomycin-resistant Enterococcus faecium from linezolid resistance to susceptibility and then back to resistance again related to linezolid therapy.

Cachexia occurs in many end stage diseases like HIV, COPD, Crohn’s disease and especially in cancer diseases. Especially in pancreatic cancer this life-threatening symptom is responsible for about 20% of the cancer death. It is a complex metabolic status with a progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. Although a lot of research work is done in this subject, it is still unclear if the cachexia is an answer of the patient to the tumor or if the tumor itself produces cachexia.

In recent years many efforts of researchers and clinicians were made to improve our knowledge of cachexia syndrome. Not only cancer, but also many chronic or end-stage diseases such as AIDS, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, tuberculosis and Crohn's disease are associated with cachexia, a condition of abnormally low weight, weakness, and general bodily decline which deteriorates quality of life and reduces the prognosis of the patients who suffer from it. In the present editorial we will focus cachexia related on cancer and provide some insight into this prognosis-limiting syndrome.

Nerve alterations and neuroimmune interactions have been suggested to participate in the generation of pain. In this study, we compared neural changes and the pattern of perineural inflammatory cell infiltrates in three different etiological forms (alcoholic, idiopathic, tropical) of chronic pancreatitis (CP).

Background: The role of preoperative biliary drainage in patients with biliary obstruction undergoing pancreatoduodenectomy remains controversial. Several authors failed to show any effect of preoperative biliary drainage, whereas others even reported an increased morbidity following pancreatoduodenectomy. Methods: Retrospective analysis was performed in a consecutive series of 257 patients undergoing pancreatoduodenectomy between November 1993 and November 1999. Results: Ninety-nine patients (38%) underwent preoperative biliary drainage for a median time period of 10 days (range 1 to 41) prior to resection. Cumulative postoperative morbidity was 47% (120 patients), the reoperation rate was 4.3% (11 patients), and mortality was 2.3% (6 patients). There was no difference in total morbidity, infectious complications, reoperation rate, mortality, or long-term survival between patients with or without preoperative biliary drainage. Conclusions: Preoperative biliary instrumentation and biliary drainage do not affect early or late outcome in patients undergoing pancreatoduodenectomy.

Background: Delayed gastric emptying is one of the most frequent postoperative complications after Whipple resection. In the present study we evaluated the role of enteral nutrition in the development of delayed gastric emptying after Whipple resection. Patients and methods: Between January 1996 and June 1998, 64 patients (30 female, 34 male) underwent a classic (n = 27) or pylorus-preserving (n = 37) Whipple resection. Two patients were excluded; 30 patients received enteral and 32 patients received no-enteral nutrition. Results: Delayed gastric emptying occurred significantly more in patients with enteral (17 of 30, 57%) than in patients with no-enteral nutrition (5 of 32, 16%) (P

Because of antibiotic prophylaxis for necrotizing pancreatitis, the frequency of fungal superinfection in patients with pancreatic necrosis is increasing. In this study we analyzed the penetration of fluconazole into the human pancreas and in experimental acute pancreatitis. In human pancreatic tissues, the mean fluconazole concentration was 8.19 ± 3.38 μg/g (96% of the corresponding concentration in serum). In experimental edematous and necrotizing pancreatitis, 88 and 91% of the serum fluconazole concentration was found in the pancreas. These data show that fluconazole penetration into the pancreas is sufficient to prevent and/or treat fungal contamination in patients with pancreatic necrosis.

In einem Zeitraum von 30 Monaten wurde bei 64 Patienten eine klassische (n = 27) oder eine pylorus-erhaltende Whipple Operation (n = 37) vorgenommen. 62 Patienten wurden in die Untersuchung eingeschlossen. 30 Patienten erhielten enterale Ernahrung (intraop. Jejunalsonde), bei 32 Patienten wurde keine enterale Ernahrung gegeben. Eine Magenentleerungsstorung war signifikant haufiger bei Patienten mit enteraler als bei Patienten ohne enterale Ernahrung. Patienten mit enteraler Ernahrung benotigten die Magensonde langer und die Hospitalisationsdauer war signifikant langer als bei Patienten ohne enterale Ernahrung. Die postoperative Komplikationsrate war in beiden Patientengruppen nicht unterschiedlich. Die fruhpostoperative enterale Ernahrung nach Whipple Operation ist mit einer hoheren Magenentleerungsstorungsrate assoziiert. Daher sollte die enterale Ernahrung bei diesen Eingriffen auf spezifische Indikationen beschrankt werden und nach Whipple OP nicht routinemasig gegeben werden.

To evaluate the parameters that mediate fibrogenesis in chronic pancreatitis (CP).Connective tissue growth factor (CTGF), which is regulated by transforming growth factor beta (TGF-beta), has recently been implicated in skin fibrosis and atherosclerosis. In the present study, the authors analyzed the concomitant presence of TGF-beta1 and its signaling receptors-TGF-beta receptor I, subtype ALK5 (TbetaR-I(ALK5)), and TGF-beta receptor II (TbetaR-II)-as well as CTGF and collagen type I in the pancreatic tissue of patients undergoing surgery for chronic pancreatitis.CP tissue samples were obtained from 40 patients (8 women, 32 men) undergoing pancreatic resection. Tissue samples of 25 previously healthy organ donors (12 women, 13 men) served as controls. The expression of TGF-beta1, TbetaR-I(ALK5), TbetaR-II, CTGF, and collagen type I was studied by Northern blot analysis. By in situ hybridization and immunohistochemistry, the respective mRNA moieties and proteins were localized in the tissue samples.Northern blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA expression of TGF-beta1 (38-fold), TbetaR-II (5-fold), CTGF (25-fold), and collagen type I (24-fold) compared with normal controls. In addition, TbetaR-I(ALK5) mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ hybridization, TGF-beta1, TbetaR-I(ALK5), and TbetaR-II mRNA were often seen to be colocalized, especially in the ductal cells and in metaplastic areas where atrophic acinar cells appeared to dedifferentiate into ductal structures. In contrast, CTGF was located in degenerating acinar cells and principally in fibroblasts surrounding these areas. Moreover, CTGF mRNA expression levels correlated positively with the degree of fibrosis in CP tissues.The concomitant overexpression of CTGF, collagen type I, TGF-beta1, and its signaling receptors in CP suggests that these proteins contribute to enhanced extracellular matrix synthesis and accumulation, resulting finally in the fibrogenesis observed in CP.

Neben der Destruktion des Pankreasparenchyms, mit nachfolgender exokriner Pankreasinsuffizienz, sind chronische Oberbauchschmerzen ein zweites klinisches Leitsymptom der chronischen Pankreatitis (CP). In der Schmerzgenese bei chronischer Pankreatitis werden Nervenveranderungen eine zunehmende Bedeutung beigemessen [1–4]. Bei chronischer Pankreatitis ist die Anzahl der Pankreasnerven erhoht, der Nervendurchmesser deutlich vergrosert, und das Perineurium weist deutliche Schadigungen auf [2]. Weiterfuhrende Untersuchungen zeigten, dass die Pankreasnerven aktiv wachsen, und das das Nervenwachstum und die perineurale Entzundungszellinfiltration mit der Oberbauch-Schmerzintensitat der CP Patienten korrelieren [4].

In recent years many efforts of researchers and clinicians were made to improve our knowledge of cachexia syndrome. Not only cancer, but also many chronic or end-stage diseases such as AIDS, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, tuberculosis and Crohn's disease are associated with cachexia, a condition of abnormally low weight, weakness, and general bodily decline which deteriorates quality of life and reduces the prognosis of the patients who suffer from it. In the present editorial we will focus cachexia related on cancer and provide some insight into this prognosis-limiting syndrome.

Pancreatic ductal adenocarcinoma (PDAC) presently has an incidence of approximately 8 to 10 cases per 100000 citizens in European countries, and the incidence has been increasing throughout the last decades. Approximately 30000 patients die every year from PDAC in Western Europe and most of the newly diagnosed patients present with an already unresectable tumor stage. Self-sufficiency in growth signals, insensitivity to antigrowth signals, and evasion of apoptosis are hallmarks of malignant growth. In PDAC a variety of growth factors are expressed at increased levels. For example, the concomitant presence of the EGF-receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. In addition, PDACs often exhibit alterations in growth inhibitory pathways such as Smad4 mutations and Smad6 and Smad7 overexpression, and evade apoptosis through p53 mutations and aberrant expression of apoptosis regulating genes such as members of the Bcl family. Taken together, the abundance of growth promoting factors and the disturbance of growth inhibitory and apoptotic pathways give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival prognosis.