Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer.

BACKGROUND: The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed. METHODS: Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival. RESULTS: We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer. CONCLUSIONS: Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.

Diabetes and pancreatic cancer.

The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients. Epidemiological studies have consistently shown a modest increase in the risk of pancreatic cancer in type 2 diabetes, with an inverse relationship to duration of disease. Additionally, recent studies suggest that anti-diabetic medications may modulate the risk of pancreatic cancer in type 2 diabetes. Subjects >50 years of age with new onset diabetes are at higher risk of having pancreatic cancer. However, to screen new-onset diabetes for pancreatic cancer, additional markers are needed that can distinguish pancreatic cancer-associated diabetes from type 2 diabetes.

Recent advances in autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is distinct from calcifying and obstructive forms of chronic pancreatitis. Clinically and histologically it has two distinct subsets: (i) lymphoplasmacytic sclerosing pancreatitis or type 1 AIP which appears to be a systemic disease characterised by abundant infiltration of affected organs with immunoglobulin G4 (IgG4)-positive plasma cells and (2) duct-centric or type 2 AIP characterised by granulocyte epithelial lesions in the pancreas without systemic involvement. In AIP a marked lymphoplasmacytic infiltrate that responds dramatically to steroid therapy suggests an autoimmune aetiology. However, the target autoantigen(s) and the effector cells in AIP remain speculative. Despite the consistent elevation in serum IgG4 levels and tissue infiltration with IgG4-positive plasma cells in type 1 AIP, the role of IgG4 in its pathogenesis remains unknown. Recent development of animal models of AIP will help improve our understanding of the pathogenesis of these newly described forms of chronic pancreatitis.

Endoscopic ultrasonography and pancreatic cancer.

Despite extensive multidisciplinary efforts, the five-year survival rate for all patients with pancreatic adenocarcinoma remains less than 3%. In the last twenty years, endoscopic ultrasound (EUS) has developed into an indispensable tool for the diagnosis and staging of malignant pancreatic lesions. EUS, in combination with helical and multidetector computed tomography scans, is currently 80-90% accurate in determining the tumor TNM stage. EUS fine-needle aspiration obtains diagnostic pathologic samples in approximately 80% of cases, and intraductal ultrasound has augmented the ability to determine the malignant potential of pancreatic strictures. In patients at high-risk for pancreatic malignancy, EUS has been advocated as a screening tool for malignancy. Finally, exciting new developments suggest the potential of EUS as a therapeutic tool, both for the management of pain from pancreatic cancer and as a novel therapeutic-delivery device.

Islet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer.

BACKGROUND & AIMS: Islet amyloid polypeptide (IAPP) levels are elevated in pancreatic cancer and may be a useful marker of pancreatic cancer-associated diabetes. The aim of this study was to compare the sensitivity and specificity for pancreatic cancer of IAPP with that of CA19-9, examine clinical characteristics of diabetes in pancreatic cancer, and define the relationship of IAPP to diabetes of pancreatic cancer. METHODS: Fasting serum glucose, IAPP, and CA 19-9 were measured in 130 subjects with pancreatic cancer, 250 subjects with other pancreatic and peripancreatic diseases, and 116 controls. In pancreatic cancer patients, we noted tumor stage and the presence and duration of diabetes. RESULTS: IAPP was markedly elevated in pancreatic cancer, especially in patients with diabetes. However, the sensitivity of IAPP for pancreatic cancer was less than that of CA 19-9 (40% vs. 75%; P < 0.001). Diabetes was present in 46% of pancreatic cancers and 55% of resectable tumors. In pancreatic cancer with diabetes, the sensitivity of IAPP was only 50%. In resectable cancer it was 27%. CONCLUSIONS: IAPP is elevated in pancreatic cancer but is not sensitive enough to replace or complement existing tests. Diabetes occurs early and frequently in pancreatic cancer. Development of a sensitive and specific marker for pancreatic-associated diabetes might lead to diagnosis of resectable pancreatic cancer.

Chronic pancreatitis.

An increasing number of novel mutations are associated with chronic pancreatitis. Some cause a high-penetrance, autosomal dominant type of clinical picture (eg, mutations at codons 29 and 122 of the cationic trypsinogen gene), whereas others have a low penetrance or are frequent in the general population (eg, mutations in Kazal type 1 [SPINK1] and in codons 16, 22, and 23 of the cationic trypsinogen gene) and act as disease modifiers. The results of recent studies indicate that smoking adversely affects the course and complications of chronic pancreatitis (more frequent and faster rate of calcification and higher risk of development of pancreatic cancer). Thus, regardless of the cause of chronic pancreatis, patients with this condition should not smoke. Using current diagnostic criteria, the accuracy of endoscopic ultrasound for the diagnosis of chronic pancreatitis is not good. For example, 39% of dyspeptic persons without any other evidence of chronic pancreatitis fulfilled the endoscopic ultrasound criteria for chronic pancreatitis. Diabetes frequently occurs in chronic pancreatitis, but it is not prevented or increased by pancreatic surgery. Islet cell autotransplantation holds promise for the prevention of diabetes in patients requiring total pancreatectomy if the pancreas is not extensively fibrotic. Splenic vein occlusion is present in 7% of patients undergoing surgery for chronic pancreatitis, but fewer than one fifth of these patients have variceal bleeding before or after surgery.

Ileocolonic anastomotic ulcers: a case series and review of the literature.

OBJECTIVE: Although gastric anastomotic ulcers have been well described, there are only a few reports in the literature, mostly in the pediatric population, of ulcers occurring at colonic anastomotic sites. Our aim was to determine the clinical profile of postoperative colonic anastomotic ulcers in adult patients undergoing colonoscopy at our institution. METHODS: We performed a retrospective review of colonoscopies done at our institution between 1993 and 1997. RESULTS: Six patients with colonic anastomotic ulcers were identified; all had ileocolonic anastomoses. All patients presented with iron deficiency anemia with evidence of gastrointestinal (GI) blood loss and this was the indication for colonoscopy. The age at the time of ileocolonic anastomoses ranged from birth to 74 yr and age at the time of colonoscopy ranged from 24 to 76 yr. The interval between surgery and detection of anastomotic ulcer ranged from 15 months to 28 yr. Only two patients had a possible etiology: one with previous small bowel Crohn's disease, and the other with significant nonsteroidal antiinflammatory drugs (NSAID) use and evidence of small-bowel ulcers in the adjacent ileum as well. Three of the patients had previously undergone surgical resection and revision of the anastomosis without benefit; the ulcers recurred at the new anastomosis and continued to bleed. CONCLUSIONS: Ulcers can develop at sites of ileocolonic anastomoses. The commonest presentation is with iron deficiency anemia due to occult blood loss. The etiology of the ulcer, in most patients, remains speculative. The therapeutic approach to these ulcers is to discontinue all NSAIDs, treat underlying inflammatory bowel disease, if present, and supplement with oral iron. Surgery should be reserved for life-threatening bleeds or for anemia refractory to oral iron therapy.

Chronic pancreatitis.

In the past year, there has been at least one important clinical paper that sheds light on the character and natural history of painful chronic pancreatitis, which has important clinical implications. In addition, several novel mutations have been described in the cationic trypsinogen gene in patients with hereditary pancreatitis. The mechanism by which these mutations cause pancreatic disease remains speculative. The diagnosis of early chronic pancreatitis is controversial. A novel noninvasive pancreatic function test (measurement of postprandial APOB-48) was reported but is unlikely to be a sensitive test of pancreatic function. Pancreatic fibrosis is frequently seen in alcoholics without chronic pancreatitis, and this makes it difficult to interpret the findings on endoscopic ultrasonogram. Recent studies highlight the difficulty in abolishing pancreatic steatorrhea. Recently fibrosing colonopathy in adult patients has been reported. Extracorporeal shockwave lithotripsy combined with endoscopic therapy failed to benefit patients with calcific chronic pancreatitis.

Chronic pancreatitis.

In the past year, numerous important papers were published on chronic pancreatitis, its causes, and its diagnosis; the cause of fibrosis; and pain in pancreatic cancer. More than 750 mutations have been described in the cystic fibrosis transmembrane regulator (CFTR) gene. Some mutations cause relatively mild reductions in CFTR function and may lead to disease in one organ without clinical involvement of other organs. Two groups of investigators recently reported that "idiopathic" chronic pancreatitis may be the sole manifestation of some CFTR mutations. Some recent reports may enhance our understanding of pancreatic fibrogenesis and may lead to therapies for painful chronic pancreatitis. Pancreatic stellate cells are vitamin A-containing cells that resemble hepatic stellate cells and were recently isolated from rat and human pancreas. They respond to inflammatory cytokines by producing collagen. Two studies show that endoscopic ultrasonography (EUS) correlates well with endoscopic retrograde cholangiopancreatography in moderate to severe chronic pancreatitis. However, in patients who have a few nondiagnostic abnormalities on EUS, these results have poor correlation with the results of endoscopic retrograde cholangiopancreatography and the secretin test. The clinical significance of these abnormalities is unclear, and the diagnosis of chronic pancreatitis should not be based on EUS findings alone. Painful chronic pancreatitis is a complex and difficult management problem. A recent study of alcoholic chronic pancreatitis suggests that the best predictors of pain relief are an intermittent pattern of pain and the presence of surgically correctable complications (eg, pseudocysts or biliary obstruction). An American Gastroenterological Association technical review of painful chronic pancreatitis emphasized the lack of controlled studies supporting any form of therapy. Further evidence that longstanding chronic pancreatitis is a premalignant condition has been provided by recent epidemiologic, pathologic, and molecular biology studies.

Fibrocalculous pancreatic diabetes. Long-term survival analysis.

OBJECTIVE: To determine the long-term survival and causes of death in fibrocalculous pancreatic diabetes, a form of diabetes secondary to tropical chronic pancreatitis. RESEARCH DESIGN AND METHODS: A cohort of 370 patients with fibrocalculous pancreatic diabetes were analyzed with respect to survival time from the date of occurrence of the first symptom of the disease as well as after the onset of diabetes. The cause of death was analyzed in the patients who died. Cumulative survival rates were calculated by the actuarial method, and life table graphs were plotted by mathematical calculations. RESULTS: Long-term survival of patients with fibrocalculous pancreatic diabetes is much better today than that described 30 years ago. About 80% of patients were alive 35 years after the first episode of abdominal pain. The median survival time after the diagnosis of diabetes was 25 years. These figures, however, are still considerably lower than the life expectancy of the age- and sex-matched general population. Diabetic nephropathy was the main cause of death. Pancreatic cancer and other chronic pancreatitis-related causes as well as malnutrition and infections were also important contributors to mortality. CONCLUSIONS: The overall prognosis for patients with fibrocalculous pancreatic diabetes appears to have improved possibly because of earlier diagnosis, better management of diabetes, and improved nutrition.

Effect of beer, yeast-fermented glucose, and ethanol on pancreatic enzyme secretion in healthy human subjects.

The effect of beer, ethanol (4% v/v), and corresponding volumetric (water), caloric (glucose 5.76% w/v), and osmotic (glucose 11.5% w/v) control solutions on pancreatic enzyme output and release of gastrin and cholecystokinin (CCK) were studied in six healthy human subjects. As a simpler model of beer, yeast-fermented glucose solution (11.5% w/v) was also studied and compared with unfermented glucose (11.5% w/v). Among the control solutions, the two glucose solutions, but not water, significantly (P < 0.05) increased the 150-min integrated trypsin and amylase output over basal levels. Beer and fermented glucose caused a significantly higher increase in trypsin and amylase output compared to water or glucose. Ethanol (4% v/v) failed to stimulate pancreatic enzyme output. Fermented glucose and beer, but not the control solutions, significantly increased plasma gastrin levels above basal values. Isotonic and hypertonic glucose, beer, and fermented glucose significantly increased plasma levels of cholecystokinin (CCK), but the effect was significantly higher after hypertonic glucose than after isotonic glucose, beer, or fermented glucose. Ethanol and water had no effect on plasma levels of gastrin and CCK. We conclude that: (1) in the doses studied intragastric beer and fermented glucose but not ethanol (4% v/v) stimulate pancreatic enzyme output and release of gastrin and CCK; (2) the lack of effect of ethanol indicates that nonalcoholic ingredients of beer and fermented glucose are responsible for this stimulatory effect; and (3) CCK could be one of the major mediators of the stimulation of pancreatic enzyme output after ingestion of beer and fermented glucose.

Comparison of two dose-response techniques to study the pancreatic secretory response to intraduodenal tryptophan in the absence and presence of the M1-receptor antagonist telenzepine.

To answer the questions if the type of continuous dose-response technique influences the pancreatic secretory response to intraduodenal tryptophan and if the M1-receptor antagonist telenzepine influences the intestinal absorption of tryptophan, we determined, in 12 conscious dogs with chronic gastric and duodenal fistulas, pancreatic bicarbonate and protein secretion and tryptophan plasma concentrations following intraduodenal tryptophan perfusion using two dose-response techniques. With an ascending continuous dose-response technique (aDRT), tryptophan was perfused in loads ranging from 0.12 to 10.0 mmol h-1, starting with the lowest load and tripling it every 45 min. With the descending continuous dose-response technique (dDRT), the order of tryptophan loads was reversed, with the highest load being given first. All studies were done on a fixed background of intravenous secretin (20.5 pmol kg-1 h-1) and repeated in the presence of the anticholinergic M1-receptor antagonist telenzepine (243 nmol kg-1 h-1). The bicarbonate and protein response as well as tryptophan plasma concentrations to the same loads of tryptophan did not differ significantly between the two techniques. Using both techniques, telenzepine significantly (p < 0.05) inhibited the overall pancreatic protein response by 65% (dDRT) to 81% (aDRT). The overall bicarbonate response was only numerically, and not statistically significantly, inhibited by telezepine. Tryptophan plasma concentrations after duodenal perfusion with tryptophan were neither influenced by the order of tryptophan loads nor altered by telenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of repeated boluses of intravenous omeprazole and primed infusions of ranitidine on 24-hour intragastric pH in healthy human subjects.

The aim of this study was to identify dosage regimens using intravenous omeprazole and ranitidine that would elevate and consistently maintain intragastric pH > 6 in the first 24 hr of therapy. In 19 healthy, fasting human subjects using continuous 24-hr gastric pH-metry, we studied two dosages of primed infusions of ranitidine (50 mg bolus followed by infusion of either 3 or 6 mg/kg body wt/24 hr) and six regimens of intravenous omeprazole (80-200 mg in 24 hr in two to five boluses). Only the two ranitidine infusions and high doses of omeprazole (> or = 160 mg/day as four or five boluses) raised the intragastric median pH above 5.4. There was no significant difference in the median intragastric pH after high dose ranitidine and high doses of omeprazole. Considerable interindividual variation in intragastric pH was observed after omeprazole therapy. The percentage of intragastric pH > 6.0 during the 24-hr study was lower after omeprazole (35-42%) than after high-dose ranitidine (58%). We conclude that it is possible to raise intragastric pH > 6.0 by use of either primed ranitidine infusion or by repeated boluses of omeprazole. However, maintenance of this high pH in the first 24 hr is difficult with both, more so with omeprazole.