The clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma.

BACKGROUND: Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) of pancreatic lesions is being increasingly used. Our aim was to determine the safety, accuracy, and clinical utility of EUS-guided FNA in both the diagnosis and staging of pancreatic cancer. METHODS: Forty-four patients (24 men/20 women) had EUS-guided FNA of pancreatic lesions (39 head/neck, 5 body, 3 tail) and/or associated lymph nodes. The mean age was 61 (range, 28 to 88 years). The indication for EUS-guided FNA was a pancreatic lesion seen initially on CT (39%), ERCP (43%), or EUS (18%). Follow-up data were collected on all patients for mean of 14.5 months (range 1 to 33 months). RESULTS: CT detected only 15 of 61 (25%) focal lesions seen by EUS, Adequate specimens were obtained by EUS-guided FNA in 44 of 47 (94%) pancreatic lesions and 14 of 14 (100%) associated lymph nodes (overall adequacy was 95%). Of the 46 lesions in which specimens were adequate and a final diagnosis was available (32 malignant, 14 benign), EUS-guided FNA had a sensitivity of 92%, specificity of 100%, and diagnostic accuracy of 95% for pancreatic lesions and 83%, 100%, and 88% for lymph nodes, respectively. Six percent of pancreatic cases had inadequate specimens and, if included, lowered the sensitivity to 83%, specificity to 80%, and diagnostic accuracy to 88% for pancreatic lesions. In 3 patients with enlarged celiac nodes on EUS, EUS-guided FNA was able to make a tissue diagnosis of metastasis, which changed the preoperative staging and precluded surgery. EUS in combination with EUS-guided FNA precluded surgery in 12 of 44 (27%) and may have precluded surgery in an additional 6 of 44 (14%). EUS-guided FNA avoided the need for further diagnostic tests, thus expediting therapy in a total of 25 (57%) patients and influenced clinical decisions in 30 of 44 (68%) patients. The estimated cost savings based on surgeries avoided was approximately $3300 per patient. There was only one complication (2%), a post-FNA fever. CONCLUSION: EUS-guided FNA of the pancreas appears to be a safe and effective method that increases both the diagnostic and staging capability of EUS in pancreatic cancer. The clinical impact of EUS-guided FNA includes avoiding surgery and additional imaging studies with a substantial cost savings.

Endoscopic ultrasound-guided fine-needle aspiration.

Thirty-eight consecutive patients underwent endoscopic ultrasound-guided fine-needle aspiration. Of 46 lesions, 34 were extraluminal (12 pancreatic masses, 8 periesophageal nodes, 6 celiac nodes, 2 pericolonic masses, 1 mediastinal mass, 1 perigastric mass, 1 liver, 1 periduodenal node, 1 perirectal mass, 1 perirectal node) and 12 were submucosal (8 gastric, 3 duodenal, 1 esophageal). One hundred sixty-three passes were made, with an average of 3.5 passes per lesion and 4.3 passes per patient (range, 1 to 8). Adequate specimens were obtained from 91% of targeted lesions. The overall diagnostic accuracy was 87%. In patients with malignant lesions, sensitivity was 91% and specificity 100%. Celiac nodes were successfully sampled and diagnostic in 5 of 6 (83%) patients. No complications occurred. Using this technique, an initial tissue diagnosis of malignancy was made in 66% of cancer patients without a previous diagnosis and the preoperative stage was changed in 44% of cancer patients. The additional information gained by this modality directly influenced the decision not to perform surgery in 26% of patients with a primary malignancy. Endoscopic ultrasound-guided fine-needle aspiration is feasible and can be safely used to evaluate submucosal and extraluminal lesions in both the upper and lower gastrointestinal tract with a high degree of diagnostic accuracy.

Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives.

Increased intestinal permeability in patients with Crohn's disease and their first degree relatives has been proposed as an aetiological factor. The nine hour overnight urinary excretion of polyethyleneglycol-400 (PEG-400) and three inert sugars (lactulose, l-rhamnose, and mannitol) was used to test the permeation in 47 patients with Crohn's disease of whom 18 had at least one first degree relative with inflammatory bowel disease (2BD) and 52 patients with ulcerative colitis of whom 16 had at least one first degree relative with IBD. A total of 17 first degree relatives with IBD and 56 healthy first degree relatives were included. Thirty one healthy subjects not related to patients with IBD served as controls. No significant differences in PEG-400 permeation were found between the groups of patients, relatives, and controls, or between diseased and healthy relatives. The permeability to lactulose, rhamnose, and mannitol similarly did not differ between the three groups. This study challenges the previously reported findings of increased PEG-400 permeation in patients with Crohn's disease and in their healthy and diseased first degree relatives. There was no increase in permeability in a similar group of ulcerative colitis patients and their families.

Practical pharmacology and cost-effective management of peptic ulcer disease.

The clinical approach to the therapy of peptic ulcer disease has changed over the years as our understanding of its pathogenesis has grown. No longer is excess acid production seen as the single cause of ulcer disease; rather, its pathogenesis is viewed as the disturbance of a complex balance of ulcerogenic and protective factors. Today, the clinician's aim is to restore the balance between protective and aggressive factors. Simultaneously, the development of new classes of medications has provided the clinician with the tools to decrease intragastric acidity, neutralize or suppress acid production, and enhance the protective and restorative properties of the mucosa.

Polyethylene glycol 400 penetration of the colonic epithelial barrier of the rat.

Permeability changes of polyethylene glycol 400 have been seen in patients with inflammatory bowel diseases. Because the colon can be involved in inflammatory bowel disease, the mechanisms, kinetics, and influence of intraluminal factors on polyethylene glycol 400 permeation of perfused colonic segments of rats were studied. The absorption rate of polyethylene glycol 400 was linearly related to its luminal concentration (r = 0.94), suggesting that passive diffusion is a significant mechanism involved in polyethylene glycol 400 absorption. Changing the perfusate pH from 6.0 to 7.5 did not affect water absorption or polyethylene glycol 400 permeation. Increasing luminal osmolarity significantly decreased water and polyethylene glycol 400 absorption (P less than 0.01). The relationship between polyethylene glycol 400 and water absorption at different luminal osmolarities was linear (r = 0.97). At luminal osmolarity of 0.3 osm/L, 14.3% of polyethylene glycol 400 absorption was mediated by passive diffusion and 85.7% was mediated by convection. The solvent drag reflection coefficient for polyethylene glycol 400 in the colon was 0.03. Taurocholic acid (10 mmol/L) and chenodeoxycholic acid (5 mmol/L) decreased polyethylene glycol 400 and water absorption (P less than 0.01). Addition of 1 micrograms/mL of 16,16-dimethyl prostaglandin E2, 2 mmol/L of dibutyryladenosine-3',5'-cyclic monophosphate, or 10 mmol/L of aminophylline significantly decreased water and polyethylene glycol 400 absorption (P less than 0.01). These studies demonstrate that polyethylene glycol 400 permeation of the colon is mediated by both passive diffusion and solvent drag. Convective absorption is the major mechanism of polyethylene glycol 400 permeation of the colon. Polyethylene glycol 400 permeation is modified by bile acids, prostaglandins, and cyclic nucleotides through changes in water flux.

Regulation of polyethylene glycol 400 intestinal permeability by endogenous and exogenous prostanoids. Influence of non-steroidal anti-inflammatory drugs.

Polyethylene glycol 400 (PEG 400) is a clinically useful intestinal permeability probe whose rate of intestinal permeation is influenced in part by solvent drag. As mucosal prostanoids are increased in inflammatory bowel disease and affect water transport we examined the possible relationship between prostaglandin E2 (PGE2) and the inhibitors of endogenous prostaglandins--the non-steroidal anti-inflammatory drugs (NSAIDS)--on PEG 400 absorption in vivo using segmental perfusion of rat small intestine. We found that the addition of exogenous PGE2 in concentrations of 0.5, 1.0, and 1.5 micrograms/ml significantly (p less than 0.01) decreased PEG 400 and water absorption. Addition of 5 mmol/l of the cyclooxygenase inhibitors acetylsalicylic acid (ASA) or indomethacin in concentrations 2.5 or 5.0 mmol/l to the perfusate significantly (p less than 0.01) increased PEG 400 and water absorption. The simultaneous addition of 1.0 micrograms/ml of exogenous PGE2 to the perfusate with 5 mmol/l of ASA or with 2.5 mmol/l of indomethacin reversed the increase of PEG 400 and water transport (p less than 0.01). There were no differences in PEG 400 and water absorption when PGE2 was given alone or in combination with ASA or indomethacin. This study suggests that endogenous or exogenous prostanoids play an important role in the regulation of PEG 400 permeation. PGE2 and NSAIDS modify PEG 400 permeation in parallel with changes in water transport indicating that their effect on permeability is through changes in solvent drag. These findings provide a mechanism which might explain the increase in PEG 400 intestinal permeability in Crohn's disease patients and the increase in intestinal permeability found in patients receiving NSAIDS.

Mechanisms of polyethylene glycol 400 permeability of perfused rat intestine.

Abnormal permeability to polyethylene glycol 400 (PEG 400) has been demonstrated in various disorders with defective intestinal barrier functions. To understand the basic mechanisms of PEG 400 permeability, we compared PEG 400 permeation in different segments of the intestine and studied the kinetics and influence of intraluminal factors on PEG 400 absorption in vivo in perfused intestinal segments of the rat. The permeation rate of PEG 400 was dependent on the luminal concentration (y = 12.99x + 3.5; r = 0.97), indicating that passive movement is the mechanism involved in PEG 400 absorption. Changing the perfusate pH from 6 to 7.4 or modifying the unstirred water layer resistance by changing luminal flow rate did not affect PEG 400 absorption. When luminal osmolarity was varied from 0.225 to 0.6 osmol/L, higher osmolarity decreased both water and PEG 400 absorption (p greater than 0.01). The relationship between PEG 400 and water absorption at different osmolarities was linear (y = 0.9x + 5.7; r = 0.98). At a luminal osmolarity of 0.3 osmol/L 43% of PEG 400 permeation was mediated by passive diffusion and 57% was mediated by solvent drag. Increasing water absorption by decreasing luminal osmolarity resulted in proportional increase of PEG 400 permeation through solvent drag or convection. The solvent drag reflection coefficient (sigma f) for PEG 400 permeation of the jejunum was 0.1. Taurocholic acid (10 mM) alone or with oleic acid (2.5 mM) did not affect PEG 400 absorption. Permeabilities of 1 mM PEG 400 and water were similar in jejunum and ileum but were markedly increased in the colon (p greater than 0.01). These studies demonstrate that PEG 400 is absorbed by both passive diffusion and by solvent drag, with the latter accounting for a greater fraction of the absorptive drive under normal conditions. Polyethylene glycol 400 uses aqueous pathways for its permeation across the intestinal epithelium.

Intestinal permeability in patients with Crohn's disease and their healthy relatives.

The healthy relatives of patients with Crohn's disease were previously found to have increased intestinal permeability to polyethylene glycol 400. To determine whether the abnormal permeability is uniquely detectable by polyethylene glycol 400, we studied the intestinal permeability of three new probes (lactulose, rhamnose, and mannitol) in 25 patients with Crohn's disease, 41 of their healthy relatives, and 29 normal controls without a family history of inflammatory bowel disease. Patients with Crohn's disease had increased lactulose permeability when compared with relatives or controls. Lactulose absorption by patients with Crohn's disease was 0.41% +/- 0.07% (mean +/- SE), whereas that of their relatives and unrelated controls was 0.28% +/- 0.03% and 0.26% +/- 0.03%, respectively. There was no significant difference between the relatives and controls, but both groups differed from the patients (p less than 0.05 and p less than 0.025, respectively). The patients' lactulose/rhamnose ratio was 70.5% +/- 9.2% vs. 37.2% +/- 3.3% in relatives and 40.6% +/- 5.7% in unrelated controls (p less than 0.0005 and p less than 0.0025, respectively). The two intermediate-sized probes, rhamnose and mannitol, did not detect permeability differences among the three groups. The inability of lactulose, rhamnose, or mannitol to detect permeability abnormalities in healthy relatives of patients with Crohn's disease suggests that these probes penetrate the intestinal barrier by routes or mechanisms that are different from those of polyethylene glycol 400. Lactulose, in particular, detects permeability changes in patients with intestinal inflammation, and polyethylene glycol 400 is able to detect permeability changes in the health relatives of our patients. These data indicate that permeability may be abnormal as a secondary result of inflammation, or as a result of a primary genetic abnormality.

Intestinal mucosal permeability and rheumatological diseases.

Rheumatological disorders frequently have gastrointestinal manifestations and, conversely, intestinal disorders frequently have rheumatological manifestations. The possibility of altered intestinal permeability in arthritic patients may provide the bridge needed to link the two organ systems. The normal intestine absorbs nutrients and excludes the remaining material. If the intestine were less discriminating or 'leaky' then material normally excluded would be able to cross the intestinal mucosa into the lamina propria. An inflammatory response to these antigens, be they dietary, bacterial, or viral in origin, could produce either local or systemic disease. This would depend upon the type of immunological response and the cross-reactivity between the host's antigens and the absorbed antigens. This theory could account for the postulated relationship between intestinal abnormalities and the pathogenesis of some forms of arthritis.