David Oh

Dysplasia and Risk of Further Neoplastic Progression in a Regional Veterans Administration Barrett's Cohort

OJECTIVES:No published data are available on the risk of further neoplastic progression in Barretts patients stratified by baseline dysplasia status. Our aims were to estimate and compare the risk of progression to high-grade dysplasia or cancer in groups of Barretts patients stratified by baseline dysplasia status.METHODS:Consecutive Barretts cases from 1988–2002 were identified via pathology databases in a regional VA health-care system and medical record data were abstracted. The risk of progression to high-grade dysplasia or cancer was measured and compared in cases with versus without low-grade dysplasia within 1 yr of index endoscopy using survival analysis.RESULTS:A total of 575 Barretts cases had 2,775 patient-years of follow-up. There were 13 incident cases of high-grade dysplasia and two of cancer. The crude rate of high-grade dysplasia or cancer was 1 of 78 patient-years for those with baseline dysplasia versus 1 of 278 patient-years for those without (p = 0.001). One case of high-grade dysplasia in each group underwent successful therapy. One incident cancer case underwent successful resection and the other was unresectable. Two cases with high-grade dysplasia later developed cancer, one died postoperatively, the other was unresectable. When these two cases were included (total of four cancers), the crude rate of cancer was 1 of 274 patient-years for those with baseline dysplasia versus 1 of 1,114 patient-years for those without.CONCLUSIONS:In a large cohort study of Barretts, incident malignancy was uncommon. The rate of progression to high-grade dysplasia or cancer was significantly higher in those with baseline low-grade dysplasia. These data may warrant reevaluation of current Barretts surveillance strategies.

Elevated Serum Ghrelin Exerts an Orexigenic Effect that May Maintain Body Mass Index in Patients with Metastatic Neuroendocrine Tumors

Ghrelin is a potent orexigenic peptide principally produced in the stomach by a distinct population of neuroendocrine cells in the oxyntic mucosa of the fundus. Exogenous ghrelin given as an intravenous infusion has been shown to increase caloric intake in patients with cancer cachexia. In this study, we hypothesized that elevated endogenous ghrelin, produced by increased neuroendocrine cell tumor burden, also exerts an orexigenic effect helping to maintain body mass index. To evaluate the effect of elevated endogenous ghrelin, 35 patients with neuroendocrine tumors were enrolled, assigning them to one of two groups depending on the presence of hepatic metastases. Following an overnight fast, serum was collected and sent for ghrelin measurement by an outside laboratory. The two groups were well matched for all other relevant clinical variables including subtype of tumor, primary location of tumor and tumor treatment history. Nearly all patients with hepatic metastases had elevated levels of ghrelin compared to the standard reference range given for matched controls. The presence of hepatic metastases was associated with significantly elevated ghrelin levels (p<0.05) and a greater mean body mass index. In addition, we report a positive correlation between serum ghrelin and total tumor surface area and between serum ghrelin and body mass index, suggesting that elevated endogenous ghrelin may be sufficient to overcome any partial ghrelin resistance typically seen in cancer cachexia. These results support the possibility that ghrelin is co-released from neuroendocrine tumors and exerts an orexigenic effect in these patients, helping to maintain their body mass index despite widely disseminated disease.

PACAP regulation of secretion and proliferation of pure populations of gastric ECL cells.

The gastric enterochromaffin-like (ECL) cell plays a major role in the regulation of gastric acid secretion. We have previously described that Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is present on myenteric neurons in the rat and colocalizes with its high-affinity receptor, PAC1, expressed on the surface of gastric ECL cells. The study of ECL cell physiology has been hampered by the inability to isolate and purify ECL cells to homogeneity. Density gradient elutriation alone yields only 65–70% purity of ECL cells. In the present study, we used fluorescence-activated cell sorting (FACS) with a novel fluorescent ligand, Fluor-PACAP-38, for isolating pure ECL cells. FACS was used to isolate ECL cells based on their relatively small size, low density, and ability to bind the fluorescent ligand Fluor-PACAP-38. The sorted cells were unambiguously identified as ECL cells by immunohistochemical analysis using anti-PACAP type-I (PAC1), anti-histidine decarboxylase (HDC), and anti-somatostatin antibodies. Further confocal microscopy demonstrated that Fluor-PACAP-38, a ligand with a higher affinity for PAC1, bound to extracellular receptors of these FACS-purified cells. FACS yielded an average of 2 million ECL cells/4 rat stomachs, and >99% of the sorted cells were positive for PAC1 receptor and HDC expression. The absence of immunohistochemical staining for somatostatin indicated lack of contamination by gastric D cells, which are similar in size and shape to the ECL cells. Internalization of PACAP receptors and a rapid Ca2+ response in purified ECL cells were observed upon PACAP activation, suggesting that these cells are viable and biologically active. These ECL cells demonstrated a dose-dependent stimulation of proliferation in response to PACAP, with a maximum of 30% proliferation at a concentration of 10−7M. Microarray studies were perfor med to confirm the expression of genes specific for ECL cells. These results demonstrate that rat gastric ECL cells can be isolated to homogeneity by using a combination of density gradient centrifugation, followed by cell sorting using Fluor-PACAP. These techniques now allow microarray studies to be performed in ECL cells to characterize their functional gene expression and will facilitate pharmacological, biochemical, and molecular studies on ECL cell function.

Differential coupling of the PAC1 SV1 splice variant on human colonic tumors to the activation of intracellular cAMP but not intracellular Ca2+ does not activate tumor proliferation

PAC1 is a recently cloned and characterized heptahelical, G protein-coupled receptor with high affinity to PACAP-27 and PACAP-38 and is differentially coupled to activate intracellular Ca2+ and cAMP. PAC1 is expressed as four major splice variants, each possessing differential coupling to inositol phosphates and intracellular Ca2+. PAC1 has been shown previously to be expressed and regulate the growth and proliferation of nonsquamous cell lung cancer cells, as well as breast cancer cell lines. PAC1 is expressed on the HCT8 human colon cancer cell line and is coupled to the activation of both intracellular cAMP and Ca2+ with consequent stimulation of growth. In the current study, we contrast the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on the HCT8 colon cancer cell lines to the HCT116 and FET cell lines wherein PAC1 is expressed as the SV1 or HIP splice variant and is coupled to the activation only of cAMP but not of intracellular Ca2+. These data indicate that human colon tumor cells express PAC1 and are differentially coupled to intracellular signal transduction molecules. The ability to activate both cAMP and Ca2+ appears to be a prerequisite for activation of tumor proliferation, indicating a potentially important factor in how PACAP potentiates the growth of certain tumors.

Pituitary adenylate cyclase-activating polypeptide: a novel peptide with protean implications.

Purpose of reviewThe purpose of this review is to highlight the importance of pituitary adenylate cyclase-activating polypeptide in physiological processes and to describe how this peptide is becoming increasingly recognized as having a major role in the body. Since its discovery in 1989, investigators have sought to determine the site of biological activity and the function of pituitary adenylate cyclase-activating polypeptide in maintaining homeostasis. Recent findingsSince its discovery, pituitary adenylate cyclase-activating polypeptide appears to play an important role in the regulation of processes within the central nervous system and gastrointestinal tract, as well in reproductive biology. Pituitary adenylate cyclase-activating polypeptide has been shown to regulate tumor cell growth and to regulate immune function through its effects on T lympocytes. These discoveries suggest the importance of pituitary adenylate cyclase-activating polypeptide in neuronal development, neuronal function, gastrointestinal tract function and reproduction. SummaryFuture studies will examine more closely the role of pituitary adenylate cyclase-activating polypeptide in regulation of malignantly transformed cells, as well as in regulation of immune function.

Neuroendocrine tumors express PAC1 receptors.

Abstract:  Neuroendocrine tumors (NETs) of the gastrointestinal tract can be grossly divided into two general types: carcinoid and pancreatic endocrine tumors. The former develop in the luminal intestine whereas the latter occur within the pancreas. To ascertain whether pituitary adenylate cyclase‐activating polypeptide (PACAP) has a biological effect on the regulation of secretion or growth, we studied the well‐established NET cell line, BON. BON cells have been shown previously to contain chromogranin A, neurotensin, and serotonin. In response to mechanical stimulation, BON cells have been demonstrated to release serotonin. The current article demonstrates that the high‐affinity PAC1 receptor is expressed on the NET cell line BON. These results indicate that PACAP may regulate the biological release of peptides and serotonin from BON cells and that, like in solid tumors, PACAP could potentially stimulate the growth of BON cells.

Duodenal Bulb Mucosa with Hypertrophic Gastric Oxyntic Heterotopia in Patients with Zollinger Ellison Syndrome

Objectives. Zollinger-Ellison Syndrome (ZES) results in hypersecretion of gastric acid (via gastrinoma) leading to peptic ulcers, diarrhea, and abdominal pain. We describe the novel discovery of hypertrophic, heterotopic gastric mucosa in the proximal duodenal bulb in patients with ZES, which we hypothesize results in an increased incidence of postbulbar ulcers in patients with ZES (a mechanism previously unreported). We determined the incidence of the novel finding of duodenal gastric oxyntic hypertrophic heterotopia (GOH) in patients with ZES. Methods. Seven patients with ZES were enrolled. The diagnosis of ZES was established by hypergastrinemia, gastric acid hypersecretion, and a positive secretin test or based on biopsy specimens (evaluated via tissue staining). Basal acid output (BAO) and baseline gastrin secretion were determined by established methods. Endoscopic examinations with methylene blue staining and biopsy of the gastric and duodenal mucosa were conducted in all patients every 3–6 months for an average of 5 years. Results. The duodenal mucosa demonstrated hypertrophic GOH in 5 out of 7 patients with ZES and an intact stomach and duodenum. Biopsies from the bowel mucosa demonstrated patchy replacement of surface epithelium by gastric-type epithelium with hypertrophic oxyntic glands in the lamina propria in 5 patients. Two of the patients had no evidence of GOH in the duodenal bulb. Patients with GOH had an average serum gastrin level of 1245 pg/mL and BAO of 2.92 mEq/hr versus 724 pg/mL and 0.8 mEq/hr in patients without GOH. Conclusions. This study demonstrated the presence of duodenal mucosa with GOH in 5 out of 7 patients with ZES and an intact stomach and duodenum. The presence of hypertrophic and heterotopic gastric mucosa is proposed to result from increased gastrin levels and may contribute to the increased incidence of postbulbar ulcers in these patients.

Rabeprazole controls GERD symptoms in a patient for whom treatment with lansoprazole failed: first report of "cluster GERD.".

Gastroesophageal reflux disease (GERD) is characterized by prolonged and repeated exposure of the esophageal mucosa to acidic gastric contents, often resulting in ulcerative and erosive damage to the esophagus. Patients typically experience symptoms of heartburn and regurgitation, although symptoms alone do not predict the presence of esophageal mucosal injury (1). The pathologic reflux can be confirmed using 24-hr ambulatory esophageal pH monitoring, and normalization of 24-hr reflux measurement correlates with symptom relief and endoscopic healing (2, 3). The newest and most effective agents currently available for the treatment of acidrelated diseases are drugs classified as proton pump inhibitors (PPIs). Rabeprazole is one of the newer drugs in the PPI class, sharing a substituted benzimidazole like omeprazole and lansoprazole (4). Although rabeprazole has the same mechanism of action as other PPIs, its differing molecular structure results in small, but potentially clinically significant, differences in chemical and physical properties (5). The rapid activation compared with other PPIs may account for rabeprazole’s faster inhibition of H+, K+-adenosine triphosphatase activity and acid secretion in vitro (6). This Case Report describes a man aged 64 years with “cluster GERD” who participated in the study entitled, “A Study of Rabeprazole 20 mg q.d. in Patients with GERD Whose Symptoms Were Not Resolved with Lansoprazole

Comparative Efficacy of Rabeprazole and Pantoprazole in the Control of Nocturnal Acid Output and Intragastric Acidity

BACKGROUND/AIMS Nocturnal reflux is a largely undiagnosed and unmanaged condition predisposing to multiple esophageal complications. We evaluated the effects of rabeprazole and pantoprazole on nocturnal intragastric pH and gastric acid output during Day 1 of therapy following the consumption of standard meals. METHODS The study had a double-blinded, randomized, two-way crossover design, and involved 15 patients with a history of mild reflux. Following an overnight fast, patients were given either rabeprazole (20 mg) or pantoprazole (40 mg) prior to the first of three standard Western meals. They then underwent overnight continuous intragastric pH monitoring and gastric acid output measurement. The drug effect was analyzed using a two-treatment, two-period crossover mixed model. RESULTS The percentage of time during which the mean intragastric pH was greater than 4.0 and gastric acid output was less than 2.0 was higher for oral rabeprazole (p<0.05). The inhibition of acid output was greater for rabeprazole at almost all time points. Furthermore, the mean time-matched pH values differed significantly over the first 8.3 hours (p<0.05). CONCLUSIONS On day 1, oral rabeprazole inhibited acid output to a greater extent and for a longer period than pantoprazole, and the intragastric pH was significantly higher for rabeprazole than for pantoprazole over the first 8.3 hours.

Cyto‐reduction of neuroendocrine tumours using Sandostatin LAR® in combination with Infergen®: results of a case series

Historically, limited trials evaluating biotherapy in treating metastatic neuroendocrine tumours have yielded mixed results. In this study, the efficacy of a novel combination therapy featuring long‐acting Sandostatin LAR® plus α‐interferon was evaluated. In a prospective case series, 12 patients with unresectable metastatic neuroendocrine tumours refractory to treatment initiated therapy with Infergen® and Sandostatin LAR®. Radiological response was followed serially at 3‐month intervals. A biochemical response was considered significant if marker levels decreased by ≥50% compared with baseline. Inhibition of tumour growth lasting for greater than 3 months (mean response 22.6 ± 17.7 months) was seen in eight patients. Complete tumour regression was observed in one patient, lasting for 40 months; three patients exhibited partial tumour regression (mean response 29.3 ± 24.0 months), and four patients maintained a stable tumour response (mean response 13.3 ± 9.2 months). Four patients showed no response to therapy (mean response 5.0 ± 6.0 months). All enrolled patients are alive currently. The biochemical response seen in seven patients did not correlate with the radiological response. These results suggest that the novel combination of long‐acting Sandostatin LAR® with an α‐interferon may be at least as effective as either combination therapy with short‐acting octreotide or monotherapy with Sandostatin LAR®.