James F. Helm

Mechanisms of Gastroesophageal Reflux in Patients with Reflux Esophagitis

We evaluated the mechanisms of gastroesophageal reflux in 10 patients with reflux esophagitis and compared the results with findings from 10 controls. The patients had more episodes of reflux (35 +/- 15 in 12 hours, as compared with 9 +/- 8 in the controls) and a lower pressure of the lower esophageal sphincter (13 +/- 8 mm Hg as compared with 29 +/- 9 in the controls) (P less than 0.001). Reflux occurred by three different mechanisms: transient complete relaxation of the lower esophageal sphincter, a transient increase in intra-abdominal pressure, or spontaneous free reflux associated with a low resting pressure of the lower esophageal sphincter. In controls 94 per cent of reflux episodes were caused by transient sphincter sphincter relaxation. In the patients 65 per cent of episodes of reflux accompanied transient sphincter relaxation, 17 per cent accompanied a transient increase in intra-abdominal pressure, and 18 per cent occurred as spontaneous free reflux. The predominant reflux mechanism in individual patients varied: some had normal resting sphincter pressure and reflux that occurred primarily during transient sphincter relaxation, whereas others with low resting sphincter pressures had spontaneous free reflux or reflux that occurred during an increase in intra-abdominal pressure.

First-Line Chemotherapy With Capecitabine and Temozolomide in Patients With Metastatic Pancreatic Endocrine Carcinomas

Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS).

Effect of esophageal emptying and saliva on clearance of acid from the esophagus

We studied clearance of acid from the esophagus and esophageal emptying in normal subjects. A 15-ml bolus of 0.1 N hydrochloric acid (pH 1.2) radiolabeled with [99mTc]sulfur colloid was injected into the esophagus, and the subject swallowed every 30 seconds. Concurrent manometry and radionuclide imaging showed nearly complete emptying of acid from the esophagus by an immediate secondary peristaltic sequence, although esophageal pH did not rise until the first swallow 30 seconds later. Esophageal pH then returned to normal by a series of step increases, each associated with a swallow-induced peristaltic sequence. Saliva stimulation by an oral lozenge shortened the time required for acid clearance, whereas aspiration of saliva from the mouth abolished acid clearance. Saliva stimulation or aspiration did not affect the virtually complete emptying of acid volume by the initial peristaltic sequence. We conclude that esophageal acid clearance normally occurs as a two-step process: (1) Virtually all acid volume is emptied from the esophagus by one or two peristaltic sequences, leaving a minimal residual amount that sustains a low pH, and (2) residual acid is neutralized by swallowed saliva.

Pathogenesis of Reflux Esophagitis

During the past decade considerable new information has accrued about reflux esphagitis and the physiology of esophageal motor function. Although numerous reports review the clinical, diagnostic, and therapeutic aspects of reflux esophagitis (1-6), few reports (7) focus primarily on the pathophysiology of esophagitis production. Our purpose here is to: (a) review critically recent findings relevant to the pathophysiology of reflux esophagitis, (b) analyze factors that may contribute to the production of reflux esophagitis, and (c) identify appropriate questions that merit further investigation. Throughout the report we will endeavor to alert the reader when the manuscript reflects our own opinion, speculation, or scientific bias as opposed to established observations. For this report the term reflux esophagitis is defined as esophageal inflammation caused by refluxed material. On endoscopy reflux esophagitis may cause visible discoloration, friability, ulceration, exudate, or luminal narrowing. In active reflux esophagitis, histologic sections demonstrate an acute polymorphonuclear or a mixed polymorphonuclear and round cell infiltrate, generally accompanied by epithelial erosion or ulceration. These gross or histologic findings are necessary for a specific diagnosis of reflux esophagitis. In some patients with clinical complaints suggesting GE reflux, the esophagus appears normal at endoscopy and no evidence of inflammation is present on biopsy. Biopsies

Comparison of pseudoachalasia and achalasia

Malignancies involving the gastric cardia or distal esophagus can result in a clinical syndrome termed pseudoachalasisa that mimics idiopathic achalasia. If not promptly recognized, pseudoachalasia can result in inappropriate pneumatic dilatation of the lower esophageal sphincter segment and delay appropriate treatment of the underlying malignancy. During the past 14 years, six patients with pseudoachalasia and 161 patients with primary idiopathic achalasia were encountered. Pseudoachalasia occurred mainly in the elderly and represented about 9 percent of these patients over 60 years of age with suspected achalasia. Five of the six pseudoachalasia cases were secondary to adenocarcinoma that originated in the gastric fundus, and one was caused by a squamous cell carcinoma of the distal esophagus. Conventional esophageal manometry did not discriminate achalasia from pseudoachalasia. On the other hand, esophagogastroscopy with biopsy resulted in a diagnosis of pseudoachalasia in five of these cases and in 24 of 32 cases reported previously. Ominous endoscopic findings are mucosal ulceration or nodularity, reduced compliance of the esophagogastric junction, or an inability to pass the endoscope into the stomach. Radiographic evaluation, particularly in conjunction with amyl nitrite inhalation, was also useful in discriminating pseudoachalasia from primary achalasia. It is concluded that pseudoachalasia generally mimics idiopathic achalasia imperfectly and can usually be diagnosed prior to surgery by fastidious endoscopic and radiographic examination.

Acid Neutralizing Capacity of Human Saliva

In this study, we evaluated the properties of human saliva relevant to its potential contribution to esophageal acid clearance. Saliva was collected by expectoration and its flow and ability to neutralize acid were assessed. In the titration of 0.1 N HCl, saliva functions as a weak base to neutralize acid. Salivas capacity for acid neutralization was defined as the quantity of 0.1 N HCl acid neutralized by 1 ml saliva. Nasoesophageal intubation, oral lozenge, and bethanechol (5 mg subcutaneously administered) increased both saliva flow and its capacity for acid neutralization. An intubated subject with a saliva flow of 1.2 mllmin produces enough saliva in 5 min to titrate 1 ml of 0.1 N HCl from a pH of 1.2 to 4.0. Atropine in a small dose of 3 μg/kg i.v. reduced saliva flow without affecting its capacity for acid neutralization, while a larger dose of 12 μ/kg i.v. abolished salivation. The capacity of saliva for acid neutralization was linearly related to its bicarbonate concentration. Bicarbonate accounted for approximately 50% of capacity for acid neutralization for resting saliva, while about 80% of the capacity for acid neutralization for lozenge-stimulated saliva was due to bicarbonate. The increase in capacity for acid neutralization for lozenge-stimulated saliva was the result of a rise in bicarbonate concentration, while the contribution of the nonbicarbonate component remained relatively constant. We conclude: (a) Saliva produced at physiologic rates and carried into the esophagus by swallowing is capable of neutralizing small amounts of intraesophageal acid within a few minutes; (b) the effect of oral lozenge, bethanechol, and atropine on salivation may explain, at least in part, why these agents alter esophageal acid clearance; (c) because intubation stimulates salivation, pH monitoring of esophageal acid clearance may underestimate the duration of acid exposure that would occur in the absence of an indwelling pH electrode; and (d) the ability of saliva to neutralize acid is due primarily to bicarbonate.

Integrity of cholinergic innervation to the lower esophageal sphincter in achalasia

The human lower esophageal sphincter (LES) is believed to be innervated by nonadrenergic, noncholinergic inhibitory nerves, and cholinergic excitatory nerves. In idiopathic achalasia, LES relaxation is abnormal because the inhibitory nerves to the sphincter are either absent or functionally impaired. The integrity of cholinergic excitatory nerves to the LES, however, has not been thoroughly evaluated. In 27 patients with untreated idiopathic achalasia, and 21 healthy volunteers, we investigated the hypothesis that postganglionic cholinergic nerves to the LES are functionally intact in achalasia. The LES responses to atropine, edrophonium, methacholine, amyl nitrite, and pentagastrin were assessed. In 2 achalasia patients, patterns of fasting motor activity in the LES were investigated during overnight manometric studies. Resting LES pressure was significantly greater in the achalasia patients, 41 +/- 4 mmHg (mean +/- SE), than in the normal subjects, 20 +/- 2 mmHg. Atropine significantly reduced LES pressure in both groups by 30%-75%. Edrophonium increased LES pressure in the achalasia patients but had negligible effect on the normal subjects. The LES in achalasia patients exhibited an increased sensitivity to both methacholine and pentagastrin compared with the normal subjects. In both patients who underwent an overnight manometric study, the LES exhibited cyclic phasic contractile activity synchronous with gastric contractions during the migrating motor complex. We conclude that the study findings support the hypothesis that postganglionic cholinergic LES innervation in achalasia patients is either normal or only minimally impaired, in contrast to the marked impairment of the inhibitory nerves governing LES relaxation.

Multipeaked esophageal peristaltic pressure waves in patients with diabetic neuropathy

We evaluated esophageal function in 14 consecutive insulin-dependent diabetic patients who had evidence of peripheral and autonomic neuropathy, but no esophageal symptoms. One to three contraction waves immediately followed a primary peristaltic contraction wave. The majority of these multipeaked pressure complexes consisted of two peaks. Multipeaked contractions were observed with all peristaltic waves in 12 of the 14 diabetic patients and with most of the peristaltic complexes in the remaining 2 patients. Multipeaked peristaltic waves were present in 1 of 6 diabetic patients without neuropathy, in 1 of 100 consecutive nondiabetic patients referred for suspected esophageal disease, and in 1 of 10 healthy volunteers. Double-peaked peristaltic pressure complexes in the nondiabetic control subjects differed from those present in the insulin-dependent patients by their low incidence and by a tendency to be limited to the distal esophagus. Pharmacologic responses to edrophonium and atropine suggested a possible increased cholinergic tone as the basis of the multipeaked peristaltic waves in diabetics with autonomic neuropathy.

Relationship between swallow rate and salivary flow

Recent studies indicate that swallow-induced, primary peristalsis is a major determinant of normal esophageal acid clearance. However, factors that regulate the rate of spontaneous swallowing in normal subjects are incompletely understood. We postulated that the rate of salivary flow influences the rate of spontaneous swallows. To test this hypothesis, we did a total of 60 studies measuring salivary flow or the rate of spontaneous swallowing in 10 healthy volunteers, age 10–30 years. Saliva was collected by expectoration. Swallow rate was recorded by a small, transnasal catheter stationed in the pharynx and also, in some circumstances, by cervical electrodes. On separate sessions, we evaluated the effect of five test manipulations on salivary flow and swallowing rate, respectively. The test manipulations consisted of: (1) pharyngeal intubation, (2) sucking of a dummy lozenge, (3) sucking of a peppermint lozenge, (4) bethanechol injection (5 mg subcutaneously), and atropine administration (12 μg/kg intravenously). Pharyngeal intubation caused a small, but significant increase in the rate of salivation and spontaneous swallows. Sucking of a peppermint lozenge caused a sixfold increase in salivary flow while nearly doubling the swallowing rate whereas the dummy lozenge caused only a modest increase in salivary flow and swallowing. Cholinergic stimulation by bethanechol elicited a substantial increase in salivary flow and swallowing rate. In contrast, atropine caused a significant decrease in both salivary flow and swallowing. We conclude that in awake, normal subjects the rate of spontaneous swallows is influenced directly by salivary flow. Because oral lozenges substantially increase both swallowing rate and salivary flow, such agents merit investigation as a potentially useful ancillary treatment for the relief of heartburn.

Dedifferentiation Precedes Invasion in the Progression from Barrett's Metaplasia to Esophageal Adenocarcinoma

Purpose: Adenocarcinoma arises in Barretts esophagus by progression from metaplasia to cancer through grades of dysplasia. Our aim in this exploratory study was to characterize the broad changes in gene expression that underlie this histologic progression to cancer and assess the potential for using these gene expression changes as a marker predictive of malignant progression in Barretts epithelium. Experimental Design: Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barretts epithelia from which three of the cancers had arisen. Pooled samples from the Barretts epithelia of six patients without cancer or dysplasia served as a reference. Results: Barretts epithelia from which cancer had arisen differed from the reference Barretts epithelia primarily by underexpression of genes, many of which function in governing cell differentiation. These changes in gene expression were found even in those specimens of Barretts epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barretts epithelium from which it had arisen primarily by an overexpression of genes, many of which were associated with tissue remodeling and invasiveness. Cancers without identifiable Barretts epithelium differed from cancers that had arisen from a Barretts epithelium by having an even greater number of these overexpressed genes. Conclusions: Histologic progression from Barretts epithelium to cancer is associated with a gradient of increasing changes in gene expression characterized by an early loss of gene function governing differentiation that begins before histologic change; gain in function of genes related to remodeling and invasiveness follows later. This correlation of histologic progression with increasing changes in gene expression suggests that gene expression changes in biopsies taken from Barretts epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.