Chemoradiotherapy, with adjuvant surgery for local control, confers a durable survival advantage in adenocarcinoma and squamous cell carcinoma of the oesophagus.

INTRODUCTION: Oesophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. AIMS: Long-term results of two simultaneous randomised controlled trials (RCTs) comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of adenocarcinoma (AC) and squamous cell carcinoma (SCC) to identical regimens compared. METHODS: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately-randomised to identical protocols of MMT or surgical monotherapy. RESULTS: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0.004), SCC (P=0.01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery (64% versus 29%, P<0.001). MMT produced a pathologic complete response (pCR) in 25% and 31% of AC and SCC, respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR versus surgical monotherapy (P=0.001); residual disease following MMT versus surgical monotherapy (P=0.008); SCC pCR versus surgical monotherapy (P=0.033). CONCLUSIONS: A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumour down-staging to extinction in 25-31% of patients, potentially permitting personalised treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localised disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease.

Dynamic electric field assisted multi-dimensional liquid chromatography of biological samples.

Complex biological samples require very high resolution separation strategies. The platform introduced here capitalises on the hyphenation of liquid chromatographic (LC) and electric potential gradient electrochromatographic multi-dimensional separation genres. First-dimension selectivity is provided by simultaneous size exclusion (SEC) and strong cation exchange (SCX) chromatography modes, while the second dimension comprises reversed phase (RP) characteristics in a dynamic (time-variant) electric field. The time-variant potential gradient with reversal of polarity is applied across the second dimension monolithic capillary throughout the duration of the solvent strength gradient elution. Hence, the platform offers comprehensive on-line sample clean-up (matrix depletion, analyte enrichment), fractionation (first dimention LC), and separation (second dimension LC) with the prospect of altering selectivity via polarity reversal dynamic electric field tuning.

Evaluation and comparison of tailor-made stationary phases based on spherical silica-based beads for capillary electrochromatography via peptide separation analysis.

Small cyclic peptides have been employed to elucidate the performance of novel sorbents as stationary phases in capillary electrochromatography (CEC). In this paper chain length dependencies for ordinary liquid chromatographic sorbents are reported together with findings acquired on beads specifically designed to suit CEC. The latter, tailor-made, spherical, porous silica exhibits a distinguished surface modification to meet the criteria anticipated to enhance performance profiles in CEC. With well-characterised peptides resembling the analytes, probing of the CEC system in a systematic manner (predominantly via the organic modifier content of the background electrolyte (BE)) reveals insight into the complex interplay occurring in such analytical systems at the molecular and sub-molecular level in particular upon various modes of interaction.

Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production.

The proinflammatory cytokines play a central role in mediating cellular and physiological responses, and levels may reflect immune system effectiveness. In this study, the effect of ageing on the inflammatory response was examined using a novel method to detect production of the proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-1beta. Peripheral blood mononuclear cells (PBMC) obtained from healthy donors of different ages were incubated for 0, 24, 48 and 72 h with or without phorbol 12-myristate 13-acetate (PMA) stimulation. At each time point these cells were permeabilized and incubated with secondary conjugated FITC MoAbs specific for each cytokine. A flow cytometric system was developed to quantify specific intracellular fluorescence in T cells (CD3+) and monocytes (CD14+). TNF-alpha, IL-6 and IL-1beta production in cell culture supernatants was also measured using ELISAs. In older subjects, flow cytometry detected significant increases in intracellular T cell TNF-alpha and IL-6 (P < 0.05). IL-1beta was not detected in any of the T cell samples. Likewise, the monocytes of older subjects demonstrated increased intracellular levels of all three cytokines, but these increases were not significant (P > 0.05). These changes in intracellular proinflammatory cytokine levels may explain some of the exaggerated inflammatory responses seen in elderly patients.

Barrett's esophagus and the presence of Helicobacter pylori.

OBJECTIVE: Although the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease and antral gastritis has been well documented, the role of H. pylori in esophageal disease has not been clearly defined. To clarify this issue, we analyzed 141 patients with histologically confirmed esophageal disease. METHODS: The study group consisted of 82 patients with Barrett's esophagus, 19 with adenocarcinoma of the esophagus arising in columnar epithelium and 40 patients with reflux esophagitis without columnar metaplasia of the esophagus. In each of these cases the presence or absence of H. pylori was assessed histologically. RESULTS: H. pylori was present in 19 of 82 patients (23%) with Barrett's esophagus, but was absent in all patients with adenocarcinoma of the esophagus and in patients with reflux esophagitis without Barrett's metaplasia. H. pylori was found only in areas of gastric type metaplasia in the patients with Barrett's esophagus. All of the 19 Barrett's esophagus group with H. pylori had chronic inflammation, and in 16 the inflammation was severe. H. pylori was significantly associated with severity of inflammation in patients with Barrett's esophagus (p < 0.001). Members of the Barrett's group with evidence of moderate to severe dysplasia were negative for H. pylori. CONCLUSION: These data confirm that the presence of gastric type mucosa within the esophagus is a prerequisite for H. pylori colonization, and that H. pylori may contribute to the severity of inflammation in Barrett's epithelium.

Oesophageal motility and digestion of cream liqueurs in combination with common alcohol mixers.

When acidic mixers are added to cream liqueur curdling occurs. Oesophageal motility was studied in normal volunteers during ingestion of this mixture and the effect of combining with gastric juice was assessed in a simulated physiological environment. Twenty-four h ambulatory manometry and pH (n = 22) and gastric studies (n = 7) were carried out. There was no detrimental effect on oesophageal motility. The precipitation is rapidly broken down by the digestive process in the stomach.

Cholecystectomy-induced gastroesophageal reflux: is it reduced by the laparoscopic approach?

OBJECTIVE: The incidence of gastroesophageal reflux and esophagitis increases significantly following cholecystectomy. Laparoscopic technique minimizes the metabolic and mechanical disturbances of cholecystectomy, but there has been no study of its effects on gastroesophageal reflux. The aim of this study was to examine the effect of laparoscopic cholecystectomy on the indices of gastroesophageal reflux. METHODS: A prospective study was carried out on patients scheduled for cholecystectomy. Informed consent was obtained. Preoperative 24-h pH studies and manometry were performed. Studies were repeated 3 months after surgery. Pathological acid reflux was defined in terms of the DeMeester acid score. RESULTS: Pre- and postoperative studies were carried out on 28 patients who had open cholecystectomy and on 22 patients who had laparoscopic cholecystectomy. The mean (SEM) DeMeester acid score increased from 14.8 (2.4) to 34.0 (6.7) following open cholecystectomy (p = 0.006) and from 13.9 (2.5) to 28.9 (4.3) following laparoscopic cholecystectomy (p = 0.002). Decrease in mean lower esophageal sphincter pressure in both groups was not significant. CONCLUSIONS: A significant increase in the incidence of gastroesophageal reflux occurred within 3 months after surgery in both study groups. Despite the less invasive nature of laparoscopic cholecystectomy, the type of surgery did not influence the degree of esophageal dysfunction.

Delay in treatment for oesophageal cancer.

BACKGROUND: Dysphagia is the cardinal symptom of oesophageal cancer, yet many patients present late. This study examined prospectively the interval between onset of dysphagia and treatment and identified reasons for delay. METHODS: Patients with histologically confirmed oesophageal carcinoma were questioned about duration of symptoms and about each step of their diagnostic work-up. Delay was estimated from date of onset of symptoms to definitive treatment. RESULTS: Median delay was 15 weeks for 78 patients with dysphagia, and 17 weeks for 22 patients with other symptoms. The most frequent cause of delay was late presentation to the family doctor (44 per cent). For patients treated with surgery alone there was a trend towards more advanced stage of disease with longer delay to treatment, but no correlation with survival (P = 0.25). CONCLUSION: Lack of awareness of the sinister significance of dysphagia is the most important cause for delay in presentation of patients with oesophageal cancer.

Acute food bolus impaction: aetiology and management.

A prospective study into the aetiology of acute food bolus obstruction (AFBO) was carried out on 17 consecutive patients who presented with this complaint. There were nine males and eight females. Twelve patients (71 per cent) had symptoms of oesophageal disease and 10 patients (59 per cent) had prior food bolus obstruction. Investigations included endoscopy, barium swallow, oesophageal pH and manometry studies. Evidence of oesophageal pathology was found in 12/14 (86 per cent) of patients investigated. No patients had malignancy and the most common abnormality, gastroesophageal reflux (GOR) was found in eight out of 14 (57 per cent) of cases. Oesophageal dysmotility was seen in five out of 12 (42 per cent) patients who had manometric studies. With such a high incidence of recurrence of AFBO, we suggest that patients with this condition be investigated to exclude malignancy and to identify benign oesophageal pathology using techniques such as oesophageal pH and manometry. Appropriate treatment of oesophageal disease may help prevent recurrence of this distressing condition.

Small cell carcinoma of the oesophagus.

Small cell carcinoma of the oesophagus is an uncommon malignancy. Only 272 cases have been reported to date. Inconsistency in therapeutic approaches reflects the paucity of individual experience and the unsatisfactory response to current management strategies. We report 11 cases drawn from a series of 1012 cases of oesophageal malignancy and perform a statistical analysis on treatment and survival data of 189 cases drawn from the world literature. Small cell carcinoma of the oesophagus was seen to have an incidence of 1%. Seven of 11 patients were female. A variety of therapeutic modalities were employed, and the median survival was 6.6 months. Statistical analysis of these and worldwide data showed a significant survival advantage for patients who received multimodality therapy.

Tumour marker detection in oesophageal carcinoma.

Levels of the tumour markers CEA, CA 19-9, CA 125 and SCC were measured in 58 patients presenting with oesophageal carcinoma and compared with levels in patients with benign oesophageal disease and levels in normal volunteers. CEA and CA 19-9 were significantly increased in the patients with oesophageal cancer, however, individual sensitivity for CEA, CA 19-9, CA 125 and SCC was only 28, 34, 10, and 32%, respectively. The combined sensitivity of all markers was 64% and specificity was 80%. There was no difference in combined tumour marker sensitivity between squamous or adenocarcinomas of the oesophagus. No consistent change in marker levels occurred with treatment, and tumour marker levels could not be significantly correlated with stage of disease or short-term survival. These results indicate that tumour marker sensitivity is too low for oesophageal cancer screening and has poor prognostic significance in those undergoing treatment.

Upper oesophageal sphincter function during general anaesthesia.

The effect of anaesthesia on the upper oesophageal sphincter response to acid in the distal oesophagus and hypopharynx, and the effect of atracurium besylate on acid migration into the hypopharynx, was studied in 102 patients undergoing elective varicose vein surgery. Group 1 (n = 48) received a general anaesthetic and the muscle relaxant atracurium besylate whereas group 2 (n = 54) received a general anaesthetic without relaxation. Upper oesophageal sphincter tone was significantly lower in patients receiving muscle relaxants ('sphinctometer output', eight versus 14, P < 0.05). Sixteen patients (16 per cent) had reflux into the distal oesophagus during anaesthesia (nine in group 1 and seven in group 2, P not significant), of whom seven had reflux to the hypopharynx. There was no difference in incidence of hypopharyngeal acid exposure between groups. Upper oesophageal sphincter tone did not alter in response to reflux into the distal oesophagus or hypopharynx in either group. The upper oesophageal sphincter fails to protect the hypopharynx under general anaesthesia even if patients do not receive a muscle relaxant.

A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.

BACKGROUND: Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery. METHODS: Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy. RESULTS: Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery, 10 and 1, respectively, were withdrawn for protocol violations. At the time of surgery, 23 of 55 patients (42 percent) treated with preoperative multimodal therapy who could be evaluated had positive nodes or metastases, as compared with 45 of the 55 patients (82 percent) who underwent surgery alone (P<0.001). Thirteen of the 52 patients (25 percent) who underwent surgery after multimodal therapy had complete responses as determined pathologically. The median survival of patients assigned to multimodal therapy was 16 months, as compared with 11 months for those assigned to surgery alone (P=0.01). At one, two, and three years, 52, 37, and 32 percent, respectively, of patients assigned to multimodal therapy were alive, as compared with 44, 26, and 6 percent of those assigned to surgery, with the survival advantage favoring multimodal therapy reaching significance at three years (P=0.01). CONCLUSIONS: Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus.

Cancer of the oesophagus.

Oesophageal cancer is the fourth most common tumour in developing countries, comprising mainly squamous cell tumours, although the incidence of adenocarcinoma has increased enormously over the last decades. Surgical resection has long been acknowledged as the mainstay of treatment, and developments in surgical technique are reviewed. The roles of radiotherapy and chemotherapy in the management of oesophageal cancer remain unclear, especially as the majority of studies to date have been uncontrolled trials. We present an analysis of 601 patients who underwent resection for carcinoma of the oesophagus between 1970 and 1994 in the Department of Clinical Surgery, St James's Hospital, Dublin. The analysis shows clearly that, while peri-operative mortality continues to improve, conventional surgery offers little prospect of cure in the majority of cases. We have therefore embarked upon a prospective controlled trial of neoadjuvant chemoradiotherapy followed by surgery versus surgery alone in patients with adenocarcinoma or squamous cell tumours of the oesophagus. Preliminary results indicate that multi-modality treatment may have a valuable role to play in the treatment of carcinoma of the oesophagus.

Cardiac ischaemia induces vagally mediated lower oesophageal sphincter relaxation.

Gastro-oesophageal reflux and coronary artery disease frequently coexist. Direct stimulation of myocardial vagal receptors impairs lower oesophageal sphincter (LOS) function but the effect of cardiac ischaemia has not been examined. Eight adult mongrel dogs were studied under general anaesthesia. Each underwent occlusion of the left circumflex coronary artery before and after bilateral cervical vagotomy. Blood pressure, heart rate and LOS responses were measured. Median (range) LOS tone was significantly reduced by coronary artery occlusion, from 9 (6-14) to 6 (3-8) sphinctometer units (P < 0.01). This was accompanied by a reduction in heart rate (P < 0.05) and blood pressure (P < 0.01). After bilateral cervical vagotomy the same ischaemic insult produced no significant alteration in LOS tone or heart rate. These data suggest a direct vagal reflex to explain the high incidence of gastro-oesophageal reflux in patients with coronary artery disease.

Ambulatory oesophageal bile reflux monitoring in Barrett's oesophagus.

Bile reflux has been implicated in the pathogenesis of Barrett's oesophagus but evaluation remains difficult. Bilitec 2000 is an ambulatory system that detects bilirubin based on its spectrophotometric properties. Oesophageal bile exposure was evaluated in three groups of patients. Group 1 (n = 11) were normal controls, group 2 (n = 13) were patients with uncomplicated gastro-oesophageal reflux and group 3 (n = 12) were patients with Barrett's oesophagus. Bile reflux was greater in patients with Barrett's mucosa than in controls or those with uncomplicated reflux. This difference was seen in the supine and interdigestive periods. The percentage of time at which gastric pH was greater than 4 and oesophageal pH was above 7 did not differ between the groups. Bilitec 2000 detects greater bile reflux in patients with Barrett's oesophagus. No corresponding gastric or oesophageal alkaline shift is found. This ambulatory bile reflux monitoring system may be a useful tool in clinical practice.