Plasma and esophageal mucosal levels of vitamin C: role in the pathogenesis and neoplastic progression of Barrett's esophagus.

Antioxidants may protect against the development of esophageal adenocarcinoma. Blood samples and endoscopic biopsies (squamous, Barrett's, and gastric mucosa) were obtained from 48 Barrett's esophagus (BE) patients, while 48 age- and sex-matched controls provided blood samples only. Plasma concentrations of vitamins A, C, and E were measured in all subjects, while vitamin C was measured in relation to the type of mucosa. Plasma total vitamin C level, but not vitamin A or E, was lower in BE patients compared to controls (P = 0.014). Tissue levels of total vitamin C were significantly lower in Barrett's compared with squamous mucosa (P = 0.047). A positive association was observed between plasma vitamin C and dietary intake of vitamin C, while there was an inverse association with alcohol consumption. The lower levels of vitamin C in plasma of BE patients and in Barrett's mucosa compared with squamous mucosa are consistent with oxidative stress being of importance in the pathogenesis and neoplastic progression of BE.

Effect of surveillance of Barrett's oesophagus on the clinical outcome of oesophageal cancer.

BACKGROUND: Surveillance programmes for Barrett's oesophagus have been implemented in an effort to detect oesophageal adenocarcinoma at an earlier and potentially curable stage. The aim of this study was to examine the impact of endoscopic surveillance on the clinical outcome of patients with adenocarcinoma complicating Barrett's oesophagus. METHOD: Consecutive patients who underwent oesophageal resection for high-grade dysplasia or adenocarcinoma arising from Barrett's oesophagus were studied retrospectively. The pathological stage and survival of patients identified as part of a surveillance programme were compared with those of patients presenting with symptomatic adenocarcinoma. RESULTS: Seventeen patients in the surveillance group and 74 in the non-surveillance group underwent oesophagectomy. Disease detected in the surveillance programme was at a significantly earlier stage: 13 of 17 versus 11 of 74 stage 0 or I, three versus 26 stage II, and one versus 37 stage III or IV (P < 0.001). Lymphatic metastases were seen in three of 17 patients in the surveillance group and 42 of 74 who were not under surveillance (P = 0.004). Three-year survival was 80 and 31 per cent respectively (P = 0.008). CONCLUSION: Patients with surveillance-detected adenocarcinoma of the oesophagus are diagnosed at an earlier stage and have a better prognosis than those who present with symptomatic tumours.

Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone.

BACKGROUND AND AIMS: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location. METHODS: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones. RESULTS: There were 4-318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1-10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29-75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6-11.8) but had 37% of foci (range 10%-75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa. CONCLUSIONS: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.

Effect of endoscopic ultrasonography on the management of 100 consecutive patients with oesophageal and junctional carcinoma.

BACKGROUND: Endoscopic ultrasonography (EUS) offers very accurate tumour and node staging information for oesophagogastric cancer. The aim was to determine whether the addition of EUS directly influenced the definitive management plan for individual patients. METHODS: Personal and staging information from 100 consecutive patients with carcinoma of the oesophagus or oesophagogastric junction were summarized and blinded. Three consultant oesophagogastric surgeons independently made a management decision for each patient, in the presence and absence of the EUS data. All scored their perceived value of the EUS staging data for each patient. RESULTS: EUS was deemed useful in 63-87 per cent of patients and its addition resulted in an increased number of concordant management plans (from 53 to 62 per cent), and increased agreement between surgeons. The greatest change in concordant management was an increased referral of patients for non-surgical palliation. CONCLUSION: The addition of EUS to the staging of patients with oesophageal and oesophagogastric junction cancer significantly altered the management strategy for some of these patients.

Randomized clinical trials to determine the role of topical glyceryl trinitrate in peripheral intravenous nutrition.

BACKGROUND: The contribution of glyceryl trinitrate (GTN) to prevention of peripheral vein thrombophlebitis (PVT) during peripheral intravenous nutrition delivered by fine-bore midline intravenous catheter is unclear. The aim of this study was to establish its role. METHODS: Two consecutive randomized clinical trials were conducted. In trial 1 patients were randomized to receive standard peripheral intravenous nutrition containing heparin and hydrocortisone with or without the placement of a topical GTN patch (triple therapy or dual therapy). In trial 2 patients were randomized to receive standard peripheral intravenous nutrition with either dual therapy or topical GTN alone (monotherapy). RESULTS: Dual therapy was as effective as triple therapy in preventing PVT (incidence 10 of 37 versus 11 of 39 patients respectively). Dual therapy reduced the incidence and increased the time to onset of PVT compared with monotherapy (14 of 41 versus 22 of 35 patients respectively, P = 0.012; median 17.3 (95 per cent confidence interval (c.i.) 13.4 to 21.1) versus 8.9 (95 per cent c.i. 6.7 to 11.0) days, P = 0.007). CONCLUSION: Use of a topical GTN patch confers no benefit when peripheral intravenous nutrition is delivered via a fine-bore midline intravenous catheter.

Dietary antioxidants and DNA damage in patients on long-term acid-suppression therapy: a randomized controlled study.

Free radicals and reactive species produced in vivo can trigger cell damage and DNA modifications resulting in carcinogenesis. Dietary antioxidants trap these species limiting their damage. The present study evaluated the role of vitamins C and E in the prevention of potentially premalignant modifications to DNA in the human stomach by supplementing patients who, because of hypochlorhydria and possible depletion of gastric antioxidants, could be at increased risk of gastric cancer. Patients undergoing surveillance for Barrett's oesophagus (n 100), on long-term proton pump inhibitors were randomized into two groups: vitamin C (500 mg twice/d) and vitamin E (100 mg twice/d) for 12 weeks (the supplemented group) or placebo. Those attending for subsequent endoscopy had gastric juice, plasma and mucosal measurements of vitamin levels and markers of DNA damage. Seventy-two patients completed the study. Plasma ascorbic acid, total vitamin C and vitamin E were elevated in the supplemented group consistent with compliance. Gastric juice ascorbic acid and total vitamin C levels were raised significantly in the supplemented group (P=0.01) but supplementation had no effect on the mucosal level of this vitamin. However, gastric juice ascorbic acid and total vitamin C were within normal ranges in the unsupplemented group. Mucosal malondialdehyde, chemiluminescence and DNA damage levels in the comet assay were unaffected by vitamin supplementation. In conclusion, supplementation does not affect DNA damage in this group of patients. This is probably because long-term inhibition of the gastric proton pump alone does not affect gastric juice ascorbate and therefore does not increase the theoretical risk of gastric cancer because of antioxidant depletion.

Multivariate analysis of clinical, operative and pathologic features of esophageal cancer: who needs adjuvant therapy?

The failure of adjuvant therapy to significantly improve the prognosis of patients undergoing esophago-gastrectomy for cancer may be because of poor patient selection. We sought prognostic factors that would identify those patients who could benefit from adjuvant therapy. Data on 15 possible prognostic factors were prospectively collected on 225 patients undergoing esophago-gastrectomy at a single institution, and univariate and multivariate analyzes performed. T, N, M and overall UICC stage, differentiation, involvement of the circumferential resection margin and number of metastatic of lymph nodes were identified as significant prognostic factors by univariate analysis. Multivariate analysis revealed that the completeness of resection (R-category), ratio of metastatic to total nodes resected and the presence of vascular invasion were independently significant prognostic factors. Following R0 or R1 resection, patients with a metastatic to total lymph node ratio > 0.2 and /or the presence of vascular invasion have a poor prognosis, and the effects of adjuvant therapy in these patients should be studied.

Evaluation of POSSUM in patients with oesophageal cancer undergoing resection.

BACKGROUND: The Physiogical and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) has been used to produce a numerical estimate of expected mortality and morbidity after a variety of general surgical procedures. The aim of this study was to evaluate the ability of POSSUM to predict mortality and morbidity in patients undergoing oesophagectomy. METHODS: POSSUM predictor equations for morbidity and mortality were applied retrospectively to 204 patients who had undergone oesophagectomy for cancer. Observed morbidity and mortality rates were compared with rates predicted by POSSUM using the Hosmer-Lemeshow goodness-of-fit test. Evaluation of the discriminative capability of POSSUM predictor equations was performed using receiver-operator characteristic (ROC) curve analysis. RESULTS: The observed and predicted mortality rates were 12.7 and 19.1 per cent respectively, and the respective morbidity rates were 53.4 and 62.3 per cent. However, the POSSUM model showed a poor fit with the data both for the observed 30-day mortality (chi2 = 16.26, P = 0.002) and morbidity (chi2 = 63.14, P < 0.001) using the Hosmer-Lemeshow test. ROC curve analysis revealed that POSSUM had poor predictive accuracy both for mortality (area under curve 0.62) and morbidity (area under curve 0.55). CONCLUSION: These data suggest that POSSUM does not accurately predict mortality and morbidity in patients undergoing oesophagectomy and must be modified.

Does pneumatic dilatation affect the outcome of laparoscopic cardiomyotomy?

BACKGROUND: Controversy surrounds the choice of laparoscopic cardiomyotomy as the primary treatment for achalasia or a second-line treatment following the failure of nonsurgical treatment. Laparoscopic cardiomyotomy can be more difficult technically following pneumatic dilatations. The aim of this study was to compare the outcome obtained with primary laparoscopic cardiomyotomy to that achieved when the procedure is performed following failed pneumatic dilatation. METHODS: Laparoscopic cardiomyotomy was performed in seven patients following a median of four pneumatic dilatations (group A) and in five patients as their primary treatment (group B). Outcome was measured using manometry, a modified DeMeester symptom scoring system, and a quality-of-life questionnaire. RESULTS: There were no significant differences between groups A and B in sex, age, preoperative modified DeMeester score, or mean barrier pressure. Six of seven group A patients had evidence of periesophageal and submucosal fibrosis at surgery, but this condition was not seen in group B patients. The operative time was slightly longer in group A patients. There was no difference in complication rates (one primary hemorrhage in group A and one esophageal perforation in group B), and both groups had a significantly improved modified DeMeester score at 6 weeks and at long-term follow-up (median, 26 months). Eleven of 12 patients said that they would choose laparoscopic cardiomyotomy as their primary treatment if newly diagnosed with achalasia. CONCLUSIONS: Laparoscopic cardiomyotomy is safe and effective as a primary or second-line treatment following pneumatic dilatations in patients with achalasia.

Laparoscopic cholecystectomy in morbidly obese patients.

BACKGROUND: Morbid obesity is generally regarded as a risk factor for laparoscopic cholecystectomy due to increases in operative time, morbidity, and conversion rate to open cholecystectomy. The aim of this study was to evaluate the feasibility and outcome of laparoscopic cholecystectomy (LC) in morbidly obese patients. METHODS: A total of 864 consecutive patients underwent LC at our institution between 1990 and 1997. This series represents a continuing policy of LC for all comers. Data were collected prospectively. There were 659 nonobese (NO: BMI 40 kg/m2). Laparoscopic bile duct exploration was performed in 28 (4.2%), nine (4.8%), and one (5.9%) patients, respectively. RESULTS: Obesity and morbid obesity were associated with trends toward an increased conversion rate (2.3% NO; 4.3% OB; 5.9% MO), a longer operative time (median, 80, 85, and 107 mins, respectively), greater postoperative morbidity (4.7%, 5.9%, and 11.8%, respectively), and a reduced ability to obtain cholangiography (86.1%, 80.1%, and 71.4%, respectively). None of these differences, however, were statistically significant (c2 test, p > 0.05). Postoperative hospital stay for LC was similar for all three groups (median, 1 day). CONCLUSION: LC in morbidly obese patients is a safe procedure, but it may be associated with increased operative difficulty and morbidity, as compared with nonobese and obese patients.

Circumferential resection margin involvement: an independent predictor of survival following surgery for oesophageal cancer.

BACKGROUND: For rectal carcinoma, the presence of tumour within 1 mm of the circumferential margin is an important independent prognostic factor for both local recurrence and survival. Similar prospective data have not been reported for oesophageal carcinoma and we wished to ascertain the prognostic importance of this variable following potentially curative resection for oesophageal carcinoma. AIM: To prospectively assess the impact of circumferential margin involvement (tumour within 1 mm) following potentially curative resection for oesophageal carcinoma. PATIENTS AND METHODS: In a prospective study, resection specimens of 135 patients treated with potentially curative oesophageal resection alone were studied for the presence of tumour within 1 mm of the circumferential margin (margin positive), using inked margins and cross sectional slicing of the specimen. All tumours were also staged using the 1987 UICC TNM classification. Patients were followed for a mean of 19 months, and overall and cancer specific survival analysed. RESULTS: The finding of tumour cells within 1 mm of the circumferential margin (CRM+) was a significant and independent predictor of survival following potentially curative oesophageal resection. Overall, 64 (47%) patients were CRM+. Median survival in this group was 21 months compared with 39 months in the CRM- group (p=0.015). The impact of CRM status on survival was only seen in patients with a low nodal metastatic burden (<25% nodes positive). The odds ratio for the risk of dying from oesophageal cancer was 2.08 when the CRM was involved (p=0.013). CONCLUSIONS: The presence of tumour within 1 mm of the circumferential margin following potentially curative resection for oesophageal carcinoma is an important independent prognostic variable and should be reported routinely.

Prospective study of cyclin D1 overexpression in Barrett's esophagus: association with increased risk of adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma commonly arises from a precancerous condition, Barrett's esophagus, in which the normal squamous epithelium is replaced by a columnar cell-lined epithelium. Genetic alterations occurring in this process could serve as biomarkers for the risk of malignant progression, improve surveillance, and contribute to early diagnosis. We examined two potential biomarkers, cyclin D1 and p53, in a prospective cohort of Barrett's esophagus patients. METHODS: A total of 307 patients were enrolled in an endoscopic surveillance cohort, and esophageal biopsy specimens were collected at each endoscopy. Incident cases of adenocarcinoma were matched to control patients within the cohort by duration of follow-up, age, sex, and length of columnar cell-lined epithelium at recruitment. Biopsy specimens were analyzed for cyclin D1 and p53 protein levels by immunohistochemistry. Statistical tests were two-sided. RESULTS: A total of 12 cases of adenocarcinoma occurred within the follow-up period, and tumor biopsy specimens from 11 cases stained positive for cyclin D1. Biopsy specimens from eight of these patients taken at recruitment also stained positive for cyclin D1. A case-control analysis of biopsy specimens obtained at recruitment revealed a statistically significantly increased risk of progression to adenocarcinoma in Barrett's esophagus patients whose biopsy specimens were cyclin D1 positive (odds ratio [OR] = 6. 85; 95% confidence interval [CI] = 1.57-29.91; P =.0106) but not in patients whose biopsy specimens were p53 positive (OR = 2.99; 95% CI = 0.57-15.76; P =.197). CONCLUSIONS: Cyclin D1-positive staining could be a useful biomarker in identifying Barrett's esophagus patients at high risk of esophageal adenocarcinoma. Given the complexity of genetic alterations in the natural history of this cancer, additional biomarkers will be required to increase the sensitivity and specificity of molecular diagnosis.

Benefiting from clinical experience: the influence of learning style and clinical experience on performance in an undergraduate objective structured clinical examination.

OBJECTIVE: To assess the relationship between clinical experience, learning style and performance in an objective structured clinical examination (OSCE) in medical students at the end of their first clinical year. DESIGN: Prospective study of undergraduate students taking an OSCE examination at the end of their first clinical year. SUBJECTS: 194 undergraduate medical students (95 male). MAIN OUTCOME MEASURES: Performance in the OSCE examination, the Entwhistle Learning Style Inventory1 and a composite self-reported score of clinical activity during the students first clinical year. RESULTS: Performance in the OSCE examination was related to well-organized study methods but not to clinical experience. A significant relationship between clinical experience and organized deep-learning styles suggests that knowledge gained from clinical experience is related to learning style. CONCLUSIONS: The relationship between clinical experience and student performance is complex. Well-organized and strategic learning styles appear to influence the benefits of increased clinical exposure. Further work is required to elucidate the most beneficial aspects of clinical teaching.

Relaparoscopy for the detection and treatment of complications of laparoscopic cholecystectomy.

BACKGROUND: Laparotomy remains the commonest intervention in patients with abdominal complications of laparoscopic surgery. Our own policy is to employ relaparoscopy to avoid diagnostic delay and unnecessary laparotomy. The results of using this policy in patients with suspected intra-abdominal complications following laparoscopic cholecystectomy are reviewed. METHODS: Data were collected from laparoscopic cholecystectomies carried out by five consultant surgeons in one center. Details of relaparoscopy for complications were analyzed. RESULTS: Thirteen patients underwent relaparoscopy within 7 days of laparoscopic cholecystectomy for intra-abdominal bleeding (2 patients) or abdominal pain (11 patients). The causes of pain were subhepatic haematoma (1), acute pancreatitis (1), small bowel injury (1), and minor bile leakage (6). In 2 patients no cause was identified. Twelve patients were managed laparoscopically and 1 patient required laparotomy. Median stay after relaparoscopy was 7 days (range 2 to 19). CONCLUSIONS: Exploratory laparotomy can be avoided by prompt relaparoscopy in the majority of patients with abdominal complications of laparoscopic cholecystectomy.

Barrett's oesophagus: results from a 13-year surveillance programme.

OBJECTIVES: To review the results of a 13-year surveillance programme of patients with Barrett's oesophagus to determine the incidence of adenocarcinoma. Although the risk of cancer in Barrett's oesophagus is well established, the magnitude of this risk is still controversial. DESIGN: Records of all patients with histologically confirmed Barrett's oesophagus in our 13-year surveillance programme were examined retrospectively. SETTING: Integrated gastroenterology and gastrointestinal surgical service in a large teaching hospital. PARTICIPANTS: During the study period, 597 patients had a diagnosis of Barrett's oesophagus; of these, 357 entered a yearly endoscopy and biopsy surveillance programme. MAIN OUTCOME MEASURES: The development of oesophageal adenocarcinoma. RESULTS: After a mean follow-up of 43 months, 12 patients, all with specialized epithelium, developed adenocarcinoma (11 men), an incidence for men of one cancer per 69 patient-years; and for women, one cancer per 537 patient-years follow-up (P < 0.01). If only patients with specialized mucosa were included the incidence of cancer was one per 95 patient-years of follow-up (men, one per 61 patient-years; women, one per 468 patient-years). CONCLUSIONS: Whilst the role of screening patients with Barrett's oesophagus remains controversial, this study supports the routine surveillance of male patients with specialized epithelium.

Dendritic cells: immunological sentinels with a central role in health and disease.

Immunological effector cells must be sensitive to the antigens or environmental signals that indicate that a pathogen is present. To this end, a group of cells known as the professional antigen-presenting cells have the ability to educate T, B and NK cells as to the fingerprints of specific infections. The most adept of these cells are a closely related family termed dendritic cells (DC). A subset of these act as peripheral sentinels, specializing in the uptake, processing and presentation of antigenic material combined with an ability to detect a wide variety of 'danger' signals. These 'danger' or activation signals induce profound changes in dendritic cell physiology, facilitating the efficient stimulation of both adaptive and innate immunity. In the present review, a number of recent advances in the understanding of DC biology are discussed. These advances offer insights into the pathogenesis of a wide variety of diseases and point towards future strategies for immunotherapy.