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OBJECTIVE: To compare overall survival of patients with a cCR undergoing active surveillance versus standard esophagectomy.SUMMARY OF BACKGROUND DATA: One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy.METHODS: A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression-free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO: CRD42020167070).RESULTS: Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 [95% confidence interval (CI): 0.62-1.87, P = 0.75] after intention-to-treat analysis and 0.93 (95% CI: 0.56-1.54, P = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95% CI: 0.83-1.58, P = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95% CI: 26%-59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection.CONCLUSIONS: Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic follow-up is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.

Laparoscopic cholecystectomy is the standard of care for symptomatic gallstone disease but when laparoscopic removal proves impossible the standard advice is to convert to open surgery. This jettisons the advantages of laparoscopy for a procedure which surgeons no longer perform routinely, so it may no longer be the safest practice. We hypothesised that gallbladder aspiration would be a safer alternative when laparoscopic removal is impossible. A retrospective analysis was performed of all laparoscopic cholecystectomies attempted under one surgeon’s care over 19 years, and the outcomes of gallbladder aspiration were compared with the standard conversion-to-open procedure within the same institution. Of 757 laparoscopic cholecystectomies attempted, 714 (94.3%) were successful, while 40 (5.3%) were impossible laparoscopically and underwent gallbladder aspiration. Interval cholecystectomy was later performed in 34/40 (85%). Only 3/757 (0.4%) were converted to open. No aspiration-related complications occurred and excessive bile leakage from the gallbladder was not observed. During this time 1209 laparoscopic cholecystectomies were attempted by other surgeons in the institution of which 55 (4.55%) were converted to open and 22 (40%) had procedure-associated complications. There was a significant difference in the mean (± SEM) post-operative hospital stay between laparoscopic gallbladder aspiration [3.12 (± 0.558) days] and institutional conversion-to-open cholecystectomy [9.38 (± 1.04) days] (p

Up to 50% of patients with esophageal cancer have a pathologically complete response after neoadjuvant chemoradiotherapy (nCRT) plus surgery. An active surveillance strategy may be feasible in patients with a complete clinical response (cCR) after nCRT. The aim of this study was to perform a meta-analysis using data of individual patients that underwent active surveillance with surgery for recurrent disease versus standard surgery after nCRT. Methods A systematic search was performed in Embase, Medline, Web of Science, Scopus and Cochrane from inception to February 2020. Studies were sought that reported on overall survival and recurrence rates in patients with cCR after nCRT that underwent active surveillance versus standard surgery. Authors were contacted to supply individual patient data. Pooled hazard ratio (HR) comparing survival outcomes and distant dissemination rates (DDR) between patients with cCR undergoing active surveillance or standard surgery were estimated using a random-effect meta-analysis. Cumulative incidence of locoregional recurrences in active surveillance were assessed using a Cox Frailty model. Results Seven studies including 788 patients (256 active surveillance and 532 surgery) were identified. All authors provided anonymized patient data. Pooled two- and five-year overall-survival was 75% and 58% for active surveillance and 76% and 60% for standard surgery with a pooled HR of 1.04 (95%CI:0.73–1.49) (Figure 1). Two-years DDR was 18% and 19% for active surveillance and standard surgery, respectively (HR 1.10,95%CI:0.75–1.63). Locoregional recurrence rate necessitating esophagectomy in patients undergoing active surveillance was 24% at one year, 33% at two years and 38% at five years. Active surveillance patients undergoing postponed surgery had R0 in 91% of cases. Conclusion Overall survival is comparable in patients undergoing active surveillance with postponed surgery compared to standard surgery after neoadjuvant chemoradiation. Distant dissemination rate is also comparable between both groups. During active surveillance, local regrowths developing after two years are rare. Although these data support an active surveillance strategy, randomized trials have to be completed before an active surveillance strategy can be actively proposed to patients with esophageal cancer.

Background Sarcopenia is associated with increased morbidity and mortality in oncologic and transplant surgery. It has a high incidence in chronic inflammatory states including inflammatory bowel disease (IBD). The validity of existing data in IBD and of sarcopenia's correlation with surgical outcomes is limited. Methods We performed a systematic review to assess the correlation of sarcopenia with the requirement for surgery and surgical outcomes in patients with IBD. Observational studies of patients with IBD in whom an assessment of sarcopenic status/skeletal muscle index was undertaken, a proportion of whom proceeded to surgical management, were selected. Results A total of 5 studies with a combined 658 IBD patients met the inclusion criteria. The majority (70%) had a diagnosis of Crohn's disease. Median (range) body mass index and skeletal muscle index were reported in 4 studies and were 16.58 (13.66-22.50) kg/m2 and 44.52 (42.90-50.64) cm2/m2, respectively. Forty-two percent of IBD patients had sarcopenia. Notably, none of the studies assessed both the anatomical and functional component required for a correct assessment of sarcopenia. Three studies noted that sarcopenic IBD patients had a higher probability of requiring surgery. The rate of major complications (Clavien-Dindo grade ≥IIIa) was significantly higher in patients with sarcopenia. Improved perioperative nutrition management may mitigate the risk of complications. Conclusion Many IBD patients are young, may be malnourished, and commonly require emergent surgery. There is considerable heterogeneity in the assessment of sarcopenia. Sarcopenia is common in the IBD population and can predict the need for surgical intervention. Sarcopenia correlates with an increased rate of major postoperative complications. Improved perioperative intervention may diminish this risk. A formal assessment, screening by a dedicated IBD dietician, and preoperative physical therapy may facilitate early intervention.

Background Cholecystectomy alters bile release dynamics from pulsatile meal-stimulated to continuous, and results in retrograde duodeno-gastric bile reflux (DGR). Bile is implicated in mucosal injury after gastric surgery, but whether cholecystectomy causes esophagogastric mucosal inflammation, therefore increasing the risk of metaplasia, is unclear. Study Design This study examined whether cholecystectomy-induced DGR promotes chronic inflammatory mucosal changes of the stomach and/or the esophagogastric junction (EGJ). Four groups of patients were studied and compared with controls. A group of patients was studied before and 1 year after cholecystectomy; 2 further groups were studied long-term post-cholecystectomy (LTPC) at 5 to 10 years and 10 to 20 years. All underwent abdominal ultrasound and upper gastrointestinal endoscopy with gastric antral and EGJ biopsies, noting the presence of gastric bile pooling. Biopsy specimens were stained for Ki67 and p53 overexpression, and the bile reflux index (BRI) was calculated. Results At endoscopy, bile pooling was observed in 9 of 26 (34.6%) controls, in 8 of 25 (32%) patients pre-cholecystectomy, in 15 of 25 (60%) 1 year post-cholecystectomy patients (p = 0.047), and 23 of 29 (79.3%) LTPC patients (p = 0.001). Bile reflux index positivity at the EGJ increased from 19% of controls through 41% of LTPC patients (p = 0.032). Ki67 was overexpressed at the EGJ in 19% of controls, but in 62% of LTPC patients (p = 0.044); p53 was overexpressed at the EGJ in 19% of controls compared with 66% of LTPC patients (p = 0.001). Conclusions Duodeno-gastric bile reflux was more common in patients with gallstones than in controls, and its incidence doubled after cholecystectomy. This was associated with inflammatory changes in the gastric antrum and the EGJ, evident in most LTPC patients. Ki67 and p53 overexpression at the EGJ suggests cellular damage attributable to chronic bile exposure post-cholecystectomy, increasing the likelihood of dysplasia. Further studies are required to determine whether DGR-mediated esophageal mucosal injury is reversible or avoidable, and whether surveillance endoscopy is indicated after cholecystectomy.

Background Acute pancreatitis is a commonly encountered emergency but accurately predicting that subset of patients who will become systemically unwell has proven difficult. Simple haematological prognostic markers, such as red cell distribution width (RDW) and neutrophil to lymphocyte ratio (NLR), could identify such patients. The aim of this study was to assess the usefulness of RDW and NLR measured on admission as predictors of mortality and intensive care (ICU) or high dependency unit (HDU) admission in patients with acute pancreatitis. Materials and methods All patient who presented to our institution with acute pancreatitis between August 2013 and August 2016 were retrospectively identified using the prospectively maintained Hospital In-Patient Enquiry (HIPE) discharge audit. Data on survival, admission to HDU or ICU, length of stay and haematological parameters including RDW and NLR on presentation to the emergency department were collected. Results A total of 185 patients with acute pancreatitis were included of which 23 (12%) patients had a RDW above the upper limit of normal (ULN), which was associated with a significantly increased likelihood of admission to ICU or HDU (RR3.5; p = 0.01); 117 (63%) patients had a NLR above 5 on presentation, which also increased the risk of ICU or HDU admission (RR 8.1; p = 0.01). Patients who had both a RDW above the ULN and a raised NLR had an increased risk of inpatient mortality (RR 9.9; p = 0.04). Conclusion RDW and NLR can identify patients at increased risk of severe acute pancreatitis on presentation to the Emergency Department.

Background Neoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy. Methods This meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors. Results Four RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone. Conclusion After neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

Background Bone marrow micrometastases are present in a high proportion of patients undergoing curative resection for esophagogastric cancer. The incorporation of preoperative systemic therapies into these patients’ treatment is widely practiced. This study investigates the effect of neoadjuvant chemoradiotherapy (CRT) on the incidence of micrometastases and the viability of detected tumor cells. Materials and methods Rib bone marrow was obtained from patients (n = 106) in three centers, who were selected for potentially curative resection. Patients received neoadjuvant CRT plus surgery (n = 55), or surgery alone (n = 51). To detect micrometastases, mononuclear cells were isolated from fresh marrow and immediately stained immunohistochemically with an anti-cytokeratin-18 antibody using the APAAP technique. Tumor cell viability was assessed by immunohistochemical staining of marrow cell cultures for cytokeratin-positive cells. Results Micrometastases were detected in fresh marrow in 42% (23/55) of patients who received neoadjuvant CRT plus surgery, and in 67% (34/51) of patients treated with surgery alone. Viable tumor cells were demonstrated in 10 of 18 marrow cultures from CRT plus surgery cases. In this patient subset, combination of results of staining fresh and cultured marrow significantly increased micromet detection to 78%. Conclusions A significant proportion of patients with esophagogastric cancer have disseminated viable tumor cells at time of surgery, irrespective of pre-operative treatment. The use of marrow culture in parallel with fresh marrow staining may increase the detection of micrometastases. The persistence of tumor cells resistant to systemic therapy may explain why these regimens fail in a majority of patients.

The role of multimodal treatment in the management of esophageal cancer is controversial. There are conflicting results from studies on the effect of neoadjuvant and/or adjuvant treatment on long-term survival. Following a search of the Medline database, the authors examine the results of randomized studies on the various treatment protocols available and discuss future therapeutic improvements.

OBJECTIVE: Gallbladder removal is associated with an increased incidence of gastroesophageal reflux, but the mechanism is unclear. Cholecystokinin (CCK) release, which causes gallbladder contraction, is inhibited by bile in the duodenum. This study investigates the effect of cholecystectomy on meal-stimulated CCK secretion. METHODS: Three groups of patients were studied. Group 1 (n = 15) were normal controls. Group 2 (n = 27) were patients with symptomatic gallstones. Group 3 (n = 25) were patients who had undergone cholecystectomy. Meal-stimulated CCK levels were measured by radioimmunoassay at defined time points for 60 min after a standard corn oil-based meal. RESULTS: Fasting CCK levels were similar in all three groups. In postcholecystectomy patients, meal-stimulated plasma CCK levels were significantly elevated compared with controls: median (range) integrated CCK values for 60 min were 116 (28–209) in controls, 123 (20–501) in gallstone patients, and 176 (63–502) after cholecystectomy. CONCLUSIONS: This study suggests that cholecystectomy causes an exaggerated meal-stimulated CCK response. Because CCK is known to relax the lower esophageal sphincter, these findings may help explain the increased incidence of gastroesophageal reflux seen after cholecystectomy.

Background: Predicting response to treatment has long been the Holy Grail of clinicians treating patients with upper gastrointestinal malignancy. The widespread use of neoadjuvant therapy for esophageal cancer has provided an added urgency to the issue and at the same time brought success a step closer because accurate response can be determined from analysis of the resected specimen. Methods: A search was undertaken of the Medline database for text references to neoadjuvant therapy, esophagus, stomach and predicting response. The references of these publications were further scanned for appropriate references in the text and reference lists. Results: Publications describing predictive markers to neoadjuvant therapy for esophageal cancer, which were most likely to be of clinical significance, were selected for inclusion in this report. Conclusions: The most reliable tissue markers of response based on analysis of pretreatment biopsy specimens include P53, Ki-67, EGFR and the most impressive serum marker for monitoring response are CYFRA 21-1 and CEA. The results, however, are inconsistent, and the markers of relatively low sensitivity and none reliably identifies individual patients who will respond.

We present a rare case of an insulin-like growth factor-2 (IGF-2)-secreting tumour of the thorax. This patient demonstrated the combination of fasting hypoglycaemia and impaired glucose tolerance on oral glucose tolerance testing, which has not been previously described in this condition. A review of the literature of IGF-2-secreting intrathoracic tumours is presented here.

Introduction: Angiogenesis is fundamental to tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic cytokines known. We have previously demonstrated that tamoxifen reduces serum VEGF in certain cancer patients. We hypothesized that tamoxifen may attenuate the angiogenetic response to VEGF. Methods: Human dermal microvessel endothelial primary cell cultures (HMEC) were incubated with tamoxifen (1.25–5.0 μg) or vehicle. Cell proliferation was quantified using 5-bromo-2′-deoxyuridine (BrdU) labelling endothelial cell proliferation assay. The effect of oral tamoxifen (20 mg/day) on VEGF-mediated angiogenesis in vivo was assessed using a Matrigel angiogenesis assay in the Sprague–Dawley rat. Results: Tamoxifen (5.0 μg/ml) significantly reduced HMEC proliferation over 24 h when compared with cells treated with vehicle alone. Oral administration of tamoxifen in the rat (20 mg/day) significantly reduced endothelial cell proliferation and migration in response to VEGF. Conclusion: Tamoxifen (5.0 μg/ml) reduces proliferation of a VEGF-dependent endothelial cell line in vitro. In vivo, orally administered tamoxifen reduces VEGF-mediated angiogenesis in the rat. These findings indicate that tamoxifen may directly inhibit the effect of VEGF on the endothelial cell, in addition to its previously described effect of reducing serum VEGF levels. This data supports a role for tamoxifen in modulation of the VEGF-dependent angiogenic response to surgical trauma, particularly as an adjuvant therapy for VEGF-dependent tumours.

Introduction: Many cancer patients have undetected micrometastatic disease at first presentation which ultimately progresses. Angiogenesis—the development of an independent blood supply—is a key event in the growth of metastases. Improved understanding of the influence of angiogenesis on micrometastatic growth may lead to new therapeutic intervention. Methods: This study examines current concepts of the significance of micrometastases and the role of angiogenesis in their development and destruction. A comprehensive review of the literature on micrometastasis and angiogenesis was performed using the Medline database between 1966 and 1999. Conclusions: Advances in technology have improved our ability to diagnose metastatic disease, but micrometastases in loco-regional lymph nodes and at distant sites can only be detected by sophisticated histological techniques. While the significance of micrometastases remains controversial, there is increasing evidence that micrometastatic status provides useful prognostic information and should be part of standard staging techniques. Anti-angiogenic therapy has the potential to favourably influence management of certain cancers by manipulating a number of key events in the metastatic process.

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.

Background The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. Methods We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. Results We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p < 0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. Conclusion Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation.

Background The time-honoured mnemonic of ‘5Fs’ is a reminder to students that patients with upper abdominal pain and who conform to a profile of ‘fair, fat, female, fertile and forty’ are likely to have cholelithiasis. We feel, however, that a most important ‘F’—that for ‘family history’—is overlooked and should be introduced to enhance the value of a useful aide memoire. Methods To assess the usefulness of each of the existing factors of a popular mnemonic, 398 patients admitted with upper abdominal pain between March 2009 and April 2010 were studied. The clinical features expressed in the cholelithiasis mnemonic in patients with sonographic evidence of cholelithiasis were compared with those of patients without. Findings In the cholelithiasis group, significantly more patients were women (150/198 (75.8%) vs 111/200 (55.5%), p30 (56/198 (28.3%) vs 19/200 (9.5%) (p Interpretation Our study found that the validated ‘students’ 5Fs’ mnemonic retains a role in clinical diagnosis of patients suspected of cholelithiasis but the factor ‘familial’ should be substituted for ‘forty’ in recognition of the role of inheritance and the changing demographics of gallstone incidence.

Background. Multimodality therapy with chemotherapy and radiotherapy followed by surgery may improve survival in patients with esophageal squamous cell carcinoma compared with each of the individual treatment options. Histologic assessment of resected tumors after chemoradiotherapy shows that some patients have a complete response with no residual tumor, whereas other patients derive no benefit. The ability to predict response to chemoradiotherapy would allow treatment to be planned accordingly. Methods. Expression of the tumor growth and proliferation proteins epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) was determined using immunohistochemical staining of pretreatment endoscopic biopsies from patients with esophageal squamous cell carcinoma who were randomized to chemoradiotherapy before surgery. Response to chemoradiotherapy was assessed by histologic examination of the resected specimens. Response to chemoradiotherapy and survival were correlated with EGFR and PCNA expression individually and with both markers combined as EGFR/PCNA. Results. Of 14 patients available for study, 6 had a complete histologic response (CR) to chemoradiotherapy with no residual tumor in the resected specimen, 3 had a partial response (PR) to chemoradiotherapy, and the remaining 5 had minimal response (MR). Of the nine patients with a CR or PR, tumors of eight patients were negative for one or both markers. Of the five patients with an MR, four tumors were positive for both EGFR and PCNA (P < 0.05, Fisher's exact test). Comparison of survival from the date of randomization shows that patients with tumors negative for one or both markers had a signiticant survival advantage (P = 0.0003, log-rank test). Conclusions. Evaluation of PCNA and EGFR status of pretreatment biopsies may identify a group of patients likely to derive the greatest benefit from chemoradiotherapy before surgery in terms of histologic response and long term survival.

Assessment of duodenogastric bile reflux has hitherto been unsatisfactory. An ambulatory system which utilizes the optical properties of bilirubin is examined. Test readings are correlated with the laboratory values for bilirubin in each of a number of physiological solutions. For dilutions of pure bile there was a linear correlation between absorbance and bilirubin concentration (r = 0.93, p0.001). In the more acidic environment of gastric juice there was also a linear correlation between absorbance and bilirubin concentration (r = 0.65, p0.001), but absorbance values were significantly higher than those of pure bile solutions (F ratio = 130, p0.0001). Normal gastric secretions and saliva give low absorbance values (0.02-0.04). Common foodstuffs such as soups, tea and coffee give higher readings and may interfere with bile reflux assessment in a clinical setting. Bilitec 2000 has potential for use as an ambulatory bile reflux monitoring system but consideration should be given to a standard diet or attention must focus on the fasting period.

The contribution of gastric acid to the toxicity of alkaline duodenal refluxate on the esophageal mucosa is unclear. This study compared the effect of duodenal refluxate when acid was present, decreased by proton pump inhibitors (PPI), or absent.We randomized 136 Sprague-Dawley rats into 4 groups: group 1 (n = 33) were controls; group 2 (n = 34) underwent esophagoduodenostomy promoting "combined reflux"; group 3 (n = 34) underwent esophagoduodenostomy and PPI treatment to decrease acid reflux; and group 4, the 'gastrectomy' group (n = 35) underwent esophagoduodenostomy and total gastrectomy to eliminate acid in the refluxate. Esophaguses were examined for inflammatory, Barrett's, and other histologic changes, and expression of proliferative markers Ki-67, proliferating cell nuclear antigen (PCNA), and epidermal growth factor receptor (EGFR).In all reflux groups, the incidence of Barrett's mucosa was greater when acid was suppressed (group C, 62%; group D, 71%) than when not suppressed (group B, 27%; P = 0.004 and P.001). Erosions were more frequent in the PPI and gastrectomy groups than in the combined reflux group. Edema (wet weight) and ulceration was more frequent in the gastrectomy than in the combined reflux group. Acute inflammatory changes were infrequent in the PPI group (8%) compared with the combined reflux (94%) or gastrectomy (100%) groups, but chronic inflammation persisted in 100% of the PPI group. EGFR levels were greater in the PPI compared with the combined reflux group (P = .04). Ki-67, PCNA, and combined marker scores were greater in the gastrectomy compared with the combined reflux group (P = .006, P = .14, and P.001).Gastric acid suppression in the presence of duodenal refluxate caused increased rates of inflammatory changes, intestinal metaplasia, and molecular proliferative activity. PPIs suppressed acute inflammatory changes only, whereas chronic inflammatory changes persisted.

The effect of cholecystectomy on oesophageal function was examined prospectively. Of 37 patients studied, 17 (46 per cent) were still symptomatic 3–4 months after surgery. Thirteen patients (35 per cent) had abnormal oesophageal pH profiles before cholecystectomy, increasing to 27(73 per cent) afterwards(P < 0·002). The mean(s.e.m.) DeMeester acid reflux score increased from 15·2(2·1) to 34·2(5·2) (P < 0·001) after operation. Lower oesophageal sphincter function, as measured by the sphincter function index, was significantly reduced in the patients with abnormal pH profiles after operation (P < 0·01). Mean(s.e.m.) supine gastric alkaline shift (proportion of time at pH > 4) increased from 9·2(2·0) to 17·7(3·7) per cent (P < 0·02) and the incidence of gastritis from eight patients (22 per cent) to 23 (62 per cent) (P < 0·001). These data suggest that cholecystectomy results in gastro-oesophageal reflux that appears to be related to compromised sphincter competence.

Esophageal adenocarcinoma is aetiologically associated with gastro-esophageal reflux, but the mechanisms responsible for the metaplasia–dysplasia sequence are unknown. Bile components are implicated. Impaired gallbladder function may contribute to duodenogastric reflux (DGR) and harmful GERD. This study aims to compare gallbladder function in patients with Barrett’s esophagus, adenocarcinoma, and controls. Three groups of patients, all free of gallstone disease, were studied. Group 1: (n = 15) were normal controls. Group 2: (n = 15) were patients with >3-cm-long segment of Barrett’s esophagus. Group 3: (n = 15) were patients with esophageal adenocarcinoma. Using real-time ultrasonography unit, gallbladder volume was measured in subjects following a 10-h fast. Ejection fraction was calculated before and after standard liquid meal and compared between the groups. The mean percentage reduction in gallbladder volume was 50% at 40 min in the adenocarcinoma group compared with 72.4% in the control group (p

In patients with severe abdominal pain, of pancreatic origin, there are a few with minimal or equivocal findings on pancreatic investigation and in whom the aetiology of their pancreatic disease is elusive. The findings and outcome in 16 of these patients (four men and 12 women) who underwent resection are reported. Pancreatic imaging showed minimal or equivocal findings in all 16; pancreas divisum was present in five. All were managed conservatively at first but resection was required for progression of symptoms. A drainage procedure was performed initially in five patients but relief of pain was at best transitory before further surgery was required. Partial resection was needed in 12, of whom eight required subsequent completion pancreatectomy and four had a one stage total resection. Nine patients are currently pain free after resection or are very much improved, while six are no better and one patient has died from an unrelated cause. Histology of resected specimens showed chronic inflammatory changes accompanied by subtle non-inflammatory changes in all but one. These changes include duct proliferation, duct complex formation, adenomatous nodules, and acinar cell atrophy, the significance of which is unclear. These findings suggest a syndrome of minimal macroscopic and radiological change chronic pancreatitis with pain as its chief clinical feature and a distinct histology, the aetiology of which is unclear. It seems that there is a distinct syndrome of minimal change pancreatitis, among the group of patients which presents with the clinical features of chronic pancreatitis.

Collagenous colitis is a microscopic colitis characterized by normal appearing colonic mucosa on endoscopy. It is regarded as a clinically benign disease which rarely results in serious complications. We report a case of toxic megacolon occurring in a patient with collagenous colitis. This is the first reported case of toxic megacolon occurring in this subset of patients.

Background Vascular endothelial growth factor (VEGF) levels are raised in the serum of patients with oesophageal carcinoma. The aim of this study was to evaluate the tumour microvasculature and the role of tumour-associated macrophages in VEGF production after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer. Methods Sections from 92 consecutively resected oesophageal tumours were stained for VEGF, von Willebrand factor and CD68. Twenty-seven patients received preoperative chemoradiation and 65 underwent surgical excision alone. The cellular source of VEGF was determined by parallel-section staining. Microvessel density and macrophage count were determined for each tumour by means of image analysis software. Results There were no significant differences between the two groups in age, sex or tumour type. Local downstaging of disease was evident in most specimens of tumours that had received preoperative chemoradiation. All tumours stained positive for VEGF, including those demonstrating a complete pathological response. Staining of parallel sections confirmed macrophages as the principal source of VEGF. Mean microvessel density was 6·4 per high-power field (h.p.f.) in tumours that received preoperative chemoradiation compared with 5·3 per h.p.f. in those treated by surgery alone (P = 0·130). A significant increase in tumour-associated macrophage infiltration was noted in tumours treated with neoadjuvant chemoradiation (22·1 per h.p.f.) compared with those treated by surgery alone (14·3 per h.p.f.) (P = 0·042). Conclusion Preoperative chemoradiation had little effect on the local angiogenic profile of the tumour in patients with oesophageal cancer. Tumour-infiltrating macrophages seem to be the source of persistent VEGF production after chemoradiotherapy and might explain the raised serum levels. Addition of an antiangiogenic agent to this regimen may be worthwhile in patients with oesophageal carcinoma.

Background The contribution of dysmotility to dysphagia in oesophageal cancer is unclear. Aim To examine oesophageal motility in patients with oesophageal carcinoma and to assess the effect of chemoradiotherapy on motility. Methods Stationary manometry and 24-hour pH-metry were performed in 12 patients with oesophageal carcinoma and one week following completion of chemoradiotherapy using 5-fluorouracil (5-FU), cisplatin and 40Gy radiotherapy. Results All patients had abnormal motility prior to treatment. Peristalsis was impaired in 11 patients with a mean (SD) of 25% (9) of waves normally propagated. Eight patients had 20% or more simultaneous waves. Following chemoradiotherapy, the percentage of waves normally propagated increased from 25% (9) to 52% (10) (p

Gastro-oesophageal reflux and coronary artery disease frequently coexist. Stimulation of myocardial vagal receptors impairs lower oesophageal sphincter (LOS) function and may explain this link. This study examined the role of bradykinin, produced in increased quantities by the ischaemic myocardium, in activating this reflex. Thirteen dogs had patches soaked in bradykinin 100 μg/ml and saline applied sequentially to the left ventricular epicardium. Eleven of these animals were further divided into two subgroups: group 1 animals (six dogs) had the above sequence repeated after obliteration of sympathetic afferent fibres with phenol and those in group 2 (five animals) underwent sequential intravenous and intra-atrial injection of bradykinin 0·2 μg/kg. Epicardial bradykinin produced a fall in mean(s.e.m.) LOS tone from 13·3(1·3) to 6·0(0·5) sphinctometer units (P< 0·002), accompanied by a reduction in mean(s.e.m.) arterial pressure from 95(4) to 83(5) mmHg (P< 0·002). Destruction of sympathetic afferent fibres did not alter the LOS effect. Intra-atrial, but not intravenous, bradykinin reproduced the LOS effect. this suggests a cardiac origin. Myocardial release of bradykinin may play a role in producing transient LOS relaxation, predisposing to gastro-oesophageal reflux.

Oesophagectomy, necessitating vagotomy, is associated with delayed gastric emptying. Cisapride and erythromycin have prokinetic effects and improve emptying of the innervated stomach. Their effect on the denervated stomach following oesophagectomy is unknown. The effect of pyloroplasty, cisapride and erythromycin on the rate of gastric emptying after oesophagectomy was studied using a radiolabelled meal. Oesophagectomy was associated with a marked delay in gastric emplying (56 per cent of the test meal remaining after 4 h) compared with age- and sex-matched normal controls (16 per cent; P

Background Angiogenesis is critical for tumour growth and metastasis. The switch to the angiogenic phenotype depends on the net balance between positive and negative angiogenic factors released by the tumour. It was hypothesized that patients with oesophageal cancer would express raised serum levels of vascular endothelial growth factor (VEGF) which would return to normal values with neoadjuvant chemoradiotherapy. Methods Forty-four patients with oesophageal cancer who were selected for treatment with neoadjuvant chemoradiotherapy had blood samples taken before treatment, during chemoradiotherapy, before operation, on days 1, 3 and 5 after surgery, and 3 months after resection. Serum levels of VEGF were measured. Values were correlated with response to treatment. Controls were patients who were undergoing surgery for non-malignant conditions. Results Serum VEGF levels were raised in patients with oesophageal cancer compared with age-matched controls (mean 247 versus 1157 pg/ml; P < 0·01). VEGF levels were unaffected by neoadjuvant treatment but fell significantly on the first day after operation (652 versus 1057 pg/ml before operation; P < 0·05). No decrease occurred in control patients. VEGF levels had returned to preoperative levels by day 5. A similar postoperative rise in VEGF levels was seen in the control subjects (1194 pg/ml on day 5 versus 71 pg/ml before operation; P = 0·001). There was no correlation between VEGF level and response to treatment or tumour stage. VEGF levels had decreased significantly at 3 months following tumour resection (594 versus 1558 pg/ml on day 5; P = 0·03). Conclusion VEGF levels are raised in patients with oesophageal cancer and are unaltered by neoadjuvant treatment, suggesting an additional source other than tumour cells for this proangiogenic agent.

BackgroundFor most solid tumours, surgery remains the most effective primary treatment. Despite apparently curative resection, significant numbers of patients develop secondary disease due to growth of undetected micrometastases. The ability of a tumour to metastasize is related to the degree of angiogenesis it induces. In addition, micrometastases rely on new vessel formation to provide the nutrients necessary for growth. A better understanding of how tumours acquire their blood supply may lead to more effective adjuvant therapies and improve survival following surgery.MethodsA systematic review of the literature on angiogenesis between 1971 and 1997 was performed using the Medline database to ascertain current thinking on angiogenesis and its relevance in oncological surgery.ResultsAngiogenesis is a physiological process subject to autocrine and paracrine regulation which has the potential to become abnormal and play a part in a number of pathological states, including cancer. Increased angiogenic stimuli in the perioperative period, associated with concomitant reduction in tumour-derived antiangiogenic factors following resection of a primary tumour, result in a permissive environment which allows micrometastases to grow.ConclusionRecognition of the role of angiogenesis in metastatic tumour growth represents a significant development in our understanding of tumour biology. The development of antiangiogenic agents offers new promise in the treatment of malignancy. Such agents may prevent or control the development and growth of primary and metastatic tumours.

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.

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.

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.

Cholecystectomy is frequently linked with duodenogastric reflux and gastritis but its effect on Helicobacter Pylori (H pylori) infection has not been examined. In a prospective study, twenty two patients with documented cholelithiasis underwent upper gastrointestinal endoscopy and biopsy and 24hr dual channel pH monitoring prior to cholecystectomy and again at 3-6 months post-operatively. The antral biopsies were histologically assessed for H pylori and gastritis and awarded an alkaline reflux score. The number of patients with H pylori infection increased from 7 (32%) preoperatively to 15 (68%) post-cholecystectomy (p0.05). Cholecystectomy was also associated with an increase in the incidence of gastritis from 7 to 15 (p0.05). The increase in H pylori infection rate occurred in association with an increase in the percentage time gastric pH4 in the supine position, from 9.6 (2.2) to 22.2 (4.8) percent, (p0.01). The median chemical gastritis score, however, did not change significantly following surgery [8(3-11) vs 7(3-11)]. Seven patients remained symptomatic following cholecystectomy all of whom were H pylori positive and had gastritis. H pylori can survive in the alkaline environment which follows cholecystectomy and may contribute to the post-cholecystectomy syndrome.

The motility of the vagally denervated transposed stomach after oesophagectomy was examined by ambulatory gastric manometry and videofluoroscopy. Two groups of subjects were studied. Group 1 comprised ten patients who had undergone oesophagectomy 6–12 months previously and group 2 consisted of six normal control subjects. Studies were performed on fasting and fed subjects, and following injection of erythromycin 8 mg/kg. No distinguishable manometric wave activity was seen in either group while fasting. Feeding generated a measurable wave pattern in the patient group only. A significant increase in the mean(s.e.m.) distal wave amplitude was identified after infusion of erythromycin in both patients (34·0(15·1) versus 12·2(3·1) mmHg, P < 0·05) and controls (15·1(3·4) versus 5·0(0·0) mmHg, P = 0·05). The response to erythromycin was more rapid in patients than in controls (mean(s.e.m.) 113(16) versus 377(133) s, P

Introduction Background: Loss of the gallbladder reservoir function at cholecystectomy may critically alter the dynamics of bile storage and release. Consequent iatrogenic duodeno-gastro-esophageal reflux (DGER) may be associated with oesophago-gastric adenocarcinoma. Aims To examine the histological and molecular effects of cholecystectomy-induced DGER on gastric and oesophageal mucosae. Methods Patients and Methods: In a retrospective study we compared 26 gallstone-free controls with 25 patients pre-cholecystectomy and 29 patients post-cholecystectomy for one or more years. In a prospective study we compared 26 controls with 25 patients before and within 1 year of cholecystectomy. All underwent oesophago-gastro-duodenoscopy (EGD) with biopsies from the antrum, esophagogastric junction (EGJ) and 5 cm above the EGJ. A histochemical bile reflux index (BRI) was calculated and immunohistochemistry was performed for p53 and Ki67. Results Results: In the retrospective study antral BRI positivity was 11% in controls vs 69% in cholecystectomy patients (p=0.001); at the EGJ BRI positivity was 19% in controls vs 41% in cholecystectomy patients (p=0.032). p53 was expressed at the antrum in 4% of controls vs 52% cholecystectomy patients(p=0.001) and in 19% vs 66% at the EGJ (p=0.001). Ki67 was expressed at the antrum in 23% vs 59% (p=0.001) and at the EGJ in 19% vs 62% (p=0.001). Prospectively, BRI positivity increased from 11% to 36% (p=0.04) at the antrum within 1 year of cholecystectomy. Ki67 expression increased from 19% to 48% (p=0.044) at EGJ in patients within 1 year of cholecystectomy while p53 remained unchanged. Conclusion Changes attributable to DGER occur early in the gastric and LES mucosae of patients following cholecystectomy. Ki67 and p53 over-expression suggests that these changes may be precursors of malignant transformation. Such concerning changes suggest that options other than cholecystectomy be considered for patients with gallstones in a functioning gallbladder. Competing interests None declared.

The presentation, oesophageal profile and management of 27 symptomatic patients with daytime (upright) gastrooesophageal reflux only is reported. Oesophagitis was a presenting feature in 11 patients and its development was most closely correlated with postprandial reflux, which was characterized by cumulative acid exposure rather than by clearance abnormalities. Upright reflux was not associated with a hypotensive lower oesophageal sphincter or with oesophageal dysmotility. Antireflux surgery is indicated when conservative measures fail and was not associated with gas-bloat syndrome after operation.

Oesophageal sphincter measurements were carried out on 80 patients using the stationary pull through technique; Normals (n = 21), Nutcracker (n = 12), Refluxers (n = 21), and Barrett's (n = 26). Sphincter pressure (LOSP), abdominal length of sphincter, and overall sphincter length were measured. The Sphincter Function Index (SFI) was calculated as the product of sphincter pressure and percentage sphincter length (AL) exposed to abdominal pressure. Patients also had routine endoscopy and 24 hour pHmetry. SFI values discriminated between all four groups. LOSP was significantly different for Barrett's (p0.01) and Nutcracker (p0.01) compared to normals. AL was significant for Refluxers (p0.001) and Barrett's (p0.001) compared to normals. SFI gives better discrimination than LOSP or AL alone and may be useful in evaluating the response to treatment.

Symptoms persist in a significant proportion of patients following cholecystectomy, some of which may have an oesophageal aetiology. The oesophagus has not previously been studied in this patient group. In this study all patients who had undergone cholecystectomy over a four year period were invited for review and symptoms were documented. Oesophageal function was examined and compared with normal controls. Patients were subdivided into symptomatic and asymptomatic subgroups and their findings compared. Symptoms were present in 53 percent of the postcholecystectomy group. The mean (sem) DeMeester acid score was higher in the post-cholecystectomy group -20.6 (3.6) than in controls -6.7 (0.9) (p = 0.01). The incidence of oesophagitis and gastritis were also increased in this group. There was a trend towards increased reflux and oesophagitis in the symptomatic compared with the asymptomatic subgroup. Other findings confined to the post-cholecystectomy group included nutcracker oesophagus in 4 and irritable bowel syndrome in 3. It is suggested that cholecystectomy may be associated with changes in oesophageal function which, in turn, may be associated with persistent symptoms.

TO THE EDITOR: The outcome for patients with esophageal carcinoma is poor. This reflects in part the aggressive nature of the disease and also the fact that the majority of patients have advanced disease at presentation. It has been previously shown that two-thirds of patients with esophageal cancer present with symptoms for 3 months or more and with at least 14 lbs weight loss (1). Furthermore, only 17% of the general population would identify difficulty swallowing as being attributable to underlying malignancy. In addition, the majority of people are not aware of “cancer of the esophagus” and only 12% are familiar with its symptoms (2). In contrast, over 90% of people are familiar with the symptoms of breast cancer. Awareness programs highlight the significance of dysphagia and weight loss, but in our experience patients frequently note persistent or distressing hiccupping. We present one such case.

INTRODUCTION Antiangiogenic therapy has the potential to moderate tumour and micrometastatic growth. Its use in the perioperative period is attractive but its potential to compromise wound and anastomotic healing is a cause for concern. Tamoxifen is antiangiogenic but also favourably modifies some aspects of wound healing. We hypothesised that tamoxifen would not adversely affect skin wound and gut anastomotic healing. METHODS A previously established model of tamoxifen, administered orally at antiangiogenic doses (20 mg/ml arachais oil/day), was used. Animals received two days pretreatment prior to laparotomy and small bowel anastomosis. Treatment was continued until completion of the study. The principal outcome measures are survival, macroscopic wound and anastomotic healing, anastomotic bursting pressure and PVA sponge granuloma hydroxyproline (OHP) content. RESULTS Tamoxifen treated animals had fewer complications of skin wound healing than controls (4.5% vs. 19.5%; chi(2) 4.65, 1 d.f., P < 0.05). There was no significant difference in adhesion formation or macroscopic complications of anastomotic healing. Anastomotic bursting pressure was greater in tamoxifen treated animals at postoperative day 3 (39 +/- 4.4 vs. 22.5 +/- 3.5 mmHg; P < 0.01) and equal to that of controls on postoperative day 5 (144.4 +/- 9.4 vs. 127.3 +/- 10.9 mmHg; P = ns). Tamoxifen treated animals weighed significantly less than placebo controls from postoperative day 3 with no difference in mortality between groups (chi(2) = 0.06, 1 d.f., P = ns). PVA sponge granuloma OHP content on day 7 was higher in tamoxifen-treated animals (2.93 +/- 0.4 vs. 1.4 +/- 0.4 mg OHP/mg dry sponge weight; P = 0.03). CONCLUSION Antiangiogenic therapy with tamoxifen has no demonstrable adverse effects on wound or anastomotic repair and its perioperative use is compatible with successful early surgical outcomes.