Mortality in Barrett's esophagus: three decades of experience at a single center.

BACKGROUND AND STUDY AIMS: There is a view that the majority of deaths in patients with Barrett's esophagus are from causes other than esophageal adenocarcinoma (EAC). The aim of this analysis was to establish the pattern of mortality for a number of causes in patients with Barrett's esophagus. PATIENTS AND METHODS: This was a single-center prospective cohort study of patients from Rotherham District General Hospital, which is a secondary referral center. The cohort consisted of 1239 patients who were diagnosed with Barrett's esophagus between April 1978 and March 2009.  Follow-up for mortality was undertaken by "flagging" the patients with the NHS Information Center. Causes of death were compared with UK Office of National Statistics age- and sex-specific mortality data for 1999, the median year of diagnosis. Analysis was by a "person - years at risk" calculation from date of diagnosis. RESULTS: The ratio of observed deaths from EAC compared with those expected in this cohort was 25.02 - a very large excess. There was no difference in mortality from colorectal cancer or circulatory disease and there were fewer deaths from cancers other than esophageal adenocarcinoma and colon cancer compared with national statistics. There was a small statistically significant difference in mortality from all causes but this disappeared completely when deaths from esophageal adenocarcinoma were excluded. CONCLUSIONS: Overall, mortality in Barrett's esophagus is increased significantly but only as a result of the large excess of deaths from EAC. This strengthens the case for endoscopic surveillance if successful interventions can be undertaken in patients with Barrett's esophagus to prevent development of esophageal adenocarcinoma.

Systematic review: the applications of nanotechnology in gastroenterology.

BACKGROUND: Over the past 30 years, nanotechnology has evolved dramatically. It has captured the interest of variety of fields from computing and electronics to biology and medicine. Recent discoveries have made invaluable changes to future prospects in nanomedicine; and introduced the concept of theranostics. This term offers a patient specific 'two in one' modality that comprises of diagnostic and therapeutic tools. Not only nanotechnology has shown great impact on improvements in drug delivery and imaging techniques, but also there have been several ground-breaking discoveries in regenerative medicine. AIM: Gastroenterology invites multidisciplinary approach owing to high complexity of gastrointestinal (GI) system; it includes physicians, surgeons, radiologists, pharmacologists and many more. In this article, we concentrate on current developments in nano-gastroenterology. METHODS: Literature search was performed using Web of Science and Pubmed search engines with terms--nanotechnology, nanomedicine and gastroenterology. Article search was concentrated on developments since 2005. RESULTS: We have described original and innovative approaches in gastrointestinal drug delivery, inflammatory disease and cancer-target treatments. Here, we have reviewed advances in GI imaging using nanoparticles as fluorescent contrast, and their potential for site-specific targeting. This review has also depicted various approaches and novel discoveries in GI regenerative medicine using nanomaterials for scaffold designs and induced pluripotent stem cells as cell source. CONCLUSIONS: Developments in nanotechnology have opened new range of possibilities to help our patients. This includes novel drug delivery vehicles, diagnostic tools for early and targeted disease detection and nanocomposite materials for tissue constructs to overcome cosmetic or physical disabilities.

Systematic review on the treatment of ischaemic colitis.

AIM: Ischaemic colitis is uncommon. Aetiological factors include abdominal aortic surgery, drugs (especially inotropics) or rheumatoid diseases, such as Takayasu's or Buerger's diseases. However, there is often no triggering factor, and it may be part of multifactorial cardiac, respiratory, renal or metabolic failure. METHOD: A systematic review of the current literature on the management of ischaemic colitis was carried out. RESULTS: Ten retrospective trials (841 patients) were included. No randomized controlled or prospective trial of the management of ischaemic colitis was found. CONCLUSION: There is very little evidence base for the management of this condition.

Doxycycline in mitochondrial mediated pathway of apoptosis: a systematic review.

Tetracyclines have been long known for their antimicrobial role. They are one of the most widely used antibiotics in clinical practice since last 5 decades. Recently their role as matrix metalloproteinase inhibitor and in apoptosis has widely attracted attention in biological field. Of them, doxycycline is one with long duration of actions and has recently been shown to have various anti-cancer properties, especially cytotoxic and anti-proliferative activities. Here, we systematically reviewed the role of doxycycline in the mitochondrial mediated apoptosis in various tissues. MEDLINE and EMBASE databases were searched using a formal search strategy with definite inclusion and exclusion criteria. Data extraction was performed for each included study using a custom designed data extraction form. A total of 81 references were identified through MEDLINE and 5 were identified through EMBASE. 74 references from MEDLINE and all 5 in EMBASE were excluded through reading titles, abstracts and full text. In total, 7 studies fulfilled inclusion criteria. Following systematic review of these studies, we concluded that doxycycline induces apoptosis through mitochondrial mediated pathway in different tissue cells however it may be cell specific. The caspase independent apoptosis as one of the mechanisms of actions of doxycycline needs further studies for better understanding.

Endothelin receptor antagonism and cancer.

The endothelin peptides have an important role in the cancer-stromal interactions that promote tumour growth. Endothelin-1 (ET-1), clinically the most investigated endothelin, is a vital agent in the growth and progression of several tumours including prostate, ovarian, colorectal, bladder, breast and lung carcinomas. ET-1 exerts its effects through the activation of two distinct receptors, ET(A) and ET(B). Once activated, these receptors transmit signals via numerous intracellular signalling pathways. The effects of ET receptor stimulation in cancer cells or cancer-associated cells include proliferation, resistance to apoptosis, angiogenesis, migration and subsequent invasion. At present, the manipulation of the endothelin axis within the pre-clinical setting is the subject of intense investigation. Recent studies into ET receptor antagonism have produced interesting results highlighting the fact that these receptors may provide novel targets for a new generation of chemotherapeutic agents in a variety of cancers.

The influence of symptom type and duration on the fate of the metaplastic columnar-lined Barrett's oesophagus.

BACKGROUND: Prolonged gastro-oesophageal reflux resulting in columnar metaplasia of the oesophagus is the main risk factor for oesophageal adenocarcinoma. AIM: To examine the duration of symptoms and associations of different symptoms with the development of columnar-lined oesophagus, dysplasia and adenocarcinoma. METHODS: UK multicentre cohort study of patients with columnar-lined oesophagus whose date of symptom onset (1082 patients) and/or types of symptoms reported (1681 patients) were documented. Follow-up was examined by analysis of histological reports from the registering centers. RESULTS: Symptoms of dysphagia/odynophagia and nausea/vomiting were associated with development of dysplasia. High-grade dysplasia and adenocarcinoma were associated with dysphagia/odynophagia and weight loss. Median duration from symptom onset to detection of columnar-lined oesophagus without intestinal metaplasia: 2.6 years, columnar-lined oesophagus with intestinal metaplasia: 5.0 years, indefinite changes for dysplasia: 19.3 years and low-grade dysplasia: 30.0 years. One tenth of patients had developed high-grade dysplasia at 9.6 years and one tenth had developed adenocarcinoma at 13.8 years from symptom onset. CONCLUSIONS: In patients with columnar-lined oesophagus, symptoms of dysphagia/odynophagia and nausea/vomiting were associated with a higher risk of development of dysplasia and adenocarcinoma. There is a trend for longer duration of symptoms to the detection of dysplasia.

Effect of Roux-en-Y surgery and medical intervention on Barrett's-type changes: an in vivo model.

In animal models, mixed acid and bile reflux into lower esophagus induces histological changes comparable to Barrett's metaplasia (BM) and neoplasia. The aim of this study was to compare the effects of Roux-en-Y (REY) surgery and medical therapy on BM in animals before the development of neoplasia. Vagus preserving esophagojejunostomy operation was performed on Sprague-Dawley rats to achieve gastroduodenal reflux (GDR) into the esophagus in 30 animals. After 3 months, changes were reversed in 10 animals (Group REY) by REY operation, 10 animals (Group proton pump inhibitor [PPI]) were given PPI during the postoperative period, and 10 animals (Group GDR) did not have further intervention. At 4 months, histological examination of the lower esophagus was performed by an experienced pathologist. Physiological parameters were also analyzed in all animals preoperatively and at 4 months postoperatively. The length of columnar mucosa, degree of acute inflammation, degree of metaplasia, and composite BM score were significantly reduced by REY surgery compared with medical therapy and with control (columnar mucosa in cm [mean +/- standard error of the mean] Group REY 0.44 +/- 0.06, Group PPI 0.92 +/- 0.08, P < 0.001/Group GDR 1.17 +/- 0.31, P < 0.03). There was no neoplasia seen in any specimen. At 4 months, postoperatively controls Group REY surgery showed significantly more normalization of physiological parameters to preoperative levels than Group PPI (P < 0.05). REY surgery is potentially more beneficial than medical therapy in reversing the histological and biochemical changes of Barrett's esophagus due to GDR.

Increased apoptosis and decreased proliferation of colorectal cancer cells using insulin-like growth factor binding protein-4 gene delivered locally by gene transfer.

OBJECTIVE: Insulin-like growth factor (IGF)-I induces proliferation of transformed cells. Its binding proteins (IGFBP) are involved in local regulation of IGF. This study assessed the effects of overexpression of IGFBP-4 on the development of cancer in vivo. METHOD: Nude mice were subcutaneously inoculated with HT-29 colorectal cancer cells (3 x 10(6)). When the tumour became visible (1 week after inoculation), animals received either 150 microg of mammalian expression vector containing IGFBP-4 cDNA or vector alone (n = 6 each) by peritumoural injection. Tumour size was measured during the growth. After 3 weeks of IGFBP-4 induction, animals were killed and tumour tissue samples were collected for examining the level of IGFBP-4 expression. Tumour mitotic activities were determined by counting numbers of mitotic cells on the tissue section. Apoptosis was investigated by terminal deoxynucleotidyl transferase-mediated dUDP nick end labelling assay. RESULTS: Following IGFBP-4 treatment, tumour showed large necrotic areas, significantly increased numbers of apoptotic cells (36.67 +/- 7.36 vs 7.07 +/- 1.91, P < 0.01 vs control), decreased cells undergoing mitosis (2.31 +/- 0.32 vs 3.61 +/- 0.27, P < 0.01 vs control) and higher expression of IGFBP-4 (P < 0.05 vs control). CONCLUSION: IGFBP-4 gene transfer increased apoptosis and decreased mitosis, but tumour volume was not significantly altered possibly due to cellular debris filling the centre of tumours.

Impact of HIV and AIDS on surgical practice.

INTRODUCTION: Surgical intervention has become a common component in the management of patients infected with the human immunodeficiency virus (HIV) or suffering from the clinical consequences of acquired immunodeficiency syndrome (AIDS). We investigated the evolution of this involvement at a tertiary referral centre for this condition over a 16-year period. PATIENTS AND METHODS: Detailed retrospective examination of the medical records of HIV-positive patients treated at the Royal Free Hospital between 1986 and 2002 was undertaken. Clinical, pathological and operative details of those patients who underwent surgical intervention were recorded. RESULTS: Of the 2100 cases reviewed, 477 patients underwent a combined total of 772 surgical procedures. Of the 772 operations, 95 (12.3%) were performed as emergencies. Anorectal surgery represented the highest group with a total of 195 procedures (25.26%) being undertaken. The majority of patients (59%) had AIDS at the time of surgery, and 27.04% had a significant co-existing medical problem. Overall postoperative complication rate was 10.1%, with the risk being significantly greater in those undergoing intra-abdominal surgery and emergency procedures. CONCLUSIONS: This is the largest study to audit the impact of HIV/AIDS in general surgical practice in the UK retrospectively. Surgery for HIV patients can be safely conducted with a low complication rate for the diagnostic and anorectal procedures that comprise the vast majority of surgery in HIV/AIDS patients. Medical treatment for patients with HIV/AIDS has developed dramatically over the last two decades. In parallel, this has resulted in a heavy, new and varied workload for general surgeons, who have also had to adapt in order to deal with the challenging spectrum of this disease.

EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges.

Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.

Angiogenesis inhibition with bevacizumab and the surgical management of colorectal cancer.

BACKGROUND: Bevacizumab is an angiogenesis inhibitor and a new therapy for the treatment of colorectal cancer. It is a humanized monoclonal antibody that targets vascular endothelial growth factor. METHODS: This review is based on a literature search of Medline, Pubmed, ISI web of knowledge and other published work for original articles, reviews and abstracts relevant to the surgical management of colorectal cancer with bevacizumab. RESULTS AND CONCLUSION: Combined with current chemotherapy regimens, bevacizumab offers a significant survival advantage, making it likely to see widespread use. Despite being generally well tolerated, serious toxicities, including wound complications and gastrointestinal perforation, have been reported that affect surgical management. Consideration should be given to the timing of surgical and adjuvant intervention when using this drug.

The insulin-like growth factor system and colorectal cancer: clinical and experimental evidence.

OBJECTIVE: The aim of this review is to clarify the involvement of the insulin-like growth factor (IGF) system in the development of colorectal malignancy. MATERIALS AND METHODS: Medline searches were used to identify key articles relating the IGF system with the development of colorectal cancer. RESULTS: The IGF system has been linked to colorectal malignancy by a convergence of data from epidemiological, clinical and laboratory-based sources. CONCLUSION: Further work is needed to characterise the IGF system expression in the colon. Such clarification could lead to the identification of targets that can be manipulated for clinical advantage.

Ischaemic preconditioning improves microvascular perfusion and oxygenation following reperfusion injury of the intestine.

BACKGROUND: Ischaemia-reperfusion (IR) injury of the intestine occurs commonly during abdominal surgery. Ischaemic preconditioning (IPC) provides a way of protecting the organ from damage inflicted by IR. This study was designed to evaluate the beneficial effect of IPC, focusing on the intestinal microcirculation and oxygenation in intestinal IR injury. METHODS: Rats were allocated to three groups. Animals in the IR and IPC groups underwent 30 min of intestinal ischaemia followed by 2 h of reperfusion. In the IPC group this was preceded by 10 min of ischaemia and 10 min of reperfusion. Animals in the third group underwent laparotomy but no vascular occlusion. Intestinal microvascular perfusion, oxygenation and portal venous blood flow (PVF) were monitored continuously. At the end of the reperfusion period, blood samples were obtained for measurement of lactate dehydrogenase (LDH) and biopsies of ileum for histological evaluation. RESULTS: : IPC improved intestinal microvascular perfusion and tissue oxygenation significantly at the end of the reperfusion period (P < 0.001). PVF improved significantly in the IPC compared with the IR group (P = 0.005). The serum LDH concentration was significantly lower in the IPC than the IR group (mean(s.e.m.) 667.1(86.8) versus 1973.8(306.5) U/l; P < 0.001) Histological examination showed that ileal mucosa was significantly less injured in the IPC group. CONCLUSIONS: This study demonstrated that IPC improves intestinal microvascular perfusion and oxygenation.

Diet and colorectal cancer: implications for the obese and devotees of the Atkins diet.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the Western world and its prevalence is increasing. Potential causes of this increase are changes in diet and the increases in obesity seen. This paper looks at the literature surrounding diet and obesity and the links to this increase in CRC. Heralded as a weight loss miracle we investigate whether the literature suggests the Atkins diet may actually do more harm than good by acting to increase an individual's risk of CRC. Obesity has been demonstrated to be a major factor in the increase in CRC although links to changes in diet are more tenuous. Published studies on diet suggest the Atkins diet may help reduce rather than increase the risk of CRC.