Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma

Purpose: Oesophageal adenocarcinoma is an exemplar model of obesity-associated cancer. Locally advanced disease is treated with neoadjuvant chemoradiotherapy, and survival rates are highest in patients demonstrating a pathological response following neoadjuvant therapy. Given that 55 % of oesophageal adenocarcinoma patients are obese, uncovering the effect of adipose tissue on radioresponse is clinically relevant. This study investigates if adipose tissue activates genomic instability events in radioresponsive (OE33P) and radioresistant (OE33R) oesophageal cancer cell lines and tumour samples. Methods: OE33R and OE33P were cultured with adiposeconditioned media derived from oesophageal adenocarcinoma patients (n = 10). Anaphase bridges, a marker of genomic instability, were enumerated in both cell lines following treatment with adipose media, and normalised to cell number. Genomic instability is regulated by the spindle assembly complex. Expression of two spindle assembly complex genes (MAD2L2, BUB1B) was assessed using qPCR, and validated in patient tumour specimens from viscerally obese (n = 46) and nonobese patients (n = 41). Results: Adipose-conditioned media increased anaphase bridging in OE33R (p < 0.0001), with a threefold increase in OE33R compared to OE33P (p < 0.01). Levels of anaphase bridges in OE33R cells correlated with visceral obesity status as measured by waist circumference (R = 0.709, p = 0.03) and visceral fat area (R = 0.794, p = 0.006). Adipose tissue altered expression of MAD2L2 in vitro. In vivo, MAD2L2 expression was higher in viscerally obese oesophageal adenocarcinoma patients compared with nonobese patients (p < 0.05). Conclusions: Anaphase bridge levels are influenced by obesity and radiosensitivity status in oesophageal adenocarcinoma. Furthermore, visceral adipose-conditioned media stimulates dysregulation of the spindle assembly complex in oesophageal adenocarcinoma patients

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The SGBS cell strain as a model for the in vitro study of obesity and cancer

INTRODUCTION: The murine adipocyte cell line 3T3-L1 is well characterised and used widely, while the human pre-adipocyte cell strain, Simpson-Golabi-Behmel Syndrome (SGBS), requires validation for use in human studies. Obesity is currently estimated to account for up to 41 % of the worldwide cancer burden. A human in vitro model system is required to elucidate the molecular mechanisms for this poorly understood association. This work investigates the relevance of the SGBS cell strain for obesity and cancer research in humans. MATERIALS AND METHODS: Pre-adipocyte 3T3-L1 and SGBS were differentiated according to standard protocols. Morphology was assessed by Oil Red O staining. Adipocyte-specific gene expression was measured by qPCR and biochemical function was assessed by glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity. Differential gene expression in oesophageal adenocarcinoma cell line OE33 following co-culture with SGBS or primary omental human adipocytes was investigated using Human Cancer Profiler qPCR arrays. RESULTS: During the process of differentiation, SGBS expressed higher levels of adipocyte-specific transcripts and fully differentiated SGBS expressed more similar morphology, transcript levels and biochemical function to primary omental adipocytes, relative to 3T3-L1. Co-culture with SGBS or primary omental adipocytes induced differential expression of genes involved in adhesion (ITGB3), angiogenesis (IGF1, TEK, TNF, VEGFA), apoptosis (GZMA, TERT) and invasion and metastasis (MMP9, TIMP3) in OE33 tumour cells. CONCLUSIONS: Comparable adipocyte-specific gene expression, biochemical function and a shared induced gene signature in co-cultured OE33 cells indicate that SGBS is a relevant in vitro model for obesity and cancer research in humans (AU)

Hyperemesis Gravidarum in a 37 Year-old Woman with a Gastric Band.

The increasing availability of bariatric surgery services has seen the emergence of a series of significant complications. Many of these will present to centres without local bariatric expertise. In recognition of this, the American Society of Metabolic and Bariatric Surgery (ASMBS) has issued guidelines for non-bariatric surgeons to aid in the management of bariatric surgery related complications(2010). Implanted devices such as the adjustable gastric band require careful follow-up. In the context of pregnancy, it is recommended by some that the adjustable balloon be deflated to avoid complications, however, the device itself can still present a risk. We present a case that illustrates the necessity for maintaining a high index of suspicion of device-related complication.

Symptoms are a poor indication of severity of reflux in Barrett's oesophagus

AIMS: Patients with Barrett's oesophagus have increased acid and duodenogastric reflux and impaired motility compared with non-Barrett's patients with reflux disease. Impaired sensitivity to acid infusion and distension have also been described, but the relationship of this visceral response to symptoms is unclear. A symptom index was used to compare Barrett's and non-Barrett's patients with reflux. METHODS: Patients with reflux (DeMeester score above 14) were studied with 24-h pH monitoring and manometry. An event marker recorded symptom events. An event was positive if it corresponded to a period greater than 10 s within 2 min either side of the drop in pH. The symptom index was calculated as the number of symptoms with pH less than 4/total number of symptoms x 100. RESULTS: Eighteen patients with Barrett's oesophagus were compared with 58 non-Barrett's patients with significant reflux. CONCLUSIONS: Patients with Barrett's oesophagus have a low symptom index compared with non-Barrett's patients with reflux disease. This occurs despite a near 100 per cent increase in acid exposure in the Barrett's group. Symptoms are thus no guide to the severity of reflux in patients with Barrett's oesophagus. Proof of efficacy of therapeutic modalities may need physiological rather than symptom-based confirmation.

Specialized intestinal metaplasia: analysis of prevalence, risk factors and association with gastro-oesophageal reflux disease

AIMS: There is an increasing awareness that short (less than 3 cm) segments of Barrett's epithelium and macroscopically normal cardia epithelium may harbour specialized intestinal metaplasia (SIM), a premalignant phenotype. This was a prospective study of both the prevalence of SIM in an unselected population of patients attending for endoscopy, and the association of SIM with symptoms, lifestyle, medication, endoscopic oesophagitis and carditis. METHODS: Two hundred consecutive patients underwent endoscopy. Biopsies taken from just below the squamocolumnar junction were stained for SIM, and were analysed for carditis and Helicobacter pylori infection. A detailed questionnaire of symptoms, tobacco consumption and the use of proton pump inhibitors was completed. RESULTS: Forty-two patients (21 per cent) had SIM, 19 of 126 (15 per cent) in an endoscopically normal oesophagus, 15 of 63 (24 per cent) in a short segment of Barrett's epithelium and eight of 11 in classical Barrett's oesophagus. Comparative analysis between the SIM positive and negative groups with respect to potential risk factors is outlined below. Table 1. CONCLUSION: SIM is prevalent in patients undergoing endoscopy, does not correlate with symptoms or with H. pylori infection, but is significantly associated with endoscopic and pathological markers of gastro-oesophageal reflux.