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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Outcomes in achalasia from a surgical unit where pneumatic dilatation is first-line therapy.

The management of achalasia remains controversial, with little consensus on the optimal patient treatment pathway. In our own esophageal unit, we offer pneumatic dilatation as the initial therapy in most patients as first-line therapy. In this study, we aimed to examine the safety and efficacy of our own approach to the management of patients with a diagnosis of achalasia, examining symptomatic outcomes, patient satisfaction, and need for further intervention, as well as examining patient factors associated with treatment failure. Sixty-seven consecutive patients underwent pneumatic dilatation as first-line therapy (53% male, mean age 46 years). All attended regular outpatient follow-up (mean 37, range 3-132 months). Twenty-five percent of patients required a second intervention because of symptom recurrence, at a median period of 4.5 months. Symptomatic outcomes were excellent or good in 80%. Significant predictors of treatment failure and poor symptom score included a younger age at the time of diagnosis and increased esophageal diameter on barium swallow. This study suggests that pneumatic dilatation is a safe and effective approach as first-line therapy in patients with newly diagnosed achalasia.