Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment - A pilot study.

AIM: In rectal cancer, not all tumours display a response to neoadjuvant treatment. An accurate predictor of response does not exist to guide patient-specific treatment. DNA methylation is a distinctive molecular pathway in colorectal carcinogenesis. Whether DNA methylation is altered by neoadjuvant treatment and a potential response predictor is unknown. We aimed to determine whether DNA methylation is altered by neoadjuvant chemoradiotherapy (CRT) and to determine its role in predicting response to treatment. PATIENTS AND METHODS: Fifty-three (n = 53) patients with locally advanced rectal cancers treated with neoadjuvant CRT followed by surgery were identified from the pathology databases of 2 tertiary referral centres over a 4-year period. Immunohistochemical staining of treatment specimens was carried out using the 5-Methylcytidine (Eurogentec, Seraing, Belgium) antibody. Quantitative analysis of staining was performed using an automated image analysis platform. The modified tumour regression grading system was used to assess tumour response to neoadjuvant therapy. RESULTS: Seven (13%) patients showed complete pathological response while 46 (87%) patients were partial responders to neoadjuvant treatment. In 38 (72%) patients, significant reduction in methylation was observed in post-treatment resection specimens compared to pre-treatment specimens (171.5 vs 152.7, p = 0.01); in 15 (28%) patients, methylation was increased. Pre-treatment methylation correlated significantly with tumour regression (p < 0.001), T-stage (p = 0.005), and was able to predict complete and partial pathological responders (p = 0.01). CONCLUSION: Neoadjuvant CRT appears to alter the rectal cancer epigenome. The significant correlation between pre-treatment DNA methylation with tumour response suggests a potential role for methylation as a biomarker of response.

Margin involvement and outcome in oesophageal carcinoma: a 10-year experience in a specialist unit.

AIMS: Positive microscopic margins after major cancer surgery adversely affect prognosis. We questioned whether the benefit of a multimodal approach in oesophageal carcinoma is due to reduced resection margin involvement and whether multimodal therapy alters the disease course when margins are involved. METHODS: Pathology specimens of 212 patients, treated with either multimodal therapy or surgery alone, were re-reviewed to assess margin involvement by tumour. Margin status was compared with recurrence and survival data. RESULTS: Margin involvement was decreased with multimodal therapy (16 of 103 patients) vs surgery (33 of 109 patients), associated with reduced tumour recurrence and a significant survival advantage. However, even with involved margins, multimodal therapy had lower recurrence vs surgery and a small survival benefit. CONCLUSIONS: Multimodal therapy significantly reduces margin involvement. The benefit of multimodal therapy remains highly significant for patients with clear margins. This study confirms for oesophageal carcinoma the value of an aggressive surgical approach in achieving negative resection margins.

Impaired visceral sensitivity to acid reflux in patients with Barrett's esophagus. The role of esophageal motility*.

Patients with Barrett's esophagus have been reported to have impaired visceral sensitivity to acid perfusion and distension compared with non-Barrett's refluxers, but the mechanism is poorly understood. Esophageal motility and clearance mechanisms may be important, and this study explored the relationship of motility with symptoms. Seventy-four patients with Barrett's esophagus were compared with 216 patients with gastro-esophageal reflux disease (GERD) with abnormal acid reflux scores, and 50 symptomatic patients who had normal acid exposure. All patients had esophageal manometry and 24-h pH monitoring. Thirty-six Barrett's patients also had 24-h bile reflux monitoring. Symptoms were assessed by Symptom Index (SI) during 24-h pH monitoring. Barrett's patients with normal motility had a significantly lower SI than GERD patients for similar acid exposure (P < 0.001). Barrett's patients with abnormal motility had higher acid exposure than those with normal motility (P < 0.05), but the SI values for this group was not significantly different from the GERD patients. SI and Bile reflux in Barrett's esophagus was not significantly different in patients with normal or abnormal motility. Barrett's patients had less sensitivity than GERD patients for similar acid exposure. Normal motility in Barrett's esophagus is associated with the poorest sensitivity and the presence of increased acid exposure is required in order to achieve sensitivity levels comparable with GERD patients.

The role of surgery and laser ablation in oesophageal carcinoma.

Between January 1990 and December 1994 oesophagectomy was carried out in 42 patients and comparison made with 38 who had palliative laser therapy. Apart from six patients referred after being unresectable at surgical exploration there were no agreed selection criteria, although the laser patients were in general older (mean 64 V 73 year) with a higher proportion of cardiorespiratory co-morbidity (14 per cent V 18 per cent). Lateral margins were involved in 14 per cent of known palliative resections with 50 per cent having positive nodes. The mean operating time was three hours and two chest drains inserted electively were removed after 3.6 days with mean drainage of 817 ml. The mean ICU stay was 5.4 days and 3 had radiological leaks; all but one settled conservatively. The 90 day mortality was 11.9 per cent for surgery and 34 per cent for laser patients. Twenty-three patients (61 per cent) required further courses of laser-therapy for benign anastomotic stenosis. Including the initial treatment of both groups 6.0 procedures per patient year were required in the laser groups compared with 1.1 for surgery. The 1, 2 and 3 year survival was 60 per cent, 31 per cent, 39 per cent for surgery compared with 24 per cent, 8 per cent, 3 per cent for laser--12 surgical patients are still alive and well at mean of 29 months (range 16-68). Surgery where possible with acceptable morbidity and mortality offers good palliation and long-term survival is possible; selection criteria for palliation only need to be defined.

High-intensity focused ultrasound in the treatment of benign prostatic hyperplasia.

OBJECTIVE: To assess the role of high-intensity focused ultrasound (HIFU) in the treatment of symptomatic benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Thirteen patients (mean age 65 years, range 58-74) were treated with HIFU as part of a phase-2 clinical trial and evaluated prospectively using the International Prostate Symptom Score, uroflowmetry, and transrectal and transabdominal ultrasonography to determine prostate size and post-void residual urine volume, respectively. The results and the patients' satisfaction were assessed at regular intervals for 2 years. RESULTS: The new procedure was learned quickly and was easy to perform. Symptom scores decreased from a mean of 23 before treatment to 5 after 12 months and 7 after 2 years. There was an initial improvement in flow rates but they then declined. The size of the prostate and the post-void residual volume were both decreased after treatment. CONCLUSIONS: The treatment is safe, easy to implement and was effective in substantially reducing symptom scores in these few patients. However, we would not encourage its use as an alternative to other well established treatment modalities until it has been assessed fully in a randomized trial.