Simon Toh

Cancer cell adaptation to chemotherapy.

BackgroundTumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors.MethodsCells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels.ResultsIn 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors.ConclusionThis study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy.

Implementation of a specialist-led service for the management of acute gallstone disease

The ‘gold standard’ treatment for acute cholecystitis and biliary colic requiring hospital admission is urgent laparoscopic cholecystectomy. This is not routinely available in all hospitals.

Open and laparoscopically assisted oesophagectomy: a prospective comparative study.

OBJECTIVES Although a number of studies have examined minimally invasive approaches for oesophagectomy, these procedures have typically been offered only to selected patients with the limited long-term follow-up data. The purpose of this prospective study was to assess the feasibility of performing laparoscopically assisted oesophagectomy (LAO) for all-comers and to compare the short- and long-term clinical outcomes of this surgical strategy with a matched cohort of patients who had undergone open surgery. METHODS From November 2009, all patients referred for trans-thoracic resection of an oesophageal cancer underwent a two-stage laparoscopically assisted Ivor-Lewis oesophagectomy. This consisted of laparoscopic mobilization of the stomach and distal oesophagus, followed by open thoracotomy, thoracic lymphadectomy and intrathoracic anastomosis. The clinical and oncological outcomes of the first 39 consecutive LAO patients were compared with those of the preceding 31 consecutive patients who had undergone open surgery. RESULTS Of the 39 LAO cases, 37 cases were completed laparoscopically and 2 were converted to an open surgery. LAO was associated with a decreased incidence of postoperative complications (specifically cardiac and infectious complications) when compared with open surgery (54 vs 77%, P = 0.04). In addition, the initial intensive care unit stay (2 vs 4 days; P = 0.04) and overall length of hospital stay (14 vs 18 days; P = 0.02) were shorter in the LAO group. In terms of pathological outcomes, the lymph node yield and R0 resection rate of the LAO and open groups were comparable, as were the 1-year survival rates (62 vs 61%, P = 0.97). CONCLUSIONS LAO can be offered to an unselected cohort of all-comers with a reduced postoperative complication rate and comparable oncological and long-term survival outcomes when compared with open surgery.

Is an involved circumferential resection margin following oesphagectomy for cancer an important prognostic indicator

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether an involved circumferential resection margin (CRM) following oesophagectomy for cancer is an independent predictor of poor long-term survival. Six hundred and fourteen papers were found using the reported search, of which seven represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. Of these studies, four were conducted on patients who predominantly did not receive preoperative chemotherapy and showed conflicting results as to the prognostic significance of CRM involvement. However, three later studies conducted on patients who predominantly did receive preoperative chemotherapy showed that CRM involvement to be an independent predictor of long-term survival. We conclude that for patients who undergo oesophagectomy alone as a treatment for oesophageal cancer, the prognostic importance of CRM involvement is unclear. However, for patients who undergo preoperative chemotherapy prior to surgery, there does appear to be emerging evidence supporting the concept that CRM involvement is an independent predictor of poor long-term outcome.

Rapid up-regulation of cyclooxygenase-2 by 5-fluorouracil in human solid tumors.

Inhibition of cyclooxygenase (COX)-2 has been associated with reduced growth of malignant cells. Current therapy of gastrointestinal carcinomas involves the use of 5-fluorouracil (5-FU)-based chemotherapy and we have therefore studied the effect of this agent on the expression of COX-2. COX-2 expression was measured by quantitative RT-PCR in biopsies from a series of 14 esophageal carcinomas, six of which had paired samples taken before and after chemotherapy, and in tumor-derived cells exposed to 5-FU in vitro from a series of 44 tumors, including breast, ovarian, esophageal and colonic carcinomas. COX-2 expression was increased by exposure to 5-FU or 5-FU combination chemotherapy in all the tumor types studied, whether measured in biopsies taken before and after 5-FU-based chemotherapy (4-fold increase, p<0.015) or in primary cells exposed to drugs in vitro (24-fold increase, p<0.001). A modest increase of COX-2 mRNA was also seen after in vitro treatment of cells with cisplatin. In contrast, doxorubicin and paclitaxel caused no up-regulation in vitro, while irinotecan caused inhibition of COX-2 (2.7-fold decrease, p<0.01). These data provide a molecular rationale for clinical trials of combination chemotherapy with COX-2 inhibitors.

Timing of urgent laparoscopic cholecystectomy does not influence conversion rate

Background: The optimal treatment of acute gallstone disease is urgent laparoscopic cholecystectomy, but there is confusion about the effect of delay in operation on conversion rates. Most reports suggest that delay beyond 3 or 4 days leads to a higher conversion rate. This study assessed the conversion rate in relation to the timing of laparoscopic surgery. Methods: This institution operates a specialist-led protocol for the urgent management of all admissions with acute gallstone disease. Data were collected prospectively over 6 months. Results: Between March and August 2002, 84 patients with acute gallstone disease underwent urgent laparoscopic cholecystectomy at the index admission with an overall conversion rate of 12 per cent. Four of 40 procedures carried out within 3 days of admission were converted, compared with six of 44 after 3 days. Five of 46 carried out within 4 days of admission were converted, compared with five of 38 after 4 days. There were no deaths and one common bile duct injury. Conclusion: As long as the procedure is carried out by experienced upper gastrointestinal surgeons working within a specialist-led protocol, the conversion rate for laparoscopic cholecystectomy can be as low as 12 per cent. The timing of urgent laparoscopic cholecystectomy has no impact on the conversion rate.