Endothelin-1 stimulates colon cancer adjacent fibroblasts.

Endothelin-1 (ET-1) is produced by and stimulates colorectal cancer cells. Fibroblasts produce tumour stroma required for cancer development. We investigated whether ET-1 stimulated processes involved in tumour stroma production by colonic fibroblasts. Primary human fibroblasts, isolated from normal tissues adjacent to colon cancers, were cultured with or without ET-1 and its antagonists. Cellular proliferation, migration and contraction were measured. Expression of enzymes involved in tumour stroma development and alterations in gene transcription were determined by Western blotting and genome microarrays. ET-1 stimulated proliferation, contraction and migration (p < 0.01 v control) and the expression of matrix degrading enzymes TIMP-1 and MMP-2, but not MMP-3. ET-1 upregulated genes for profibrotic growth factors and receptors, signalling molecules, actin modulators and extracellular matrix components. ET-1 stimulated colonic fibroblast cellular processes in vitro that are involved in developing tumour stroma. Upregulated genes were consistent with these processes. By acting as a strong stimulus for tumour stroma creation, ET-1 is proposed as a target for adjuvant cancer therapy.

The UK proposals for revalidation of physicians: Implications for the recertification of surgeons.

The editorial titled "For the Protection of the Public and the Good of the Specialty: Maintenance of Certification" (published in the February 2009 issue of the Archives of Surgery) has prompted us to offer the following article to inform the debate about how assessing surgical care and sorting out the variables to be included in maintenance of certification may develop worldwide. The proposals for revalidation of UK physicians involve the relicensing of all physicians and recertification of all specialists on the specialist register of the General Medical Council. The process will be on a 5-year cycle and is currently under development by the General Medical Council. The Royal Colleges have been charged with creating the standards for recertification, and the responsibility will fall on the Royal Colleges to support their fellows and members as the new regulation is introduced and as it develops. This article outlines developments so far, with particular reference to surgeons.

Multidisciplinary Rectal Cancer Management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2).

BACKGROUND AND PURPOSE: During the first decade of the 21st century a number of important European randomized studies were published. In order to help shape clinical practice based on best scientific evidence from the literature, the International Conference on 'Multidisciplinary Rectal Cancer Treatment: Looking for an European Consensus' (EURECA-CC2) was organized in Italy under the endorsement of European Society of Medical Oncology (ESMO), European Society of Surgical Oncology (ESSO), and European Society of Therapeutic Radiation Oncology (ESTRO). METHODS: Consensus was achieved using the Delphi method. The document was available to all Committee members as a web-based document customized for the consensus process. Eight chapters were identified: epidemiology, diagnostics, pathology, surgery, radiotherapy and chemotherapy, treatment toxicity and quality of life, follow-up, and research questions. Each chapter was subdivided by a topic, and a series of statements were developed. Each member commented and voted, sentence by sentence thrice. Sentences upon which an agreement was not reached after voting round # 2 were openly debated during a Consensus Conference in Perugia (Italy) from 11 December to 13 December 2008. A hand-held televoting system collected the opinions of both the Committee members and the audience after each debate. The Executive Committee scored percentage consensus based on three categories: "large consensus", "moderate consensus", and "minimum consensus". RESULTS: The total number of the voted sentences was 207. Of the 207, 86% achieved large consensus, 13% achieved moderate consensus, and only 3 (1%) resulted in minimum consensus. No statement was disagreed by more than 50% of the members. All chapters were voted on by at least 75% of the members, and the majority was voted on by >85%. CONCLUSIONS: This Consensus Conference represents an expertise opinion process that may help shape future programs, investigational protocols, and guidelines for staging and treatment of rectal cancer throughout Europe.

Why do we need a core curriculum in surgical oncology in Europe?

Patients with cancer are often treated by multidisciplinary collaboration between many specialities where thorough knowledge about cancer, and surgical expertise is necessary. Most European surgeons with an interest in surgical oncology were trained according to their local organisations and national regulations. Formal education as per a national training programme is rare and little collaborative effort has taken place within Europe to standardize training between the relevant national surgical societies. The outcome measure of completion of training is vague. Surgical oncology is at present only recognised by a few European countries. Training in surgical oncology has been guided by tradition and common sense rather than by specific aims within the framework of a recognised internationally established core curriculum. Any educational initiative has to be delivered during restricted working hours as determined by European regulation. Accordingly, the actual number of surgical procedures that each trainee will perform under supervision is limited. A modern core curriculum necessitates an evidence-based approach, rather than common sense medicine.

Adjuvant chemotherapy after resection of liver metastases from colorectal cancer.

Colorectal liver metastases are common and found in almost 50% of patients with colorectal cancer. Surgical excision, whenever possible, is the optimum form of treatment and should be carried out with the intention of removing all macroscopic disease (R0 resection). However, recurrence frequently occurs within the remaining liver as well as at extra-hepatic sites. The role of adjuvant systemic chemotherapy in an attempt to reduce the incidence of recurrence has been investigated in several studies. This review discusses the possible incorporation of adjuvant systemic chemotherapy following liver resection.

Selecting the optimum treatment for colorectal liver metastases.

There has been much improvement in the management of patients with colorectal liver metastases over the last 20 years. Appropriate selection of both treatment and patients can result in enhanced outcome. The main modalities of treatment are surgery, ablation, and combinations of chemotherapy drugs. Frequently, a combination of the above are required. This article summarises the most appropriate treatments designed to enhance outcome in these patients.

Altered endothelin receptor subtypes in colorectal cancer.

BACKGROUND: The vasoactive peptide endothelin-1 (ET-1) acts via two endothelin receptor subtypes, ETA (ETAR) and ETB (ETBR). ET-1 and ETAR are overexpressed in colorectal cancer tissues. In vitro, ET-1 acting via ETAR, is a mitogen for colorectal cancer cells. To identify other potential stimulatory loops, we investigated the distribution and cell-specific localization of both ETAR and ETBR in tissue sections from patients with colorectal cancer. METHODS: Frozen sections from specimens of colorectal cancer (n=9) and normal colon (n=9) were cut and subjected to either (i) autoradiography or (ii) a combination of cell type-specific immunohistochemistry, using antibodies against fibroblasts (AS02), endothelial cells (CD31) or nerve fibres (NF200) and in-vitro receptor microautoradiography, using ETAR-specific and ETBR-specific radioligands. RESULTS: ETARs were upregulated in all cell types, apart from nerve, in cancer compared with normal colon (1:1.59 normal to cancer). Specifically, ETAR binding was highest in cancer-associated blood vessels and fibroblasts and to a lesser extent in epithelial cancer cells. In contrast, ETBRs were the predominant receptors in normal colon (1:0.59 normal to cancer) and were markedly down-regulated in cancer-associated blood vessels, fibroblasts and to a lesser extent in epithelial cells. Nerve colocalization was demonstrated, but remained unchanged for all tissues. CONCLUSION: The shift in ET receptor binding observed in epithelial cancer cells and cancer-associated fibroblasts and endothelial cells may favour ET-1 signals contributing to colorectal cancer growth and neovascularization via ETAR. This may provide the basis for therapeutic use of specific ETAR antagonists as adjuvant treatment of colorectal cancer.

Endothelin-1 and angiogenesis in cancer.

Tumours require oxygenation, nutrition and a route for dissemination. This necessitates the development of new vessels or angiogenesis. High levels of new vessel development are indicators of poor prognosis in cancer; they also provide new avenues of anti-tumour therapy. Angiogenesis in cancer produces structurally different vessels from angiogenesis in wound healing and inflammation. This article reviews the differences between vessels in tumour angiogenesis and normal angiogenesis. The main focus of the article is the role of the vasoactive peptide endothelin-1 (ET-1) in tumour angiogenesis. The role of ET-1 in tumour development is reviewed, before the direct and indirect effects of ET-1 in angiogenesis are examined. ET-1 has a direct angiogenic effect on endothelial and peri-vascular cells. It also has an indirect action through the increased release of the potent pro-angiogenic substance vascular endothelial growth factor (VEGF), via hypoxia inducible factor-1. ET-1 also indirectly stimulates angiogenesis by stimulating fibroblasts and cancer cells to produce pro-angiogenic proteases. ET-1 is a novel stimulator of tumour angiogenesis and warrants further examination as an anti-angiogenic treatment target.

Intraoperative radiotherapy for breast cancer.

Postoperative radiotherapy, which forms part of breast-conserving therapy, may not need to encompass the whole breast. Apart from the consumption of huge resources and patients' time, postoperative radiotherapy deters many women from receiving the benefits of breast-conserving surgery, forcing them to choose a mastectomy instead. If radiotherapy could be given in the operating theatre immediately after surgery, many of these disadvantages could be overcome. One striking fact about local recurrence after breast-conserving surgery is that most occurs in the area of breast immediately next to the primary tumour; this is despite the finding that two-thirds of mastectomy samples have microscopic tumours distributed throughout the breast, even when radiotherapy is omitted. Thus, only the area adjacent to the tumour may need treatment with radiotherapy. On the basis of this premise, clinical scientists have used new technology to administer radiotherapy to the area at greatest risk of local recurrence, with the aim of completing the whole local treatment in one sitting. In this review, we have elaborated on the rationale and different methods of delivery of intraoperative radiotherapy. If this approach is validated by the results of current randomised trials, it could save time, money, and breasts.

Good practice and quality assurance in surgical oncology.

The Halstedian era of radical surgical extirpation for solid tumours dominated the first half of the 20th century. But as understanding of cancer biology increased, a paradigm shift occurred which moved the focus away from extensive surgery towards less radical procedures. Although surgery is a recognised factor in local disease control, prognosis is now believed to be predetermined at the time of diagnosis by the presence of micrometastatic deposits. Modern cancer management consists of more skilled and conservative surgery to remove the primary tumour; adjuvant therapies are also given before and after the operation to target the subclinical metastatic deposits. The most important components of high-quality care in surgical oncology are: sound clinical judgment, surgical skill, and multidisciplinary care. These prerequisites are best achieved by specialisation, but high operative volume is not essential for excision of many types of tumour. Quality assurance using several readily available tools can ensure that the process of care from presentation to outcome is constantly improved and that institutional variations in number of cases and quality of care are monitored.

Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial.

BACKGROUND: The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver. METHODS: We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat. FINDINGS: 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival. INTERPRETATION: Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.