Jurgen Mulsow

Fibrogenesis in Crohn's Disease

INTRODUCTION:Over one-third of patients with Crohns disease (CD) will develop an intestinal stricture and the great majority of these will require at least one surgical procedure. While the pathogenesis of inflammation in CD has been extensively investigated, knowledge of stricture pathogenesis remains limited. The aim of this review is to discuss the current understanding of fibrogenesis in CD and to outline potential directions in research and therapeutics.METHODS:The electronic literature (January 1966 to May 2006) on CD-associated fibrosis was reviewed. Further references were obtained by cross-referencing from key articles.RESULTS:CD-associated fibrosis results from chronic transmural inflammation and a complex interplay among intestinal mesenchymal cells, cytokines, and local inflammatory cells. The fibroblast is the key cell type mediating stricture formation. The cytoarchitecure of the bowel wall is altered with disruption of the muscularis mucosa, thickening of the muscularis propria, and deposition of collagen throughout. The cytokine TGF-β appears critical in this process, acting to increase growth factor and extracellular matrix (ECM) production and dysregulate ECM turnover. Potential therapeutic interventions are likely to concentrate on modulating down-stream targets of TGF-β.CONCLUSIONS:Greater understanding of the biology of fibrostenosis is likely to yield significant advances in our ability to care for patients with stricturing CD. Potential dividends of this approach include identification of novel therapeutic targets and biomarkers useful for prognostication and therapeutic monitoring.

Transforming Growth Factor-β Promotes Pro-fibrotic Behavior by Serosal Fibroblasts via PKC and ERK1/2 Mitogen Activated Protein Kinase Cell Signaling

Objective:To assess the role of fibroblasts, transforming growth factor (TGF)-β, and cell signal pathways in promoting fibrosis in Crohns disease (CD). Summary Background Data:Intestinal strictures are a major source of morbidity in CD. Fibroblasts found at sites of stricture promote fibrogenesis. The mechanisms underlying this pro-fibrotic behavior remain elusive. Methods:Fibroblasts were isolated from strictured and macroscopically normal serosa in patients with CD and from normal serosa in patients with colorectal cancer. Whole cell connective tissue growth factor (CTGF) and fibronectin expression were determined by Western blot analysis. Fibroblast type I collagen expression was evaluated by real-time PCR, while fibroblast contractile activity was measured using fibroblast populated collagen lattices. Cells were stimulated with TGF-β1 and inhibitors of the protein kinase C (PKC) and ERK 1/2 mitogen activated protein (MAP) kinase cell signaling pathways. Results:Stricture fibroblasts displayed enhanced constitutive expression of fibronectin. TGF-β promoted fibroblast CTGF, fibronectin, and type I collagen expression and enhanced fibroblast contractile activity. Inhibition of PKC reduced basal collagen expression and contractile activity in Crohns fibroblasts and attenuated the effect of TGF-β on fibroblast CTGF, fibronectin, and collagen I expression as well as fibroblast contractility. ERK 1/2 inhibition had a similar effect on TGF-β-induced CTGF and fibronectin expression. Conclusions:TGF-β is a critical pro-fibrotic growth factor in CD, and its effects are mediated via PKC and ERK 1/2 MAP kinase cell signaling. These pathways may represent novel therapeutic targets for patients with CD characterized by recurrent intestinal stricture formation.

Sentinel lymph node mapping in colorectal cancer

Ultrastaging, by serial sectioning combined with immunohistochemical techniques, improves detection of lymph node micrometastases. Sentinel lymph node mapping and retrieval provides a representative node(s) to facilitate ultrastaging. The impact on staging of carcinoma of the colon and rectum in all series emphasizes the importance of this technique in cancer management. Now the challenge is to determine the biological relevance and prognostic implications.

Expression and regulation of connective tissue growth factor by transforming growth factor β and tumour necrosis factor α in fibroblasts isolated from strictures in patients with Crohn's disease

Connective tissue growth factor (CTGF) stimulates fibroblast proliferation and extracellular matrix production. Fibroblasts may initiate stricture formation in Crohns disease through overexpression of CTGF. Stricturing that occurs in patients with Crohns disease after treatment with anti‐tumour necrosis factor (TNF) α may be due to dysregulation of CTGF homeostasis. The aim of this study was to examine CTGF expression and regulation in fibroblasts isolated from patients with Crohns disease.

Sphincter preservation for distal rectal cancer--a goal worth achieving at all costs?

To assess the merits of currently available treatment options in the management of patients with low rectal cancer, a review of the medical literature pertaining to the operative and non-operative management of low rectal cancer was performed, with particular emphasis on sphincter preservation, oncological outcome, functional outcome, morbidity, quality of life, and patient preference. Low anterior resection (AR) is technically feasible in an increasing proportion of patients with low rectal cancer. The cost of sphincter preservation is the risk of morbidity and poor functional outcome in a significant proportion of patients. Transanal and endoscopic surgery are attractive options in selected patients that can provide satisfactory oncological outcomes while avoiding the morbidity and functional sequelae of open total mesorectal excision. In complete responders to neo-adjuvant chemoradiotherapy, a non-operative approach may prove to be an option. Abdominoperineal excision (APE) imposes a permanent stoma and is associated with significant incidence of perineal morbidity but avoids the risk of poor functional outcome following AR. Quality of life following AR and APE is comparable. Given the choice, most patients will choose AR over APE, however patients following APE positively appraise this option. In striving toward sphincter preservation the challenge is not only to achieve the best possible oncological outcome, but also to ensure that patients with low rectal cancer have realistic and accurate expectations of their treatment choice so that the best possible overall outcome can be obtained by each individual.

Analysing the operative experience of basic surgical trainees in Ireland using a web-based logbook

BackgroundThere is concern about the adequacy of operative exposure in surgical training programmes, in the context of changing work practices. We aimed to quantify the operative exposure of all trainees on the National Basic Surgical Training (BST) programme in Ireland and compare the results with arbitrary training targets.MethodsRetrospective analysis of data obtained from a web-based logbook (http://www.elogbook.org) for all general surgery and orthopaedic training posts between July 2007 and June 2009.Results104 trainees recorded 23,918 operations between two 6-month general surgery posts. The most common general surgery operation performed was simple skin excision with trainees performing an average of 19.7 (± 9.9) over the 2-year training programme. Trainees most frequently assisted with cholecystectomy with an average of 16.0 (± 11.0) per trainee. Comparison of trainee operative experience to arbitrary training targets found that 2-38% of trainees achieved the targets for 9 emergency index operations and 24-90% of trainees achieved the targets for 8 index elective operations. 72 trainees also completed a 6-month post in orthopaedics and recorded 7,551 operations. The most common orthopaedic operation that trainees performed was removal of metal, with an average of 2.90 (± 3.27) per trainee. The most common orthopaedic operation that trainees assisted with was total hip replacement, with an average of 10.46 (± 6.21) per trainee.ConclusionsA centralised web-based logbook provides valuable data to analyse training programme performance. Analysis of logbooks raises concerns about operative experience at junior trainee level. The provision of adequate operative exposure for trainees should be a key performance indicator for training programmes.

Endoglin negatively regulates transforming growth factor β1‐induced profibrotic responses in intestinal fibroblasts

Fibroblasts isolated from strictures in Crohns disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) β1. TGF‐β1, acting through the smad pathway, is critical to fibroblast‐mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF‐β1.

Hiccups: An Unrecognized Symptom of Esophageal Cancer?

TO THE EDITOR: The outcome for patients with esophageal carcinoma is poor. This reflects in part the aggressive nature of the disease and also the fact that the majority of patients have advanced disease at presentation. It has been previously shown that two-thirds of patients with esophageal cancer present with symptoms for 3 months or more and with at least 14 lbs weight loss (1). Furthermore, only 17% of the general population would identify difficulty swallowing as being attributable to underlying malignancy. In addition, the majority of people are not aware of “cancer of the esophagus” and only 12% are familiar with its symptoms (2). In contrast, over 90% of people are familiar with the symptoms of breast cancer. Awareness programs highlight the significance of dysphagia and weight loss, but in our experience patients frequently note persistent or distressing hiccupping. We present one such case.

Non-surgical factors influencing lymph node yield in colon cancer

There are numerous factors which can affect the lymph node (LN) yield in colon cancer specimens. The aim of this paper was to identify both modifiable and non-modifiable factors that have been demonstrated to affect colonic resection specimen LN yield and to summarise the pertinent literature on these topics. A literature review of PubMed was performed to identify the potential factors which may influence the LN yield in colon cancer resection specimens. The terms used for the search were: LN, lymphadenectomy, LN yield, LN harvest, LN number, colon cancer and colorectal cancer. Both non-modifiable and modifiable factors were identified. The review identified fifteen non-surgical factors: (13 non-modifiable, 2 modifiable) which may influence LN yield. LN yield is frequently reduced in older, obese patients and those with male sex and increased in patients with right sided, large, and poorly differentiated tumours. Patient ethnicity and lower socioeconomic class may negatively influence LN yield. Pre-operative tumour tattooing appears to increase LN yield. There are many factors that potentially influence the LN yield, although the strength of the association between the two varies greatly. Perfecting oncological resection and pathological analysis remain the cornerstones to achieving good quality and quantity LN yields in patients with colon cancer.

Registries on peritoneal surface malignancies throughout the world, their use and their options.

Abstract Aim: The treatment of peritoneal surface malignancies ranges from palliative care to full cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy, HIPEC. Ongoing monitoring of patient recruitment and volume is usually carried out through dedicated registries. With multiple registries available worldwide, we sought to investigate the nature, extent and value of existing worldwide CRS and HIPEC registries. Methods: A questionnaire was sent out to all known major treatment centres. The questionnaire covers: general purpose of the registry; inclusion criteria in the registry; the date the registry was first established; volume of patients in the registry and description of the data fields in the registries. Finally, the population size of the catchment area of the registry was collected. Results: Twenty-seven questionnaires where returned. National databases are established in northwest European countries. There are five international general databases. Most database collect data on patients who have undergone an attempt to CRS and HIPEC. Two registries collect data on all patients with peritoneal carcinomatosis regardless the treatment. Most registries are primarily used for tracking outcomes and complications. When correlating the number of cases of CRS and HIPEC that are performed to the catchment area of the various registry, a large variation in the number of performed procedures related to the overall population was noted, ranging from 1.3 to 57 patients/million year with an average of 15 patients/1 million year. Conclusions: CRS and HIPEC is a well-established treatment for peritoneal surface malignancies worldwide. However, the coverage as well as the registration of treatment procedures differs widely. The most striking difference is the proportion of HIPEC procedures per capita which ranges from 1.3 to 57 patients per million. This suggests either a difference in patient selection, lack of access to HIPEC centres or lack of appropriate data collection.