Among the earliest and most important stages during tumorigenesis is the activation of the angiogenic process, an event that is termed the ''switch to the angiogenic phenotype.'' We have developed an in vivo system that can reliably recapitulate the stages in tumor development that represent this transition. Using this model, we have harvested and studied tumor nodules that can be distinguished from each other on the basis of their degree of vascularization. Angiogenic tumor nodules were characterized by the presence of capillary vessels as determined by factor VIII immunohistochemistry, and both angiogenic and proteolytic activities in vitro. In contrast, preangiogenic nodules were devoid of microvessels and showed little angiogenic or proteolytic activity in vitro. Addition of a specific metalloproteinase inhibitor resulted in the abrogation of both angiogenic and proteolytic activities of the angiogenic nodules in vitro. Comparative substrate gel electrophoresis detected the presence of a prominent matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides in the vascular nodules resulted in the loss of angiogenic potential both in vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in vivo by approximately 70%. These results strongly implicate the activity of MMP-2 as a requirement for the switch to the angiogenic phenotype and validate this model as a reliable and reproducible tool by which to study other cellular and biochemical factors involved in the acquisition of the angiogenic phenotype. O ne of the earliest events during the transition of a tumor from the preneoplastic to the tumorigenic phenotype is the acquisition of the angiogenic phenotype. This transition is marked by changes in the remodeling of both the pericapillary membrane and of its surrounding extracellular matrix (ECM), by endothelial cell proliferation, and by capillary tube formation (1). It is now widely appreciated that a major rate-limiting step in ECM remodeling is the activity of matrix metalloproteinases (MMPs). This multigene family of metal-dependent ectoenzymes includes more than 25 members to date, generally organized into five broad categories originally based on their substrate specificity (2).Much research attention has been focused on the role of MMPs in tumor invasion and metastasis (3-5); however, relatively little is known about the functional consequences of MMP expression during the onset of the angiogenic phenotype during tumorigenesis. Our laboratory and those of others have shown that certain endogenous MMP inhibitors are potent inhibitors of angiogenesis both in vivo and in vitro (6-10). Synthetic MMP inhibitors recently have been shown to inhibit neovascularization as well (11-13), and currently, a number of these synthetic inhibitors are in various stages of clinical testing as inhibitors of angiogenesis and as...

Granular Cell Tumours are rare mesenchymal soft tissue tumours that arise throughout the body and are believed to be of neural origin. They often present as asymptomatic, slow-growing, benign, solitary lesions but may be multifocal. 1-2% of cases are malignant and can metastasise. Described series in the literature are sparse. We identified eleven cases in ten patients treated surgically and followed-up for a period of over 6 years in our regional bone and soft tissue tumour centre. Five tumours were located in the lower limb, four in the upper limb, and two in the trunk. Mean patient age was 31.2 years (range 8–55 years). Excision was complete in one case, marginal in five cases and intralesional in five cases. No patients required postoperative adjuvant treatment. Mean follow-up was 19.3 months (range 1–37 months). One case was multifocal, but there were no cases of local recurrence or malignancy. Histopathological and immunohistochemical analysis revealed the classical granular cell tumour features in all cases. We believe this case series to be the largest of its type in patients presenting to an orthopaedic soft tissue tumour unit. We present our findings and correlate them with findings of other series in the literature.

A 48-year-old female school-bus driver presented with a 3-month history of loin pain in the absence of any change in bowel habit, excessive menstrual bleeding, or urinary symptoms. On examination, she was clinically anaemic, and routine blood screening revealed hypochromic and microcytic anaemia (Hb 9.8 g/dl, MCV 72.4 fl, MCH 23.4 pg). Barium enema radiography, colonoscopy and oesophago-gastro-duodenoscopy with duodenal mucosal biopsy were normal, as were an intravenous ureterogram and an ultrasound scan of the abdomen.Barium follow-through radiography ( Fig. 1) revealed oval filling defects in the distal ileum suggestive of enteroliths within a diverticulum. There was no evidence of intraluminal strictures and the initial diagnosis was presumed to be enteroliths within a Meckel's diverticulum.Laparotomy revealed a 10-cm diameter cystic mass containing enteroliths on the mesenteric border at the level of mid-jejunum. The rest of the small bowel appeared normal. A small bowel resection including the cystic mass (Fig. 2) was carried out and an end-to-end anastomosis was performed.Slicing the cyst revealed its contents to include multiple round, dark stones (Fig. 3). These were subsequently analysed and found to be 100% organic in nature possibly glycine. There was a single 0.3-cm diameter communication between the cystic mass and the adjacent small bowel (Fig. 4). The muscularis propria appeared in continuity between the bowel and the cyst. Microscopically, the cyst was lined with gastric epithelium. The lining of the communication showed pyloric metaplasia with adjacent mucosal erosions. Overall, these features amounted to those of an enterogenous (duplication) cyst lined with heterotopic gastric mucosa.Postoperatively, the patient recovered well. Three months following discharge from hospital, blood parameters have returned to normal (Hb 11.6 g/dl, MCV 84.7 fl, MCH 28.7 pg). DiscussionEnteric duplication cysts are rare developmental anomalies of the small intestine thought to arise at about 8-9 weeks of gestation when all layers of the bowel wall are 'pinched off'. Enterogenous duplication cysts are rare, but recognised, developmental anomalies. Duplications in the midgut are the commonest of these rare anomalies with a high proportion of them being found in the jejunum. Enterolith formation within these duplication cysts is uncommon as is heterotopic mucosa giving rise to peptic ulceration. Mode of presentation depends on whether symptoms due to mass effect or gastrointestinal bleeding predominate. We present a case of iron-deficiency anaemia caused by an enterolith-filled jejunal duplication cyst diagnosed at laparotomy and treated by surgical excision and small bowel resection.

A n 83-year-old female underwent a left total knee arthroplasty (replacement) as treatment for knee pain secondary to osteoarthrosis. The patient attended a routine pre-operative assessment a fortnight prior to an elective admission; she had no other past medical history and was found to be fit to proceed to surgery. She underwent an uncomplicated procedure under a combined spinal epidural anaesthetic implanting a Genesis II Total Knee Replacement prosthesis. A pneumatic tourniquet was used around the left thigh to achieve a bloodless field. A layer of cotton wool padding (velband) was applied over the left thigh and the tourniquet was applied over the padding. The limb was elevated and exsanguinated using a rubber limb exsanguinor and the tourniquet was then inflated to a pressure of 350 mmHg for a period of 90 min until the knee capsule and wound were ready to be closed in layers.Adequate haemostasis was achieved using diathermy and the knee capsule was closed over two drains. The subcutaneous tissue and skin were then closed, and the wound was dressed and padded with a compression dressing. Prior to leaving the operating theatre, the patient pressure points were checked as per routine protocol, and there was no evidence of an injury.The patient made an uncomplicated, early postoperative recovery and was discharged home 6 days later when she was able to mobilise safely with crutches. She was due to be followed up as an out-patient 6 weeks following her operation.She was reviewed a week later in clinic at her general practitioner's request because of the raised concern of a reported painful lump felt in her thigh suspected to be a superficial abscess. The clinical appearance was that of a soft, lobulated, mobile mass with a poorly defined edge covered by an area of indurated skin.Ultrasound examination was performed with a high resolution 7-12 MHz linear array probe (ATL HDI 5000, Philips Medical Systems, Andover, MA, USA). This demonstrated a relatively echogenic mass within the subcutaneous fat, with no discrete fluid collection and Subcutaneous thigh fat necrosis as a result of tourniquet control during total knee arthroplasty George S Tamvakopoulos 1 , Andoni P Toms 2 , Malcolm Glasgow