Tissue Inhibitor of Metalloproteinase-1 Is Confined to Tumor-Associated Myofibroblasts and Is Increased With Progression in Gastric Adenocarcinoma.

The tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the extracellular matrix-degrading activity of several matrix metalloproteinases, thereby regulating cancer cell invasion and metastasis. Studies describing the expression pattern and cellular localization of TIMP-1 in gastric cancer are, however, highly discordant. We addressed these inconsistencies by performing immunohistochemistry and in situ hybridization analyses in a set of 49 gastric cancer lesions to reexamine the TIMP-1 localization. In addition, we correlated these findings to clinicopathological parameters. We show that strong expression of TIMP-1 protein and mRNA was observed in a subpopulation of stromal fibroblast-like cells at the periphery of the cancer lesions. In a few cases, a small fraction of cancer cells showed weak expression of TIMP-1 protein and mRNA. The stromal TIMP-1-expressing cells were mainly tumor-associated myofibroblasts. In the normal-appearing mucosa, scattered TIMP-1 protein was only found in chromogranin A positive cells. TIMP-1-positive myofibroblasts at the invasive front of the tumors were more frequently seen in intestinal than in diffuse histological subtype cases (p=0.009). A significant trend to a higher number of cases showing TIMP-1 staining in myofibroblasts with increasing tumor, node, metastasis (TNM) stage was also revealed (p=0.041). In conclusion, tumor-associated myofibroblasts are the main source of increased TIMP-1 expression in gastric cancer.

Prognosis in adenocarcinomas of lower oesophagus, gastro-oesophageal junction and cardia evaluated by uPAR-immunohistochemistry.

Adenocarcinomas of lower oesophagus, gastro-oesophageal junction and cardia in humans are highly invasive tumours with poor prognosis. The localisation of urokinase-type plasminogen activator receptor (uPAR) was determined in 66 patients; 60 with adenocarcinomas and six cases with Barrett's oesophagus. uPAR was expressed in nearly all cases of invasive adenocarcinomas by populations of cancer cells, macrophages and myofibroblasts at both the invasion front and the tumour core. In areas with high-grade dysplasia or with Barrett's metaplasia adjacent to the tumour tissue, no uPAR-immunoreactivity was found. High local expression of uPAR, therefore, appears to be a characteristic marker for invasive behaviour in this tumour, suggesting that uPAR's contribution to matrix degradation during invasive growth is a late event in carcinogenesis. Using a scoring system for semiquantitative estimation of uPAR-positivity on immmunohistochemically stained specimens, a significant association was found between poor overall survival and high uPAR-score for cancer cells in the tumour core and for macrophages peripherally at the tumour invasion zone. In multivariate analysis, these two uPAR-scores were confirmed as highly significant prognostic parameters independent of Tumour, Node, Metastasis (TNM)-stage and World Health Organization (WHO) classification. The proteolytic action of these malignant and nonmalignant accessory cells thus seemed to follow two main patterns: one dominated by uPAR positive cancer cells and one by uPAR-positive macrophages. Scoring of uPAR-positivity might be a useful parameter for onset of invasion and prognosis in these adenocarcinomas.

Urokinase plasminogen activator receptor on invasive cancer cells: a prognostic factor in distal gastric adenocarcinoma.

Gastric cancer is the second cancer causing death worldwide. The five-year survival for this malignancy is below 25% and few parameters have shown an impact on the prognosis of the disease. The receptor for urokinase plasminogen activator (uPAR) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation, and its presence on gastric cancer cells is linked to micrometastasis and poor prognosis. Using immunohistochemistry, the prognostic significance of uPAR was evaluated in tissue samples from a retrospective series of 95 gastric cancer patients. uPAR was expressed by neoplastic cells, macrophages, myofibroblasts and neutrophils in both intestinal and diffuse subtypes. No association was demonstrated between the expression of uPAR on cancer cells and histological subtype (p = 0.64) or TNM stage (p = 0.75). Univariate analysis revealed a significant association between the expression of uPAR on tumor cells in the peripheral invasion zone and overall survival of gastric cancer patients (HR = 2.16; 95% CI: 1.13-4.14; p = 0.02). Multivariate analysis showed that uPAR immunoreactivity in cancer cells at the invasive front is an independent prognostic factor for overall survival in gastric cancer (HR = 2.39; 95% CI: 1.22-4.69; p = 0.011). In consequence, scoring of uPAR-positive cancer cells may be a direct measure for the invasive potential of gastric adenocarcinomas.

Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries.

Gastric cancer is the second cancer causing death worldwide. Both incidence and mortality rates vary according to geographical regions. The receptor for urokinase plasminogen activator (uPAR) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation, and its presence on gastric cancer cells is linked to micro-metastasis and poor prognosis. Immunohistochemical analyses of a set of 44 gastric cancer lesions from Costa Rica showed expression of uPAR in cancer cells in both intestinal subtype (14 of 27) and diffuse subtype (10 of 17). We compared the expression pattern of uPAR in gastric cancers from a high-risk country (Costa Rica) with a low-risk country (Norway). We found uPAR on gastric cancer cells in 24 of 44 cases (54%) from Costa Rica and in 13 of 23 cases (56%) from Norway. uPAR was seen in macrophages and neutrophils in all cases. We also examined the nonneoplastic mucosa and found that uPAR was more frequently seen in epithelial cells located at the luminal edge of the crypts in cases with Helicobacter pylori infection than in similar epithelial cells in noninfected mucosa (p = 0.033; chi(2) = 4.54). In conclusion, the expression of uPAR in cancer cells in more than half of the gastric cancer cases suggests that their uPAR-positivity do not contribute to explain the different mortality rates between the 2 countries, however, the actual prevalence of uPAR-positive cancer cells in the gastric cancers may still provide prognostic information.

Utilisation of specialist care in patients with incurable rectal cancer. a population-based study from Western Norway.

INTRODUCTION: About 25% of patients with rectal cancer have incurable disease at the time of diagnosis. In the current study from Western Norway (population of 981 000) we focused on the utilisation of specialist care in patients with primarily incurable rectal cancer. PATIENTS AND METHODS: Between 1997 and 2002, 1 167 patients were diagnosed with rectal cancer, of whom 297 (25%) had incurable disease, according to consecutive and prospective reporting to the Norwegian Colorectal Cancer Registry. Consumption of specialist care facilities was studied with regard to outpatient contacts, hospital admissions, and various treatment modalities. Data were analysed with regard to age, sex, marital status, type of residence, and geographical access to hospital facilities. Data were available for 287 patients (97%). RESULTS: The median age was 77 years. Elderly patients (>77 years) more often lived in nursing homes without a spouse. About 60% of the patients were treated with major surgery, chemotherapy or radiotherapy, either alone or in combination. Of those who did not receive such treatment, 87% were elderly. Oncological treatment, either alone or combined with surgery, predicted increased hospital admissions and outpatient contacts. Age >77 years predicted fewer hospital admissions. Survival varied statistically significantly with the various treatment modalities, and was highest for major resections combined with oncological treatment. The majority of the patients living at home died in hospitals (54%) and only 26% died in their homes, while two-thirds of residents of nursing homes died there. DISCUSSION: Patients with primary incurable rectal cancer are heterogeneous with regard to their needs of treatment. While younger patients receive extensive tumour-related treatment, elderly patients are most commonly treated according to their symptoms. Prospective studies of the effect of various treatment options on the ease of symptoms and improved quality of life in unselected populations are needed.

Prolapse of the rectum, long-term results of surgical treatment.

AIMS: This study evaluates patency and functional results of abdominal and perineal treatment approaches to prolapse of the rectum. METHODS: A database search identified patients operated upon for prolapse of the rectum. The operations were abdominal or perineal approaches. The patient's records were reviewed, patients alive were contacted, and a self-report form evaluated functional results. Patients were followed until the prolapse recurred. RESULTS: A primary operation for prolapse of the rectum was performed in 56 patients. Median age was 59 years (range 20-87) and 78 (40-91) for abdominal and perineal approaches, respectively (p < 0.001). The average length of the prolapses was 8.7 cm (2-25) and 8.6 cm (2-15) for abdominal or perineal approaches. All prolapses treated with a Thiersch's operation recurred within a few months and all prolapses treated with the Delorme's operation recurred within 5 years, whereas the 5-year patency of the abdominal approach was 93% (p < 0.001). No prolapses recurred after mesh rectopexy and the 5-year patency of resection rectopexy was 86%. The abdominal approaches improved stool evacuation and constipation significantly, and anal leakage improved somewhat (p = 0.065). The median hospital stay was 11 (4-20) and 7 (2-155) days after abdominal and perineal approaches (p = 0.003). Complications occurred in 20% of patients. CONCLUSIONS: The patency of abdominal approach to prolapse of the rectum is better than that of perineal repairs. The abdominal approaches also have a favorable effect on constipation and anal insufficiency. Perineal approaches should be reserved for patients with a very short life expectancy.

Crohn's disease but not chronic ulcerative colitis induces the expression of PAI-1 in enteric neurons.

OBJECTIVES: Chronic inflammation of the intestinal wall is the common characteristic of Crohn's disease and ulcerative colitis; disorders, which in some cases can be difficult to distinguish. The inflammation also affects the local neuronal plexuses of the enteric nervous system. It is known that plasminogen activator inhibitor-1 (PAI-1) and urokinase receptor (uPAR) are upregulated in neurons after experimental peripheral nerve injury and have been linked to nerve regeneration. METHODS: The expression of PAI-1 and uPAR in neuronal cells in lesions of the gastrointestinal tract was analyzed by immunohistochemical techniques. RESULTS: PAI-1 was found in a subset of neurons primarily located in the submucosal plexus of the small and large intestine in 24 of 28 cases (86%) with Crohn's disease, but in none of 17 cases with chronic ulcerative colitis and other severe inflammatory conditions in the intestinal wall. The PAI-1 was seen in the perikarya of the neurons and a few proximal axons, whereas nerves were negative. uPAR was seen in nerves in all types of lesion varying from 21% to 88% of the cases, most frequent in colon adenocarcinomas. No uPAR-positive nerves were detected in normal colon. CONCLUSIONS: PAI-1-positive neurons in inflammatory bowel disease are linked to chronic inflammation in Crohn's disease, implying PAI-1 as a potential parameter for the differential diagnosis between Crohn's disease and ulcerative colitis. The findings also suggest that PAI-1 in neurons is related to pain and that both PAI-1 and uPAR are involved in neuronal repair in the inflamed tissue.

Crohn's disease: Comparison of in vitro ultrasonographic images and histology.

OBJECTIVE: To examine some typical histological findings in Crohn's disease using high-frequency ultrasound and to define the echo properties of these findings. MATERIAL AND METHODS: Bowel resection specimens from 14 patients operated on for Crohn's disease were examined with a 10 MHz linear array ultrasound transducer in a saline reservoir. Needles were placed in the specimen corresponding to the ultrasound plane. After formalin fixation, histological sections were taken according to these markings. Fifty-eight ultrasonographic images with 123 regions of interest were compared with corresponding histology. RESULTS: A thickened muscularis mucosae (>0.3 mm) was found in 48 of 69 regions of interest on histology. Submucosa with slight to moderate fibrosis was imaged as an echo-rich layer with sporadic, echo-poor elements (36/56), while severe fibrosis was seen as an echo-rich layer with diffuse, echo-poor elements (40/55). Muscularis propria with slight to moderate fibrosis was seen as an echo-poor layer with sporadic, echo-rich elements (49/66) while severe fibrosis was seen as an echo-poor layer with diffuse, echo-rich elements (17/22). Crohn's rosary was seen as echo-poor extensions of the 4th echo layer (31/50). CONCLUSIONS: Typical histological findings in Crohn's disease such as a thickened muscularis mucosae and Crohn's rosary can be imaged with high-frequency ultrasound in vitro. Fibrosis in the submucosa and muscularis propria is associated with decreasing and increasing echogenicity, respectively.

Clinical characteristics and outcomes in patients with advanced rectal cancer: a national prospective cohort study.

PURPOSE: At the time of diagnosis, approximately one third of patients with rectal cancer present with advanced disease. In this study we focus on a group of patients with primary advanced rectal cancer considered as not operable. We address various clinical aspects relevant for decision-making in a group of patients in need of palliative care. METHODS: Between January 1997 and December 2001, 4831 consecutive patients with rectal cancer were prospectively registered in the Norwegian Rectal Cancer Registry. In this national population-based cohort, 386 patients (8 percent) without surgical interventions were identified. These patients comprise the study population. Clinical characteristics and survivals were addressed. RESULTS: Patients not surgically treated were significantly older compared with other treatment groups (median age, 80 years; interquartile range, 72-86 vs. median age, 71 years; interquartile range, 62-79 years) (P<0.001). Median survival time was 4.5 (range, 3.5-5.4) months, regardless of age, gender, or hospital category. Patients who received radiotherapy had a significantly increased survival (P<0.001) compared with patients not treated with radiation, with a median survival time of 10.2 (range, 7.3-12.1) months vs. 2.8 (range, 2.1-3.6) months, respectively. Use of chemotherapy was not associated with improved survival. In multivariate analysis, only stage of disease and radiotherapy were independent predictors of better survival. CONCLUSION: Higher age and comorbidity seem to influence choice of treatment in this subgroup of patients with advanced rectal cancer disease. In nonsurgically treated patients, radiotherapy was associated with an improved survival. Our prospective, population-based cohort study emphasizes the dismal prognosis of these patients, which also should challenge our efforts and clinical approaches in palliative care.

Treatment of rectal cancer: reduction of local recurrence after the introduction of TME - experience from one University Hospital.

BACKGROUND: Local recurrence (LR) of cancer after rectal surgery is followed by significant morbidity and mortality. Since the introduction of total mesorectal excision (TME) the rates of LR have decreased in many centres. The aim of this retrospective study was to investigate the effect of TME on the recurrence rates of rectal cancer and the impact of the surgeons. METHODS: All patients resected for invasive rectal cancer from 1990 until 2000 were initially included in the study. From February 1994, TME was adopted as the standard treatment (TME group). Before this period, rectal surgery was performed by the non-TME technique (non-TME group). To obtain homogeneity, patients who underwent preoperative irradiation, emergency operations, pre- or intraoperative bowel perforation, residual tumour stage (R1,2) including Dukes' D stage and postoperative mortality within 31 days, were excluded. 139 patients in the non-TME group and 181 patients in the TME group were found eligible for analyses. RESULTS: The estimated LR rate at 1, 3 and 5 years was 7, 15 and 17% (non-TME) versus 4, 9 and 9% (TME) (p = 0.046, log-rank test). The anastomotic leakage rate was 6% (non-TME) versus 4% (TME) (not significant). Perioperative blood loss >500 ml, reoperations during the hospital stay and lymph node (N) stage were the independent risk factors for LR in the multivariate analysis. The case volume did not significantly influence LR rates. However, the variability of individual surgical results was reduced after the introduction of TME. CONCLUSIONS: TME yields significantly lower LR rates compared with traditional surgery. Since the introduction of TME, experience with rectal surgery has been gathered by a limited number of surgeons. The results of individual surgeons have consistently improved and the variability of individual surgical results is now at a lower level.