Hypoxia Marker GLUT-1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy.

BACKGROUND: Tumour hypoxia, which is frequent in many cancer types, is associated with treatment resistance and poor prognosis. The role of hypoxia in surgically treated bladder cancer (BC) is not well described. We studied the role of hypoxia in two independent series of urothelial bladder cancers treated with radical cystectomy. METHODS: 279 patients from the University Hospital Network (UHN), Toronto, Canada, and Turku University, Finland were studied. Hypoxia biomarkers (HIF1-α, CAIX, GLUT-1) and proliferation marker Ki-67 were analyzed with immunohistochemistry using defined tissue microarrays. Kaplan-Meier methods and Cox proportional hazards regression models were used to investigate prognostic role of the factors. RESULTS: In univariate analyses, strong GLUT-1 positivity and a high Ki-67 index were associated with poor survival. In multivariate model containing clinical prognostic variables, GLUT-1 was an independent prognostic factor associated with worse disease-specific survival (HR 2.9, 95% CI 0.7-12.6, Wald p = 0.15 in the Toronto cohort and HR 3.2, 95% CI 1.3-7.5, Wald p = 0.0085 in the Turku cohort). CONCLUSION: GLUT-1 is frequently upregulated and is an independent prognostic factor in surgically treated bladder cancer. Further studies are needed to evaluate the potential role of hypoxia-based and targeted therapies in hypoxic bladder tumours.

DNA image cytometry predicts disease outcome in stage II colorectal carcinoma.

BACKGROUND: Approximately 30% of all colorectal cancer (CRC) patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well established that a subgroup of patients with stage II are at high risk for recurrence within their lifetime and should be considered for adjuvant chemotherapy. The present work was designed to study the prognostic value of nuclear DNA content in stage II CRC of patients with long-term followup. PATIENTS AND METHODS: Isolated nuclei from 50 microm-thick paraffin sections of tissue samples from 253 patients with stage II CRC, who had undergone bowel resection at Turku University Central Hospital were cytocentrifuged on slides, stained with Feulgen staining, and DNA was measured using a computer-assisted image analysis cytometry system. Different approaches were applied in analysis of DNA histograms. RESULTS: DNA content did not show any relation with age (p < 0.96), sex (p < 0.35), tumor invasion (p < 0.77), or grade (p < 0.31). Aneuploid DNA content was significantly more frequent in the cancer of the left colon and rectum than the right colon (p = 0.02). S-phase fraction analysis revealed that a higher proportion (62%) of the older patients (>65 years) had high proliferation rates than did the younger patients (p < 0.05). Patients with narrow range histograms had a better disease-free survival (DFS) (narrow range: 70%, wide range: 60% at 10 years). Tumors with >9c nuclei were associated with significantly better DFS and disease-specific survival (DSS) as compared with the patients who did not have >9c nuclei in their tumor samples (p < 0.003 and p < 0.0001, respectively). Multivariate survival (Cox) model showed that only classification of the basic pattern of the histogram [odds ratio OR) = 29.14; 95% confidence interval (CI) 2.350-361.57] (p = 0.009) and recurrence (OR = 165.35; 95% CI 48.42-564.7) (p = 0.0001) proved to be independent predictors of clinical outcome. CONCLUSION: Our results seem to suggest it truly is possible, by using DNA cytometry, to find groups with different prognosis among stage II cases. Those with a high recurrence rate should be considered for adjuvant chemotherapy.

PLA2 (group IIA phospholipase A2) as a prognostic determinant in stage II colorectal carcinoma.

BACKGROUND: Approximately 30% of all colorectal cancer (CRC) patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well established that a subgroup of patients with stage II are at high risk for recurrence within their lifetime and should be considered for adjuvant chemotherapy. The present work was designed to assess the value of group IIA phospholipase A2 (PLA2) as a predictor of disease outcome in stage II CRC patients with long-term follow-up. PATIENTS AND METHODS: The present study comprises a series of 116 patients who underwent bowel resection for stage II CRC during 1981-1990 at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with PLA2. RESULTS: Fifty-five percent of all tumors were positive for PLA2. There was no significant correlation between PLA2 expression and age, sex, depth of invasion and lymph node status. In Kaplan-Meier survival analysis, there was a significant (P = 0.010) difference in disease-free survival (DFS) between patients with negative tumors (longer DFS) and those with positive tumors. The same was true with disease-specific survival (DSS), patients with PLA2-negative tumors living significantly longer (P = 0.025). In multivariate (Cox) survival analysis, however, PLA2 was not an independent predictor of DFS or DSS. In subgroup analysis, the right-sided tumors with negative PLA2 staining had remarkably better prognosis (P = 0.010) than PLA2-positive left-sided tumors. CONCLUSIONS: Quantification of PLA2 expression seems to provide valuable prognostic information in stage II CRC, particularly in selecting the patients at high risk for recurrent disease who might benefit from adjuvant therapy.

The cleansing result of oral sodium phosphate is inversely correlated with time between the last administration and colonoscopy.

BACKGROUND: There is some evidence that the timing of sodium phosphate (NaP) ingestion affects the cleansing result. The objective of this study was to evaluate the correlation of cleansing result with the timing of ingestion of NaP. METHODS: 214 consecutive outpatients scheduled to undergo colonoscopy were enrolled in the study. All patients filled out a detailed questionnaire concerning the execution of bowel cleansing. Concomitant with colonoscopy, patient characteristics were recorded and after the procedure the cleansing result was scored. The correlation between cleansing score and time from the last dose of NaP to colonoscopy was evaluated. For further analysis, patients were divided into three groups regarding the time lag from NaP taking to colonoscopy (group 1, 6 h or less; group 2, 6-12 h; group 3, 12 h or more). RESULTS: 204 patients had complete colonoscopy and enough data to be analyzed for the study. The Pearson correlation coefficient for the time between the last dose of NaP and colonoscopy was -0.450 (p=0.0001) showing an inverse correlation. The mean cleansing score (+/-SEM) of group 1 was 4.00+/-0.12, for group 2 it was 3.56+/-0.12, and for group 3 it was 2.64+/-0.14. There were statistically significant differences between all groups. CONCLUSION: The cleansing result of NaP is inversely correlated with the time between last dose of NaP and colonoscopy. Colonoscopy should be preferably performed within 12 hours of taking the second dose of NaP.

Prognostic factors in prostate cancer.

Prognostic factors in organ confined prostate cancer will reflect survival after surgical radical prostatectomy. Gleason score, tumour volume, surgical margins and Ki-67 index have the most significant prognosticators. Also the origins from the transitional zone, p53 status in cancer tissue, stage, and aneuploidy have shown prognostic significance. Progression-associated features include Gleason score, stage, and capsular invasion, but PSA is also highly significant. Progression can also be predicted with biological markers (E-cadherin, microvessel density, and aneuploidy) with high level of significance. Other prognostic features of clinical or PSA-associated progression include age, IGF-1, p27, and Ki-67. In patients who were treated with radiotherapy the survival was potentially predictable with age, race and p53, but available research on other markers is limited. The most significant published survival-associated prognosticators of prostate cancer with extension outside prostate are microvessel density and total blood PSA. However, survival can potentially be predicted by other markers like androgen receptor, and Ki-67-positive cell fraction. In advanced prostate cancer nuclear morphometry and Gleason score are the most highly significant progression-associated prognosticators. In conclusion, Gleason score, capsular invasion, blood PSA, stage, and aneuploidy are the best markers of progression in organ confined disease. Other biological markers are less important. In advanced disease Gleason score and nuclear morphometry can be used as predictors of progression. Compound prognostic factors based on combinations of single prognosticators, or on gene expression profiles (tested by DNA arrays) are promising, but clinically relevant data is still lacking.

The epidemiology and treatment patterns of postoperative adhesion induced intestinal obstruction in Varsinais-Suomi Hospital District.

BACKGROUND AND AIMS: The epidemiology and treatment patterns of postoperative adhesion induced intestinal obstruction have been poorly investigated in Finland. This study evaluated the epidemiology and treatment patterns of postoperative adhesion induced intestinal obstruction in a well defined geographical area (Hospital District). MATERIAL AND METHODS: All inpatient episodes between 1.1.1999 and 31.12.1999 due to postoperative adhesion induced intestinal obstruction in Varsinais-Suomi Hospital District were evaluated retrospectively using individual patient records. RESULTS: 123 hospitalizations due to postoperative adhesion-related intestinal obstruction were observed during the study period. The total number of preceding operations was 176 considering altogether 101 patients. The most prevalent single initial operations causing adhesion induced intestinal obstruction were colorectal, upper abdominal, and female reproductive system procedures. Of all treatment episodes 32% were operative and mortality was 2%. The median days of hospital stay (range) of all inpatient episodes, operative episodes, and conservative episodes were 6 (1-58), 11 (2-34) and 4 (1-58), respectively. Patient dependent factors associated with increased likelihood to operative treatment of obstruction were: female gender (40% in females vs 23% in males, P = 0.042) and previous gynaecological surgery (70% of the patients, P = 0.032). Intraoperative findings were obstruction in 70%, strangulation in 20%, necrosis in 8%, and perforation in 2% of operations. Bowel resection was needed in 38% of operations. Preceding gynaecological surgery increased the likelihood of bowel strangulation as an intraoperative finding. CONCLUSION: The epidemiology, treatment patterns and results of postoperative adhesion induced intestinal obstruction are of the average international level in the Varsinais-Suomi Hospital District. The treatment patterns among the different hospitals in the Hospital District are similar. Female gender is associated with increased risk for operative treatment of adhesive obstruction. Previous gynaecological surgery increases the likelihood of operative treatment and complicated obstruction.

Sodium phosphate is superior to polyethylene glycol in bowel cleansing and shortens the time it takes to visualize colon mucosa.

BACKGROUND: Both sodium phosphate (NaP) and polyethylene glycol-electrolyte (PEG-EL) have been used to cleanse the bowel prior to colonoscopy, and recent reviews suggest that the former is the more effective and convenient cleansing regimen. The aim of this study was to compare the bowel cleansing effect of NaP solution with that of PEG-EL solution and to evaluate whether the cleansing effect correlates with the time needed to perform colonoscopy. METHODS: 111 patients admitted for colonoscopy were randomized to receive either 90 mL oral NaP or 4 litres of PEG-EL solution. Cleansing was scored blindly by one colonoscopist and the following times were recorded: caecal intubation, withdrawal and total colonoscopy. RESULTS: Of all the patients included in the study, 99 were evaluable. The mean and standard error of the mean (+/-S(chi)-) cleansing score was 3.64 +/- 0.16 in the NaP group and 2.69 +/- 0.9 in the PEG-EL group (P = 0.005). The mean (+/-S(chi)-) caecal intubation times were 6.39 +/- 0.50 min and 5.39 +/- 0.41 min (P = 0.13), the withdrawal times 4.26 +/- 0.20 min and 5.78 +/- 0.34 min (P = 0.0001) and the total colonoscopy times 10.65 +/- 0.52 min and 11.17 +/- 0.56 min (P = 0.50) in the NaP and PEG-EL groups, respectively. The subgroup of patients with a cleansing score of 3 or more was associated with shortened colonoscopy withdrawal time compared to the group scoring below 3. CONCLUSIONS: Better cleansing of the large bowel shortens colonoscopy withdrawal time. Sodium phosphate is a more effective bowel-cleansing regimen than polyethylene glycol, and the better cleansing result is associated with shortened colonoscopy withdrawal time.

Population-based study of the surgical workload and economic impact of bowel obstruction caused by postoperative adhesions.

BACKGROUND: Intestinal obstruction is the most severe consequence of adhesion formation. This study examined the annual surgical workload and costs of intestinal obstruction caused by postoperative intra-abdominal adhesions. METHODS: The study was a retrospective case-note review of patients hospitalized for intestinal obstruction caused by postoperative adhesions in a well defined geographical area. The surgical workload and direct costs of inpatient care were analysed. RESULTS: There were 138 admissions for postoperative adhesion-related intestinal obstruction during the study with a total of 1118 inpatient days. The median hospital stay was 4 (range 1-58) days among patients who had non-operative treatment and 11 (range 2-34) days for those who had surgery. Surgery was necessary in 40 patients (29.0 per cent). The mean operating time (time from skin incision to last stitch) and the mean time spent in the operating theatre were 79 and 141 min respectively. The cumulative operating time for the surgical group was 52 h 20 min and the cumulative theatre time was 93 h 44 min. The annual direct hospital cost for postoperative adhesional intestinal obstruction was pound 181 653 in the district studied and the estimated cost for the whole of Finland was pound 2 077 796. CONCLUSION: This population-based study indicates that the workload and costs associated with bowel obstruction caused by postoperative adhesions are substantial.

Novel serum inflammatory markers in acute appendicitis.

BACKGROUND: Cytokines and leukocyte adhesion molecules are activated and found in increased concentrations in bacterial infection. The purpose of this study was to investigate whether some of these new serum markers could be feasible as a single on-admission test to predict acute appendicitis (AA). METHODS: In an open prospective study the diagnostic potentials of two cytokine measurements (interleukin-6 and interleukin-8), soluble leukocyte adhesion molecule (CD44), C-reactive protein (CRP) and white blood cell (WBC) count were compared in 80 consecutive patients who had undergone surgery for suspected AA. The diagnostic performance of each parameter was tested by using receiver operating characteristic (ROC) curves. RESULTS: Phlegmonous AA was found in 34%, gangrenous AA in 40% and perforated AA in 5% of the patients. The proportion of negative explorations was 21%. Preoperative serum concentrations of IL-6 and CRP were elevated only in gangrenous and perforated AA. The concentrations of IL-8 and CD44 remained unchanged in AA. The sensitivity (84%), specificity (79%) and diagnostic accuracy (82%) of IL-6 were higher than the values for CRP, WBC, IL-8 and CD44 in predicting AA. CONCLUSION: ROC analysis confirmed that IL-6 showed the best trend in the diagnosis of AA. However, the diagnosis of AA was not greatly improved by any of the new serum markers as single on-admission tests.

CD 99 and CD 106 (VCAM-1) in human testis.

AIM: The expression of the cytokines IL-2, IL-6, IL-10, IFN-g and TNF-a and the adhesion proteins CD99 and CD106 was studied in the human testis at the protein level. METHODS: The expression of the cytokines and the adhesion proteins was assessed using immunohistochemistry and immunoblotting. RESULTS: None of the cytokines studied was present in the human testis, but CD99 and CD106 (VCAM-1) strongly were expressed in all the testes investigated. CD99 was present in the interstitial tissue of the human testis as well as in the Sertoli cells. The identity of the CD99+ interstitial cells is unclear. CD106 (VCAM-1) was present in Leydig cells as well as the basal parts of the Sertoli cells in the seminiferous tubules. In immunoblotting, CD99 was demonstrated at molecular ratios of 46-57 (kD). This is a novel isoform of the molecule. CONCLUSION: The human testis produces both CD99 and CD106 and as CD106 mediates cell binding to lymphocytes, it is possible that the human Leydig cells adhere to lymphocytes like the rodent Leydig cells.

Increased expression of FGF-8 isoforms and FGF receptors in human premalignant prostatic intraepithelial neoplasia lesions and prostate cancer.

SUMMARY: Fibroblast growth factor 8 (FGF-8) is implicated in growth of prostate cancer. Alternative splicing of the human FGF-8 gene potentially allows coding for four protein isoforms (a, b, e, and f). These isoforms differ in their binding to FGF receptors (FGFR) and in their mitogenic and transforming capacity in transfection assays. Here, we used RT-PCR and immunohistochemistry to study the expression of FGF-8 and FGFR isoforms in human prostate cancer (n = 31). Nonmalignant prostate specimens from cystoprostatectomies (n = 24) were examined as controls. Most prostate cancer samples and some control prostates also contained prostatic intraepithelial neoplasia (PIN) lesions. FGF-8a and e were expressed at significantly higher frequencies in prostate cancer (FGF-8a, 55%; FGF-8e, 45%) than in control samples (FGF-8a, 17%, p = 0.0052; FGF-8e, 8%, p = 0.0031). On the contrary, FGF-8b was found at an equal frequency in prostate cancer (55%) and in control prostates (50%). Furthermore, a combination of two or three FGF-8 isoforms (a, b, and/or e) was also expressed at a higher frequency in prostate cancer than in control samples (45% and 8%, respectively, p = 0.0031). Immunohistochemistry with an antibody recognizing all FGF-8 isoforms was more strongly immunoreactive in prostate cancer cells and PIN lesions than in normal-type epithelium. The receptor splicing variants FGFR1IIIc and FGFR2IIIc, which are activated by FGF-8, were found both in prostate cancer and control samples. Interestingly, immunoreactivity for FGFR1 and FGFR2 was much stronger in prostate cancer cells and PIN than in normal epithelium. These results demonstrate, for the first time, that FGF-8 isoforms and their receptors FGFR1IIIc and FGFR2IIIc are expressed at an increased level not only in prostate cancer but also in premalignant PIN lesions. These data suggest that FGF-8 may have an important autocrine role in the development of human prostate cancer. In addition to FGF-8b, the FGF-8 isoforms a and e may be involved in this process.

Differential effects of hexoses and sucrose, and platelet-derived growth factor isoforms on cyclooxygenase-1 and -2 mRNA expression in keloid, hypertrophic scar and granulation tissue fibroblasts.

Cyclooxygenase (COX) is the key enzyme in the formation of prostaglandins in inflammation. In the present study the effects of biomedically relevant hexose sugars (glucose, fructose, galactose, mannose) and sucrose disaccharide on the expression of COX-1 and COX-2 genes were evaluated in granulation tissue fibroblasts, hypertrophic scar fibroblasts and keloid fibroblasts. The effects of three isoforms (AA, AB and BB) of PDGF on COX gene expression in granulation tissue fibroblasts were also examined. All cell lines expressed COX-1 mRNA, whilst fibroblasts derived from abnormal scars did not express COX-2 mRNA. COX-1 mRNA expression was decreased by sugars in granulation tissue fibroblasts and increased in hypertrophic scar fibroblasts. No major changes were seen in keloid fibroblasts. On the other hand, COX-2 mRNA expression in granulation tissue fibroblasts was decreased dramatically in the presence of fructose, mannose and sucrose and moderately in the presence of galactose. All isoforms of PDGF increased COX-1 and COX-2 mRNA expression in granulation tissue fibroblasts, the most marked increases being elicited by PDGF-BB. All fibroblast cell lines studied expressed the COX-1 gene while the COX-2 gene was not expressed by abnormal scar-derived fibroblasts. Further, granulation tissue fibroblasts seemed to behave differently under the influence of sugars compared to hypertrophic scar fibroblasts whilst keloid fibroblasts seemed to be relatively unaffected by sugars. In addition, the PDGF-BB isoform is a potent inducer of COX-2 gene expression in wound fibroblasts. These findings may be relevant to the development of abnormal scars and indicate the need for further studies.

Effect of sucrose on collagen metabolism in keloid, hypertrophic scar, and granulation tissue fibroblast cultures.

Sucrose has been used to treat wounds with excellent results and with minimal abnormal scarring. In this study the effects of sucrose on collagen metabolism in fibroblast culture was evaluated. Sucrose (5.5, 15, or 25 mM) was added to granulation tissue, hypertrophic scar, and keloid fibroblast cultures, mRNA levels and procollagen aminopropeptides for type I and III collagens in cell culture medium were studied. Sucrose decreased mRNA levels for pro alpha 1(I) and pro alpha 1(III) collagens in fibroblast cultures derived from hypertrophic scar and keloid. In normal granulation tissue fibroblast cultures, 5.5 mM sucrose increased mRNA levels for pro alpha 1(I) and pro alpha 1(III) collagen, and higher concentrations decreased them. The synthesis of type I collagen decreased dose-dependently in all cell strains, whereas the synthesis of type III collagen decreased only in granulation tissue fibroblasts. To conclude, in vitro high concentrations of sucrose down-regulate both collagen gene expression and synthesis in normal granulation tissue fibroblasts, whereas in fibroblasts derived from abnormal scar sucrose down-regulates only type I collagen gene expression and synthesis, changing the pattern of collagen metabolism toward normal.

Interferon-alpha inhibits cyclooxygenase-1 and stimulates cyclooxygenase-2 expression in bladder cancer cells in vitro.

The enzymes cyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2) catalyze the initial step in the formation of prostaglandins (PGs). PGs are known to be involved in numerous processes, for example inflammation, immune responses, carcinogenesis, and tumor angiogenesis. The formation of PGs is stimulated in various cancers since the expression of Cox-2 is upregulated. Interferon (IFN)-alpha is used in the treatment of bladder cancer, although not all of the effects of such treatment are thoroughly known. Therefore, we investigated the expression of cyclooxygenases in two bladder cancer cell lines, 5637 and T24, under basal conditions and in the presence of human recombinant IFN-alpha (100, 1,000, and 10,000 U/ml). The mRNA of Cox-1 and Cox-2 was expressed in both cultured bladder carcinoma cell lines. The level of Cox-1 expression was low in 5637 cells and higher in T24 cells. In contrast, Cox-2 expression was prominent in 5637 cells and low in T24 cancer cells. The highest IFN-alpha concentration (10,000 U/ml) decreased the expression of Cox-1 to 47 and 28% of the control levels in 5637 and T24 cells, respectively. In contrast, Cox-2 expression increased in both cell lines. In 5,637 cells, Cox-2 expression increased 1.3-fold with 10,000 U/ml of IFN-alpha. In T24 cells, the maximum effect was achieved by 1,000 U/ml of IFN-alpha, which increased the expression of Cox-2 up to 2.4-fold. These findings may have relevance in the outcome of patients treated with IFN-alpha because upregulated Cox-2 expression may suppress the cell-mediated defense system. On the other hand, the inhibition of Cox-1 could be beneficial because Cox-1 is known to stimulate angiogenesis.

Management of testicular cancer--16 years' experience from southwest Finland.

OBJECTIVE: This study investigated the outcome of testicular cancer treatment in Finland. MATERIAL AND METHODS: Data on 88 testicular cancer patients treated in Turku University Central Hospital between 1976 and 1992 were studied to analyse outcome and survival. RESULTS: The histological diagnosis was seminoma for 39 patients and non-seminoma for 49 patients. Two seminoma patients relapsed (5%) and one patient died of progressive disease (3%; initially stage II seminoma). Eleven non-seminoma patients relapsed (22%), nine of whom were cured with chemotherapy. Four non-seminoma patients died of progressive disease (8%; initially one stage I non-seminoma and three stage III non-seminomas). The median time to relapse after the completion of treatment was 9 months (range 3-50 months). Non-seminoma patients had significantly more relapses than seminoma patients (p = 0.03). Most relapses (73% of the non-seminoma relapses) were found among the stage I non-seminoma patients who had not received adjuvant chemotherapy, while none of the stage I seminoma patients relapsed (p = 0.007). CONCLUSIONS: Close surveillance is important for all non-seminoma patients to guarantee the early detection and treatment of recurrent disease. Treatment and surveillance should be covered by national guidelines and be conducted in centres with special interest in this rare but mostly curable cancer.

Expression of cyclooxygenase-1 and -2 in urinary bladder carcinomas in vivo and in vitro and prostaglandin E2 synthesis in cultured bladder cancer cells.

Cyclooxygenases (Coxs) are the rate-limiting enzymes catalysing the formation of prostaglandins, which are involved in various of physiological processes. Increased Cox-2 expression has been observed in several malignancies, but the exact role of Cox-2 in carcinogenesis remains unsolved. We studied the expression of both Cox-1 and Cox-2 by immunohistochemistry in 29 transitional cell carcinomas of the urinary bladder. Diffuse cytoplasmic immunosignal for Cox-2 was detected in all cancer specimens. The expression was moderate in 55% and strong in 31% of the carcinomas. The normal urothelium in the samples stained also for Cox-2, but the intensity of the immunosignal was weak in most specimens. Cox-1 was expressed in the stroma of bladder wall, whereas in the tumour cells, Cox-1 immunosignal was either absent or weak. No correlation was detected between Cox-1 or Cox-2 expression and tumour differentiation or stage of invasion. We also evaluated the mRNA expression of Cox-1 and Cox-2 and synthesis of prostaglandin E2 (PGE2) in three bladder carcinoma cell lines (RT4, 5637, and T24). All cell lines expressed high levels of Cox-2 mRNA, whereas Cox-1 mRNA expression was detected only in T24 cells. There was great variation in the basal levels of PGE2 synthesis in these cell lines. Indomethacin inhibited the synthesis of PGE2 in all three cell lines, although the level of Cox-2 mRNA tended to increase by indomethacin. These results indicate that Cox-2 is widely expressed in human bladder carcinomas and that the role of Cox-2 inhibition in bladder cancer should be further studied.

Interferon-gamma-induced inhibition of wound healing in vivo and in vitro.

This work was undertaken to study the effects of various doses of interferon-gamma (IFN-gamma) on developing granulation tissue in rats and on granulation tissue-derived fibroblasts in culture. For in vivo studies cylindrical hollow sponge implants were used as an inductive matrix for the growth of granulation tissue. In the test groups the implants were injected daily for four days with a solution containing 160, 800, 4000, or 20000 units of IFN-gamma while the implants of the control group were treated correspondingly with the carrier solution only. Analyses of granulation tissue in the sponge cylinders, carried out 7 days after implantation, showed an IFN-gamma-related decrease in the formation of new granulation tissue. The largest, dose-dependent effect was seen in the accumulation of collagen. For in vitro studies, cultures of rat granulation tissue fibroblasts were treated with 100, 500, 1000, or 5000 units/ml of IFN-gamma. IFN-gamma decreased collagen synthesis to about 50 per cent of that in controls. IFN-gamma treatment also decreased type I procollagen mRNA levels maximally by 41 per cent from the control level. It is concluded that IFN-gamma inhibits the formation of new granulation tissue by decreasing collagen synthesis.

The effects of sialic acid on the gene expression of fibrillar collagens: different changes in normal and fibrotic scar derived fibroblasts.

OBJECTIVE: To investigate the effect of free sialic acid on collagen gene expression in fibroblasts. DESIGN: Cell culture study. SETTING: University hospital, Finland. CELL LINES: Human granulation tissue fibroblasts, human hypertrophic scar fibroblasts and human keloid fibroblasts. INTERVENTIONS: Treatment of cell cultures with 3 microM, 30 microM and 300 microM N-acetyl-neuraminic acid. MAIN OUTCOME MEASURES: The measurement of steady state level of mRNA for type I and type III collagen. RESULTS: Fibroblast lines react dissimilarly under the influence of sialic acid. Granulation tissue fibroblasts showed decrease in the gene expression of type I and III collagen, while keloid fibroblasts contrastingly showed an increase. Hypertrophic scar derived fibroblasts showed no change. CONCLUSIONS: Sialic acids may decrease collagen gene expression in granulation tissue and that disturbed wound healing in diabetics and smokers may in part be due to direct effect of sialic acids on fibroblasts. Sialic acids may in part induce keloid formation.

Innervation of normal and hypertrophic human scars and experimental wounds in the rat.

The present study was designed to investigate the role of nerve elements in normal and aberrant human wounds, and in experimental rat wound healing model. The innervation of normal and hypertrophic human scars was studied using indirect immunofluorescence labeling with antibodies specific for neurofilament protein. Furthermore, in-growth of axons into experimental rat wounds was assayed. The results demonstrated that, in contrast to normal wounds, hypertrophic scars were traversed by a high number of bundles of axons. Our results also demonstrated that experimental rat granulation tissue which represented early phases of wound healing attracted axonal growth. To conclude, our findings indicate that normal wound healing is accompanied with innervation of the scars, and that hypertrophy of scars is accompanied with hypertrophy of nerves within the scars. Our results also suggest that aberrations in the innervation of scars may either cause aberrant wound healing, or neural hypertrophy may be a result of disturbed interplay in wound healing mechanisms.