IFN-alpha induced adenosine production on the endothelium: a mechanism mediated by CD73 (ecto-5'-nucleotidase) up-regulation.

CD73 (ecto-5'-nucleotidase; EC 3.1.3.5) participates in lymphocyte binding to endothelial cells and converts extracellular AMP into a potent anti-inflammatory substance adenosine. However, the regulation of expression and function of CD73 has remained largely unknown. In this study, we show that IFN-alpha produces a time- and dose-dependent long-term up-regulation of CD73 on endothelial cells, but not on lymphocytes both at protein and RNA levels. Moreover, CD73-mediated production of adenosine is increased after IFN-alpha treatment on endothelial cells, resulting in a decrease in the permeability of these cells. Subsequent to induction with PMA, FMLP, dibutyryl cAMP, thrombin, histamine, IL-1beta, TNF-alpha, and LPS, no marked changes in the level of CD73 expression on endothelial cells are observed. We also show that CD73 is up-regulated in vivo on the vasculature after intravesical treatment of urinary bladder cancers with IFN-alpha. In conclusion, distinct behavior of lymphocyte and endothelial CD73 subsequent to cytokine treatment further emphasizes the existence of cell type-specific mechanisms in the regulation of CD73 expression and function. Overall, these results suggest that IFN-alpha is a relevant in vivo regulator of CD73 in the endothelial-leukocyte microenvironment in infections/inflammations, and thus has a fundamental role in controlling the extent of inflammation via CD73-dependent adenosine production.

Differences between local and review urinary cytology in diagnosis of bladder cancer. An interobserver multicenter analysis.

OBJECTIVES: The objective of the study is to evaluate the agreement of local and review urinary cytology in patients with newly diagnosed bladder cancer and in those being followed for their disease. In addition, the effect of the type of institution on agreement was determined. METHODS: A total of 652 consecutive patients with bladder cancer from 19 institutions were evaluated; 575 (88.2%) of the patients had cytopathological sample available for central review and were eligible for analysis. One hundred and twenty nine (22.4%) of the patients had newly diagnosed bladder cancer, whereas the remaining 446 (77.6%) patients were under follow-up. A voided urine sample was obtained prior to transurethral resection of the bladder (TURB) or routine follow-up cystoscopy and split for culture and cytology. The cytopathological samples were first analysed by a local pathologist, and then re-analysed by a central reviewer. The agreement of cytological readings was determined by Kappa coefficient. RESULTS: The sensitivities of local and review cytology in detection of primary bladder cancer were 38.8 and 31.0%, respectively. Recurrence was observed in 119 of the 446 (26.7%) patients under follow-up, of which both local and review cytology detected 21 (17.6%) cases. Specificities of local and review cytology were 97.6 and 96.6%, respectively. Overall agreement of urine cytology was good in patients with primary bladder cancer and moderate in those being followed for their disease as Kappa coefficients were 0.70 and 0.60, respectively. However, some disagreement was found when results were analysed according to type of institution, to type of primary tumour, and to result of follow-up cystoscopy. In patients with primary bladder cancer the Kappa coefficient was 0.86 (very good) in university hospitals and 0.36 (fair) in city hospitals. Accordingly, in patients under follow-up the Kappa coefficient was 0.65 (good) in university hospitals and 0.39 (fair) in district hospitals. Although the stage of primary tumour had no effect on agreement, agreement was moderate (Kappa coefficient 0.45) in those with low grade tumour and good (Kappa coefficient 0.67) in those with high grade tumour. In addition, Kappa coefficients were 0.65 (good) and 0.40 (fair) in those with and without recurrence at follow-up cystoscopy. CONCLUSIONS: Although overall agreement of routine cytology was from moderate to good in both diagnosis and monitoring of bladder cancer, there is some variation in agreement according to the type of institution. Accordingly, grade of primary tumour and the result of follow-up cystoscopy had effect on agreement reflecting subjectiveness and weak reproducibility of this test. This not only emphasises the need for continuing education and quality control for urine cytologic analysis, but also inspires the development of more objective tests.

Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma.

OBJECTIVES: To study the factors determining new recurrences in patients with frequently recurring superficial bladder tumors. METHODS: Of all 205 eligible patients, each received 5 weekly intravesical instillations of mitomycin C (MMC), with the first instillation given perioperatively. This was followed, according to randomization, by BCG instillations alone or by alternating instillations of interferon-alpha and BCG monthly for up to 1 year. Impact of 12 variables on time to first recurrence was retrospectively studied with the Cox multiple hazards regression and Kaplan-Meier analysis. RESULTS: Type of regimen was the most significant factor determining new recurrences, with preceding recurrence rate being the most important prognostic factor. Timing of the first MMC was the third significant predictor in the main multivariate analysis, with more than a two-fold relative risk for a new recurrence if the first MMC instillation was given later than on day 0. CONCLUSION: Preceding recurrence rate, most accurately reflects, in patients with frequently recurring tumors, the inherent risk for new recurrences. This risk can be considerably reduced by use of an effective chemoimmunotherapy regimen, and in addition, by inclusion of an early perioperative chemotherapy instillation in such a regimen.

Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study--FinnBladder III long-term results.

PURPOSE: We evaluated the long-term efficacy of a single dose of interferon or epirubicin administered immediately after transurethral resection compared with transurethral resection alone for primary superficial bladder cancer recurrence. MATERIAL AND METHODS: A total of 200 patients with primary superficial stages Ta to T1, grades 1 to 3 bladder cancer were randomized into 3 treatment groups, including transurethral resection alone, transurethral resection plus 50 milliunits interferon-alpha2b and transurethral resection plus 100 mg. epirubicin. The primary end point was time to first recurrence. RESULTS: At a median followup of 72 months we observed a sustained effect of a single epirubicin instillation compared with other treatments. To date only 46% of the patients in group 3 have experienced recurrence in contrast to 73% and 68% in groups 1 and 2, respectively (p = 0.002). At 72 months the Kaplan-Meier disease-free estimates were 24%, 31% and 51% in groups 1 to 3, respectively (p = 0.002). The Cox multivariate model revealed a more than 2-fold relative risk of recurrence in group 1 versus group 3 (p <0.001). Other significant variables predicting recurrence were grade and the number of tumors. CONCLUSIONS: A single perioperative instillation of 100 mg. epirubicin causes a significant and sustained decrease in primary superficial bladder cancer recurrence, whereas a single dose of 50 milliunits interferon-alpha2b is ineffective for prophylaxis.