Cancer-Specific Survival Stratification Derived from Tumor Expression of Tissue Inhibitor of Metalloproteinase-2 in Non-Metastatic Renal Cell Carcinoma.

Degradation of the extracellular matrix is a prerequisite for the processes of cancer cell invasion and metastasis. The purpose of our study was to assess the association of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9) and their inhibitors (TIMP-1 and TIMP-2) with renal cell carcinoma (RCC) progression and cancer-specific survival (CSS), using immunohistochemical analysis of 60 formalin-fixed, paraffin-embedded sections of tumor tissue and normal tissue near the tumor from surgical T1-3bN0 M0 RCC specimens. Significant overexpression of MMP-2 in tumor and normal tissue was correlated with advanced stages, tumor size, sarcomatous differentiation and clinical symptoms. Overall survival was 31.7% (55.2% M0, 9.7% M1) and CSS 56.7% (100% M0, 16.1% M1) with a follow-up of 76 (5-230) months. Fuhrman grade [HR 2.87 (95% CI: 1.28-6.45); p = 0.01], tumor size [HR 1.13 (95% CI: 1.03-1.26); p = 0.009] and low TIMP-2 expression [HR 0.35 (95% CI: 0.16-0.78); p = 0.01] were independent predictive factors of CSS and stratified the patients into three groups with different rates of 10-year CSS; [100%, 73.9% and 20.5% for the good, intermediate and poor prognosis group respectively (p = 0.000006)] . This study offers strong evidence that TIMP-2 expression in tumor tissue may play a crucial role in progression and poor prognosis in human localized and locally advanced RCC.

Prognostic value of microRNA expression pattern in upper tract urothelial carcinoma.

OBJECTIVE: To examine the microRNA (miRNA) expression pattern in tumour samples from patients with progressing and non-progressing upper tract urothelial carcinoma (UTUC) in order to identify putative miRNAs that may be used as prognostic markers. PATIENTS AND METHODS: We conducted a multicentre, retrospective study of formalin-fixed paraffin-embedded tissue samples from 150 patients with UTUC who had undergone radical nephroureterectomy. Global miRNA expression patterns were analysed in 18 selected samples from patients with UTUC using TaqMan arrays. The differential expression of five key miRNAs was validated by quantitative polymerase chain reaction in an independent cohort of 132 samples from patients with UTUC. Models to predict tumour progression and cancer-specific survival that included miRNA expression patterns were developed by Cox regression analysis. RESULTS: Twenty-six miRNAs were found to be aberrantly expressed between samples from patients with progressing and non-progressing UTUC and five of these were selected for subsequent studies. The regression analysis identified tumour stage and miR-31 and miR-149 expression as independently associated with tumour progression and tumour stage and miR-149 expression as independently associated with cancer-specific survival. The risk scores derived from these miRNA models were able to discriminate two groups with a highly significantly different probability of tumour progression (hazard ratio [HR] 4.78; P < 0.001) and death (HR 276; P = 0.004). CONCLUSIONS: There is a differential miRNA expression pattern between patients with progressing and non-progressing UTUC. The identification of new miRNAs associated with a high probability of tumour recurrence and cancer-specific survival in patients with UTUC and their combination in a robust, easy-to-use and reliable algorithm may help tailor treatment and surveillance strategies in these patients.

HER-2/AKT expression in upper urinary tract urothelial carcinoma: prognostic implications.

AIM: To assess HER-2 and p-AKT expression in upper urinary tract urothelial carcinoma (UTUC) in order to determine their value as prognostic factors of tumour progression and cancer-specific survival. PATIENTS AND METHODS: One hundred consecutive UTUC patients were retrospectively included, between 1990-2004, in 4 tissue microarrays for immunostaining. Median follow-up: 33.03 months. RESULTS: Positive HER-2 expression was found in 10 cases and cytoplasmic p-AKT expression in 84 cases; the expression intensity was strong: 30 cases, moderate: 28 and weak: 26. Nuclear p-AKT expression was found in 6 patients: 1 with strong, and 5 with moderate intensity. Nuclear p-AKT expression was an independent factor for tumour progression (HR=4.145, p=0.013), together with grade (HR=4.557, p=0.009) and stage (HR=2.085, p=0.003). In cancer-specific survival analysis, nuclear p-AKT expression (HR=4.268, p=0.017), together with grade (HR=5.214, p=0.035) and stage (HR=2.666, p=0.002) were identified as independent prognostic factors. CONCLUSION: Nuclear p-AKT expression together with stage and grade constitute independent prognostic factors for tumour progression and cancer-specific survival.

Hoffa's fat pad resection in total knee arthroplasty.

The authors have studied the consequences of resection of Hoffa's fat pad during total knee arthroplasty (TKA). Sixty eight patients undergoing primary TKA were randomised to have Hoffa's fat pad either resected or preserved. Biopsy specimens of Hoffa's fat pad were taken for pathological study in all patients. Radiological, functional and clinical evaluation was made after surgery, before discharge from hospital, after one month and after six months. Thirty six percent of the patients were found to present inflammatory infiltration of Hoffa's fat pad, and severe fibrosis was found in 33 %. A progressive decrease in postoperative anterior knee pain was found in 95% of the patients in both groups. Hoffa's fat pad resection did not appear to result in a change in patellar tendon length during the first six months after TKA. Preoperative fibrosis of Hoffa's fat pad may play a role in postoperative pain and range of motion.

Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis.

OBJECTIVE: Neovascularization, with an increased number of synovial vessels with a characteristic morphology, seems to contribute to the progression of psoriatic arthritis (PsA). Accordingly, angiogenesis may be an important therapeutic target in PsA. The aim of this study was to analyze the effects of infliximab on angiogenesis in the synovial membrane of patients with PsA who responded to this therapy. METHODS: The study group comprised 9 patients with PsA who were selected for the presence of active polyarthritis (including knee synovitis) despite methotrexate therapy. Clinical and biologic evaluations were performed at each visit. Arthroscopy and synovial biopsies were performed at week 0, before infliximab therapy was initiated, and at week 8, after administration of 3 intravenous infusions of infliximab (5 mg/kg). We used immunohistochemistry to identify changes in infiltrating cells and in the angiogenesis modulators alphavbeta3 integrin, vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang-2), flt-1 (VEGF receptor 1 [VEGFR-1]), kinase insert domain receptor [KDR]/flk-1 (VEGFR-2), and stromal cell-derived factor 1 (SDF-1). Neovascularization was assessed by automated histomorphometry of CD31+ vessels and by measuring alphavbeta3 expression. RESULTS: Rapid and significant clinical and biological improvement were observed after treatment in all patients. In the synovium, infliximab therapy induced a significant reduction in macrophages, the CD31+ vascular area, alphavbeta3+ neovessels/Ulex europaeus agglutinin+ vessels, VEGF and its receptor KDR/flk-1 (VEGFR-2), and SDF-1+ vessels. Expression of flt-1 (VEGFR-1), and SDF-1 in lining cells showed a nonsignificant reduction, whereas expression of Ang-2 increased. In 3 patients, reverse transcription-polymerase chain reaction confirmed the changes in some of these markers at the messenger RNA level. CONCLUSION: These results show consistent changes in several factors involved in angiogenesis regulation, in parallel with the clinical response to infliximab in patients with PsA. The pattern of reduced VEGF with increased Ang-2 suggests vascular regression as a potential mechanism underlying the antiangiogenic effect of infliximab.