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An evidence-based consensus meeting was held with urologists, a pharmacist and a cardiologist to perform a structured benefit-risk analysis of reclassifying tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor for treatment of erectile dysfunction (ED), to be available without prescription in Germany. As per the Brass process endorsed by regulatory authorities, an evidence-based Brass value tree was developed, which identified the incremental benefits and risks that should be considered above the safety and efficacy evidence required for prescription medicines. During the Group Delphi consensus meeting, the expert panel rated the likelihood and clinical impact of each benefit and risk on a scale of 0 (none) to 3 (high). Overall attribute scores were calculated from the product of the mean likelihood and mean clinical impact scores giving a possible score of 0–9. The overall benefit attribute scores ranged from 2.8 to 5.4. The overall risk attribute scores ranged from 0.2 to 2.2 though most were 1.0 or less (3 or more is generally considered to be of concern). On balance, the independent meeting scored the benefits of reclassification of tadalafil higher than the risks and considered the risk mitigation strategies of the packaging label and patient information leaflet (PIL) sufficient.

In experienced hands, laparoscopic pyeloplasty is an effective alternative treatment for symptomatic ureteropelvic junction obstruction (UPJO). Although laparoscopic surgery can clearly benefit patients, laparoscopic pyeloplasty using conventional instrumentation is complex. The purpose of this report is to evaluate the feasibility of robot assisted laparoscopic surgery. Eleven pyeloplasties for UPJO were performed via a laparoscopic transperitoneal approach exclusively with the da Vinci Surgical System. The mean procedure time was 197 min (range 110-310 min). All operations were completed laparoscopically with no intraoperative complications and negligible blood loss. All patients recovered rapidly after surgery with excellent functional results at the 1 year follow-up. Our initial experience suggests that robot assisted Anderson-Hynes pyeloplasty is a safe and effective alternative to conventional laparoscopic surgery. In our opinion, robot assisted surgery will allow urologists to perform complex procedures with greater precision, confidence, and better results, as well as enable them to adapt the whole spectrum of laparoscopic procedures to their field.

Purpose Maspin belongs to the serpin family and has been shown to suppress tumor growth and metastasis in several tumor types. The role of maspin in bladder carcinoma has not been fully elucidated, and the object of this study was to investigate whether maspin contributes to bladder tumor adhesion to vascular endothelial cells (HUVEC). Methods Expression of maspin-coding mRNA was evaluated in a panel of bladder carcinoma cell lines. Maspin distribution in maspin mRNA high versus maspin mRNA low cells was further analyzed by flow cytometry and confocal microscopy. Adhesion to HUVEC was measured in a coculture model and correlated with the surface-bound maspin. Results Maspin high (RT-4, RT-112) cell lines strongly attached to HUVEC, whereas maspin low (UMUC-3, MGH-U1) cell lines poorly adhered to HUVEC. Distinct cytoplasmic maspin accumulation and moderate surface-bound maspin was found in RT-4 cells. Blocking maspin surface receptors prevented tumor cell attachment to HUVEC, indicating that surface-bound maspin is responsible for triggering cell adhesion. PMA-triggered elevation of surface-bound maspin was accompanied by an enhanced adhesion capacity of RT-4 cells, compared to controls. Finally, exposing the bladder carcinoma cells to the differentiation-inducing agent valproic acid led to a surface-bound (but not cytoplasmic) maspin decrease, paralleled by a significant reduction in tumor cell binding to HUVEC. Conclusion Surface-bound maspin directly controls bladder carcinoma cell adhesion to the vascular wall. Blocking this process may prevent transendothelial migration and tumor cell dissemination. Therefore, therapeutic down-regulation of surface-bound maspin might become an option to prevent tumor spread into distant organs.

Angiogenesis, the induction of vessel growth is involved in numerous physiological and pathological processes. While the anti-tumor effect of angiogenesis inhibitors has been extensively investigated in malignant tumors, there is very little information on the effect of angiogenesis inhibitors on inflammation induced angiogenesis. In this report, we utilized a murine model of acute chemically induced cystitis to investigate the ability of three different angiogenesis inhibitors, angiostatin, endostatin and TNP-470, to inhibit the angiogenesis stimulated by this injury. We demonstrate herein, that prophylactic application of the angiogenesis inhibitors led to a significant reduction of each of the inflammatory parameters that were measured. We conclude that anti-angiogenic therapy with angiostatin, endostatin and TNP-470 inhibits inflammation associated angiogenesis induced in this model. We also propose that anti-angiogenic agents may serve as a valuable addition to a standard cyclophosphamid chemotherapy regimen to help reduce the chemotherapy-related side effects while potentially adding an anti-tumor effect.

The potential role of angiogenesis stimulators in the pathogenesis of different tumor entities has been confirmed in several studies. We measured the serum levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in 51 patients with testicular germ cell tumors and in 39 healthy volunteers. Serum concentrations of bFGF, VEGF and PDGF-AB were determined by enzyme-linked immunosorbent assay. The median serum bFGF level for tumor patients was 3.46 pg/ml (range 0-61.6) compared to 0.7 pg/ml (0-11) in the control group (P<0.01). In patients with metastatic disease, the median serum bFGF level was 10.3 pg/ml (0-61.6) in contrast to 2.8 pg/ml (0-50) in patients with localized disease (P<0.01). The median serum VEGF and PDGF levels were 270 pg/ml (0-1,903) and 37,837 pg/ml (9,075-108,800), respectively, for tumor patients and 200 pg/ml (44-585) and 23,000 pg/ml (4,250-70,650) in the control group ( P<0.05). Our data suggest that angiogenesis, as reflected by serum concentrations of bFGF, VEGF and PDGF, plays a functional role in the growth and progression of testicular germ cell tumors.

Invasive cell carcinoma of the bladder often develops after complete transurethral excision of superficial transitional cell carcinoma. It has been postulated that primary tumors release angiogenesis-blocking proteins which suppress distant metastases. We have identified an endogenous protein which might be responsible for tumor dormancy. A transitional cell carcinoma cell line was developed (UMUC-3i) which inhibits the growth of a tumor implant at a distant site in SCID mice. Conditioned media of UMUC-3i cultured cells was first pooled and then fractioned, and the capacity of individual components to block endothelial cell growth was tested. The protein fraction responsible for blocking endothelial cell growth was identified by N-terminal amino acid sequencing as well as by mass-spectrometry. The effects of the purified protein in preventing endothelial cell proliferation and tube formation in an in vitro angiogenesis assay was investigated. The plasma protein beta(2)-glycoprotein-I (beta(2)gpI) was isolated and identified from conditioned medium of UMUC-3i cultured cells. Based on the in vitro angiogenesis assay, beta(2)gpI strongly inhibited endothelial cell growth and tube formation, whereby the inhibitory activity corresponded to the clipped version of beta(2)gpI (cbeta(2)gpI). Clipping was induced by adding plasmin at a molar ratio 1:15 (plasmin:substrate). Further analysis indicated that cbeta(2)gpI effects were mediated by annexin II surface receptors expressed on endothelial cells. cbeta2gpI may be involved in blocking angiogenic processes and bladder cancer progression. In this case, cbeta2gpI may be a promising tool in bladder cancer therapy.

Angiogenesis is essential for tumor growth and progression and is mediated by possitive and negative regulators of vessel growth. Since angiogenic mediators found in patient serum have been postulated to reflect the angiogenic potential of a malignant tumor, we investigated the angiogenic activity in the serum of patients with transitional cell carcinoma (TCC). The data were correlated to tumor characteristics and the clinical course of the patients. Eightyone patients with transitional cell carcinoma and 53 control persons were included in the study. Preoperative serum samples were collected and both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were quantified by ELISA. Additionally, the serum evoked proliferative activity on human umbilical vein endothelial cells (HUVEC) was evaluated. Data were compared to the clinical course of the patients. Serum of tumor patients significantly enhanced the proliferative capacity of HUVEC, compared to cells grown in standard culture medium (p = 0.0032), but not when compared to serum from control persons. Serum from patients with superficial TCC and well differentiated tumors induced a significantly higher angiogenic response (ANGhi) than serum from patients with poorly differentiated and invasive carcinomas (ANG10; p=0.037). VEGF level of ANGhi serum was 384.22 ± 247.76 pg/ml (n=37) which significantly differed from mean VEGF level detected in ANG10 serum (247.72 ± 211.93 pg/ml, n=42; p=0.019). Similarly, mean bFGF levels were 9.58 ± 5.91 pg/ml in ANGhi serum versus 5.74 + 3.52 pg/ml) in ANG10 serum (p=0.0043). A negative correlation was established between VEGF/bFGF serum concentration and patient prognosis. The experiments demonstrate a positive correlation between VEGF and bFGF serum level and endothelial proliferation in vitro. The inverse relationship between angiogenic activity and tumor stage might disclose information about angiogenesis and tumor progression in TCC.

Invasive cell carcinoma of the bladder often develops after complete transurethral excision of superficial transitional cell carcinoma. It has been postulated that primary tumors release angiogenesis-blocking proteins which suppress distant metastases. We have identified an endogenous protein which might be responsible for tumor dormancy. A transitional cell carcinoma cell line was developed (UMUC-3i) which inhibits the growth of a tumor implant at a distant site in SCID mice. Conditioned media of UMUC-3i cultured cells was first pooled and then fractioned, and the capacity of individual components to block endothelial cell growth was tested. The protein fraction responsible for blocking endothelial cell growth was identified by N-terminal amino acid sequencing as well as by mass-spectrometry. The effects of the purified protein in preventing endothelial cell proliferation and tube formation in an in vitro angiogenesis assay was investigated. The plasma protein beta(2)-glycoprotein-I (beta(2)gpI) was isolated and identified from conditioned medium of UMUC-3i cultured cells. Based on the in vitro angiogenesis assay, beta(2)gpI strongly inhibited endothelial cell growth and tube formation, whereby the inhibitory activity corresponded to the clipped version of beta(2)gpI (cbeta(2)gpI). Clipping was induced by adding plasmin at a molar ratio 1:15 (plasmin:substrate). Further analysis indicated that cbeta(2)gpI effects were mediated by annexin II surface receptors expressed on endothelial cells. cbeta2gpI may be involved in blocking angiogenic processes and bladder cancer progression. In this case, cbeta2gpI may be a promising tool in bladder cancer therapy.