Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer.

There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here the anti-tumor effect of the angio-inhibitory pigment epithelium-derived factor (PEDF) in the metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy in combination with low-dose chemotherapy. Androgen-sensitive LNCaP and CRPC PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that PEDF limited the proliferation of all prostatic cell lines tested; an effect attributed to interleukin 8 (IL8)-CXCR1/IL8RA inhibition. PEDF also reduced the number and size of 3D tumor spheroids in vitro, but only induced cell differentiation in CRPC spheroids. Similarly, PEDF inhibited the migration of CRPC cells suggesting both anti-proliferative and anti-migratory functions. In vivo, PEDF decreased by 85% and 65% the growth of subcutaneous (s.c.) PC3 and CL1 tumors, respectively. In the CL1 orthotopic model, tumor intake with lethal metastases was found in all animals; nevertheless, PEDF prolonged the median survival of tumor-bearing mice (95% confidence interval: 53 ± 0.001 to 57 ± 1 days). Accordingly, PEDF delayed the emergence of skeletal-related event in intra-tibial xenografts. Next, we evaluated low-dose docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10-20 mg/kg) on established s.c. PC3 tumors that conditionally express PEDF anti-tumoral epitope/NT3. Although NT3-DTX-5 mg/kg combination was inefficient, NT3-DTX-1 mg/kg and -0.5 mg/kg inhibited by 95% and 87.8%, respectively, tumor growth compared with control and induced tumor stasis. Both NT3-CTX combinations were advantageous. Inversely, PEDF-DTX-5 mg/kg and PEDF-CTX-10 mg/kg delayed the most CL1 tumor growth (15, 11 and 5 days for PEDF-DTX-5 mg/kg, PEDF-CTX-10 mg/kg and single treatments, respectively) with elevated apoptosis and serum thrombospondin-1 as possible mechanism and marker, respectively. As well, both PEDF-CTX-10 mg/kg and PEDF-DTX-5 mg/kg prolonged significantly the survival of tumor-bearing mice compared with single treatments. Metastases were reduced in PEDF-DTX-5 mg/kg compared with other treatments, suggesting that PEDF-DTX delayed metastases formation. Our results advocate that PEDF/low-dose chemotherapy may represent a new therapeutic alternative for CRPC.

The BioMotionBot: a robotic device for applications in human motor learning and rehabilitation.

Robotic manipulanda are an established tool for the investigation of human motor control and learning. Potentially, robotic manipulanda could also be valuable in the investigation of skill learning in more natural movement tasks. Most current designs have been developed for studying dynamic learning and rehabilitation and are restricted to 2D space. However, natural upper limb movements take place in 3D space, sometimes with high underlying forces. In this paper, we introduce a robotic device, the BioMotionBot, that can be used in established applications of dynamic learning and rehabilitation but also enables the investigation of skill learning in more natural 3D movement tasks with large dynamic perturbations. The design of the BioMotionBot is based on a mechanism with hybrid serial and parallel kinematics. We first describe the BioMotionBot's mechanical design, the electronic components, the software structure and the control system. To investigate the performance of the BioMotionBot, its stiffness, endpoint mass, endpoint viscosity, haptic resolution, force depth and impedance ratio are evaluated. Additionally, we develop a detailed multi-body simulation model to validate aspects of the structure and behavior of the BioMotionBot. Finally, we present experimental data from a dynamic learning task in 2D and test a 3D scenario with virtual walls. Our results demonstrate that the BioMotionBot can be used for research in human motor learning and rehabilitation and also has potential for the investigation of skill learning in more natural 3D movement tasks.

Extraluminal colonic carcinoma invading into kidney: a case report and review of the literature.

Renal metastasis from primary colon cancer is very rare, comprising less than 3% of secondary renal neoplasms. There are just 11 cases reported in the medical literature of colonic adenocarcinoma metastatic to the kidney. Of these cases, none occurred via direct invasion. We report a unique case of a 51-year-old female with extraluminal colonic adenocarcinoma which directly invaded into the kidney. Additionally, we investigate the causal relationship between the site of invasion and a previous stab injury by reviewing the role of the peritoneum and Gerota's fascia in preventing the spread of metastatic cancer into the perirenal space. Due to the rarity of this event, we present this case including a review of the existing literature relative to the diagnosis and treatment.

TFE3 Translocation-Associated Renal Cell Carcinoma Presenting as Avascular Necrosis of the Femur in a 19-Year-Old Patient: Case Report and Review of the Literature.

In the United States, renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of all neoplasms arising from the kidney. According to the National Cancer Institute, 58 240 new cases and 13 040 deaths from renal cancer will occur in 2010. RCC usually occurs in older adults between the ages of 50 and 70 and is rare in young adults and children. We describe a case of a TFE3 translocation-associated RCC in a 19-year-old patient presenting as avascular necrosis of the femur. Due to the rarity of this malignancy, we present this case including a review of the existing literature relative to diagnosis and treatment.

Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature.

PURPOSE: Castration-refractory prostate cancer remains a therapeutic challenge even after introduction of docetaxel as first-line treatment. Castration-refractory prostate cancer cannot be cured by any available therapeutic option, and chemotherapy still needs to be considered palliative. The survival benefit is modest, and treating physicians are searching for alternative treatment options. Despite new drugs currently under investigation, some conventional and well known chemotherapeutic drugs are experiencing a renaissance. The development of anti-angiogenic approaches in cancer treatment has led to the development of metronomic dosing of conventional chemotherapeutic drugs including cyclophosphamide. The intention of this review is to evaluate the efficacy and toxicity of oral/metronomic cyclophosphamide in the treatment of patients with castration-refractory prostate cancer. MATERIALS AND METHODS: A comprehensive literature search was performed in different databases using various key words. Relevant articles and references between 1962 and 2010 were reviewed and analyzed for data regarding the association between oral cyclophosphamide treatment and prostate cancer. RESULTS: Oral cyclophosphamide is active in the treatment for castration-refractory prostate cancer even in patients treated with previous chemotherapy including docetaxel. It yields symptomatic and objective remissions. The side effects are usually grade 1-2 and easy to manage. Grade three to four side effects are less common. CONCLUSIONS: Oral cyclophosphamide treatment for patients with castration-refractory prostate cancer deserves more attention and validation, and warrants further testing of various treatment combinations. Given the fact that castration-refractory prostate cancer includes an extremely heterogeneous group of patients with variability of tumor growth rates, the combination of cyclophosphamide with other active agents such as angiogenesis inhibitors and immunomodulatory compounds need to be explored.

[Self-inflicted penile strangulation]. / Die Strangulationsverletzung des Penis.

INTRODUCTION: Constricting devices or misappropriated means are either used to increase sexual performance or for autoerotic actions. They can lead to edema, maceration, to local infections up to Fournier gangrene or penile necrosis with or without involvement of the urethra. Injuries by these means are often challenging for the treating urologist. CASE REPORT: A 22-year-old patient presented to the urological emergency clinic with strong penile pain and voiding difficulties. Within the scope of the clinical investigation a foreign body (frying pan handle) was found around the penis. The penis appeared to be edematous, and necrosis of the distal superficial penis segments was noted. Under local anesthesia the frying pan handle, after procurement of suitable instruments, was removed. Subsequently, a suprapubic catheter was inserted and a broad antibiotic therapy was initiated. An antiseptic local therapy completed the primary treatment. Eight weeks after the event an orthograde urethrogram was performed. The urethra appeared to behave a normal caliber without evidence for strictures or other patho-morphological changes. The final examination showed a nearly completely epithelialized glans penis, with an approximately 1-cent piece small epithelial defect. CONCLUSIONS: Constricting devices for the penis are used to increase the sexual performance or with autoerotic intentions. Removal of the constricting devices can become impossible secondary to a hefty swelling of the penis. The treatment consists, primarily, of an immediate decompression of the strangulated penis to ensure a free blood flow and an uninhibited micturition. The removal of the various objects requires in part craft instruments. A supplementary therapy must be selected based on existing additional complications.

PSA surge/flare-up in patients with castration-refractory prostate cancer during the initial phase of chemotherapy.

BACKGROUND: Docetaxel-based chemotherapy has shown great promise for the treatment of CRPC and is considered the current standard of care. PSA is mainly used as marker to monitor the treatment response. Several articles were published reporting an initial PSA surge/flare-up after starting chemotherapy. The cause and the impact of this phenomenon are discussed controversially. The intention of this review is to define the significance of initial PSA surge/flare-up and to increase awareness to this phenomenon in the urological community. MATERIALS AND METHODS: A comprehensive literature search was performed in different data bases using various key words. Relevant articles and references between 1999 and 2009 were reviewed and analyzed for data on the association between chemotherapy and initial PSA surge/flare. RESULTS: The incidence of a PSA surge/flare-up ranges according to the reported studies between 7.6% and 13.6%. A PSA surge/flare-up was reported up to 404% from baseline PSA level followed by PSA response. The median duration of a PSA surge/flare-up is 2-3 weeks and can last up to 6-8 weeks. However, the occurrence of a PSA surge/flare-up did not impact outcome and survival negatively compared to patients with an immediate PSA response. CONCLUSIONS: A considerable portion of CRPC patients experience an initial PSA surge/flare-up under systemic chemotherapy. The definitions used for PSA surge/flare-up differ slightly in the literature. This issue needs to be solved since it might impact defining treatment response. As a PSA surge/flare-up did not impact outcome and survival negatively, chemotherapy should be continued according to the literature addressing specifically the phenomenon of a PSA surge/flare-up for a minimum of 8 weeks or 3 rounds of a 3-weekly cycle chemotherapy regimen before further decisions are made about efficacy. However, Scher et al. recommended a 12-week period drug exposure based on their results on PSA progression-free survival and overall survival. This dilemma needs to be addressed in further data analysis in order to establish a general rule regarding when to stop chemotherapy. Physicians should be aware of this effect to avoid inadequate early discontinuation of chemotherapy. The underlying mechanisms of a PSA surge/flare-up are still elusive and need further clarification.

Transitional cell carcinoma due to chronic UroLume stent irritation.

UroLume stents have been used for >15 years to improve the voiding dynamics in patients with benign prostatic hyperplasia and urethral stricture disease. Common complications include stent migration, stricture within the stent, and urothelial hyperplasia, any of which could require stent removal, which itself carries morbidity. We report a case of high-grade urothelial carcinoma associated with chronic UroLume application.

Characterization of PEDF: a multi-functional serpin family protein.

Pigment epithelium-derived factor (PEDF) is a 50 kDa secreted glycoprotein that belongs to the non-inhibitory serpin family group. PEDF has been described as a natural angiogenesis inhibitor with neurotrophic and immune-modulation properties; it balances angiogenesis in the eye and blocks tumor progression. The mechanisms underlying most of these events are not completely clear; however, it appears that PEDF acts via multiple high affinity ligands and cell receptors. In this review article, we will summarize the current knowledge on the biochemical properties of PEDF and its receptors, the multimodal activities of PEDF and finally address the therapeutic potential of PEDF in treating angiogenesis-, neurodegeneration- and inflammation-related diseases.

[Idiopathic retroperitoneal fibrosis (Ormond's disease)]. / Die idiopathische retroperitoneale Fibrose (Morbus Ormond).

INTRODUCTION: Idiopathic retroperitoneal fibrosis (RPF) represents a rare inflammatory disease, which leads to extensive fibrosis of the retroperitoneal space. In the course of the progressive fibrosis, fibrous tissue compresses the retroperitoneal structures with the development of consecutive ureteral obstruction. Because of the unknown aetiology, no consensus between conservative and surgical treatment exists. CASE REPORT: A 60-year-old patient was admitted to hospital with left-sided flank pain, hydronephrosis, and retroperitoneal tumour. A CT scan-guided biopsy revealed RPF. The hydronephrosis was treated by endoluminal urinary diversion. Under simultaneous administration of steroids, an almost complete regression of the RPF was noted. CONCLUSIONS: First goal in the treatment of RPF is urinary diversion to protect the renal function. A simultaneous therapy with steroids can cause a complete regression of the RPF. Surgical intervention is only recommended in refractory cases.

In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment.

Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR-DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.