[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.

[V.A.C. (Vacuum Assisted Closure) therapy as a treatment option in complications following lymphadenectomy in patients with penile cancer]. / Die V.A.C. (Vacuum Assisted Closure) Therapie als Behandlungsalternative bei Komplikationen nach Durchführung einer Lymphadenektomie bei fortgeschrittenen Peniskarzinomen.

INTRODUCTION: Penile cancer is a rare tumor entity. Primary therapy consists of tumor excision (laser therapy, circumcision, partial or complete penectomy). Therapy of advanced or metastasized penile cancer is still challenging due to high morbidity with postoperative lymph edema, fistula, wound infection and resulting secondary wound healing. METHODS: In this series we retrospectively investigated clinical and diagnostic data from 28 patients (1995-2005) with penile cancer regarding their follow-up, especially in respect to morbidity after lymphadenectomy and the resulting therapy. We evaluated the efficacy of V.A.C. therapy as an alternative in this setting regarding costs and duration of hospital stay. RESULTS: 11/28 pats. underwent lymphadenectomy (LA) because of tumor stage or suspicious lymph node status. Eight of those pats. developed complications, as there were: lymph edema, and/or secondary wound healing with fistula. 4/8 pats. were treated with V.A.C. therapy. In this group a significant advantage regarding cost and time of hospitalization was observed. DISCUSSION: Despite higher primary introduction costs an early V.A.C. therapy in patients with secondary wound healing and lymph obstruction is advisable and resulted in a shortened hospitalization and reduced overall costs per patient.

[Ambulatory vasectomy. Risks and complications]. / Die ambulante Vasektomie. Risiken und Komplikationen.

Vasectomy is the simplest and most effective method of permanent sterilization in men. In most cases, the surgical technique includes conventional vasoresection with incision of the scrotal skin or no-scalpel vasectomy as a minimally invasive method. The most important complications following surgery are haemorrhage and haematoma (1.2%), infection (3.5%), epididymitis/epididymo-orchitis (2.1%), sperm granuloma (2-70%), and chronic pain (3-8%). No long-term negative organic effects have been proven in clinical studies. The surgeon's experience and the technique applied are essential for the postoperative course, whereas performing vasectomy either on an in-patient or out-patient basis does not seem to have an influence. To evaluate the success of the vasectomy, follow-up spermiograms are obligatory. If immotile spermatozoa are present further follow-ups are necessary. Vasectomy needs to be reperformed if motile spermatozoa are detected. The chance of an unsuccessful vasectomy is below 1%. Unprotected intercourse must not be performed before two consecutive spermiograms show azoospermia.

Thrombospondin-1, vascular endothelial growth factor and fibroblast growth factor-2 are key functional regulators of angiogenesis in the prostate.

BACKGROUND: Prostate cells secrete many molecules capable of regulating angiogenesis; however, which of these actually function as essential regulators of neovascularization is not yet clear. METHODS: Functional angiogenic mediators secreted by normal and diseased prostate cells were identified using an in vitro angiogenesis assay. These factors were quantified by immunoblot or ELISA and localized in tissue by immunohistochemistry. RESULTS: Normal prostate epithelial cell secretions were anti-angiogenic due to inhibitory thrombospondin-1 (TSP-1) whereas this inhibitor was decreased in the pro-angiogenic secretions derived from benign prostatic hyperplasia (BPH) and cancer cells. This pro-angiogenic activity depended primarily on fibroblast growth factor-2 (FGF-2) and/or vascular endothelial growth factor (VEGF) whose secretion was increased. Immunolocalization studies confirmed that the changes detected in vitro also occurred in vivo. CONCLUSIONS: During disease progression in the prostate, production of TSP-1, the major inhibitor, is down-regulated while that of stimulatory FGF-2 and/or VEGF rise, leading to the induction of the new vessels necessary to support tumor growth.

c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1.

Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis that acts directly on endothelial cells via the CD36 surface receptor molecule to halt their migration, proliferation, and morphogenesis in vitro and to block neovascularization in vivo. Here we show that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK). Rather, TSP-1 induced a rapid and transient activation of c-Jun N-terminal kinases (JNK). JNK activation by TSP-1 required engagement of CD36, as it was blocked by antagonistic CD36 antibodies and stimulated by short anti-angiogenic peptides derived from TSP-1 that act exclusively via CD36. TSP-1 inhibition of corneal neovascularization induced by bFGF was severely impaired in mice null for JNK-1, pointing to a critical role for this stress-activated kinase in the inhibition of neovascularization by TSP-1.

In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects.

Thrombospondin 1 (TSP1) is a multifunctional protein able to activate TGFbeta and to inhibit angiogenesis in vivo. Although usually thought of as an inhibitor of tumor growth, TSP1 may sometimes be present at high levels during tumor progression, suggesting that tumors can eventually overcome their anti-tumor effects. Using a tet-repressible expression system, we demonstrate that murine TSP1 delayed the onset of tumor growth when produced in the tumor bed by rat fibrosarcoma tumor cells or by stromal fibroblasts coinjected with unmodified C6 glioma tumor cells. Yet upon prolonged exposure to TSP1, tumors came to grow at the same rate in the presence as in the absence of TSP1 and transplantation experiments showed that they had become insensitive to inhibition by TSP1 in both syngeneic and immune compromised hosts. Tumor resistance to TSP1 developed as a result of the in vivo outgrowth of pre-existing tumor cell variants that (1) secreted increased amounts of angiogenic factors that counterbalanced the inhibitory effect of TSP1 on neovascularization and (2) grew more efficiently in the presence of TSP1-activated TGFbeta. These results indicate that prolonged and continuous local delivery of a single multifunctional angiogenesis inhibitor like TSP1 to fast-growing tumors can lead to tumor resistance in vivo by fostering the outgrowth of subpopulations that are a by-product of the genetic instability of the tumor cells themselves.

The role of hypoxia and p53 in the regulation of angiogenesis in bladder cancer.

PURPOSE: Our previous studies defined thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF) as the primary mediators of angiogenesis in the bladder and the loss of inhibitory TSP-1 as a key event in the transition to an angiogenic phenotype during bladder cancer development. We evaluated the role of p53, which is commonly inactivated in bladder cancer, and hypoxia in the regulation of angiogenesis in the bladder. MATERIALS AND METHODS: The p53 status was modulated in normal urothelial and bladder cancer cells, and conditioned media was collected under normal oxygen or hypoxic (0.5% O2) conditions. Angiogenic activity was evaluated with the endothelial cell migration assay, and the levels of secreted TSP-1 and VEGF were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. RESULTS: Retroviral mediated expression of the E6 oncoprotein reduced wild-type p53 levels in normal urothelial cells by greater than 90% but did not significantly alter TSP-1 or VEGF levels, while total inductive and inhibitory activities remained unchanged. Adenoviral mediated expression of wild-type p53 was confirmed in 4 bladder cancer cell lines by Western blot analysis for p53 and its downstream effector protein p21 (2.5 to 5.0-fold increase). TSP-1 levels remained unchanged but the levels of secreted VEGF in the high grade UMUC-3 and 253J cell lines were significantly decreased 5 to 50-fold and a corresponding decrease in net angiogenic activity was observed. However, (increased expression) of p53 had no effect on the angiogenic activity of the low grade RT4 or high grade HT1376 bladder cancer cells. Hypoxia converted normal urothelial cell derived conditioned media from anti-angiogenic to angiogenic and increased the angiogenic activity of bladder cancer cell derived conditioned media. This change was due to 2.5 to 6-fold hypoxic up-regulation of VEGF because the expression of inhibitory TSP-1 was not significantly altered. CONCLUSIONS: Our results suggest that p53 does not regulate angiogenesis in the bladder in the setting of an otherwise normal genome and gene therapy with wild-type p53, which is currently being studied for this cancer, may have only limited effects on angiogenesis. In contrast, hypoxia regulates angiogenesis in this system, primarily through its effects on VEGF.

Antiangiogenic approaches to renal cell carcinoma : assays for inhibitors and clinical trials.

Angiogenesis-the formation of new blood vessels from preexisting ones-is a complex process regulated by a number of soluble factors as well as important interactions between endothelial cells, extracellular matrix components, and adjacent cells (1-5). Activation of the endothelial cell, which occurs when the balance between proangiogenic and antiangiogenic signals within a given microenvironment tilts in a positive direction, leads initially to increased expression of proteases, allowing the endothelial cell to mobilize itself and release inducers sequestered within the matrix (1,6,7). This is followed by endothelial-cell proliferation and migration and culminates in reorganization of the endothelial cell plexus to form tubules and eventually capillary structures that can conduct blood. Most proangiogenic factors-such as VEGF and basic fibroblast growth factor (bFGF)-are peptide growth factors that bind to transmembrane-receptor tyrosine kinases on the surface of the endothelial cell, initiating intracellular transduction pathways resulting in cellular activation (8,9). Other important angiogenic factors-the angiopoietins-further modulate this process by stabilizing or destabilizing interactions between small blood vessels and adjacent pericytes (10 ). Expression of angiopoietin 2 results in dissociation of pericytes, which can lead to endothelial-cell activation or vascular regression, depending on whether angioinductive or angioinhibitory signals predominate (10,11). In contrast, angiopoietin 1 stabilizes interactions with pericytes and promotes vascular quiescence (10,12).

[Acute upper gastrointestinal hemorrhage as a complication of hepatic artery port catheter]. / Akute obere gastrointestinale Blutung als Komplikation eines Arteria-hepatica-Portkatheters.

We report a case of a 56-year-old patient with an acute upper gastrointestinal bleeding following penetration of an aneurysm of the gastroduodenal artery in the duodenal bulb. The patient received an i.a. portsystem five month before the reported acute gastrointestinal bleeding. The portsystem was implanted for treatment of multiple liver metastases of an neuroendocrine tumor. This life-threatening situation could not controlled endoscopically. Also an embolisation was impossible so we carried out a laparotomy with ligation of the proper hepatic artery. The postoperative course was uneventful. Due to her tumor disease the patient died 13 month after surgery.

Hepatic artery aneurysm associated with upper gastrointestinal bleeding after intrahepatic artery chemotherapy.

We present the course of illness of a 56 year-old patient with acute gastrointestinal bleeding after penetration of an aneurysm of the hepatic artery in the duodenal bulb. A diffuse intrahepatic metastasis of a carcinoid was treated with a loco-regional intraarterial chemotherapy via a catheter system implanted in the gastroduodenal artery. Five months after the catheter implantation melena occurred. The gastrointestinal arterial bleeding from the penetrating aneurysm presented a life-threatening situation. This cause of bleeding could not be brought under control endoscopically. Immediate surgical management became necessary.

Results of immunochemotherapy with interleukin-2, interferon-alpha2 and 5-fluorouracil in the treatment of metastatic renal cell cancer.

OBJECTIVE: In patients with advanced metastatic renal cell carcinoma (RCC) seen at a single institution, the toxicity and long-term clinical effects of a combination therapy with recombinant interleukin-2 (rIL-2), recombinant interferon-alpha2 (rIFN-alpha2) and 5-fluorouracil (5-FU) were evaluated. METHOD: From August 1992 through August 1997, 47 consecutive patients (38 men) with metastatic RCC were treated using rIL-2 and rIFN-alpha2 subcutaneously in combination with intravenous 5-FU. An average of 2. 4 cycles/patient (range 1-9) was administered. RESULTS: Toxicity grades II and III (World Health Organization) were observed in 24 and 17 patients, respectively. We achieved 9 major responses (7 complete responses (CR) and 2 partial responses (PR)) for an objective response rate of 19.1% (95% confidence interval 9.1-33.3%). A further 13 patients (27.7%) had a stabilization of disease. After a mean follow-up of 17.9 (2-53) months, 4 patients are alive with no evidence of disease. The 1- and 3-year survival probability was 70 and 37%, respectively. In an univariate analysis, two prognostic factors were correlated with disease outcome: Karnofsky performance index (p = 0.01) and the presence of bone metastases (p = 0.023). CONCLUSION: This triple-drug combination therapy was effective in the treatment of progressive RCC in almost every fifth patient.