A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX®) and interferon-alpha-2a in metastatic renal cell carcinoma patients.

PURPOSE: To evaluate the efficacy and safety of WX-G250, a chimeric monoclonal antibody that binds to carboxy anhydrase IX, combined with low-dose interferon-alpha (LD-IFNα) in patients with progressive metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Thirty-one patients, nephrectomized for the primary tumor, clear cell progressive mRCC, were enrolled to receive weekly infusions of WX-G250 (20 mg i.v.; week 2-12) combined with LD-IFNα (3 MIU s.c. 3 times/week; week 1-12). At week 16, patients were evaluated for response and stratified into two groups: (a) responders into the extended treatment group for an additional 6 weeks of treatment or (b) the progressive group with no further study treatment. RESULTS: Of the 31 treated patients, 26 were evaluable for response to treatment. Two patients showed partial remission and 14 patients had stable disease as assessed in week 16. One patient experienced partial remission resulting in a complete remission lasting at least 17 months. Nine patients had durable stable disease of 24 weeks or longer. Clinical benefit was obtained in 42% (11/26) patients. The median overall survival achieved was 30 months and the 2-year survival was 57%. Patients receiving extended treatment showed a significantly longer 2-year survival rate than discontinued patients (79 vs. 30%; P=0.0083). In general, treatment was well tolerated with little toxicity. CONCLUSION: Treatment with the antibody WX-G250 in combination with LD-IFNα is safe, well tolerated, led to clinically meaningful disease stabilization and demonstrated clinical benefit in this progressive mRCC patient population.

Targeted agents for the treatment of advanced renal cell carcinoma.

Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival--such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.

[Complete remission of pulmonary metastasis from renal cell carcinoma through inhalation therapy with Interleukin-2 after unsuccessful systemic immunochemotherapy]. / Komplette Remission beim pulmonal metastasierten Nierenzellkarzinom durch Inhalationstherapie mit Interleukin-2 nach erfolgloser systemischer Immunchemotherapie.

Therapy of metastasized renal cell carcinoma is based on systemic immunotherapeutic strategies, if surgical resection is not possible. The costs of inhalative Interleukin-2 therapy in case of pulmonary metastases as off-label-use are not accepted by compulsory health insurance yet.We report on a female patient with pulmonary metastasized renal cell carcinoma who had tumor progression after immunochemotherapy that followed complete response after inhalative therapy with Interleukin-2.

The German approach to emergency/disaster management.

Disaster control and disaster relief in Germany are public tasks. But the government has shifted the responsibility of the administration of these tasks to the 16 states, the so called "Lander", because the EFG is a federal republic. The same is valid for the civil defense and the civil protection in the case of military or international risks. The 16 states are also responsible for the legislation of rescue service, fire fighting service and disaster control (natural and technical disasters). Counties and district-free cities are responsible for the organisation of these services. The German system is based on the principle of subsidiary between official and private institutions. A lot of official and private relief organisations are responsible for the execution of disaster relief tasks. In Germany the following organisations exist: Official (GO): Technisches Hilfswerk (THW/Federal Technical Support Service), Feuerwehren (Fire Brigades/professionals and volunteers) Academie of Emergency Planning and Civil Defense Private (NGO): Arbeiter-Samariter-Bund Deutschland (ASB/Workers' Samaritan Association Germany), Deutsche Gesellschaft zur Rettung Schiffbruchiger (DGzRS, German Lifesaving Association), Deutsches Rotes Kreuz (DRK/German Red Cross), Johanniter-Unfall-Hilfe (JUH/St. John's Ambulance), Malteser Hilfsdienst (MEID/Maltese-Relief-Organisation). ASB, DRK, JUH and MHD are specialised in the field of rescue, medical and welfare services and medical disaster relief. 80% of the German rescue service and 95% of the German disaster medical relief are realised by these NGO's. NGO's and GO's employ more than 1.2 million volunteers and appr. 100,000 professionals. Rescue service is carried out by professionals, disaster relief by volunteers. The German constitution allows to call the federal army in case of disaster, to support the disaster relief organisations (for example: flood Oder River 1997, train-crash "ICE" 1998). In all counties and district free cities disaster control staffs are set up by the administration. During disaster relief operations a operational command is on site. Most of the counties and district free cities, medical executives, rescue staff executives along with fire executive officers are responsible for the medical rescue organisation. All emergency physicians and medical executives have attended special training or a 520 hours-training-course (Paramedics). All volunteers of the medical service in the disaster relief organisations are trained in separate special courses (90 hours). Over the last years, civil protection, disaster relief and rescue services in the FRG have been reorganised. In 1997, the civil protection was reformed by a new federal act. Disaster relief of the "Lander" is supported by Federal Government with about 9000 vehicles and a budget for training. Emergency physicians have to take part in a (80) eighty hours lasting course on emergency medicine from an interdisciplinary point of view; they are only allowed to do rescue missions after having proved basic experience in emergency medicine as well as having completed a (18) eighteen-months-postgraduate training period at least. Senior emergency physicians receive and additional (40) forty-hours-lasting theoretical and practical training-after three years practice in rescue services as a minimum. There are special training courses offered for Medical and Non-Medical Personal to cope with disaster situation by different institutions and organisations.

Two N-acetylgalactosaminyltransferase are involved in the biosynthesis of chondroitin sulfate.

Two N-acetylgalactosaminyltransferases, designated I and II, have been purified from the microsomal fraction of calf arterial tissue and separated on Bio-Gel A. N-Acetylgalactosaminyltransferase I was purified 450-fold. It requires Mn2+ for maximal activity and transfers N-acetylgalactosamine residues from UDP-[1-3H]GalNAc in beta-glycosidic configuration to the non-reducing terminus of the acceptor substrates GlcA(beta 1-3)Gal(beta 1-3)Gal, GlcA(beta 1-3)Gal(beta 1-4)Glc and GlcA(beta 1-3)Gal. Even-numbered chondroitin oligosaccharides serve as acceptors for N-acetylgalactosaminyltransferase II, which transfers N-acetylgalactosamine from UDP-[1-3H]GalNAc to the non-reducing glucuronic acid residues of oligosaccharide acceptor substrates. Maximum transfer rates were obtained with a decasaccharide derived from chondroitin. Longer or shorter-chain chondroitin oligosaccharides are less effective acceptor substrates. All reaction products formed by N-acetylgalactosaminyltransferases I and II are substrates of beta-N-acetylhexosaminidase, which splits off the transferred [1-3H]GalNAc completely. In the microsomal fraction N-acetylgalactosaminyltransferase II had a 300-fold higher specific activity than N-acetylgalactosaminyltransferase I. In contrast to enzyme I, enzyme II loses much of its activity during the purification procedure and undergoes rapid thermodenaturation. GlcA-Gal-Gal is a characteristic sequence of the carbohydrate-protein linkage region of proteochondrioitin sulfate. The acceptor capacity of this trisaccharide suggests that N-acetylgalactosaminyltransferase I is involved in the synthesis of the carbohydrate-protein linkage region. Since N-acetylgalactosaminyltransferase II is highly specific for chondroitin oligosaccharides, we conclude that it participates in chain elongation during chondroitin sulfate synthesis.