Effectiveness of Carboplatin and Paclitaxel as First- and Second-Line Treatment in 61 Patients with Metastatic Melanoma

BACKGROUND: Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination. METHODS: Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP) at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria. RESULTS: 61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c) received CP as first-line treatment, 41 patients (90.2% M1c) had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD) (49 weeks) compared to patients with progressive disease (18 weeks). CONCLUSIONS: Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses.

Treatment options for pancreatic cancer are limited and often ineffective. Immunotherapeutic approaches are one possible option that needs to be evaluated in appropriate animal models. The aim of the present study was to analyze tumor-specific immune responses in a mouse model of pancreatic cancer, which mimics the human disease closely. C57BL/6 EL-TGF-alpha x Trp53-/- mice, which develop spontaneous ductal pancreatic carcinoma, were generated. EL-TGF-alpha x Trp53-/- mice developed spontaneous pancreatic tumors with pathomorphologic features close to the human disease. Tumor-specific CD8+ T-cell responses and IgG responses were analyzed in EL-TGF-alpha x Trp53-/- mice during tumor development and compared with mice with s.c. growing pancreatic tumors. In contrast to spontaneous pancreatic tumors, cell lines generated from these tumors were rejected after s.c. injection into wild-type mice but not in nude or RAG knockout mice. Direct comparison of spontaneous and s.c. injected tumors revealed an impaired infiltration of CD8+ T cells in spontaneous pancreatic tumors, which was also evident after adoptive transfer of tumor-specific T cells. Intratumoral cytokine secretion of tumor necrosis factor-alpha, IFN-gamma, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells. Our data provide clear evidence for tumor-specific immune responses in a genetic mouse model for pancreatic carcinoma. Comparative analysis of s.c. injected tumors and spontaneous tumors showed significant differences in tumor-specific immune responses, which will help in improving current immune-based cancer therapies against adenocarcinoma of the pancreas

The F-actin modulator SWAP-70 controls podosome patterning in osteoclasts

Osteoclasts are bone resorbing cells acting as key mediators of bone disorders. Upon adhesion to bone, osteoclasts polarize and reorganize their cytoskeleton to generate a ring-like F-actin-rich structure, the sealing zone, wherein the osteoclast's resorptive organelle, the ruffled border, is formed. The dynamic self-organization of actin-rich adhesive structures, the podosomes, from clusters to belts is crucial for osteoclast-mediated bone degradation. Mice lacking the protein SWAP-70 display an osteopetrotic phenotype due to defective bone resorption caused by impaired actin ring formation in Swap-70−/− osteoclasts. To further elucidate the mechanisms underlying this defect, we investigated the specific function of SWAP-70 in the organization and dynamics of podosomes. These detailed studies show that the transition from podosome clusters to rings is impaired in Swap-70−/− osteoclasts. Live cell imaging of dynamic F-actin turnover and SWAP-70 localization during podosome patterning indicate that SWAP-70 is dispensable for cluster formation but plays a key role in F-actin ring generation. Our data provide insights in the role of SWAP-70's F-actin binding domain and pleckstrin homology (PH) domain in the proper localization of SWAP-70 and formation of a peripheral podosome belt, respectively. Ex vivo bone analyses revealed that SWAP-70-deficient osteoclasts exhibit defective ruffled border formation and V-ATPase expression. Our findings suggest an important role of membrane binding of SWAP-70 for the regulation of actin dynamics, which is essential for podosome patterning, and thus for the resorptive activity of osteoclasts