Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.

In reviewing the clinical safety data of dasatinib in its current use as a Src inhibitor in a wide variety of solid malignancies, dasatinib appears to be safe and is a promising agent for the treatment of metastatic solid tumors refractory to standard therapies.

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5091 Background: Castleman's disease (CD), or angiofollicular lymph node hyperplasia, is a rare lymphoproliferative disorder that creates both diagnostic and therapeutic challenges. Three distinct histological variants including hyaline-vascular, plasmacytic and mixed were described. Clinically, patients can manifest with unicentric (UCD) or multicentric (MCD) Castleman's disease (Keller et al. Cancer 1972). Methods: Patients with a histologic diagnosis of CD from January 1999 to December 2009 at Moffitt Cancer Center and Tampa General Hospital were identified and their charts were reviewed. Relevant clinical, pathologic, laboratory data and treatment variables were recorded. Results: This case series consists of 20 consecutive patients including 11 unicentric cases and 9 multicentric cases. Median follow-up was 43 months. Unicentric CD (UCD): In the UCD group, 8/11 patients presented with mass and/or related compressive symptoms. The remaining 3 patients were asymptomatic. Only 2 patients had plasma cell (PC) histology, while the rest had hyaline vascular (HV) type. 2 patients had clonal B or plasma cell populations identified in the involved tissue. 4 (36%) patients had hypergammaglobulinemia. 9 (82%) patients received local therapy (surgery and/or radiation therapy) only. 4 patients achieved complete remission (CR) while 5 patients had recurrence after initial resection. Monoclonal antibodies including rituximab and CNTO 328, an anti-interleukin (IL)-6 monoclonal antibody were tested in 2 patients without response. Multicentric CD (MCD): In the MCD group, 67% patients had comorbidities including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), Hepatitis C, acquired immunodeficiency syndrome (AIDS), and myelodysplastic syndromes (MDS). 4 patients had PC type and 5 had HV type. The majority of the patients (7/9) presented with constitutional symptoms, or hepatosplenomegaly or effusion/edema. Prognostic markers for plasma cell dyscrasia including beta-2 microglobulin, gammaglobulin or monoclonal protein were abnormal in 6 patients. Inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) or IL-6 were elevated in 3 patients. Local therapy as the main treatment modality resulted in CR in 2 patients. The 3rd patient achieved CR after autologous stem cell transplant (SCT). 2 patients died of the disease after 10 months and 56 months respectively. 3 patients were alive with disease and mild to moderate symptoms at the end of follow-up (36-44 months). All 4 patients that received high dose steroids had improvement of symptoms. 2 patients were treated with CNTO 328. One patient didn't tolerate secondary to infusional reaction while the other one had partial response (PR) and significant symptom improvement. Chlorambucil, melphalan and prednisone were used in one case following local therapy, leading to sustained CR. 2 patients were treated with high dose melphalan followed by autologous SCT. In the patient with POEMS, a CR was achieved while the patient with primary CD only had transient response. Rituximab was used alone or in combination with lenalidomide in 2 patients. The responses were either stable disease or short-lived PRs. Conclusion: We report here one of the largest recent retrospective cohort of patients with CD. The UCD is occasionally associated with hypergammaglobulinemia, monoclonal gammopathy (MGUS) and clonal plasma cells, mimicking clinical manifestation of plasma cell dyscrasias or lymphoplasmacytic lymphoma. Surgical resection is the primary curative treatment used for localized disease, although recurrences do frequently occur. Radiation therapy can be successfully used in patients with multiple relapses or in patients who are not surgical candidates. Systemic therapy has been attempted without much benefit. MCD is often associated with plasma cell dyscrasias and viral infections. Local therapy can be successfully used in selected cases. However, a majority (7) of cases with MCD will require systemic therapy including steroids or chemotherapy. Recently, anti–IL 6 monoclonal antibodies demonstrated efficacy in patients with MCD in phase I clinical study suggesting a role of IL-6 in pathophysiology of this disease. Disclosures: Off Label Use: There's no standard of care or FDA-approved drug for the treatment of Castleman's disease. All the agents discussed in this study including chlorambucil, melphalan, Rituximab, lenalidomide, CNTO 328(Siltuximab), bortezomib are considered off-label drug use.