Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas.

PURPOSE: Plexiform neurofibromas (pNF) are pathognomonic nerve and soft tissue tumors of neurofibromatosis type I (NF1), which are highly resistant to conventional chemotherapy and associated with significant morbidity/mortality. Disruption of aberrant SCF/c-Kit signaling emanating from the pNF microenvironment induced the first ever objective therapeutic responses in a recent phase 2 trial. Sunitinib malate is a potent, highly selective RTK inhibitor with activity against c-Kit, PDGFR, and VEGFR, which have also been implicated in the pathogenesis of these lesions. Here, we evaluate the efficacy of sunitinib malate in a preclinical Krox20;Nf1(flox/-) pNF murine model. EXPERIMENTAL DESIGN: Proliferation, ß-hexosaminidase release (degranulation), and Erk1/2 phosphorylation were assessed in sunitinib treated Nf1(+/-) mast cells and fibroblasts, respectively. Krox20;Nf1(flox/-) mice with established pNF were treated sunitinib or PBS-vehicle control for a duration of 12 weeks. pNF metabolic activity was monitored by serial [(18)F]DG-PET/CT imaging. RESULTS: Sunitinib suppressed multiple in vitro gain-in-functions of Nf1(+/-) mast cells and fibroblasts and attenuated Erk1/2 phosphorylation. Sunitinib treated Krox20;Nf1(flox/-) mice exhibited significant reductions in pNF size, tumor number, and FDG uptake compared to control mice. Histopathology revealed reduced tumor cellularity and infiltrating mast cells, markedly diminished collagen deposition, and increased cellular apoptosis in sunitinib treated pNF. CONCLUSIONS: Collectively, these results demonstrate the efficacy of sunitinib in reducing tumor burden in Krox20;Nf1(flox/-) mice. These preclinical findings demonstrate the utility of inhibiting multiple RTKs in pNF and provide insights into the design of future clinical trials.

Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow.

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.

Disseminated toxoplasmosis resulting in graft failure in a cord blood stem cell transplant recipient.

Toxoplasmosis is an infrequent infection with a high mortality rate in hematopoietic stem cell transplant recipients, and is usually caused by reactivation of prior, latent infection upon intensive immunosuppression. We report a case of fatal disseminated toxoplasmosis, diagnosed at autopsy, in a 7-year-old boy who received a cord blood graft for recurrent acute lymphoblastic leukemia. This case represents both the first reported case of toxoplasmosis in an engrafted cord blood recipient, and also of graft failure due to toxoplasmosis. Recommendations for toxoplasmosis diagnosis, treatment, and prophylaxis in stem cell transplant recipients are reviewed.

Spindle cell lipoma of the oral cavity.

Spindle cell lipoma is typically seen in the neck/trunk region of middle-aged and older men. Rare cases of oral spindle cell lipoma have been reported. An entity described as myxoid lipoma of the oral cavity has rarely been reported but appears to be more properly classified as spindle cell lipoma. We describe the largest series yet of oral spindle cell lipoma involving the tongue (4), buccal mucosa (1), floor of mouth (1), and lip (1). The patients (3M; 4F) ranged from 31 to 88 years old. All presented with mass lesions. All were circumscribed and composed of mature adipocytes admixed with bland spindled cells. In two cases the adipocytes appeared atrophic, imparting a pseudo-lipoblastic appearance. No true lipoblasts were seen and none had the characteristic vasculature of a myxoid liposarcoma or the characteristic hyperchromatic cells of well-differentiated liposarcoma. The stromal background of all cases contained characteristic wiry collagen and myxoid ground substance. The myxoid ground substance was prominent in four cases. Immunohistochemical stains for CD34 highlighted the bland spindle cells in all cases. The combination of the histologic features and the immunoreactivity for CD34 confirmed the diagnosis. Spindle cell lipoma should be considered in the differential diagnosis of oral cavity mesenchymal tumors.