The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma.

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.

Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model.

BACKGROUND: Captopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril's known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril's effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo. METHODS: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue. RESULTS: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively). CONCLUSIONS: Captopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.

Anthropometric and Dental Measurements in Children with Obstructive Sleep Apnea.

STUDY OBJECTIVES: A number of authors have shown that children with OSA are more likely to have certain physical characteristics than healthy controls. With this in mind, our objectives were to collect normative baseline data and determine if there was a significant difference in anthropometric and dental measurements between children with OSA and age-matched nonsnoring controls. METHODS: Children 2 to 12 y of age, in whom OSA was diagnosed by overnight polysomnography, were recruited to our experimental group. Age-matched nonsnoring controls were screened for signs of sleep-disordered breathing. Anthropometric measurements, including waist, neck, and hip circumferences, and waist-hip and neck-waist ratios, were obtained on all study participants preoperatively. Dental casts were acquired to determine intertooth distances and palatal height. RESULTS: Sixty-one children (42 with OSA [69%] and 19 controls [31%]) with a mean age of 4.7 y participated in the study. Waist and hip circumferences were significantly larger in children with OSA (p = 0.001 and 0.001, respectively). However, there was no difference in neck circumference and waist-hip ratios between the two groups. Neck-waist ratio in children with OSA was significantly smaller than in controls (p = 0.001). Intertooth distance for the first (p < 0.0001) and second deciduous (p = 0.0002) and first permanent molars (p = 0.022) were significantly narrowed in children with OSA; however, no difference was seen in palatal height between groups. Body mass index was similar between groups (p = 0.76). CONCLUSIONS: Anthropometric and dental measurements were significantly different in children with OSA compared to nonsnorers. Future studies with a large sample size may allow us to determine if these measurements can be used by clinicians to identify children at risk for OSA. COMMENTARY: A commentary on this article appears in this issue on page 1213.