Combination mTOR and SHP2 inhibitor treatment of lymphatic malformation endothelial cells.

Mammalian target of rapamycin (mTOR) inhibitors are clinically effective at treating some complex lymphatic malformations (LM). The mTOR inhibitor rapamycin blocks the phosphoinositide 3-kinase (PI3K) pathway, which is commonly mutated in this condition. Although rapamycin is effective at controlling symptoms of LM, treatment courses are long, not all LMs respond to treatment, and many patients relapse after treatment has stopped. Concurrent rat sarcoma virus (RAS) pathway abnormalities have been identified in LM, which may limit the effectiveness of rapamycin. Protein tyrosine phosphatase-2 (SHP2) controls the RAS pathway upstream, and SHP2 inhibitors are being investigated for treatment of various tumors. The objective of this study was to determine the impact of SHP2 inhibition in combination with rapamycin on LM growth in vitro. Using primary patient cells isolated from a surgically resected LM, we found that combination treatment with rapamycin and the SHP2 inhibitor SHP099 caused a synergistic reduction in cell growth, migration and lymphangiogenesis. These results suggest that combination treatment targeting the PI3K and RAS signaling pathways may result in effective treatment of LMs of the head and neck.

Button battery taping prevents oesophageal injury.

AIM: Most button battery (BB) ingestions in children are unwitnessed leading to prolonged exposures and severe complications. One third of ingestions occur from free BB, that are stored or awaiting disposal. Recommendations have been made to cover the terminals of discarded BB with adhesive tape; however, it is unclear if this practice prevents injury. Our aim was to determine if tape could prevent oesophageal injury in a cadaveric porcine model. METHODS: Electrical, masking, packing and duct tape were compared. One BB was left untaped. Taped BBs were placed in a cadaveric porcine oesophagus controlled for temperature and humidification. Specimens were assessed at 0, 0.5, and hourly for 6 h by visual inspection, temperature and pH. BB voltage was measured before and after testing. All tests were repeated in triplicate. RESULTS: Oesophageal specimens demonstrated burn prevention in the packing and duct tape trials. Burns were seen in 2/3 trials with electrical tape and 3/3 trials with masking tape. pH remained neutral throughout the study for all packing and duct tape specimens. pH remained neutral initially for masking tape but increased rapidly to 12 by 2 h. There was no change in battery voltage for the packing tape and duct tape trials. There was a 16.3% reduction in voltage for masking tape which was similar to controls. CONCLUSIONS: Taping BB with packing tape and duct tape prevented oesophageal burns. This may provide a novel method of burn prevention for loose BB intended for disposal.

Propranolol versus nadolol for treatment of pediatric subglottic hemangioma.

PURPOSE: The beta-blocker propranolol is the standard medical therapy for subglottic hemangioma (SGH), but side effects and incomplete response rates require close monitoring. Nadolol has been identified as a potential alternative but its use has not been examined for SGH. METHODS: Single institution retrospective cohort study of pediatric SGH treated with propranolol or nadolol. RESULTS: Thirteen children (1 male, 12 female) with SGH were included: 6 were treated with propranolol (2.0-3.5 mg/kg/d) and 7 with nadolol (2.0-4.0 mg/kg/d). The most common presenting symptom was stridor (85%) and mean (SD) symptom duration prior to diagnosis was 4.6 (3.8) weeks. Cutaneous vascular lesions were present in 54%. There were 7 right-sided, 5 left-sided and 1 bilateral SGH. The mean (SD) percentage of airway obstruction was 60.6% (27.4). The response rate was 100% (6/6) for propranolol and 85.7% (6/7) for nadolol (p = 0.36). Mean (SD) time to symptomatic improvement was 2.6 (2.2) days with no difference across groups (p = 0.71). There was no hypotension, hypoglycemia, weight loss, or sleep disturbances in either group. One patient in the propranolol group experienced vomiting. Two patients in the nadolol group required dosage reduction due to asymptomatic bradycardia. The mean (SD) duration of admission was 14.4 (12.6) days and duration of treatment was 13.8 (11.2) days with no difference across groups (p = 0.23; p = 0.31, respectively). All patients had treatment initiated as inpatients and completed as outpatients. CONCLUSION: Children with SGH treated with propranolol or nadolol had similar response rates and side effect profiles.

Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma.

Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective ß-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the ß2, and not ß1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express ß2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.

Propranolol as a novel adjunctive treatment for head and neck squamous cell carcinoma.

OBJECTIVE: To investigate propranolol as a novel treatment for head and neck squamous cell carcinoma (HNSCC) in vitro. METHODS: HNSCC cell lines were cultured and treated with propranolol alone and in combination with cisplatin or γ-irradiation. The alamarBlue assay was performed to assess cell viability, and apoptosis was confirmed via Western immunoblot for cleaved poly-ADP-ribose polymerase (PARP) and caspase-3/7 assays. RESULTS: Propranolol reduced cell viability and induced apoptosis. In response to propranolol, ΔNp63α decreased, whereas TAp73ß and downstream proapoptotic p53 family target genes increased. Expression of the proangiogenic protein vascular endothelial growth factor (VEGF) also decreased. Combination treatment with propranolol and cisplatin resulted in synergistic effects. Propranolol treatment also enhanced the effects of γ-irradiation on cell viability. CONCLUSIONS: Our results demonstrate that propranolol reduced HNSCC viability, induced apoptosis, and inhibited production of the proangiogenic protein VEGF. These changes may be due to modulation of p53 family proteins, which are critical regulators of chemotherapy-induced apoptosis in HNSCC. Moreover, propranolol is synergistic in combination with cisplatin and reduces HNSCC viability postradiation in vitro, which may have important implications for novel treatments of HNSCC patients.