No abstract

Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.

We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML) .

Agents inhibiting the phosphoinositide 3–kinase–Akt–mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.

Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with

Activating mutations in the RAS oncogenes are among the most common genetic alterations in human cancers, including patients with acute lymphoblastic leukemia (ALL). We sought to define the frequency and spectrum, and possible prognostic importance, of N-and K-RAS mutations in children with ALL treated with contemporary therapy. Leukemic blast DNA from 870 children was analyzed for the presence of activating mutations in the N-or K-RAS oncogenes using a sensitive mutation detection algorithm. RAS mutations were present in the blasts of 131 (15.1%) pediatric ALL patients. The spectrum of mutations included 81 (9.3%) mutations of codons 12/13 of N-RAS, 12 (1.4%) mutations of codon 61 of N-RAS, 39 (4.5%) mutations of codons 12/13 of K-RAS, and 2 (0.2%) mutations of codon 61 of K-RAS. The presence of N-or K-RAS mutations was not associated with white blood cell count at diagnosis, sex, race, extramedullary testicular involvement, central nervous system disease, or NCI/CTEP ALL Risk Group. Patients with an exon 1 K-RAS mutation (codons 12/13) were significantly younger at diagnosis (P ¼ 0.001) and less frequently B-lineage phenotype (P ¼ 0.01). RAS mutation status did not predict overall survival, event-free survival and disease-free survival. While N-and K-RAS mutations can be identified in 15% of children with newly diagnosed ALL, they do not represent a significant risk factor for outcome using contemporary chemotherapy regimens.

Several epidemiologic studies have demonstrated that high birthweight is associated with an increased risk of infant leukemia; however, the reason for this relationship is unclear. Biologic data demonstrate that birth weight is correlated positively with circulating levels of insulin-like growth factor-1 (IGF-1). IGF-1 is important in blood formation and regulation and has been shown to stimulate the growth of both myeloid and lymphoid cells in culture. Since infants who develop leukemia are likely to have had at least one transforming event occur in utero, we hypothesize that high levels of IGF-1 may both produce a larger baby and contribute to leukemogenesis.

This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients.