Sandler, Eric

AbstractBackgroundPediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT).ProcedureUsing an IRB‐approved prospective outcomes registry, we evaluated patient, tumor, and treatment‐related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT.ResultsFifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow‐up was 4.8 years. No patients were lost to follow‐up. Five‐year disease‐free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in‐field basal cell skin cancer.ConclusionsA multimodality approach for pediatric EN results in excellent local control. Despite the moderate‐dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow‐up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.

Abstract Background Out‐of‐field neutron dissemination during double‐scattered proton therapy has raised concerns of increased second malignancies, disproportionally affecting pediatric patients due to the proportion of body exposed to scatter dose and inherent radiosensitivity of developing tissue. We sought to provide empiric data on the incidence of early second tumors. Methods Between 2006 and 2019, 1713 consecutive children underwent double‐scattered proton therapy. Median age at treatment was 9.1 years; 371 were ≤3 years old. Thirty‐seven patients (2.2%) had tumor predisposition syndromes. Median prescription dose was 54 Gy (range 15–75.6). Median follow‐up was 3.3 years (range 0.1–12.8), including 6587 total person‐years. Five hundred forty‐nine patients had ≥5 years of follow‐up. A second tumor was defined as any solid neoplasm throughout the body. Results Eleven patients developed second tumors; the 5‐ and 10‐year cumulative incidences were 0.8% (95% CI, 0.4–1.9%) and 3.1% (95% CI, 1.5–6.2%), respectively. Using age‐ and gender‐specific data from the Surveillance, Epidemiology, and End Results (SEER) program, the standardized incidence ratio was 13.5; the absolute excess risk was 1.5/1000 person‐years. All but one patient who developed second tumors were irradiated at ≤5 years old ( p < .0005). There was also a statistically significant correlation between patients with tumor predisposition syndromes and second tumors ( p < .0001). Excluding patients with tumor predisposition syndromes, 5‐ and 10‐year rates were 0.6% (95% CI, 0.2–1.7%) and 1.7% (95% CI, 0.7–4.0%), respectively, with all five malignant second tumors occurring in the high‐dose region. Conclusion Second tumors are rare within the decade following double‐scattered proton therapy, particularly among children irradiated at >5 years old and those without tumor predisposition syndrome.

Abstract Background In the U.S. over 14,000 new cancer cases occur annually in people under 21 years of age; approximately 21% of cases are acute lymphoblastic leukemia (ALL) and ∼ 30% classify as Burkitt lymphoma (BL). Most cases of ALL and BL are due to malignant B-cells that have acquired disease-defining oncogenic lesions that facilitate their rapid proliferation. To maintain a state of homeostasis, the malignant cells rely heavily on the ability of the internal degradation and recycling systems to match the high rate of protein turnover. As such, the ubiquitin proteasome system (UPS) is central in this operation where it prevents buildup of misfolded proteins while also regulating the availability of anti-apoptotic proteins such as BCL2 and MCL1. These observations coupled with the observation that UPS disruption leads to cellular demise have resulted in the development of several proteasome inhibitors (PI). These PI have primarily been examined in adult B-cell malignancies. The feasibility of a bortezomib-containing regimen for use in pediatric malignancies has been examined by the TACL consortium and demonstrated a 73% response rate in relapsed/refractory ALL patients. However, a major limitation of bortezomib-based therapy is an increased incidence of peripheral neuropathy (PN), which was also noted in the TACL study. As such, more potent and reportedly less toxic PI have been developed that seem to carry considerably lower risk for development of PN. Such agents that maintain a high response rate and carry reduced long-term adverse effects are highly desirable in pediatric age patients. Aim Investigation of the novel proteasome inhibitors carfilzomib and MLN9708 (Millennium Pharmaceuticals) in preclinical models of pediatric B-lymphocytic cancer. Methods Representative preclinical models of BL (Raji cell line) and B-ALL (ALL-1 cells) were used in this study. Proteasomal activity was measured using synthetic fluorogenic peptide substrates. Cell viability was measured by MTS assay. Apoptosis was determined by annexin-v/PI staining and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiling was performed via immunoblot. Results In an effort to understand the effect of carfilzomib and MLN9708 in our pediatric cancer models, we first assessed their ability to inhibit proteasomal activity. While chymotrypsin-like activity, which is the target of both PIs, is inhibited by more than 90% in both cell lines, inhibition (∼ 35%) of caspase-like function conferred by the b1 subunit was more significantly pronounced in MLN9708 treated Raji and ALL-1 cells. Next we performed an MTS assay to determine the growth inhibitory effects of these PI in vitro. Both PI inhibited the growth of the Raji and ALL-1 cells in a dose dependent manner. Carfilzomib showed a more potent effect (IC50 ∼1nM in both cell lines) as compared to MLN9708 (IC50 ∼30nM in ALL-1 cells and ∼50nM in Raji cells). To further understand mechanisms of growth inhibition we examined both tumor cell lines for induction of apoptosis along with corresponding markers. As compared to Raji cells, we observed ALL-1 cells to be more sensitive to the effects of both PI, albeit with MLN9708 (50nM) inducing more cell death (65%) as compared to carfilzomib (10nM, 50% cell death). Further, we observed altered MOMP, cleavage of caspases 9, 3 and PARP-1 were found to occur in both cell lines in presence of carfilzomib or MLN9708. These changes indicate the apoptotic effects of novel PI in ALL-1 and Raji cells are via mitochondrial destabilization and caspase activation. As inhibition of the UPS aids NOXA and BIM (pro-apoptotic BCL2 proteins) mediated cell death, we examined the expression of BCL2 family proteins changes in Raji and ALL-1 cells in response to novel PI. Indeed protein levels of both BCL2 and MCL1 were reduced in carfilzomib and MLN9708 treated cells. Reduced BCL2 expression was more pronounced in ALL-1 cells as compared to Raji cells and downregulation was noted to be dose-dependent. Summary Our data show that both carfilzomib and MLN9708 potently inhibit the viability of malignant ALL and BL cells in vitro. We conclude that PI are promising anti-neoplastic therapeutics that target not only the UPS but also modulate the expression of critical anti-apoptotic proteins. Data from mechanistic studies conducted herein underscore the need for further research in in vivo models of these diseases. Disclosures: Foran: Celgene: Research Funding.

Ectomesenchymomas (EM) are rare malignant neoplasms usually consisting of rhabdomyosarcoma (RMS) with a neural component. Only 21 cases have been previously reported. Here we extend the clinicopathologic spectrum of EM by describing our findings in 15 cases. Only 5 patients were infants; 10 were ≤3 years old and 5 were ≥6 years old. No male predilection was observed; 7 were female. The originating institutional diagnoses were; RMS (12), undifferentiated sarcoma (1), or EM (2), suggesting underdiagnosis of this entity. The primary tumor sites included external genital (5), pelvis/abdomen (6), head and neck (3), and extremity (1). The size of the primary neoplasm was usually ≥5 cm at diagnosis but dissemination only occurred in a minority. Local infiltration was not uncommon. These neoplasms were typically multilobate, thinly encapsulated, hemorrhagic, and necrotic. Light microscopic features were highly variable, but embryonal RMS with scattered or clustered ganglion cells, often in lacunae, was characteristic. In some cases, primitive neuroblastic or neuroectodermal areas were found and/or a component of alveolar RMS was seen. Focal anaplasia was occasionally observed. Mitotic activity appears higher than previously appreciated and some necrosis was invariably present. Electron microscopy was performed in 11 cases, which confirmed skeletal muscle ± neural differentiation. Cytogenetic studies performed in five cases revealed no specific abnormality. Monoclonal neuron-specific enolase was the best marker of ganglion cells and primitive neural elements. MIC-2 (CD99) membrane expression was not definitively present in any of the six cases examined. A number of the above parameters appear to be of some prognostic significance, but overall, these neoplasms appear to have a similar outcome as would be predicted for their RMS element alone (exclusive of any neural component), with respect to the RMS subtype, age of the patient, and anatomic location of the neoplasm.