Faculty Bibliography

Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft-tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1 associated) or after radiotherapy. Using comprehensive genomic approaches, we identified loss-of-function somatic alterations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the lost PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 levels and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), both of which significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2 components, NF1 and CDKN2A highlights their critical and potentially cooperative roles in MPNST pathogenesis.

In the current health care system, high costs without proportional improvements in quality or outcome have prompted widespread calls for change in how we deliver and pay for care. Value-based health care delivery models have been proposed. Multiple impediments exist to achieving value, including misaligned patient and provider incentives, information asymmetries, convoluted and opaque cost structures, and cultural attitudes toward cancer treatment. Radiation oncology as a specialty has recently become a focus of the value discussion. Escalating costs secondary to rapidly evolving technologies, safety breaches, and variable, nonstandardized structures and processes of delivering care have garnered attention. In response, we present a framework for the value discussion in radiation oncology and identify approaches for attaining value, including economic and structural models, process improvements, outcome measurement, and cost assessment.

Primary intraocular lymphoma (PIOL) treatment in the absence of other involvement of the central nervous system is controversial. We evaluated the outcome of ocular radiation therapy (RT) alone in 18 patients with PIOL who had no imaging evidence of brain or meningeal involvement, treated from 1999 to 2011. Median age at diagnosis was 64 years (range 32-82). Median follow-up was 25 months. Eleven had bilateral ocular involvement. All received external-beam orbital RT to a median dose of 36 Gy. Twelve patients received ocular RT alone; seven remain relapse-free at a median follow-up of 30 months. Five experienced brain or eye recurrence and were effectively salvaged with chemotherapy ± RT. Six patients received chemotherapy before ocular RT; three relapsed and received salvage therapy. Overall survival (OS) at 2 years was 94%. Two-year freedom-from-relapse was not different between the groups. Ocular RT alone resulted in excellent ocular control of PIOL, and relapses were effectively salvaged.

BACKGROUND:Brain metastases (BM) and leptomeningeal disease (LMD) are uncommon in epithelial ovarian cancer (EOC). We investigate the outcomes of modern radiation therapy (RT) as a primary treatment modality in patients with EOC BM and LMD. METHODS:We evaluated 60 patients with EOC treated at our institution from 1996 to 2010 who developed BM. All information was obtained from chart review. RESULTS:At EOC diagnosis, median age was 56.1 years and 88% of patients were stage III-IV. At time of BM diagnosis, 46.7% of patients had 1 BM, 16.7% had two to three, 26.7% had four or more, and 10% had LMD. Median follow-up after BM was 9.3 months (range, 0.3-82.3). All patients received RT, and 37% had surgical resection. LMD occurred in the primary or recurrent setting in 12 patients (20%), 9 of whom received RT. Median overall survival (OS) after BM was 9.7 months for all patients (95% CI 5.9-13.5), and 16.1 months (95% CI 3.8-28.3) in patients with one BM. On multivariate analysis, Karnofsky performance status less than 70 (hazard ratio [HR] 2.86, p = 0.018), four or more BM (HR 3.18, p = 0.05), LMD (HR 8.22, p = 0.013), and uncontrolled primary tumor (HR 2.84, p = 0.008) were significantly associated with inferior OS. Use of surgery was not significant (p = 0.31). Median central nervous system freedom from progression (CNS-FFP) in 47 patients with follow-up was 18.5 months (95% CI, 9.3-27.9). Only four or more BM (HR 2.56, p = 0.04) was significantly associated with poorer CNS-FFP. CONCLUSIONS:Based on our results, RT appears to be an effective treatment modality for brain metastases from EOC and should be routinely offered. Karnofsky performance status less than 70, four or more BM, LMD, and uncontrolled primary tumor predict for worse survival after RT for EOC BM. Whether RT is superior to surgery or chemotherapy for EOC BM remains to be seen in a larger cohort.

PURPOSE/OBJECTIVE:To report long-term outcomes of high-dose-rate (HDR) intraoperative radiotherapy (IORT) at the time of radical resection for recurrent head-and-neck cancer and determine potential prognostic factors. METHODS AND MATERIALS/METHODS:Between 7/1998 and 11/2011, 57 patients with recurrent head-and-neck cancer underwent radical resection with curative intent and single-fraction IORT to 59 sites using a Harrison-Anderson-Mick applicator with remotely after-loaded (192)Ir HDR brachytherapy. RESULTS:One- and 3-year in-field progression-free survival (IFPFS) was 67% and 57%, respectively. In a multivariate model, IORT dose >15Gy (hazard ratio [HR] = 0.11; p = 0.02), and prerecurrence disease-free interval >12 months (HR = 0.29; p = 0.04) independently predicted for superior IFPFS; nodal extracapsular extension (HR = 4.62; p = 0.003) predicted for inferior IFPFS. Three-year overall survival (OS) was 50% vs. 32% in those achieving in-field control vs. those not achieving in-field control (p = 0.04). Grade 3+ toxicity occurred in 37% and was unrelated to IORT dose. CONCLUSIONS:HDR-IORT combined with radical surgical resection is associated with durable IFPFS and long-term overall survival in select patients with acceptable treatment-related morbidity. IORT dose >15Gy should be used to increase the likelihood of disease control. The ability to achieve in-field local control in this poor prognostic cohort was associated with improved survival outcomes.

Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.