Faculty Bibliography

Radiotherapy with ionizing radiation is an effective therapeutic tool for benign and malignant brain tumors in children, but it also contributes to late toxicity experienced by survivors of childhood cancer. The more frequently used external beam radiotherapy techniques with photons (X-rays) or protons will be discussed, as well as special applications such as stereotactic radiosurgery and less commonly used techniques such as brachytherapy. Common indications for central nervous system radiotherapy in the pediatric population will be reviewed. Advances in treatment technology including image guidance, intensity-modulated radiation therapy, and proton therapy have resulted in decreased radiation exposure of normal tissues and should decrease the incidence and severity of late effects of radiotherapy.

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma^1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor^4-6. The latter is essential for achieving abscopal responses in murine cancers⁶. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy^7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.

PURPOSE/OBJECTIVE:Hypofractionated whole-breast radiation therapy (RT) has proved to be equivalent to conventionally fractionated RT in multiple randomized trials. There is controversy regarding its use in younger women because of their underrepresentation in trials and the concern for late toxicity. We evaluated disease control and cosmetic outcomes in patients aged <50 years treated with hypofractionated RT in 4 prospective single-institutional trials. METHODS AND MATERIALS/METHODS:From 2003 to 2015, 1313 patients were enrolled in 4 prospective protocols investigating the use of adjuvant hypofractionated RT after breast-conserving surgery with a daily or weekly concomitant boost. We identified the records of 348 patients aged <50 years at consultation for this analysis. Overall survival, disease-free survival, and local recurrence-free survival were estimated using the Kaplan-Meier method by study and across studies using meta-analytic methods. The late effects of RT, clinician-rated cosmesis, and patient-rated cosmesis were also evaluated. RESULTS:With a median follow-up period of 66.9 months, the overall survival rate was 99.6%, the disease-free survival rate was 96.3%, and the local recurrence-free survival rate was 97.7% at 3 years. Clinician-rated cosmesis (n = 242) was excellent or good in 93.4% of cases and fair or poor in 6.6%. Patient-rated cosmesis (n = 259) was excellent or good in 86.1% and fair or poor in 13.9%. When patients rated themselves differently than their physicians, patients more often rated themselves poorly compared with their physicians (P = .0044, Cochran-Mantel-Haenszel test). CONCLUSIONS:At a median follow-up of 5 years, an analysis of patients aged <50 years demonstrated that hypofractionated RT was safe and effective, with good to excellent cosmesis as assessed by both clinicians and patients.

Background: Bone sarcomas present a unique diagnostic challenge because of the considerable morphologic overlap between different entities. The choice of optimal treatment, however, is dependent upon accurate diagnosis. Genome-wide DNA methylation profiling has emerged as a new approach to aid in the diagnosis of brain tumors, with diagnostic accuracy exceeding standard histopathology. In this work we developed and validated a methylation based classifier to differentiate between osteosarcoma, Ewing's sarcoma, and synovial sarcoma. Methods: DNA methylation status of 482,421 CpG sites in 15 osteosarcoma, 10 Ewing's sarcoma, and 11 synovial sarcoma samples were measured using the Illumina HumanMethylation450 array. From this training set of 36 samples we developed a random forest classifier using the 400 most differentially methylated CpG sites (FDR q value < 0.001). This classifier was then validated on 10 synovial sarcoma samples from TCGA, 86 osteosarcoma samples from TARGET-OS, and 15 Ewing's sarcoma from a recently published series (Huertas-Martinez et al., Cancer Letters 2016). Results: Methylation profiling revealed three distinct molecular clusters, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were correctly classified as synovial sarcoma (10/10, sensitivity and specificity 100%). All but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and all but one sample from the Ewing's sarcoma series was classified as Ewing's sarcoma (14/15, sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample was classified as Ewing's sarcoma, and was later determined to be a misdiagnosed Ewing's sarcoma based on RNA-Seq demonstrating high EWRS1 and ETV1 expression. An additional clinical sample that was misdiagnosed as a synovial sarcoma by initial histolopathology, was accurately recognized as osteosarcoma by the methylation classifier. Conclusions: Osteosarcoma, Ewing's sarcoma and synovial sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide an accurate diagnosis when histological and standard techniques are inconclusive

BACKGROUND: Patients undergoing implant-based reconstruction in the setting of postmastectomy radiation therapy suffer from increased complications and inferior outcomes compared with those not irradiated, but advances in radiation delivery have allowed for more nuanced therapy. The authors investigated whether these advances impact patient outcomes in implant-based breast reconstruction. METHODS: Retrospective chart review identified all implant-based reconstructions performed at a single institution from November of 2010 to November of 2013. These data were cross-referenced with a registry of patients undergoing breast irradiation. Patient demographics, treatment characteristics, and outcomes were analyzed. RESULTS: Three hundred twenty-six patients (533 reconstructions) were not irradiated, whereas 83 patients (125 reconstructions) received radiation therapy; mean follow-up was 24.7 months versus 26.0 months (p = 0.49). Overall complication rates were higher in the irradiated group (35.2 percent versus 14.4 percent; p < 0.01). Increased maximum radiation doses to the skin were associated with complications (maximum dose to skin, p = 0.05; maximum dose to 1 cc of skin, p = 0.01). Different treatment modalities (e.g., three-dimensional conformal, intensity-modulated, field-in-field, and hybrid techniques) did not impact complication rates. Prone versus supine positioning significantly decreased the maximum skin dose (58.5 Gy versus 61.7 Gy; p = 0.05), although this did not translate to significantly decreased complication rates in analysis of prone versus supine positioning. CONCLUSIONS: As radiation techniques evolve, the maximum dose to skin should be given consideration similar to that for heart and lung dosing, to optimize reconstructive outcomes. Prone positioning significantly decreases the maximum skin dose and trends toward significance in reducing reconstructive complications. With continued study, this may become clinically important. Interdepartmental studies such as this one ensure quality of care. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.