Faculty Bibliography

Background: Osteosarcoma is one of the most common bone malignancies in the pediatric population, although it affects a wide age range. While pathognomonic genomic alterations have been identified in other pediatric bone and soft tissue tumors such as Ewing sarcoma and synovial sarcoma, no such alterations are seen in osteosarcoma. Epigenetic modifications such as global or specific changes in DNA methylation are gaining recognition as a primary mechanism of oncogenesis in pediatric and adult cancers. Identifying unique epigenetic modifications in tumors lacking known fusions could contribute to both diagnosis and selection of potential therapeutic targets. Methods: Using the Illumina Infinium Human Methylation450 BeadChip Array (450K array) platform, we performed genome-wide DNA methylation analysis on 15 osteosarcomas with tissue meeting criteria for methylation analysis, including formalin-fixed paraffin-embedded, frozen, and fresh tissue obtained from NYU and Memorial Sloan Kettering Cancer Center (mean age = 26 years; range 6-80 years). Comparison was made to 10 Ewing sarcomas and 11 synovial sarcomas in the same pilot cohort. Diagnosis was based on histologic criteria and, where available, absence of a known non-osteosarcoma genomic fusion. Unsupervised hierarchical clustering analysis was performed to classify tumor type and to assess for differentially methylated target regions. Results: Osteosarcomas formed a unique subtype on unsupervised hierarchical clustering analysis of DNA methylation. Of the 15 tumors profiled, molecular testing confirming the absence of a known fusion was previously done on 5, and fusion status did not impact clustering. Pathway analysis through MSig

Preventing adverse events among chronically ill older adults living in the community is a national health priority. The purpose of this study was to generate distinct risk profiles and compare these profiles in time to: hospitalization, emergency department (ED) visit or death in 371 community-dwelling older adults enrolled in a Medicare demonstration project. Guided by the Behavioral Model of Health Service Use, a secondary analysis was conducted using Latent Class Analysis to generate the risk profiles with Kaplan Meier methodology and log rank statistics to compare risk profiles. The Vuong-Lo-Mendell-Rubin Likelihood Ratio Test demonstrated optimal fit for three risk profiles (High, Medium, and Low Risk). The High Risk profile had significantly shorter time to hospitalization, ED visit, and death (p < 0.001 for each). These findings provide a road map for generating risk profiles that could enable more effective targeting of interventions and be instrumental in reducing health care costs for subgroups of chronically ill community-dwelling older adults.

PURPOSE: Inguinal herniorrhaphy is the most common general surgical procedure. It is associated with frequent complications such as recurrence (1.9% with mesh), post-operative hematoma (4.5%), reduced sensation (0 - 42.8%), chronic post-operative pain (5.1%), vasal injury (0.1 - 0.53%) and infection (3 - 6%)1-5. Drawing on our experience utilizing the operating microscope for varicocelectomy, vasectomy reversal and repair of iatrogenic vasal obstruction from hernia repair, we employed it for inguinal hernia repair. This paper describes the rationale, technique and outcomes of microsurgically assisted inguinal hernia repair. MATERIALS AND METHODS: 291 microsurgically assisted inguinal hernia repairs were performed on 253 men by the same urologist (MG). Simultaneous microsurgical varicocelectomy or other testicular procedures were performed in 83% of cases. All were open repairs through an inguinal incision with the vas deferens, ilioinguinal nerve, genital branch of the genitofemoral nerve and spermatic vasculature identified and preserved. Median follow up was 8.6 months, and outcomes were assessed through examination, pain reporting and pathology reports. RESULTS: Chronic postoperative pain, sensory loss, infection, hematoma, vasal injury and recurrence were assessed. The incidence of hematoma was 0.85%. No hernia recurrences, chronic postoperative pain, sensory loss, infection or vasal injury was reported. CONCLUSIONS: Using an operating microscope, complications of inguinal hernia repair such as vasal obstruction, testicular atrophy, recurrence, infection, hematoma, chronic postoperative pain and loss of sensation are minimized. Microsurgically assisted hernia repair is a promising technique, especially when employed by a urologist performing simultaneous microsurgical varicocelectomy or procedures involving spermatic cord structures or testis.

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.

OBJECTIVE: Examine oral complications 6 months after modern radiation therapy (RT) for head and neck cancer (HNC). METHODS: Prospective multi-center cohort study of HNC patients receiving Intensity-Modulated Radiation Therapy (IMRT) or more advanced RT. Stimulated whole salivary flow, maximal mouth opening, oral mucositis, oral pain, oral health-related quality of life (OH-QOL), and oral hygiene practices, were measured in 372 subjects pre-RT and 216 at 6 months from start of RT. RESULTS: Mean stimulated whole salivary flow declined from 1.09 ml/min to 0.47 ml/min at 6 months (p < 0.0001). Mean maximal mouth opening reduced from 45.58 mm to 42.53 mm at 6 months (p < 0.0001). 8.1% of subjects had some oral mucositis at 6 months, including 3.8% with oral ulceration. Mean overall pain score was unchanged. OH-QOL was reduced at 6 months, with changes related to dry mouth, sticky saliva, swallowing solid foods, and sense of taste (p