Faculty Bibliography

Brain metastases in malignant melanoma carries a poor prognosis with minimal response to any therapy. The purpose of this pilot analysis was to find the effectiveness of vemurafenib, an oral BRAF inhibitor, and radiation therapy in V600 mutated melanoma with brain metastases. BRAF mutation status of the melanoma patients was determined by real-time PCR assay. Retrospective analysis was performed on twelve patients who had the mutation and were treated with either stereotactic radiosurgery or whole brain radiation therapy prior to or along with vemurafenib at a dose of 960 mg orally twice a day. Clinical and radiological responses, development of new brain metastases, overall survival and toxicity were assessed. Improvement in neurological symptoms was seen in 7/11 (64 %) following therapy. Radiographic responses were noted in 36/48 (75 %) of index lesions with 23 (48 %) complete responses and 13 (27 %) partial responses. Six month local control, freedom from new brain metastases and overall survival were 75, 57 and 92 %. Four patients had intra-tumoral bleed prior to therapy and two patients developed steroid dependence. One patient experienced radiation necrosis. This retrospective study suggests that melanoma patients with brain metastases harboring BRAF mutation appear to be a distinct sub-group with a favorable response to vemurafenib and radiation therapy and acceptable morbidity.

BACKGROUND:Paragangliomas are rare, vascular, and predominantly benign neoplasms of neural crest origin. They typically arise in the head and neck from the carotid body, jugulotympanic, or vagal paraganglia. Rarely, paragangliomas occur in the larynx. Only 2 cases of hypopharyngeal paraganglioma have been reported. We discuss the case of a hypopharyngeal paraganglioma and review the literature concerning laryngopharyngeal paragangliomas. METHODS AND RESULTS/RESULTS:We present the case of a woman with 2 months of dysphagia and hoarseness that was found to have a hypopharyngeal paraganglioma. The patient underwent embolization and resection of the mass via a lateral thyrotomy approach. Pathologic analysis and selective staining confirmed the presence of a paraganglioma. CONCLUSIONS:Proper histopathologic identification of these tumors is tantamount to guiding treatment. The preferred operative approach is a lateral thyrotomy to minimize patient morbidity. We present the third documented case of a hypopharyngeal paraganglioma and the first in the English-language literature.

Recent molecular studies have described a number of abnormalities associated with the pathogenesis of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development and may serve as prognostic factors and therapeutic targets. A better understanding of the mechanisms involved in thyroid cancer pathogenesis, will hopefully help translate these discoveries to improved patient care.

Retropharyngeal lymph node (RPLN) metastases can occur from advanced head and neck malignancies. Surgical access to RPLNs can be challenging. Considering the more aggressive conventional approach methods, there is an increasing need for minimally invasive techniques. Applying transoral robotic surgery (TORS) to access the RPLN has never been reported in the literature. The purpose of this study was to describe our experience with transoral robotic RPLN dissection for oropharyngeal and hypopharyngeal squamous cell carcinomas. We conducted a retrospective review of TORS cases performed at Severance Hospital, a tertiary care medical center from December 2011 to July 2012. Demographic, clinicopathologic, and treatment characteristics were abstracted from the medical record as well as complications and were analyzed descriptively. A total of 5 TORS procedures with transoral robotic RPLN dissection have been performed at Severance Hospital. Of these, 4 patients were treated for oropharyngeal squamous cell carcinoma and 1 for hypopharyngeal squamous cell carcinoma. The mean operation time for TORS including the robotic RPLN dissection was 84 ± 18.5 minutes. The operation time included time for docking of the robotic arms (4.8 ± 1.3 minutes), console working time for primary tumor removal (50 ± 8.9 minutes), and console working time for RPLN dissection (29.2 ± 9.4 minutes). No patients experienced complications related to the transoral robotic RPLN dissection. Transoral robotic RPLN dissection is a feasible approach for accessing retropharyngeal lymph nodes. This particular operative technique can serve as a minimal invasive surgery in removing pathologic RPLNs.

Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.

Advances in imaging and cell-labeling techniques have greatly enhanced our understanding of developmental and neurobiological processes. Among vertebrates, zebrafish is uniquely suited for in vivo imaging owing to its small size and optical translucency. However, distinguishing and following cells over extended time periods remains difficult. Previous studies have demonstrated that Cre recombinase-mediated recombination can lead to combinatorial expression of spectrally distinct fluorescent proteins (RFP, YFP and CFP) in neighboring cells, creating a 'Brainbow' of colors. The random combination of fluorescent proteins provides a way to distinguish adjacent cells, visualize cellular interactions and perform lineage analyses. Here, we describe Zebrabow (Zebrafish Brainbow) tools for in vivo multicolor imaging in zebrafish. First, we show that the broadly expressed ubi:Zebrabow line provides diverse color profiles that can be optimized by modulating Cre activity. Second, we find that colors are inherited equally among daughter cells and remain stable throughout embryonic and larval stages. Third, we show that UAS:Zebrabow lines can be used in combination with Gal4 to generate broad or tissue-specific expression patterns and facilitate tracing of axonal processes. Fourth, we demonstrate that Zebrabow can be used for long-term lineage analysis. Using the cornea as a model system, we provide evidence that embryonic corneal epithelial clones are replaced by large, wedge-shaped clones formed by centripetal expansion of cells from the peripheral cornea. The Zebrabow tool set presented here provides a resource for next-generation color-based anatomical and lineage analyses in zebrafish.

BACKGROUND: Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes. METHODS: We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months. RESULTS: The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [+/-SD] improvement, 7.1+/-13.9 in the early-adenotonsillectomy group and 5.1+/-13.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%). CONCLUSIONS: As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.).

PURPOSE: Promoter hypermethylation has been recently proposed as mean for HNSCC detection in salivary rinses. In a prospective study of high-risk population, we showed that EDNRB promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. EXPERIMENTAL DESIGN: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was performed and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by Quantitative methylation-specific PCR. RESULTS: HOXA9, EDNRB and DCC methylation were associated (p=0.012; p<0.0001; p=0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (p=0.0003) or DCC (p=0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (p=0.008; p=0.026; p=0.046) and multivariate analysis (p=0.012; p=0.037; p=0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with similar AUC (0.61, 95%CI=0.60-0.81) when compared to EDNRB and DCC combined AUC (0.60, 95%CI=0.51-0.69), sensitivity of 46% and specificity of 72%. Combination of EDNRB, DCC and CRC was optimal AUC (0.67, 95%CI=0.58-0.76). CONCLUSION: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available.

OBJECTIVE: The reasons why adenotonsillectomy (AT) is less effective treating obese children with obstructive sleep apnea syndrome (OSAS) are not understood. Thus, the aim of the study was to evaluate how anatomical factors contributing to airway obstruction are affected by AT in these children. METHODS: Twenty-seven obese children with OSAS (age 13.0 +/- 2.3 y, body mass index Z-score 2.5 +/- 0.3) underwent polysomnography and magnetic resonance imaging of the head during wakefulness before and after AT. Volumetric analysis of the upper airway and surrounding tissues was performed using commercial software (AMIRA(R)). RESULTS: Patients were followed for 6.1 +/- 3.6 mo after AT. AT improved mean obstructive apnea-hypopnea index (AHI) from 23.7 +/- 21.4 to 5.6 +/- 8.7 (P < 0.001). Resolution of OSAS was noted in 44% (12 of 27), but only in 22% (4 of 18) of those with severe OSAS (AHI > 10). AT increased the volume of the nasopharynx and oropharynx (2.9 +/- 1.3 versus 4.4 +/- 0.9 cm(3), P < 0.001, and 3.2 +/- 1.2 versus 4.3 +/- 2.0 cm(3), P < 0.01, respectively), reduced tonsils (11.3 +/- 4.3 versus 1.3 +/- 1.4 cm(3), P < 0.001), but had no effect on the adenoid, lingual tonsil, or retropharyngeal nodes. A small significant increase in the volume of the soft palate and tongue was also noted (7.3 +/- 2.5 versus 8.0 +/- 1.9 cm(3), P = 0.02, and 88.2 +/- 18.3 versus 89.3 +/- 24.4 cm(3), P = 0.005, respectively). CONCLUSIONS: This is the first report to quantify volumetric changes in the upper airway in obese children with OSAS after adenotonsillectomy showing significant residual adenoid tissue and an increase in the volume of the tongue and soft palate. These findings could explain the low success rate of AT reported in obese children with OSAS and are important considerations for clinicians treating these children.

Robotic surgical systems have been developed to augment the capabilities of the surgeon when applied to limited access surgical situations. The adaption of robotic technology to the management of oropharyngeal pathology may represent a paradigm shift in the management of early stage oral malignancies that have commonly been treated with chemoradiation due to the morbidity associated with standard open surgical techniques. The creation of a surgical defect with this approach also creates the need to develop and adapt techniques for reconstruction. Fortunately, the surgical robot is easily applied to the transposition of local flaps to meet these reconstructive needs. © 2013 Elsevier Inc.