Faculty Bibliography

OBJECTIVE: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. METHODS: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. RESULTS: Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1wt) patients and in 59%-74% of IDH1mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. CONCLUSIONS: The D2HG product of IDH1mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas.

Applications of antibody de novo sequencing in the biopharmaceutical industry range from the discovery of new antibody drug candidates to identifying reagents for research and determining the primary structure of innovator products for biosimilar development. When murine, phage display, or patient-derived monoclonal antibodies against a target of interest are available, but the cDNA or the original cell line is not, de novo protein sequencing is required to humanize and recombinantly express these antibodies, followed by in vitro and in vivo testing for functional validation. Availability of fully automated software tools for monoclonal antibody de novo sequencing enables efficient and routine analysis. Here, we present a novel method to automatically de novo sequence antibodies using mass spectrometry and the Supernovo software. The robustness of the algorithm is demonstrated through a series of stress tests. Graphical Abstract .

Monopolar Virtual Channels (MPVCs) use current steering to increase the number of spectral channels provided to cochlear implant users beyond the physical number of electrodes. The current spread created with a current steered channel is similar to the spread found for monopolar stimulation, and this spread may be one of the bottlenecks for improved performance with an increased number of channels. Quadrupolar Virtual Channels (QPVCs) use current focusing in combination with steering in an attempt to increase the number of channels while reducing channel interaction. However, due to the potentially asymmetric current field generated by QPVCs, there may be distortions in the place pitch representation using this mode. A Virtual Tripole (VTP) is introduced as a current focused virtual channel with a relatively symmetrical electric field distribution. In this study, we looked at pitch ranking in cochlear implant users with QPVC, VTP, and MPVC configurations to determine if place pitch shifts similarly across the cochlea or if any of the stimulation modes shift non-monotonically. Results suggest that MPVC and VTP stimulation provide a consistent monotonic shift across cochlear positions while the place shift provided by QPVCs was more variable. The use of VTP stimulation would be recommended instead of QPVC for a speech processing strategy.

BACKGROUND:Postoperative cerebrospinal fluid leak after endoscopic pituitary surgery ranges from 1.9% to 10% in different series. Vascularized flaps have reduced the incidence of leak; however, this carries nasal morbidity. This study presents a technique for sellar reconstruction with free mucosal graft from the nasal cavity floor including inferior meatus mucosa. This technique aims to standardize sellar reconstruction without the use of the nasoseptal flap and to keep the advantage of mucosal coverage of the defect in all cases. METHODS:Fifty consecutive patients who had endoscopic surgery for pituitary tumors and reconstruction with nasal cavity floor free mucosal graft were retrospectively reviewed. There were a total of 50 patients with postoperative follow-up from 3 to 16 months. Collagen dural graft was used inlay and free mucosal graft overlay to cover the sellar defect. No fat grafts or lumbar drains were used. A Sinonasal Outcome Test-22 (SNOT-22) was performed before, 1 and 3 months after surgery. RESULTS:There were 40% detected intraoperative leaks and no postoperative leaks. Nasal endoscopy performed at 1 month follow-up showed complete healing of the graft to the skull base and near total or complete mucosalization of the donor site. No significant difference was found in the SNOT-22 comparing the total preoperative and 1-month scores. CONCLUSIONS:The nasal cavity floor free mucosal graft is an easy and safe technique, with minimal nasal morbidity. There were no postoperative cerebrospinal fluid leaks, despite aggressive tumor resection. No lumbar drains or fat graft were used. The harvest of mucosal graft does not worsen the quality of life measured with the SNOT-22 test.

Objective Although thyroglossal duct cysts (TGDCs) are relatively common, malignancies within these lesions are infrequent. As a result, there are no large-scale series describing clinical characteristics. Our objectives were to perform a systematic review of the literature evaluating patient demographics, pathology, management, and prognosis of these patients. Data Sources PubMed, Embase, Cochrane reviews, and Google Scholar were searched for relevant articles. Articles meeting inclusion criteria were reviewed for data detailing epidemiology, treatment, and outcomes. Review Methods Inclusion criteria included English-language articles with original reports on human subjects. Two investigators independently reviewed all articles for the data collected, including epidemiology, treatment, and outcomes. Results Ninety-eight articles comprising 164 patients were included in the final analysis. The mean age at presentation was 39.5 years (9-83 years); 68.3% of patients were female. In total, 73.3% of cases were found on final pathologic analysis. The most common pathology was papillary cancer (92.1%). Of the patients, 98.9% underwent a Sistrunk procedure and 61.0% underwent total thyroidectomy. There was a 4.3% recurrence rate with a mean time to recurrence of 42.1 months from initial treatment. One patient died of TGDC carcinoma, while all other patients were disease free at the time of last follow-up (mean follow-up was 46.1 months). Conclusion TGDC carcinoma is typically diagnosed on final pathology. While management encompasses a Sistrunk procedure, further consideration should be given to thyroidectomy among patients ≥45 years of age and individuals with aggressive disease. TGDC carcinoma harbors an exceedingly low rate of mortality.

According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

Providing affordable, high-quality care for the 10 million persons who are dual-eligible beneficiaries of Medicare and Medicaid is an ongoing health-care policy challenge in the United States. However, the workforce and the care provided to dual-eligible beneficiaries are understudied. The purpose of this article is to provide a narrative of the challenges and lessons learned from an exploratory study in the use of clinical and administrative data to compare the workforce of two care models that deliver home- and community-based services to dual-eligible beneficiaries. The research challenges that the study team encountered were as follows: (a) comparing different care models, (b) standardizing data across care models, and (c) comparing patterns of health-care utilization. The methods used to meet these challenges included expert opinion to classify data and summative content analysis to compare and count data. Using descriptive statistics, a summary comparison of the two care models suggested that the coordinated care model workforce provided significantly greater hours of care per recipient than the integrated care model workforce. This likely represented the coordinated care model's focus on providing in-home services for one recipient, whereas the integrated care model focused on providing services in a day center with group activities. The lesson learned from this exploratory study is the need for standardized quality measures across home- and community-based services agencies to determine the workforce that best meets the needs of dual-eligible beneficiaries.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To evaluate subsite-specific differences in survival between squamous cell carcinomas of the base of tongue and tonsillar fossa in a modern cohort likely to have been treated with intensity-modulated radiation therapy, chemotherapy for stage III and IV, and have had a high incidence of human papillomavirus-associated tumors. STUDY DESIGN/METHODS:Retrospective cohort analysis utilizing data from the Surveillance, Epidemiology, and End Results program of patients with base of tongue and tonsillar fossa squamous cell carcinoma from 2004 to 2011. METHODS:The cohort included 15,299 primary base of tongue and tonsillar fossa squamous cell carcinoma patients without distant metastases treated between 2004 and 2011. Subsite differences in overall survival and disease-specific survival were examined with Kaplan-Meier curves. Multivariate cox proportional hazard ratios were estimated for overall and disease-specific survival. RESULTS:The cohort included 7,220 (47.2%) base of tongue and 8,079 (52.8%) tonsillar fossa squamous cell carcinoma patients. Overall survival with all stages combined favored tonsillar fossa (P < .001) and remained superior when stratified by stage. In multivariate analyses adjusted for age, gender, race, and treatment, the hazard ratio for overall survival was superior for tonsillar fossa tumors compared to base of tongue tumors for all stages (stage 1, P = .041; stage 2, P = .006; stages 3 and 4, P < .001). Disease-specific survival also favored improved outcomes for tonsillar fossa. CONCLUSIONS:In this large modern cohort, overall and disease-specific survival favored outcomes in tonsillar fossa compared with base of tongue. Further study is required to evaluate factors that influence survival differences between tonsillar fossa and base of tongue despite modern therapy. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 127:1087-1092, 2017.

The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.

Background/Purpose: The reconstruction of the wide Tessier #4 cleft is classically limited by persistent lower lid ectropion/medical canthal disruption or the incorporation of unaesthetically located scars which violate the subunit border principle of facial reconstruction. We present a novel repair technique which: can be applied at infancy; does not require tissue expansion; restores stable lower eyelid and medial canthal position; and respects the subunit border principle of facial repair. Methods/Description: A neonate with a complete, wide, Tessier #4 facial cleft presents with an over 2/3rd lower eyelid loss. Presurgical tape therapy was applied to lengthen the lateral tissues transversely and vertically. A Tenzel flap extended to a Schrudde cervicofacial flap was planned to radically mobilize the lower eyelid to the medial canthus in a tension-free manner. A robust vascular supply was maintained to this large flap using a deep plane dissection. Results: Surgical repair was performed at 3 months of age. No tissue expansion was used. A Tenzel pattern flap was mobilized in the subcutaneous plane. This flap was raised in continuity with a Schrudde cervicofacial flap raised in the deep plane. Facial nerves were directly visualized and preserved during the operation. A conjunctival flap was raised from the floor of the orbit was used to reconstruct the posterior lamella of the lower eyelid. The Tenzel/Schrudde flap was rotated, without tension over the defect and to the nose/cheek junction. At the time of inset, there was redundant flap skin superiorly at the level of the lower eyelid and medially at the area of the medial canthus. This redundancy was incorporated into the reconstruction to prevent ectropion and medial canthus disruption. Suspensory sutures were applied to the infraorbital rim and pyriform aperture to prevent sagging of the flap. A Millard repair was used to reconstruct the lip at the level of the philtrum. The flap demonstrated 100% take despite radical mobilization. The final scar followed the philtral line, the nasal/cheek junction, the subcilliary line and the anterior auricular/retro auricular border. Lower eyelid and medial canthal position was stable after 6 months. Facial nerve function was preserved with this approach. Conclusions: A Tenzel/Schrudde deep-plane cervicofacial flap can be safely applied to infants with a wide Tessier #4 facial cleft. No tissue expansion is needed. This is the first repair technique which places final scars perfectly along the subunit borders of the face while preserving lower eyelid and medial canthal position, even in the patient with significant lower eyelid loss