Faculty Bibliography

PURPOSE/OBJECTIVE:Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. METHODS AND MATERIALS/METHODS:From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m(2) on day -7 and then 250 mg/m(2) on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. RESULTS:Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. CONCLUSIONS:SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time.

OBJECTIVES: True vocal fold (TVF) paralysis is a common cause of neonatal stridor and airway obstruction, though bilateral TVF paralysis is seen less frequently. Rare cases of familial congenital TVF paralysis have been described with implied genetic origin, but few genetic abnormalities have been discovered to date. The purpose of this study is to describe a novel chromosomal translocation responsible for congenital bilateral TVF immobility. METHODS: The charts of three patients were retrospectively reviewed: a 35 year-old woman and her two children. The mother had bilateral TVF paralysis at birth requiring tracheotomy. Her oldest child had a similar presentation at birth and also required tracheotomy, while the younger child had laryngomalacia without TVF paralysis. Standard karyotype analysis was done using samples from all three patients and the parents of the mother, to assess whether a chromosomal abnormality was responsible. RESULTS: Karyotype analysis revealed the same balanced translocation between chromosomes 5 and 14, t(5;14) (p15.3, q11.2) in the mother and her two daughters. No other genetic abnormalities were identified. Neither maternal grandparent had the translocation, which appeared to be a spontaneous mutation in the mother with autosomal dominant inheritance and variable penetrance. CONCLUSIONS: A novel chromosomal translocation was identified that appears to be responsible for familial congenital bilateral TVF paralysis. While there are other reports of genetic abnormalities responsible for this condition, we believe this is the first describing this particular translocation.

Importance: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) in children describes neuropsychiatric symptom exacerbations that relate temporally to streptococcal infections. Recent case reports suggest tonsillectomy may effectively reduce these symptoms; however, no consensus treatment guidelines exist. This study examines whether tonsillectomy improves neuropsychiatric symptoms in children with PANDAS who have incomplete response to antibiotic therapy. Observations: Ten patients met strict diagnostic criteria for PANDAS. Comparisons were made between parental reports of symptom severity at diagnosis, after antibiotic treatment (in 10 patients), and after tonsillectomy (in 9). From a baseline severity score of 10, antibiotics alone improved symptoms to a median (interquartile range [IQR]) score of 8 (6.5-10.0) (P = .03). Nine children who subsequently underwent tonsillectomy reported symptom improvement in comparison with treatment with antibiotics alone, including those with no response to antibiotics. Symptom severity improved at all periods after tonsillectomy compared with antibiotics alone. The median score [IQR] 3 months postoperatively was 3 (0.0-6.5) (P = .01); 6 months postoperatively, 3 (0.0-5.0) (P = .02); 1 year postoperatively, 3 (0.0-5.0) (P = .02); and 3 years postoperatively, 0.5 (0.0-2.3) (P = .03). Four of the 9 had complete resolution after tonsillectomy. Conclusions and Relevance: This PANDAS cohort whose neuropsychiatric symptoms did not respond sufficiently to antibiotics may have gained benefit from tonsillectomy.

Objectives Intraoperative vagus nerve monitoring during skull base surgery has been reported with the use of an oral nerve monitoring endotracheal tube. However, the intraoral presence of an endotracheal tube can limit exposure by its location in the operative field during transfacial approaches and by limiting superior mobilization of the mandible during transcervical approaches. We describe a transnasal vagus nerve monitoring technique. Design and Participants Ten patients underwent open skull base surgery. Surgical approaches included transcervical (five), transfacial/maxillary swing (three), and double mandibular osteotomy (two). The vagus nerve was identified, stimulated, and monitored in all cases. Main Outcome Measures Intraoperative nerve stimulation, pre- and postoperative vagus nerve function through the use of flexible laryngoscopy in conjunction with assessment of subjective symptoms of hoarseness, voice change, and swallowing difficulty. Results Three patients had extensive involvement of the nerve by tumor with complete postoperative nerve deficit, one patient had a transient deficit following dissection of tumor off of nerve with resolution, and the remaining patients had nerve preservation. One patient experienced minor epistaxis during monitor tube placement that was managed conservatively. Conclusions Transnasal vagal nerve monitoring is a simple method that allows for intraoperative monitoring during nerve preservation surgery without limiting surgical exposure.

BACKGROUND: Background noise has been found to negatively affect working memory. Numerous studies have also found that older adults perform more poorly on working memory tasks than young adults (YA). Hearing status has often been a confounding factor in older individuals. Therefore, it would be beneficial to investigate working memory functions in adverse listening conditions early in the aging process (i.e., middle-age), when hearing function is relatively unaffected. PURPOSE: The focus of this study was to determine the influence of background babble on working memory in YA and middle-aged adults (MA) with normal hearing. RESEARCH DESIGN: Before testing was begun, we established that all participants could correctly identify words in a degraded experimental testing environment with 100% accuracy. Then, the participants listened to lists composed of five pairs of words in quiet and in 20-talker babble. After the final word pair, the participants were cued with the first word of one of the previous five word pairs. The participants were required to write down the second word of the pair. The percent correct scores for each of the five serial positions were analyzed comparing the two listening conditions for YA and MA. Ten YA and ten MA with normal hearing between 250-8000 Hz and a score of at least 26/30 on the Mini-Mental State Examination participated in the study. As different cognitive processes are used for initial, middle, and final serial positions, averaged scores were obtained for Positions 2 and 3 and for Positions 4 and 5. Subsequently, repeated-measures analyses of variance (ANOVAs) were conducted on mean scores of correctly recalled word pairs with serial positions (initial, middle, and final) and listening condition (quiet, babble) as the within-participant variables and age group (YA, MA) as the between-participant independent variable. This OMNIBUS repeated-measures ANOVA was then followed up with separate repeated-measures ANOVAS for the initial, middle, and final positions. RESULTS: Correct recall scores were lower for early positions compared with the latter positions, irrespective of listening condition. For Position 1, YA-but not MA-performed significantly better in babble than in quiet. For the middle positions (Positions 2 and 3), MA performed significantly more poorly than the YA irrespective of listening condition. For the final positions (Positions 4 and 5), no age differences or effects of listening condition were found. CONCLUSIONS: The results indicate that both YA and MA have trouble recalling earlier pieces of information in quiet and in babble. However, MA exhibited significantly poorer recall scores than YA in babble for Position 1, which suggest that cognitive processes related to memory encoding and retrieval are different in background babble for MA and YA.

OBJECT Physicians are often solicited by patients or colleagues for clinical recommendations they would make for themselves if faced by a clinical situation. The act of making a recommendation can alter the clinical course being taken. The authors sought to understand this dynamic across different neurosurgical scenarios by examining how neurosurgeons value the procedures that they offer. METHODS The authors conducted an online survey using the Congress of Neurological Surgeons listserv in May 2013. Respondents were randomized to answer either as the surgeon or as the patient. Questions encompassed an array of distinct neurosurgical scenarios. Data on practice parameters and experience levels were also collected. RESULTS Of the 534 survey responses, 279 responded as the "neurosurgeon" and 255 as the "patient." For both vestibular schwannoma and arteriovenous malformation management, more respondents chose resection for their patient but radiosurgery for themselves (p = 0.002 and p = 0.001, respectively). Aneurysm coiling was chosen more often than clipping, but those whose practice was >/= 30% open cerebrovascular neurosurgery were less likely to choose coiling. Overall, neurosurgeons who focus predominantly on tumors were more aggressive in managing the glioma, vestibular schwannoma, arteriovenous malformation, and trauma. Neurosurgeons more than 10 years out of residency were less likely to recommend surgery for management of spinal pain, aneurysm, arteriovenous malformation, and trauma scenarios. CONCLUSIONS In the majority of cases, altering the role of the surgeon did not change the decision to pursue treatment. In certain clinical scenarios, however, neurosurgeons chose treatment options for themselves that were different from what they would have chosen for (or recommended to) their patients. For the management of vestibular schwannomas, arteriovenous malformations, intracranial aneurysms, and hypertensive hemorrhages, responses favored less invasive interventions when the surgeon was the patient. These findings are likely a result of cognitive biases, previous training, experience, areas of expertise, and personal values.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:The goal of this study was to present a classification based on the degree of pneumatization of the sphenoid sinus in the coronal plane that can be used to instruct preoperative planning for endoscopic endonasal surgery (EES). STUDY DESIGN/METHODS:Observational anatomical study. METHODS:The geometry of sphenoid sinus pneumatization was characterized (n = 204 hemisinus) on high-resolution computed tomography scans, and its associations with the location of the foramen rotundum (FR) and the vidian canal (VC) were measured. Based on these findings, we propose a simple classification of pneumatization of the sphenoid sinus relevant for EES. RESULTS:The lateral recess of the sphenoid sinus was pneumatized lateral to the FR in the coronal plane in 54% of patients. The distance separating the FR and the VC correlated strongly with the depth of the lateral recess. Based on these findings, we propose three types of pneumatization: type I, where the pneumatization extends from the midline to the medial edge of the VC (25%); type II, where the pneumatization reaches the medial edge of the FR (39%); and type III, where the pneumatization extends beyond the medial border of the FR (37%). CONCLUSIONS:The proposed sphenoid sinus pneumatization classification in the coronal plane is simple and reproducible. It predicts the distance between vidian and maxillary nerve, determines the size of the surgical window to access the middle cranial fossa transnasally, and instructs on the potential risk to neurovascular structures during surgery.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Head and neck squamous cell carcinoma (HNSCC) cells are resistant to cell death induced by tumor necrosis factor ligands such as tumor necrosis factor α (TNFα) or TNF-related apoptosis-inducing ligand (TRAIL) and cytotoxic chemotherapies. Recently, genetic alterations in cell death pathways, including inhibitor of apoptosis proteins, have been demonstrated in HNSCC. We investigated the effects of birinapant, a novel, second mitochondria-derived activator of caspases (SMAC)-mimetic that targets inhibitor of apoptosis proteins, alone and in combination with TNFα, TRAIL, or chemotherapy docetaxel. STUDY DESIGN/METHODS:Experimental study using human HNSCC cell lines in vitro and xenograft mouse model in vivo. METHODS:A panel of HNSCC cell lines with varying genetic alterations in cell death pathway components were treated with birinapant ± TNFα, TRAIL, and docetaxel and were assessed for effects on cell density, cell cycle, and death. Synergism was determined at varying concentrations of treatments using the Chou-Talalay method. Combination studies using birinapant ± docetaxel were performed in a xenograft mouse model. RESULTS:Birinapant, alone or in combination with TNFα or TRAIL, decreased cell density in cell lines, with IC50 s ranging from 0.5 nM to > 1 µM. Birinapant alone or with TNF significantly increased subG0 cell death in different lines. Docetaxel showed synergism with birinapant ± TNFα in vitro. Birinapant monotherapy-inhibited growth in a tumor xenograft model resistant to docetaxel, and combination treatment further delayed growth. CONCLUSIONS:Birinapant alone or in combination with TNFα or TRAIL and docetaxel decreased cell density, increased cell death, and displayed antitumor activity in a preclinical HNSCC xenograft exhibiting aberrations in cell death pathway components and docetaxel resistance.

OBJECTIVE:In a human cadaver study, a single-port operator-controlled flexible endoscope (Flex® System), facilitated with a high-definition camera and two accessory channels was tested for skull base surgery. DESIGN/METHODS:Skull base surgery was performed on human cadavers (n=4) using the Flex® System. A modified surgical midfacial approach, performed by rigid standard tools, was used for access to the sinus system, the skull base, and the middle cranial fossa. RESULTS:Endoscopic skull base visualization with the Flex® System is feasible. Surgical procedures performed included extended sinus surgery, anterior skull base approach, and visualization of the brain stem in the posterior cranial fossa. Important landmarks of the anterior skull base were visualized and manipulated by flexible compatible tools. CONCLUSION/CONCLUSIONS:The Flex® System allows for manipulation of the anterior skull base and visualization of the posterior cranial fossa in a preclinical setting. Further studies as well as development of supplemental tools are in progress.

OBJECTIVES/OBJECTIVE:Pitch plasticity has been observed in Hybrid cochlear implant (CI) users. Does pitch plasticity also occur in bimodal CI users with traditional long-electrode CIs, and is pitch adaptation pattern associated with electrode discrimination or speech recognition performance? The goals of this study were to characterize pitch adaptation patterns in long-electrode CI users, to correlate these patterns with electrode discrimination and speech perception outcomes, and to analyze which subject factors are associated with the different patterns. DESIGN/METHODS:Electric-to-acoustic pitch matches were obtained in 19 subjects over time from CI activation to at least 12 months after activation, and in a separate group of 18 subjects in a single visit after at least 24 months of CI experience. Audiometric thresholds, electrode discrimination performance, and speech perception scores were also measured. RESULTS:Subjects measured over time had pitch adaptation patterns that fit one of the following categories: (1) "Pitch-adapting," that is, the mismatch between perceived electrode pitch and the corresponding frequency-to-electrode allocations decreased; (2) "Pitch-dropping," that is, the pitches of multiple electrodes dropped and converged to a similar low-pitch; and (3) "Pitch-unchanging," that is, the electrode pitches did not change. Subjects measured after CI experience had a parallel set of adaptation patterns: (1) "Matched-pitch," that is, the electrode pitch was matched to the frequency allocation; (2) "Low-pitch," that is, the pitches of multiple electrodes were all around the lowest frequency allocation; and (3) "Nonmatched-pitch," that is, the pitch patterns were compressed relative to the frequency allocations and did not fit either the matched-pitch or low-pitch categories. Unlike Hybrid CI users which were mostly in the pitch-adapting or matched-pitch category, the majority of bimodal CI users were in the latter two categories, pitch-dropping/low-pitch or pitch-unchanging/nonmatched-pitch. Subjects with pitch-adapting or matched-pitch patterns tended to have better low-frequency thresholds than subjects in the latter categories. Changes in electrode discrimination over time were not associated with changes in pitch differences between electrodes. Reductions in speech perception scores over time showed a weak but nonsignificant association with dropping-pitch patterns. CONCLUSIONS:Bimodal CI users with more residual hearing may have somewhat greater similarity to Hybrid CI users and be more likely to adapt pitch perception to reduce mismatch with the frequencies allocated to the electrodes and the acoustic hearing. In contrast, bimodal CI users with less residual hearing exhibit either no adaptation, or surprisingly, a third pattern in which the pitches of the basal electrodes drop to match the frequency range allocated to the most apical electrode. The lack of association of electrode discrimination changes with pitch changes suggests that electrode discrimination does not depend on perceived pitch differences between electrodes, but rather on some other characteristics such as timbre. In contrast, speech perception may depend more on pitch perception and the ability to distinguish pitch between electrodes, especially since during multielectrode stimulation, cues such as timbre may be less useful for discrimination.