Faculty Bibliography

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Advances in cancer treatment have increased survival for many patients, prompting a need for greater recognition of the long-term complications of treatment. Chemotherapy agents have the potential to induce carcinogenesis and can increase the risk of secondary malignancy. Pegylated liposomal doxorubicin (PLD) used for maintenance treatment of recurrent high-grade serous cancers has been associated with the development of oral cavity squamous cell carcinoma (SCC). STUDY DESIGN/METHODS:Retrospective review. METHODS:Cases of oral cavity SCC in patients with recurrent high-grade serous cancer treated with PLD between 1997 and 2017 at a single institution were reviewed. RESULTS:). Seven patients tested positive for BRCA mutations (four BRCA 1+, three BRCA 2+). No patients had a history of alcohol or tobacco use. All had early-stage oral cavity disease; five were T1N0, two were T2N0, and one had carcinoma in situ. All patients underwent surgery, and two received adjuvant radiation. Four developed locoregional recurrence requiring additional treatment. Of these, one patient died from complications of oral SCC, one developed recurrent ovarian cancer, and two had no evidence of disease of the oral cavity or ovarian cancer at the last follow-up. CONCLUSIONS:Long-term PLD therapy may be associated with the development of oral cavity SCC. A high index of suspicion and routine head and neck examination should be included in follow-up for exposed patients. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2019.

PURPOSE/OBJECTIVE:To describe the surgical technique and outcome in a series of patients who underwent revision cochlear implantation using a double array or split electrode device. All patients developed ossified cochleae due to meningitis and were functioning poorly with the previous implant. METHODS:Four patients between the ages of 4-15 years underwent revision with five double-array cochlear implant devices. One patient underwent bilateral revision surgery. All patients had previous meningitis with CT and MRI imaging studies that demonstrated completely ossified cochleae. The time interval range between the disease and the initial cochlear implantation and was 4 months to 3 years. The patient's data were retrospectively analyzed with emphasis on the surgical technique, the number of electrodes inserted, and the number of active electrodes at follow-up. In addition, pre and post-revision surgery function was compared. RESULTS:The revision surgery was carried out 2-11 years after the initial surgery. Two tunnels, basal and apical, were drilled in the ossified cochlea. In each of the tunnels, 5 to 11 electrodes were inserted. While the number of active electrodes before revision was 0-5, after revision with the double array, it was increased to 8-12, resulting in improved auditory and speech function. CONCLUSION/CONCLUSIONS:Revision cochlear implantation with a double array implant using the two tunnel technique can increase the number of active electrodes. This leads to a better outcome in post-meningitis children with completely ossified cochleae and a poor functioning previous device.

STUDY OBJECTIVES/OBJECTIVE:The effectiveness of hypoglossal nerve stimulation (HGNS) in the treatment of obstructive sleep apnea (OSA) depends upon the selective stimulation of nerve fibers that innervate tongue muscles that produce tongue protrusion (genioglossus) and stiffening (transverse/vertical), while avoiding fibers that innervate muscles that produce tongue retraction (styloglossus/hyoglossus). Post-operative treatment failures can be related to mixed activation of retractor and protrusor muscles despite intraoperative efforts to identify and avoid nerve fibers that innervate retractor muscles. This study describes a novel intraoperative protocol that more optimally identifies mixed activation by utilizing an expanded set of stimulation/recording parameters. METHODS:Case series in a university hospital setting of patients undergoing unilateral HGNS implantation for OSA. Data included EMG responses in genioglossus and styloglossus/hyoglossus to intraoperative stimulation with an implantable pulse generator (IPG) using unipolar (---, o-o) and bipolar (+-+) settings. RESULTS:In a subset of patients (3/55), low-intensity unipolar IPG stimulation revealed significant mixed activation of styloglossus/hyoglossus and genioglossus muscles that was not evident under standard bipolar IPG stimulation conditions. Additional surgical dissection and repositioning of the electrode stimulation cuff reduced mixed activation. CONCLUSIONS:A novel intraoperative neurophysiological monitoring protocol was able to detect significant mixed activation during HGNS that was otherwise absent with standard parameters. This enabled successful electrode cuff repositioning and dramatic reduction of mixed activation.

Sequential activation of neurons has been observed during various behavioral and cognitive processes, but the underlying circuit mechanisms remain poorly understood. Here, we investigate premotor sequences in HVC (proper name) of the adult zebra finch forebrain that are central to the performance of the temporally precise courtship song. We use high-density silicon probes to measure song-related population activity, and we compare these observations with predictions from a range of network models. Our results support a circuit architecture in which heterogeneous delays between sequentially active neurons shape the spatiotemporal patterns of HVC premotor neuron activity. We gauge the impact of several delay sources, and we find the primary contributor to be slow conduction through axonal collaterals within HVC, which typically adds between 1 and 7.5 ms for each link within the sequence. Thus, local axonal "delay lines" can play an important role in determining the dynamical repertoire of neural circuits.

IMPORTANCE/OBJECTIVE:Foreign body (FB) aspiration into the airway is a significant cause of pediatric morbidity and mortality, yet the clinical presentation is diverse and dynamic. There are conflicting recommendations which pre-procedural findings support performing a bronchoscopy, the gold standard for diagnosis and removal of FBs, however a procedure that entails general anesthesia and possible risks. OBJECTIVE:Decision whether to proceed to a bronchoscopy may be challenging. Our goal was to enhance decision-making by analyzing the diagnostic values of the different pre-procedural findings in this setting. DATA SOURCES/METHODS:A comprehensive search was performed in PUBMED, EMBASE and Cochrane Review databases to find studies from the last 19 years that reported pre-procedural history, physical examination and radiological findings in patients who had bronchoscopies. STUDY SELECTION/METHODS:Studies were included of pediatric populations if they contained bronchoscopy results (positive and negative for foreign body) with a breakdown according to pre-intervention findings. DATA EXTRACTION AND SYNTHESIS/METHODS:Titles and abstracts retrieved from our search were screened. Thereafter, full-texts were carefully reviewed and selected for inclusion if the aforementioned criteria were met. PRISMA guidelines for systematic review and meta-analyses were followed. MAIN OUTCOME(S) AND MEASURE(S)/UNASSIGNED:Cumulative weighted prevalence, sensitivity, specificity, positive and negative predictive values of each pre-procedural finding were calculated, as well as for the "classic triad" (history of an acute event, wheezing, and unilateral decreased breath sounds). Calculation for other combinations of findings, or optimally, constructing a weighted score based on all the findings for each specific patient were not possible to perform, as the specific data breakdown is rarely reported. RESULTS:Fifteen studies met inclusion criteria, totaling 5606 patients who underwent bronchoscopies. All studies but one were single center based and all except one were retrospective. No single finding has both positive and negative predictive values over 50%. The "classic triad" has 90% specificity, however only 35% sensitivity. CONCLUSIONS:The data is very heterogeneous with regard to pre-procedural findings and how best to guide treatment according to them. This meta-analysis provides cumulative weighted metrics for each finding, to optimize decision-making for the individual patient. Future reporting of data should be enhanced, so that combinations of findings for a specific patient can be used to optimize management. LEVEL OF EVIDENCE/METHODS:4.

Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.

Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.

Importance/UNASSIGNED:Cochlear implants are a treatment option for individuals with severe, profound, or moderate sloping to profound bilateral sensorineural hearing loss (SNHL) who receive little or no benefit from hearing aids; however, cochlear implantation in adults is still not routine. Objective/UNASSIGNED:To develop consensus statements regarding the use of unilateral cochlear implants in adults with severe, profound, or moderate sloping to profound bilateral SNHL. Design, Setting, and Participants/UNASSIGNED:This study was a modified Delphi consensus process that was informed by a systematic review of the literature and clinical expertise. Searches were conducted in the following databases: (1) MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE, (2) Embase, and (3) the Cochrane Library. Consensus statements on cochlear implantation were developed using the evidence identified. This consensus process was relevant for the use of unilateral cochlear implantation in adults with severe, profound, or moderate sloping to profound bilateral SNHL. The literature searches were conducted on July 18, 2018, and the 3-step Delphi consensus method took place over the subsequent 9-month period up to March 30, 2019. Main Outcomes and Measures/UNASSIGNED:A Delphi consensus panel of 30 international specialists voted on consensus statements about cochlear implantation, informed by an SR of the literature and clinical expertise. This vote resulted in 20 evidence-based consensus statements that are in line with clinical experience. A modified 3-step Delphi consensus method was used to vote on and refine the consensus statements. This method consisted of 2 rounds of email questionnaires and a face-to-face meeting of panel members at the final round. All consensus statements were reviewed, discussed, and finalized at the face-to-face meeting. Results/UNASSIGNED:In total, 6492 articles were identified in the searches of the electronic databases. After removal of duplicate articles, 74 articles fulfilled all of the inclusion criteria and were used to create the 20 evidence-based consensus statements. These 20 consensus statements on the use of unilateral cochlear implantation in adults with SNHL were relevant to the following 7 key areas of interest: level of awareness of cochlear implantation (1 consensus statement); best practice clinical pathway from diagnosis to surgery (3 consensus statements); best practice guidelines for surgery (2 consensus statements); clinical effectiveness of cochlear implantation (4 consensus statements); factors associated with postimplantation outcomes (4 consensus statements); association between hearing loss and depression, cognition, and dementia (5 consensus statements); and cost implications of cochlear implantation (1 consensus statement). Conclusions and Relevance/UNASSIGNED:These consensus statements represent the first step toward the development of international guidelines on best practices for cochlear implantation in adults with SNHL. Further research to develop consensus statements for unilateral cochlear implantation in children, bilateral cochlear implantation, combined electric-acoustic stimulation, unilateral cochlear implantation for single-sided deafness, and asymmetrical hearing loss in children and adults may be beneficial for optimizing hearing and quality of life for these patients.