Faculty Bibliography

Oral cavity cancer has a low 5-y survival rate, but outcomes improve when the disease is detected early. Cytology is a less invasive method to assess oral potentially malignant disorders relative to the gold-standard scalpel biopsy and histopathology. In this report, we aimed to determine the utility of cytological signatures, including nuclear F-actin cell phenotypes, for classifying the entire spectrum of oral epithelial dysplasia and oral squamous cell carcinoma. We enrolled subjects with oral potentially malignant disorders, subjects with previously diagnosed malignant lesions, and healthy volunteers without lesions and obtained brush cytology specimens and matched scalpel biopsies from 486 subjects. Histopathological assessment of the scalpel biopsy specimens classified lesions into 6 categories. Brush cytology specimens were analyzed by machine learning classifiers trained to identify relevant cytological features. Multimodal diagnostic models were developed using cytology results, lesion characteristics, and risk factors. Squamous cells with nuclear F-actin staining were associated with early disease (i.e., lower proportions in benign lesions than in more severe lesions), whereas small round parabasal-like cells and leukocytes were associated with late disease (i.e., higher proportions in severe dysplasia and carcinoma than in less severe lesions). Lesions with the impression of oral lichen planus were unlikely to be either dysplastic or malignant. Cytological features substantially improved upon lesion appearance and risk factors in predicting squamous cell carcinoma. Diagnostic models accurately discriminated early and late disease with AUCs (95% CI) of 0.82 (0.77 to 0.87) and 0.93 (0.88 to 0.97), respectively. The cytological features identified here have the potential to improve screening and surveillance of the entire spectrum of oral potentially malignant disorders in multiple care settings.

BACKGROUND:To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS:once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS:Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION/CONCLUSIONS:Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

Mycobacterium avium-intracellulare complex (MAC) is one of the most common forms of non-tuberculous mycobacterial (NTM) infection. MAC is a ubiquitous bacterium that resides in both natural and man-made environments. Surgical intervention is well established in NTM infections causing cervical lymphadenitis, but its role in airway disease is not well understood. Invasive pulmonary infection is usually associated with immunocompromised patients, but it occurs in otherwise healthy children as well. We present a challenging clinical case of an 18-month-old female with severe mediastinal MAC causing bilateral bronchogenic obstruction and respiratory compromise requiring emergent intubation and intervention, likely due to a genetic predisposition secondary to Interferon Gamma Receptor 2 (IFNGR2) haploinsufficiency. During the initial bronchoscopy, the left bronchus was 99% obstructed while the right bronchus was 60% obstructed. The right lesion was biopsied and drained whitish fluid with improvement in clinical status shortly thereafter. A culture was sent. Follow-up bronchoscopy with excision of residual right mass allowed for extubation in the operating room with discharge on azithromycin, rifabutin, and ethambutol. Repeat bronchoscopy after discharge revealed recurrence of bilateral lesions. The patient was started on nebulized amikacin in addition to her current regimen with full resolution after treatment. Despite subtotal removal of MAC lesions possibly increasing the chances of recurrence, surgical intervention in this patient resulted in rapid improvement in respiratory status, and it may represent the preferred treatment in patients with any airway concerns.

PURPOSE:Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA. PATIENTS AND METHODS:E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections. RESULTS:120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients. CONCLUSIONS:We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Infant cries evoke powerful responses in parents^1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter^5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval^10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To assess the safety and efficacy of autologous cultured fibroblasts (ACFs) to treat dysphonia related to vocal fold scar and age-related vocal atrophy (ARVA). STUDY DESIGN/METHODS:Randomized, double-blinded, placebo-controlled, multi-institutional, phase II trial. METHODS:cells or placebo saline was performed at 4-week intervals for each vocal fold. Follow-up was performed at 4, 8, and 12 months. The primary outcome was improved mucosal waves. Secondary outcomes included Voice Handicap Index (VHI)-30, patient reported voice quality outcomes, and perceptual analysis of voice. RESULTS:Fifteen subjects received ACF and six received saline injections. At 4, 8, and 12 months after ACF treatments, a significant improvement in mucosal wave grade relative to baseline was observed in both vocal scar and ARVA groups. Relative to control group, mucosal waves were significantly improved in the ARVA group at 4 and 8 months. Perceptual analysis significantly improved in the vocal scar group 12 months after ACF treatments compared to controls. Vocal scar group reported significantly improved vocal quality from baseline. VHI and expert rater voice grade improved in both groups, but did not achieve significance. No adverse events related to fibroblast injections were observed. CONCLUSIONS:In this cohort, injection of ACFs into the vocal fold lamina propria (LP) was safe and significantly improved mucosal waves in patients with vocal scar and ARVA. ACF may hold promise to reconstruct the LP. LEVEL OF EVIDENCE/METHODS:1 Laryngoscope, 2019.

OBJECTIVE:To investigate and improve compliance of thyroid function monitoring in head and neck cancer patients who received radiotherapy to the cervical region before and after instituting quality improvement interventions. METHODS:Using the Plan, Do, Study, Act (PDSA) methodology, patients with head and neck malignancies who received radiotherapy to the cervical region from 2013-2015 were identified at a tertiary medical center. The status of the patients' thyroid monitoring and related characteristics were recorded. A quality improvement project was subsequently implemented by data sharing and providing feedback to practitioners involved in head and neck cancer care and creating a tracking database for all patients who received radiotherapy to the neck. After implementation of these interventions, data was collected on patients meeting the inclusion criteria from 2015-2017. RESULTS:One hundred fifty-six patients met criteria pre-intervention and ninety-eight patients met criteria post-intervention. Compliance of thyroid monitoring went up from 34% to 80% after interventions (P < .0001). There was a significant increase in thyroid testing performed by radiation oncologists after interventions from 2% to 21%, while medical oncologists and otolaryngologists remained consistent in their compliance rates. CONCLUSION/CONCLUSIONS:It is possible to improve compliance with evidence-based recommendations and improve the quality-of-care for head and neck cancer survivors through simple, cost effective interventions. LEVEL OF EVIDENCE/METHODS:2 Laryngoscope, 2019.

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. PNI induced afterdischarge in A high threshold mechanoreceptors (AHTMRs), mechanical sensitization (i.e., decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low threshold mechanoreceptors (LTMRs). PNI resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically-insensitive and electrically-unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.