Faculty Bibliography

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory central nervous system. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABA_A and GABA_B receptor-mediated inhibitory postsynaptic potentials (IPSPs) in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes, but when administered after the critical period it only restored GABA_B receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate α1 subunit-dependent GABA_A responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABA_A and GABA_B IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented.SIGNIFICANCE STATEMENTEven a temporary period of childhood hearing loss can induce communication deficits that persist long after auditory thresholds return to normal. These deficits may arise from long-lasting central impairments, including the loss of synaptic inhibition. Here, we asked whether hearing loss-induced behavioral deficits could be reversed by reinstating normal inhibitory strength. Gerbils reared with transient hearing loss displayed both learning and perceptual deficits. However, when animals were treated with a selective GABA reuptake inhibitor during or after hearing loss, behavioral deficits were entirely corrected. This behavioral recovery was correlated with the return of normal thalamic and cortical inhibitory function. Thus, some perceptual and cognitive deficits induced by developmental hearing loss were prevented with a treatment that rescues a central synaptic property.

Background/UNASSIGNED:Annually, over 65,000 persons are diagnosed with head and neck cancer in the United States. During treatment, up to 50% of patients become severely symptomatic with pain, fatigue, mouth sores, and inability to eat. Long term complications are lymphedema, fibrosis, dysphagia, and musculoskeletal impairment. Patients' ability to perform daily activities and to interact socially may be impaired, resulting in poor quality of life. A pragmatic, clinically useful assessment is needed to ensure early detection and intervention for patients to report symptoms and functional limitations over time. We developed the Electronic Patient Visit Assessment (ePVA) that enables patients to report 42 symptoms related to head and neck cancer and 17 limitations of functional status. This manuscript reports (I) the development of the ePVA, (II) the content validity of the ePVA, and (III) the usability and reliability of the ePVA. Methods/UNASSIGNED:Usability was evaluated using the "Think Aloud" technique to guide the iterative process to refine the ePVA based on participants' evaluations. After signing the informed consent, 30 participants with head and neck cancer completed the ePVA using digital tablet devices while thinking aloud about ease of use. All patient conversations were recorded and professionally transcribed. Reliability of the ePVA symptom and functional limitation measures was estimated using the Kuder-Richardson test. Convergent validity of the ePVA was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 global QoL/health scale. Transcribed qualitative data were analyzed using directed content analysis approach. Quantitative analyses consisted of descriptive statistics and correlation analyses. Results/UNASSIGNED:Among participants, 90% strongly agreed or agreed that the ePVA system was easy to use and 80% were very satisfied. Only minor usability problems were reported due to formatting and software "bugs". Reporting of usability problems decreased in frequency over the study period and no usability problems were reported by the last 3 participants who completed the ePVA. Based on participants' suggestions during the iterative process, refinement of the ePVA included increased touch sensitivity of the touch screen technology and customized error messages to improve ease of use. The ePVA also recorded patient reported symptoms (mouth symptoms: 93%, fibrosis: 60%, fatigue: 60%). The ePVA demonstrated acceptable reliability (alpha =0.82-0.85) and convergent validity (ePVA total number of reported symptoms and function limitations was negatively correlated with EORTC QLQ-C30 global QOL/health scale: r=-0.55038, P<0.01). Conclusions/UNASSIGNED:The ePVA was rigorously developed, accepted by patients with satisfaction, and demonstrated acceptable reliability and convergent validity. Future research will use data generated by the ePVA to determine the impact of symptom trajectories on functional status, treatment interruptions and terminations, and health resource use in head and neck cancer.

The BRAF-V600E mutation is found in 15-20% of pediatric low grade gliomas (PLGG) and result in worse outcome and higher risk of transformation to high grade gliomas (PHGG). Although ongoing trials are assessing the role of BRAF inhibitors (BRAFi) in these children, data are still limited. We aimed to report overall response rates and predictors of outcome in childhood BRAF-V600E gliomas. We collected clinical, imaging and molecular information of patients treated with BRAFi outside trials from centers participating in the PLGG taskforce. Response was calculated by RANO criteria and follow up data were collected for all patients. Sixty-six patients were treated with BRAFi (55 PLGG and 11 PHGG); median follow-up time was 1.5 years (0.1-5y). In PLGG, objective response (tumor reduction of >25%) was observed in 77% compared to 15% in a cohort treated with conventional chemotherapy (pCDKN2A deletion was not associated with lack of response, while specifc enhancing patterns correlated strongly with response to BRAFi. Two-year PFS for the BRAF-V600E PLGG was 74% vs 47% for BRAFi vs chemotherapy, respectively (p=0.02). Our data reveal rapid, dramatic and sustained response of BRAF-V600E PLGG to BRAFi. These are in contrast to BRAF-V600E PHGG and non-enhancing PLGG. Additional molecular analyses are being performed to identify poor responders and emerging mechanisms of resistance in these tumors

BACKGROUND:H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS:Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS/RESULTS:Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION/CONCLUSIONS:The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

BACKGROUND:Is posttreatment functional status prognostic of overall survival in patients with head and neck cancer (HNC). METHODS:In an HNC clinical trial, 495 patients had two posttreatment functional assessments measuring diet, public eating, and speech within 6 months. Patients were grouped by impairment (highly, moderately, modestly, or not impaired) and determined if they improved, declined, or did not change from the first assessment to the second. Multivariable Cox models estimated overall mortality. RESULTS:Across all three scales, the change in posttreatment patient function strongly predicted overall survival. In diet, patients who declined to highly impaired had three times the mortality of patients who were not impaired at both assessments (hazard ratio [HR] = 3.60; 95% confidence interval, 2.02-6.42). For patients improving from highly impaired, mortality was statistically similar to patients with no impairment (HR = 1.38; 95% CI, 0.82-2.31). CONCLUSIONS:Posttreatment functional status is a strong prognostic marker of survival in patients with HNC.

A growing number of patients are seeking answers for their health concerns online. This study assesses the reliability, quality, and readability of online materials patients have access to through the Internet and evaluates the social media presence of information providers. An online search was conducted for facial rejuvenation by utilizing three ubiquitously used web search engines: Google, Bing, and Yahoo. The first 25 result pages were collected from each search engine, and exclusionary criteria were applied to exclude online stores and advertisements. Website reliability and quality were assessed via the DISCERN method. Readability was measured through six measurements: Flesch-Kincaid Grade Level (FKGL), Gunning Fox score, SMOG index, Coleman Liau index, and automated readability index. Social media presence and profile followers on Facebook, Twitter, and Instagram were determined to gauge social media presence. Exclusionary criteria yielded 41 unique websites, with the majority of websites authored by physicians (54%) followed by professional organizations (19%). The DISCERN method demonstrated that journal websites yielded the highest overall quality (4.00) and physician websites yielded the lowest (2.72). Readability analysis demonstrated that online forums proved the most challenging to read, and encyclopedia articles were the least challenging. Physician websites maintained the highest social media presence (95%) followed by professional organizations (75%). However, professional organizations had more social media followers in comparison to physician websites. Physician websites and professional organizations overwhelmingly command social media presence compared to other information providers and provide information with serious deficits in reliability and quality. A strong majority of online information also surpasses the health care literacy of patients. This poses a serious concern for physicians who need to provide and guide patients to high quality and reliable information.

Purpose: The purpose of this study is to quantify interfractional dosimetric variations in radiotherapy of oropharyngeal cancer and investigate the application of statistical process control (SPC) to determine significantly deviated fractions for management.
Method(s): Thirteen oropharyngeal cancer patients treated by IMRT or VMAT with daily CBCT were retrospectively reviewed. CBCT images of every other fraction were imported to the software Velocity and registered to planning CT using the 6DOF couch shifts generated during patient setup. Using Velocity Adaptive Monitoring module, the setup-corrected CBCT was matched to planning CT using a deformable registration. The module also generated dose volume histograms (DVHs) at each CBCT from planning doses for the deformed plan structure sets. Volumes and dose metrics at each fraction were calculated and rated with plan values to evaluate interfractional dosimetric variations using a SPC framework. T-tests between plan and fraction volumes were performed to find statistically insignificant fractions. Average, upper and lower process capacity limits (UCL, LCL) of each dose metric were derived from these fractions using conventional SPC guidelines.
Result(s): GTV and OAR volumes in first 13 fractions had no significantly changes from the plan, subsequently reduced by 10% to treatment completion, except oral cavity. There were 3%-4% increases in parotid mean doses, but no significant differences in dose metrics of GTVand other OARs. The changes were organ and patient dependent. Control charts for various dose metrics were generated to assess the metrics for individual patient. The occurrences of one or several dose metrics out of the control limits warrant immediate investigation of the fraction.
Conclusion(s): Daily CBCT could be used to monitor dosimetric variations of targets and OARs resulting from volume changes and tissue deformation in oropharyngeal cancer radiotherapy. Treatment review with guidance of a SPC tool may enable objectively and consistently identify significantly deviated fractions

Purpose: Concurrent chemotherapy with radiotherapy is the standard of care for locally advanced oropharyngeal cancer patients. However, the main drawback of this approach is the high toxicities experienced by the patients. This has motivated new clinical trials that investigate the role of imaging biomarkers in dose de-escalation to mitigate the side effects of treatments.
Method(s): Ten patients from an institutional phase II clinical trial were CE-CT (Contrast-Enhanced-CT) simulated prior to starting radiotherapy treatment and at week-four as part of the protocol. A radiation oncologist manually contoured the GTVn (primary nodal disease) on both scans. Based on GTVn volume variation (>=40%) patients were eligible/ineligible for dose de-escalation. CE-CT scans and contours were transfer to IBEX for texture-feature calculation. The relative net change for 77 texture-features was calculated. The Pearson correlation coefficient (r) was used to correlate the volume change with the feature changes. Texture-features that presented an r >0.5 are possible candidates for treatment assessment. Significance level was evaluated using the t-test (P < 0.05) Results: Eight patients met criteria for mid-treatment nodal response and were de-escalated. For the two patients who proceeded with standard treatment, shape texture-features variation were low, ranging [-6% to 14%] when compared to de-escalated patients range [-0% to 60%]. Across all the patients two shape features (surface area and surface area density) showed high correlation with node-tumor volume changes, with r-values of 0.81 (P < 0.05) and -0.66 (P < 0.05). Histogram-based-likeskewness showed a medium correlation with r-value of 0.52 (P > 0.05), whereas dissimilarity feature from the Gray-Level-Occurrence-Matrix showed correlation of 0.63 (P < 0.05).
Conclusion(s): Features with high Pearson correlation values are potential candidates to be used as additional metrics for treatment assessment. The study includes other imaging modalities (e.g MRI and PET) which will be included as a future work. More analysis will be added to the study as more patients are continually enrolled in the protocol

OBJECTIVES/OBJECTIVE:To examine the correlation between pharyngeal residue severity and clearance to penetration/aspiration on fiber-optic endoscopic examination of swallowing (FEES). DESIGN/METHODS:Retrospective cohort. SETTING/METHODS:Kaplan Medical Center dysphagia clinic. PARTICIPANTS/METHODS:Patients (N=110) visiting a dysphagia clinic between 2014 and 2016 undergoing FEES. INTERVENTIONS/METHODS:FEES were scored for penetration/aspiration with the Penetration Aspiration Scale (PAS), for residue severity using the Yale Pharyngeal Residue Severity Rating Scale (YPR-SRS). The numbers of swallows required to clear the pharynx were recorded. The first and the worst bolus challenges for each consistency (liquid, purée, solid) were analyzed. MAIN OUTCOME MEASURES/METHODS:YPR-SRS and number of clearing swallows were correlated with the PAS of the same bolus challenge. RESULTS:The study population's mean age was 67±13.4 years; 54% were men (n=58). A significant correlation was found between the YPR-SRS and the PAS for all consistencies tested, in each anatomical site (vallecula or pyriform sinus) and for both the first and worst bolus challenges (P<.001 for all). The correlation of residue with aspiration was stronger when vallecula and pyriform sinuses scores were summated (Pearson product-moment correlation coefficient=0.573/0.631/0.446 for liquid/purée/solid for worst bolus challenge). Incorporating the number of clearing swallows to the YPR-SRS strengthened the correlation with PAS. CONCLUSIONS:Residue severity and clearance correlate with penetration/aspiration on FEES. The YPR-SRS can be applied to standardize description of residue in FEES and to aid in dysphagia evaluation.