Patterns of recurrence and disease progression in patients with positive-margin olfactory neuroblastoma following primary resection.

OBJECTIVE: Olfactory neuroblastoma (ONB) is a rare, malignant tumor of the sinonasal tract that arises from olfactory epithelium. Although surgery is the preferred first-line treatment, tumor involvement of adjacent structures may preclude the ability to achieve negative margins during initial resection. Herein, the authors examine the oncological outcomes of patients with positive margins after primary resection of ONB, with the aim of determining predictors of disease progression and patterns of recurrence. METHODS: The authors performed an institutional review of 25 patients with positive-margin ONB after resection. Cox survival analyses were used to determine any statistically significant predictors of worse progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 93 patients who were diagnosed with ONB were identified, of whom 25 patients had positive margins following their primary resection. Eleven (44%) had a delayed finding of positive margins that were initially negative in the operating room but returned as positive on final pathology. Four patients had subtotal resection (STR), whereas the remaining patients underwent gross-total resection. Twenty-four patients received adjuvant radiotherapy (96%), and 15 additionally received adjuvant chemotherapy (60%). Fourteen patients (56%) experienced recurrence/progression at a median time of 35 months following resection (IQR 19-70 months). Local recurrence occurred in 10 patients (40%), regional in 9 (36%), and distant metastasis in 2 (8%). In Cox survival analyses, the 5-year PFS and OS were 55.1% and 79.2%, respectively. Kadish stage D was predictive of worse PFS in univariate (hazard ratio [HR] 15.67, 95% CI 3.38-72.61, p < 0.001) and multivariate (HR 15.46, 95% CI 1.45-164.91, p = 0.023) analyses. Hyams grade, adjuvant chemotherapy, and primary radiotherapy were not associated with PFS. Furthermore, Kadish stage D and STR were predictive of worse OS in univariate analysis (HR 12.64, 95% CI 2.03-78.86, p = 0.007; HR 7.31, 95% CI 1.45-36.84, p = 0.016; respectively). However, local and regional recurrence was not associated with worse OS. CONCLUSIONS: Approximately half of patients with positive-margin ONB may experience disease recurrence. Patients with an advanced disease stage (Kadish D) may have a higher likelihood of developing recurrence/progression. Furthermore, patients with tumor burden following resection (STR and Kadish D) may have worse OS. However, in positive-margin ONB with no gross disease following initial resection, the presence of disease recurrence does not significantly alter survival when receiving salvage therapy.

Association Between Social Determinants of Health, Distance from Treatment Center, and Treatment Type with Outcomes in Human Papillomavirus Associated Oropharyngeal cancer.

OBJECTIVES: Social determinants of health (SDOH) can influence access to cancer care, clinical trials, and oncologic outcomes. We investigated the association between SDOH, distance from treatment center, and treatment type with outcomes in human papillomavirus associated oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] patients treated at a tertiary care center. STUDY DESIGN: Retrospective review. METHODS: HPV(+)OPSCC patients treated surgically from 2006 to 2021 were selected from our departmental Oropharyngeal Cancer RedCap database. Demographic data, treatment, and oncologic outcomes were extracted. Distance was calculated in miles between the centroid of each patient zip code and our hospital zip code (zipdistance). RESULTS: 874 patients (89 % male; mean age: 58 years) were identified. Most patients (96 %) reported Non-Hispanic White as their primary race. 204 patients (23 %) had a high-school degree or less, 217 patients (25 %) reported some college education or a 2-year degree, 153 patients (18 %) completed a four-year college degree, and 155 patients (18 %) had post-graduate degrees. Relative to those with a high-school degree, patients with higher levels of education were more likely to live further away from our institution (p < 0.0001). Patients who received adjuvant radiation therapy elsewhere lived, on average, 104 miles further away than patients receiving radiation at our institution (Estimate 104.3, 95 % CI 14.2-194.4, p-value = 0.02). In univariable Cox PH models, oncologic outcomes did not significantly differ by zipdistance. CONCLUSIONS: Education level-and access to resources-varied proportionally to a patient's distance from our center. Patients travelling further distances for surgical management of OPSCC were more likely to pursue adjuvant radiation therapy at an outside institution. Distance traveled was not associated with oncologic outcomes. Breaking down barriers to currently excluded populations may improve access to clinical trials and improve oncologic outcomes for diverse patient populations.

The Effects of Gross Cranial Nerve Invasion on Oncologic Outcomes in Patients with HPV(+)OPSCC.

OBJECTIVES: This study examines oncologic outcomes in patients with HPV-related oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) who had evidence of gross cranial nerve invasion (CNI) identified at the time of surgery. STUDY DESIGN: Retrospective cohort study comparing demographics, clinical features, and outcomes of HPV(+)OPSCC patients with and without gross CNI. METHODS: Patients with biopsy proven HPV(+)OPSCC involving the base of tongue, tonsil, or unknown primary site, who underwent surgery as a part of their treatment between 1/1/2006-12/31/2020 (n = 874), were included in this study. Gross CNI was identified during operative intervention (n = 36). Statistical analyses were performed using SAS version 9.4 and R version 3.6.2. P-values <0.05 were considered statistically significant. RESULTS: HPV(+)OPSCC patients with gross CNI were nearly 5 times as likely to suffer death by cancer (HR = 5.41, 95% CI 2.51 to 11.67, p < 0.0001), over 4 times as likely to see disease progression (HR = 4.25, 95% CI 2.31 to 7.84, p < 0.0001), and nearly 5 times as likely to experience metastasis (HR = 4.46, 95% CI 2.20 to 9.06, p < 0.0001) when compared to patients without CNI. Patients with gross CNI had significantly lower overall survival, cancer-specific survival, progression-free survival, and distant-metastasis free survival (p < 0.0001). Patients with gross CNI were significantly more likely to present with higher clinical N stage, higher pathological N stage and extracapsular spread than patients without gross CNI. CONCLUSIONS: Our findings indicate that the presence of CNI is associated with significantly poorer oncologic outcomes in HPV(+)OPSCC patients. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:170-177, 2024.

Risk of Monopolar Electrosurgery in Cochlear Implant Recipients is Nominal: Evidence to Guide Clinical Practice.

OBJECTIVE: Comprehensively assess the prevalence of monopolar electrosurgery-related device complications among cochlear implant (CI) recipients. STUDY DESIGN: Multifaceted retrospective review and survey. SETTING: Tertiary medical center. METHODS: Multifaceted approach including: (i) review of the current literature; (ii) historical review of institutional data from an academic, tertiary CI center; (iii) review of industry data provided by 3 Food and Drug Administration-approved CI manufacturers; and (iv) survey of high-volume CI centers. RESULTS: Literature review identified 9 human studies, detailing 84 devices with 199 episodes of device-cautery exposure. From studies reporting on patients records, no implant showed evidence of damage after exposure. One cadaveric study using dental cautery reported 1 episode of device damage. Review of institutional records did not identify any CI damage in 84 instances of exposure. Data from the 3 major implant manufacturers showed a single report of damage that could be reasonably linked to monopolar electrosurgery, out of a possible 689,426 CIs. Last, a survey of 8 high-volume CI centers did not identify any adverse events associated with monopolar cautery. CONCLUSION: These data estimate the risk of adverse device-related events or tissue injury to be extraordinarily low. Short of operating in immediate proximity to the CI (ie, the ipsilateral temporoparietal scalp), these data indicate that monopolar electrosurgery can be used in the body and the head-and-neck of CI recipients with nominal risk. These findings may guide decision-making in cases that are optimally or preferably performed with monopolar electrocautery and can be used to counsel CI patients following inadvertent exposures.

Assessing the capacity of methylated DNA markers of cervical squamous cell carcinoma to discriminate oropharyngeal squamous cell carcinoma in human papillomavirus mediated disease.

OBJECTIVE: Early identification of human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) is challenging and novel biomarkers are needed. We hypothesized that a panel of methylated DNA markers (MDMs) found in HPV(+) cervical squamous cell carcinoma (CSCC) will have similar discrimination in HPV(+)OPSCC tissues. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissues were obtained from patients with primary HPV(+)OPSCC or HPV(+)CSCC; control tissues included normal oropharynx palatine tonsil (NOP) and cervix (NCS). Using a methylation-specific polymerase chain reaction, 21 previously validated cervical MDMs were evaluated on tissue-extracted DNA. Discrimination between case and control cervical and oropharynx tissue was assessed using area under the curve (AUC). RESULTS: 34 HPV(+)OPSCC, 36 HPV(+)CSCC, 26 NOP, and 24 NCS patients met inclusion criteria. Within HPV(+)CSCC, 18/21 (86%) of MDMs achieved an AUC ≥ 0.9 and all MDMs exhibited better than chance classifications relative to control cervical tissue (all p < 0.001). In contrast, within HPV(+)OPSCC only 5/21 (24%) MDMs achieved an AUC ≥ 0.90 but 19/21 (90%) exhibited better than chance classifications relative to control tonsil tissue (all p < 0.001). Overall, 13/21 MDMs had statistically significant lower AUCs in the oropharyngeal cohort compared to the cervical cohort, and only 1 MDM exhibited a statistically significant increase in AUC. CONCLUSIONS: Previously validated MDMs exhibited robust performance in independent HPV(+)CSCC patients. However, most of these MDMs exhibited higher discrimination for HPV(+)CSCC than for HPV(+)OPSCC. This suggests that each SCC subtype requires a unique set of MDMs for optimal discrimination. Future studies are necessary to establish an MDM panel for HPV(+)OPSCC.

Cochlear Implant Outcomes between Patients with Sporadic and Neurofibromatosis Type 2-Associated Vestibular Schwannoma.

OBJECTIVE: Compare cochlear implant (CI) performance between patients with ipsilateral sporadic vestibular schwannoma (VS) and NF2-related schwannomatosis (NF2). Compare CI performance according to VS management modality. STUDY DESIGN: Historical cohort. SETTING: Tertiary academic center. PATIENTS: Forty-nine patients (52 ears) undergoing cochlear implantation in the setting of ipsilateral sporadic (n = 21) or NF2-associated VS (n = 28). INTERVENTIONS: CI ipsilateral to VS. MAIN OUTCOME MEASURES: Auditory thresholds, consonant-nucleus-consonant (CNC) word scores, and AzBio sentences in quiet scores. RESULTS: Among all patients, median post-CI pure tone average was 28 dB HL (interquartile range [IQR], 21-38), CNC word score was 39% (IQR, 6-62), and AzBio sentences in quiet score was 60% (IQR, 11-83) at a median of 12.5 months postimplantation. Despite the NF2 cohort having larger tumors, when comparing patients with sporadic versus NF2-associated VS, there were no statistically significant differences in CNC word (49% [30-70] vs. 31% [0-52]) or AzBio sentences in quiet (66% [28-80] vs. 57% [5-83]) scores. Regardless of NF2 status, all patients managed with observation, and radiosurgery achieved open-set speech. In patients who underwent microsurgery, 6 (46%) of 13 with NF2 achieved open-set speech recognition compared with 4 (67%) of 6 with sporadic disease. CONCLUSION: Select patients with VS achieve successful hearing rehabilitation with a CI. In this cohort, tumor management strategy significantly influenced CI performance, whereas differences in NF2 status exhibited less effect. Specifically, all patients managed with observation or radiosurgery achieved open-set speech perception, whereas approximately half of people with NF2-related VS and two-thirds of people with sporadic VS achieved this outcome after tumor microsurgery. When disease permits, observation and radiosurgery should be considered in patients who may later pursue a CI.

Optimization of Subglottic View During Flexible Laryngoscopy With Patient Positioning.

OBJECTIVE: Determine the ideal head position to optimize visualization of the subglottis using flexible laryngoscopy. STUDY DESIGN: Prospective cohort study. SETTING: Outpatient multidisciplinary airway clinic at a tertiary care center. METHODS: Patients presenting to a multidisciplinary airway clinic undergoing nasoendoscopic airway examination were enrolled. Three head positions were utilized to examine the subglottis during laryngoscopy: "sniffing," chin tuck, and stooping positions. In-office reviewers and blinded clinician participants evaluated views of the airway based on Cormack-Lehane (CL) scale, airway grade (AG), and visual analog scale (VAS). Demographic data were obtained. Statistical analysis compared head positions and demographic data using Student's t test, analysis of variance, and Tukey's post hoc analysis. RESULTS: One hundred patients participated. No statistical differences existed among in-clinic or blinded reviewers for the CL score in any head position (p = .35, .5, respectively). For both AG and VAS, flexed and stooping positions were rated higher than the sniffing positions by both in-clinic and blinded reviewers (p < .01 for all analyses), but there was no statistical difference between these two positions (p = .28, .18, respectively). There was an inverse correlation between age and scores for AG and VAS in the flexed position for both sets of reviewers (p = .02, <.01 respectively), and a higher body mass index was significantly associated with the need to perform tracheoscopy for full airway evaluation (p < .01). CONCLUSION: Both flexion and stoop postures can be implemented by an experienced endoscopist in awake, transnasal flexible laryngoscopy to enhance visualization of the subglottic airway.

Low postoperative lymphocyte count increases risk of progression in human papillomavirus associated oropharyngeal cancer.

BACKGROUND: We aim to explore the prognostic role of absolute lymphocyte count (ALC) before, during, and after treatment on oncologic outcomes in human papillomavirus associated oropharyngeal cancer (HPV(+)OPSCC). METHODS: Retrospective cohort at a tertiary center, 2006-2018. Multivariable Cox regressions were used to determine the effect of ALC on risk of progression. Univariate linear regression was performed to determine clinical factors associated with lower ALC. RESULTS: All 197 patients underwent primary surgery. Mean (SD) ALC nadirs (×109  cells/L) were: baseline (N = 149): 1.69 (0.56); postoperative (N = 126): 1.58 (0.59); post-RT (N = 141): 0.68 (0.35) and long-term (N = 105): 0.88 (0.37). Lower baseline ALC nadir was associated with worse overall survival (HR 3.85, 95%CI: 1.03-14.29, p = 0.04). Lower postoperative ALC nadir was associated with higher risk of progression (HR 2.63, 95%CI: 1.04-6.67, p = 0.04). CONCLUSIONS: Lower baseline ALC is associated with worse survival, whereas lower postoperative ALC is associated with increased risk of progression in surgically treated HPV(+)OPSCC.

Ultrasound Guided Biopsy in Patients With HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: To identify the differences in sensitivity and accuracy between ultrasound-guided and palpation-guided fine needle aspirations (FNA) of suspicious lymph nodes in patients with human papillomavirus (HPV) (+) oropharyngeal squamous cell carcinoma (OPSCC). Additional objectives included identifying patient specific factors affecting biopsy accuracy and evaluating potential differences in accuracy between fine and core needle biopsies. STUDY DESIGN: Retrospective chart review. MATERIALS AND METHODS: A retrospective study of diagnostic sensitivity was completed at a single tertiary care center between 1/1/2006-12/31/2016. Participants included patients who underwent pretreatment FNA biopsy with HPV(+)OPSCC confirmed pathologically following neck dissection or excisional lymph node biopsy. A true positive (TP) on FNA biopsy was defined as an FNA biopsy concerning for squamous cell carcinoma (SCC) that was confirmed on excisional biopsy or neck dissection. A false negative (FN) was defined as a negative FNA but metastatic disease identified on excisional biopsy or neck dissection. Sensitivity was calculated as TPs/(TPs + FNs). Sensitivity was compared among techniques using chi-square and Fisher exact tests. RESULTS: A total of 209 FNA biopsies among 198 patients were included in the study, including 31 (15%) palpation-guided FNAs, 160 (77%) ultrasound-guided FNAs, and 18 (9%) ultrasound-guided FNA + core biopsies. Sensitivity was significantly different among palpation-guided FNA, ultrasound-guided FNA, and ultrasound-guided FNA + core biopsies (48% vs. 83% vs. 94%, respectively; P < .001) but there was no significant difference in sensitivity between ultrasound-guided FNA versus ultrasound-guided FNA + core biopsies (P = .31). CONCLUSION: The use of ultrasound guidance in FNA biopsies of nodal metastases in HPV(+)OPSCC improves sensitivity compared to palpation guidance alone. Ultrasound guided biopsies are preferred in patients with suspected nodal metastasis from HPV(+)OPSCC. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2396-2402, 2022.

Hearing loss caused by CMV infection is correlated with reduced endocochlear potentials caused by strial damage in murine models.

Congenital cytomegalovirus (CMV) infection is a significant cause of neonatal hearing loss. However, at the cochlear level, the anatomical lesions and pathophysiological mechanisms that underlie hearing loss are still not clearly understood. In murine models of CMV infection, we have observed early damage to the capillary networks in stria vascularis, as well as hearing loss manifested in ABR threshold elevations. Our experimental hypothesis is that strial damage causes a reduced endocochlear potential (EP) resulting in impaired haircell activation and consequent hearing loss. We have studied strial damage, EP, and ABR threshold elevations in two mouse models (BALB/c and C57BL6 strains) infected with murine CMV. Neonatal (P3) pups were inoculated with murine CMV (2µl of 200pfu) by intra cerebral injection. Control mice were saline injected. At 6 weeks, ABR thresholds to tonal stimuli at 8, 16 and 32 kHz were determined for each ear. At 8 weeks a sub-group of treated and control animals was prepared for study of cochlear capillary networks using scanning electron microscopy of corrosion cast specimens. In a second group, at 8 weeks, EP measurements from both cochleas were made. We report that in both mouse strains, CMV infection caused capillary loss in the stria vascularis, initially at the cochlear apex, and extending to lower cochlear turns in some subjects. After CMV infection, in both BALB/c and C57BL6 mice, reduced EPs and ABR threshold elevations were observed, and there was a within-animal correlation between loss of EP and ABR threshold elevations across the sound frequencies tested. These results suggest that CMV induced damage to stria vascularis results in EP reduction that is correlated with ABR threshold elevations. Extrapolating to the human condition, we suggest that strial damage and its physiological consequences may contribute to the initial hearing loss in congenital CMV infection. The early involvement of cochlear capillary damage may encourage a focus on therapeutic interventions that can prevent vascular damage, or subsequently promote vascular healing or angiogenesis.

Role of cochlear synaptopathy in cytomegalovirus infected mice and in children.

OBJECTIVES: Determine whether a murine model of cytomegalovirus (CMV) and CMV- infected children show evidence of synaptopathy. STUDY DESIGN: Murine model of CMV infection and case series. SUBJECTS AND METHODS: C57 BL/6 mice were inoculated with murine-CMV (mCMV). Auditory function was assessed using Auditory Brainstem Response (ABR) and distortion product otoacoustic emission (DPOAE) testing. Temporal bones from mCMV-infected mice were used for both ribbon synapse and hair cell quantification. Four groups of children (non-CMV normal hearing, non-CMV hearing impaired, CMV normal hearing and CMV hearing impaired) underwent ABRs between 2014 and 2018. The outcomes included raw amplitude, wave I:V amplitude ratio, absolute latency, and interpeak latency. RESULTS: Mice at 8 weeks post mCMV infection had higher ABR and DPOAE (P < 0.05) thresholds and increased outer hair cell loss compared to uninfected mice and mCMV-infected mice at 4 and 6 weeks post infection, indicating progressive hearing loss. A reduction in the wave I amplitude and synaptic counts were noted earlier at 4 weeks in CMV-infected mice (P < 0.05). The human data indicated that the wave I:V amplitude ratio was lower on average in CMV-infected groups when compared to the uninfected cohorts. The wave I:V amplitude ratio for the click and 4k stimuli were not significantly different between the congenital CMV-infected and uninfected children with normal or with hearing loss. CONCLUSION: This study suggests mCMV infection results in a synaptopathy before hair cell damage. Additional studies need to be performed to determine whether this effect is also observed in CMV-infected children. LEVEL OF EVIDENCE: Animal studies and basic science- NA; human studies: level 4.

Should hearing targeted screening for congenital cytomegalovirus infection Be implemented?

Since 2013, after Utah became the first state to implement hearing targeted early CMV screening, a national debate has been percolating about whether this approach should be introduced nationally. Currently Utah, Iowa, Connecticut, and New York have passed legislation mandating early CMV screening, and over 100 birth hospitals across the United States have voluntarily implemented early CMV screening programs as part of their standard of care. We reviewed the evidence related to this approach and used the Wilson and Jungner (1968) criteria to evaluate this method of screening. Based on these criteria, there is substantial rationale and evidence to support a hearing targeted approach to screen for congenital CMV. Given this evidence, we currently recommend that infants who fail newborn hearing screen should undergo CMV screening.

Role of Free Radical Formation in Murine Cytomegalovirus-Induced Hearing Loss.

OBJECTIVES: The goal of the study was to determine whether reactive oxygen species (ROS) mediates cytomegalovirus (CMV)-induced labyrinthitis. STUDY DESIGN: Murine model of CMV infection. SETTING: University of Utah laboratory. SUBJECTS AND METHODS: Nrf2 knockout mice were inoculated with murine CMV. Auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) were then performed on these and uninfected controls. BALB/c mice were inoculated with murine CMV to determine whether a marker for ROS production, dihydroethidium (DHE), is expressed 7 days after inoculation. Finally, 2 antioxidants-D-methionine and ACE-Mg (vitamins A, C, and E with magnesium)-were administered 1 hour before and after infection in inoculated mice for 14 days. Temporal bones were harvested at postnatal day 10 for DHE detection. ABR and DPOAE testing was done at postnatal day 30. Scanning electron microscopy was also performed at postnatal day 30 to evaluate outer hair cell integrity. RESULTS: Nrf2-infected mice had worse hearing than uninfected mice (P < .001). A statistically significant increase in DHE fluorescence was detected in BALB/c-infected mice as compared with uninfected mice 7 days after inoculation. D-methionine- and ACE-Mg-treated mice demonstrated an attenuation of the DHE fluorescence and a significant improvement in ABR and DPOAE thresholds when compared with untreated infected controls (P < .0001). Scanning electron microscopy demonstrated less outer hair cell loss in the treated versus untreated infected controls. CONCLUSION: These results demonstrate for the first time that excessive ROS mediates CMV-induced hearing loss in a mouse model.

Effects of ganciclovir treatment in a murine model of cytomegalovirus-induced hearing loss.

OBJECTIVE: To determine whether ganciclovir (GCV) treatment reduces sensorineural hearing loss in cytomegalovirus (CMV)-infected mice. The effects of GCV on viral load, absolute neutrophil count (ANC), and outer hair cell (OHC) integrity were also investigated. METHODS: Infected BALB/c mice were inoculated with murine CMV on postnatal day 3. Those treated with GCV received an intraperitoneal injection twice a day for 14 days. Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing 4 weeks after inoculation. Temporal bones were used for determination of viral load by quantitative polymerase chain reaction and hair cell quantification by scanning electron microscopy. ANCs were completed by an automated hematology analyzer, with manual review for confirmation. RESULTS: GCV-treated CMV-infected mice had lower ABR (P < 0.0001, Kruskal-Wallis test) and DPOAE (P < 0.0001) thresholds compared to CMV-infected untreated mice, indicating that GCV protected mice from CMV-induced hearing loss. Viral load in infected populations undergoing GCV treatment was significantly decreased (P = 0.03) relative to untreated mice. GCV treatment alone had no effect on ABR and DPOAE compared to untreated, uninfected controls (P = 0.1, P = 0.24, respectively). GCV-treated mice received increased protection from OHC loss when compared to untreated groups, with total OHC losses of approximately 7% and 14%, respectively (P < 0.05). Neutropenia was absent after 7 days of GCV treatment. CONCLUSION: Ganciclovir effectively ameliorated SNHL and partially protected from OHC loss in a preclinical model of congenital CMV infection, seemingly by reducing viral load. LEVEL OF EVIDENCE: NA Laryngoscope, 130:1064-1069, 2020.