Predictors of Subjective Olfactory Dysfunction and Sinonasal Quality-of-Life After Endoscopic Transsphenoidal Pituitary Surgery.

BACKGROUND: This is the largest study in North America investigating olfactory outcomes after pituitary surgery to date. OBJECTIVE: Characterize factors associated with subjective olfactory dysfunction (OD) and worsened sinonasal quality-of-life (QOL) after endoscopic TSA. METHODS: Patients undergoing primary TSA for secreting and non-secreting pituitary adenomas between 2017 and 2021 with pre- and post-operative SNOT-22 scores were included. Subjective OD was determined by the smell/taste dysfunction question on the SNOT-22 (smell-SNOT). RESULTS: 159 patients with pre- and post-operative SNOT-22 scores were included. Average total SNOT-22 scores worsened from pre-operative (16.91 ± 16.91) to POM1 (25.15 ± 20.83, P < .001), with no difference from pre-operative (16.40 ± 15.88) to POM6 (16.27 ± 17.92, P = .936) or pre-operative (13.63 ± 13.54) to POM12 (12.60 ± 16.45, P = .651). Average smell-SNOT scores worsened from pre-operative (0.40 ± 1.27) to POM1 (2.09 ± 2.01, P < .001), and pre-operative (0.46 ± 1.29) to POM6 (1.13 ± 2.45, P = .002), with no difference from pre-operative (0.40 ± 1.07) to POM12 (0.71 ± 1.32, P = .100). Female gender had a 0.9-point (95% CI 0.1 to 1.6) P = .021, increase in smell-SNOT at POM1, resolving by POM6 (0.1 [-0.9 to 1.1], P = .800) and POM12 (0.0 [-1.0 to 0.9], P = .942). Septoplasty with tunnel approach had a 1.1 [0.2 to 2.0] out of 5-point (P = .023) increase in smell-SNOT at POM1, resolving by POM6 (0.2 [-1.1 to 1.6], P = .764) and POM12 (0.4 [-0.9 to 1.6], P = .567). Female gender had a 9.5 (4.0 to 15.1)-point (P = .001) increase in SNOT-22 scores at POM1, resolving by POM6 (3.4 [-3.0 to 9.8], P = .292) and POM12 (6.4 [-5.4 to 18.2], P = .276). Intra-operative CSF leak had an 8.6 [2.1 to 15.1]-point (P = .009) increase in SNOT-22 scores at POM1, resolving by POM6 (5.4 [-1.7 to 12.5], P = .135), and POM12 (1.1 [-12.9 to 15.1], P = .873). CONCLUSION: Changes in subjective olfaction and sinonasal QOL after TSA may be associated with gender, operative approach, and intra-operative CSF leak, resolving 6-12 months post-operatively.

Medication utilization for patients with chronic rhinosinusitis with nasal polyposis and asthma in 12 months pre- and post-dupilumab initiation.

KEY POINTS: This study examines the impact of dupilumab on medication use for chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma patients. Patients on dupilumab had a reduction in oral/inhaled/topical steroids, antibiotics, and leukotriene receptor antagonists (LTRAs). The reduction in medication use had no impact on total polyp or SNOT-22 scores.

Optimizing the timing of biologic and surgical therapy for patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP).

INTRODUCTION: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is often treated with endoscopic sinus surgery (ESS); however, patients may require revision surgery due to recurrence. To date, no studies have compared outcomes for combined surgery and biologic therapy for CRSwNP compared with biologic therapy alone. METHODS: Retrospective case-control study of CRSwNP patients who underwent ESS while on dupilumab or mepolizumab (ESS-biologic cohort) compared with CRSwNP patients on biologic therapy (biologic-only controls). Cohorts were matched according to indication, aspirin-exacerbated respiratory disease (AERD), sinonasal outcome test-22 (SNOT-22), and total polyp scores. RESULTS: Sixteen patients underwent ESS while on biologic therapy (13 dupilumab and 3 mepolizumab). Sixteen patients were biologic-only controls. There were no significant differences between indication, baseline SNOT-22 scores, polyp scores, and AERD status between cohorts. Patients underwent surgery a median of 33 days after starting biologic therapy. After 12 months of follow-up, the total polyp score for the ESS-biologic cohort decreased from 4.73 to 0.09 compared with a decrease from 5.22 to 3.38 for the biologic-only controls (95% confidence interval [CI] of difference: -5.37 to -1.38, Cohen's d: 2.40, p = 0.005). In the ESS-dupilumab subanalysis, the ESS-dupilumab cohort had a significant reduction in polyp burden from 4.85 to 0.00 compared with 4.88 to 3.50 for the controls (95% CI of difference: -5.68 to -1.32, Cohen's d: -1.69, p = 0.009). CONCLUSION: In CRSwNP patients, combined ESS and biologic therapy results in a significant and sustained decrease in polyp burden compared with biologic therapy alone. Larger studies are warranted to further examine the impact of combined therapy.

Benefits of Immunoglobulin (Ig) Replacement Therapy for Primary and Secondary Immunodeficiency in Chronic Rhinosinusitis.

This is the first study to examine chronic rhinosinusitis (CRS) outcomes after starting immunoglobulin (Ig) replacement therapy for patients with primary (PID) and secondary immunodeficiency (SID). This is a retrospective review of patients diagnosed with CRS from 2018 to 2022 prior to initiating Ig therapy for the treatment of PID or SID. Outcomes included medication use and Sinonasal Outcome Test (SNOT-22) scores. Ten patients met the inclusion criteria. PID and SID patients had a decrease in antibiotics (PID: 9.40 to 3.20, P = .05, SID: 8.20 to 2.00, P = .04) and steroids (PID: (5.40 to 0.60; P = .06; SID: 2.20 to 0.20, P = .047) prescribed in the year after Ig compared to the year prior. Patients with SID had a decrease in mean SNOT-22 scores by 12 months after Ig (47.50 to 20.50, P = 0.03). Patients receiving Ig for PID and SID showed decreased medication use and SID patients experienced subjective improvement in CRS symptoms in year-over-year comparison.

Trends in Endoscopic and Microscopic Approaches to Transsphenoidal Pituitary Surgery in the US.

OBJECTIVES: Among the transsphenoidal (TSS) approaches to pituitary tumors, the microscopic approach (MA) has historically been the predominant technique with the increasing adoption of the endoscopic approach (EA). This study investigates national trends in TSS approaches and postoperative outcomes for MA and EA through 2021. METHODS: The TriNetX database was queried for patients undergoing TSS (MA and EA) between 2010 and 2021. Data were collected on demographics, geographic distribution of surgical centers, postoperative complications, stereotactic radiosurgery (SRT), repeat surgery, and postoperative emergency department (ED) visits. RESULTS: 8644 TSS cases were queried between 2010 and 2021. MA rates were highest until 2013 when rates of EA (52%) surpassed MA (48%) and continued to increase through 2021 (81%). From 2010 to 2015 EA had higher odds of a postoperative CSF leak (OR 3.40) and diabetes insipidus (DI (OR 2.30)) versus MA (p < 0.05); from 2016 to 2021 differences were not significant. Although there was no significant difference among approaches from 2010 to 2015 for syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia, or bacterial meningitis, from 2016 to 2021 EA had lower odds of SIADH (OR 0.54) and hyponatremia (OR 0.71), and higher odds of meningitis (OR 1.79) versus MA (p < 0.05). EA had higher odds of additional surgery (either EA or MA) after initial surgery from 2010 to 2021. From 2010 to 2015 EA had lower odds of postoperative SRT compared to MA, whereas in 2016-2021 there was no statistical difference among approaches. CONCLUSION: This study demonstrates increasing EA adoption for TSS in the United States since 2013. Complication rates have overall improved for EA compared to MA, potentially as a result of improving surgeon familiarity and experience. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2135-2140, 2023.

Factors affecting polysomnography compliance and delays to surgical treatment of obstructive sleep apnea.

OBJECTIVE: To evaluate adherence to polysomnography in pediatric patients and determine if demographics, socioeconomic status, polysomnography indication, or prior otolaryngology intervention are associated with polysomnography adherence and time to definitive surgery. STUDY DESIGN: Retrospective review study. SETTING: Tertiary-care children's hospital. METHODS: Electronic medical record was queried to identify patients ordered for a sleep study between January and May 2019. Demographic information, time to sleep study, and time to surgery were collected and calculated. RESULTS: 304 patients were recommended to obtain polysomnography, with adherence rate of 65.4%. There was no significant difference in adherence or loss to follow-up rates based on patient sex, age, language, socioeconomic status, state of residence, single-parent status, or polysomnography indication. There was no difference between time to surgery for patients who did or did not obtain polysomnography (181 vs. 161 days, P = .51). Patients with prior otolaryngology intervention were more likely to obtain polysomnography and less likely to be lost to follow-up (P < .05). Median household income demonstrated a significant inverse relationship with time to polysomnography (P < .05) as well as time to surgery (P < .05). Medically complex patients tended to experience longer time to surgery compared with non-complex patients. CONCLUSION: Families with lower socioeconomic status or medically complex children may require assistance to obtain polysomnography and pursue surgery for sleep-disordered breathing. Patients without prior otolaryngology intervention may be less likely to follow up and may need assistance with navigating the polysomnography process.

Sleep Subdomain of the Sinonasal Outcome Test as a Potential Screening Tool for Sleep Apnea in Chronic Rhinosinusitis.

OBJECTIVES: Approximately 20% of patients with chronic rhinosinusitis (CRS) have comorbid obstructive sleep apnea (OSA). Patients with undiagnosed OSA are at high risk for perioperative complications. The Sinonasal Outcomes Test (SNOT-22) Questionnaire is commonly administered to CRS patients, whereas OSA screening tools are less routinely employed. This study compared SNOT-22 sleep subdomain (Sleep-SNOT) scores among non-OSA CRS versus OSA-CRS patients undergoing ESS, and assessed sensitivity, specificity, and diagnostic accuracy of the Sleep-SNOT for OSA screening. METHODS: Retrospective review of patients that underwent endoscopic sinus surgery (ESS) for CRS from 2012 to 2021. Patients either carried a reported OSA diagnosis and completed the SNOT-22, or had undocumented OSA status and completed both STOP-BANG and SNOT-22. Demographics, questionnaire scores, and OSA status were collected. A receiver operating characteristic (ROC) curve assessed cutoff scores, sensitivity, and specificity of the Sleep-SNOT for OSA screening. RESULTS: Of 600 patients reviewed, 109 were included. 41% had comorbid OSA. OSA patients had a higher BMI (32.1 ± 7.7 vs. 28.35 ± 6.7 kg/m2 ; p = 0.02), Sleep-SNOT (21.96 ± 12.1 vs. 16.8 ± 11.2; p = 0.021) and STOP-BANG (3.1 ± 1.44 vs. 2.06 ± 1.27; p = 0.038) scores. A Sleep-SNOT score of 17.5 had a sensitivity of 68.9%, specificity of 55.7%, and diagnostic accuracy of 63% for OSA detection (p = 0.022). CONCLUSIONS: Sleep-SNOT scores are greater for CRS-OSA patients. The Sleep-SNOT ROC curve demonstrates a high sensitivity, specificity, and accuracy for OSA screening in CRS patients. A Sleep-SNOT score of ≥17.5 should prompt further OSA evaluation. The Sleep-SNOT may be considered as a surrogate OSA screening tool when other validated tools are not employed. LEVEL OF EVIDENCE: Retrospective chart review, Level 3 Laryngoscope, 133:2029-2034, 2023.

Postoperative opioid-prescribing practices in otolaryngology: Evidence-based guideline outcomes.

Objectives: We previously reported that >50% of postoperative opioids prescribed at our institution went unused for common otolaryngologic procedures. Based on these findings, we instituted multimodal, evidence-based guidelines for postoperative pain management. In the second part of our multiphasic study, we evaluated the effects of these guidelines on (1) quantity of unused opioids, (2) patient satisfaction, and (3) institutional perceptions toward the opioid epidemic and prescribing guidelines. Methods: Standardized, procedure-specific opioid prescription guidelines were created using prospective data from the first phase of our study and evidence from current literature. Again, we examined sialendoscopy, parotidectomy, parathyroidectomy/thyroidectomy, and transoral robotic surgery (TORS). Patients were surveyed at their first postoperative appointment. Groups from Phases I and II were compared. Attending physicians were surveyed before the start of the multiphasic project and after prescribing guidelines were implemented. Results: Prescribing guidelines led to an average reduction in prescribed morphine milligram equivalents (MME) per patient by: 48% (sialendoscopy), 63% (parotidectomy), 60% (para/thyroidectomy), and 42% (TORS). Average used MME per patient for parotidectomy was significantly reduced (64%). The proportion of unused MME per patient and patient satisfaction scores did not significantly change after guidelines were implemented. Conclusion: Implementation of opioid-prescribing guidelines and the use of multimodal analgesia substantially reduced the amount of opioids prescribed across all procedures without impacting patient satisfaction. Level of Evidence: 2.

Otolaryngology Subspecialty Surgical Rescheduling Rates During the COVID-19 Pandemic.

Objective: In the beginning of the COVID-19 pandemic in spring 2020, elective and oncologic surgical cases were cancelled. After adequate safety protocols were established, each subspecialty within otolaryngology faced unique challenges in reengaging patients for surgical scheduling. Study Design: Retrospective review from March to May 2020. Setting: Single academic institution. Methods: Patients whose otolaryngology surgery was cancelled due to COVID-19 hospital precautions were identified. Rescheduling rates were analyzed by subspecialty. Case completion was determined as the percentage of initially cancelled cases that were completed within 6 months of their original planned dates. Results: Of 833 otolaryngology cases scheduled between March 16 and May 29, 2020, a total of 555 (66.63%) were cancelled due to COVID-19 precautions, and 71.17% were rescheduled within 6 months. Cancellation and rescheduling rates per subspeciality were as follows, respectively: head and neck surgery, 42.79% and 88.76%; sleep surgery, 83.92% and 64.07%; rhinology and skull base, 72.67% and 64.80%; facial plastic and reconstructive surgery, 80.00% and 74.17%; otology and neurotology, 71.05% and 66.67%; and laryngology, 68.57% and 79.17%. The case completion rates were as follows: head and neck surgery, 95.2%; laryngology, 85.7%; facial plastic and reconstructive surgery, 79.3%; otology and neurotology, 76.3%; rhinology and skull base, 74.4%; and sleep surgery, 69.9%. Conclusion: Differences for surgical rescheduling rates during the COVID-19 pandemic shutdown exist among otolaryngology subspecialties. Our experience suggests that subspecialties that functioned on an elective nature were more likely to face lower rates of case completion.

Methods for extracellular vesicle isolation from cancer cells.

Cells are known to release different types of vesicles such as small extracellular vesicles (sEVs) and large extracellular vesicles (LEVs). sEVs and LEVs play important roles in intercellular communication, pre-metastatic niche formation, and disease progression; both can be detected cell culture media and biological fluids. sEVs and LEVs contain a variety of protein and RNA cargo, and they are believed to impact many biological functions of the recipient cells upon their internalization or binding to cell surface proteins. It has recently been established that standard isolation techniques, such as differential ultracentrifugation, yield a mixed population of EVs. However, density gradient ultracentrifugation has been reported to allow the isolation of sEVs without cellular debris. Here, we describe the most common methods used to isolate sEVs from cell culture medium, mouse and human plasma, and a new technique for isolating sEVs from tissues as well. This article also provides detailed procedures to isolate LEVs.

Postoperative opioid-prescribing practices in otolaryngology: A multiphasic study.

OBJECTIVES: In otolaryngology, postoperative pain management lacks evidence-based guidelines. We designed a prospective, multiphasic study aimed to develop evidence-based guidelines for postoperative pain management within our institution. In this first phase of our project, we investigated opioid prescription and consumption as well as pain trends for common otolaryngologic procedures. METHODS: Patients (n = 161) who underwent procedures between July 2018 and February 2019 were surveyed on their postoperative opioid usage and pain from day of discharge to first clinic visit. Opioid prescriptions were converted to standardized units of morphine milligram equivalents (MME). The procedures selected for analysis were parathyroidectomy/thyroidectomy, parotidectomy, sialendoscopy, and transoral robotic surgery resection (TORS). RESULTS: In total, 19,748 MME were prescribed: 8,588 MME (43.5%) were used, leaving 11,159 MME (56.5%) unused. TORS average MME used: 221 ± 227; total MME unused: 38%. Sialendoscopy average MME used: 31 ± 46; total MME unused: 67%. Parathyroidectomy/thyroidectomy average MME used: 30 ± 37; total MME unused: 66%. Parotidectomy average MME used: 43 ± 53; total MME unused: 65%. Male gender, smoking (current and former), and psychiatric medication use were positive predictors of opioid consumption in postoperative patients (P < 0.001). CONCLUSION: At our institution, over 50% of prescribed postoperative opioids went unused. This was most pronounced for nonmucosal surgeries. Postoperative pain management should account for this to minimize unnecessary opioid prescriptions. Based on our findings and review of current literature, we are in the process of developing prescribing recommendations to be implemented within our institution. LEVEL OF EVIDENCE: 2 Laryngoscope, 130:659-665, 2020.

Prostate cancer sheds the αvß3 integrin in vivo through exosomes.

The αvß3 integrin has been shown to promote aggressive phenotypes in many types of cancers, including prostate cancer. We show that GFP-labeled αvß3 derived from cancer cells circulates in the blood and is detected in distant lesions in NOD scid gamma (NSG) mice. We, therefore, hypothesized that αvß3 travels through exosomes and tested its levels in pools of vesicles, which we designate extracellular vesicles highly enriched in exosomes (ExVs), and in exosomes isolated from the plasma of prostate cancer patients. Here, we show that the αvß3 integrin is found in patient blood exosomes purified by sucrose or iodixanol density gradients. In addition, we provide evidence that the αvß3 integrin is transferred through ExVs isolated from prostate cancer patient plasma to ß3-negative recipient cells. We also demonstrate the intracellular localization of ß3-GFP transferred via cancer cell-derived ExVs. We show that the ExVs present in plasma from prostate cancer patients contain higher levels of αvß3 and CD9 as compared to plasma ExVs from age-matched subjects who are not affected by cancer. Furthermore, using PSMA antibody-bead mediated immunocapture, we show that the αvß3 integrin is expressed in a subset of exosomes characterized by PSMA, CD9, CD63, and an epithelial-specific marker, Trop-2. Finally, we present evidence that the levels of αvß3, CD63, and CD9 remain unaltered in ExVs isolated from the blood of prostate cancer patients treated with enzalutamide. Our results suggest that detecting exosomal αvß3 integrin in prostate cancer patients could be a clinically useful and non-invasive biomarker to follow prostate cancer progression. Moreover, the ability of αvß3 integrin to be transferred from ExVs to recipient cells provides a strong rationale for further investigating the role of αvß3 integrin in the pathogenesis of prostate cancer and as a potential therapeutic target.

The Role of Free Tissue Transfer in the Management of Chronic Frontal Sinus Osteomyelitis.

OBJECTIVES/HYPOTHESIS: Chronic frontal sinus infection is managed with a combination of medical and surgical interventions. Frontal bone osteomyelitis due to recurrent infection following trauma or prior open surgery may require more significant debridement. Free tissue transfer may allow for extensive debridement with replacement of tissue, and definitive eradication of osteomyelitis. STUDY DESIGN: Retrospective chart review. METHODS: Patients undergoing free flap obliteration of the frontal sinus for frontal bone osteomyelitis at a single institution were included in the study. Clinical, radiologic, and surgical data were collected. Surgeries before and after free flap obliteration were compared by Wilcoxon signed rank test. RESULTS: Fifteen patients were identified; however, one patient had less than 6 months of follow-up and was excluded from analysis. Of the remaining 14 patients, mean follow-up duration was 26 months (range, 6-120 months). Mean number of surgeries prior to free flap was 3.7 (range, 1-8 surgeries). Free flap obliteration resolved chronic frontal sinusitis in all patients. Two patients experienced postoperative infection, and the overall complication rate was 29%. Eight patients underwent cranioplasty (six immediate, two delayed) without complication. All patients received planned courses of postoperative antibiotics. A statistically significant decrease in the number of surgeries after free flap obliteration was observed P ≤ .01). CONCLUSIONS: Extensive debridement followed by free tissue transfer and antibiotics offers a definitive treatment for complicated, recurrent frontal osteomyelitis. Simultaneous cranioplasty provides immediate protective and aesthetic benefit without complication. Consideration should be given for free tissue transfer and cranioplasty earlier in the algorithm for treatment of refractory frontal sinus osteomyelitis. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1497-1504, 2019.

ß1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation.

Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (ß1wt /TRAMP) mice as well as in mice carrying a conditional ablation of ß1 integrins in the prostatic epithelium (ß1pc-/- /TRAMP). Since JNK is known to be suppressed by ß1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in ß1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in ß1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of ß1wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the ß1/IGF-IR crosstalk and report that ß1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that ß1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.