Cabergoline Targets Multiple Pathways to Inhibit PRL Secretion and Increases Stromal Fibrosis.

OBJECTIVE: Unravel potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumor and neighboring stromal and immune cells. DESIGN AND METHODS: Five surgically resected prolactinomas from 3 cabergoline (CBG)-treated and 2 treatment naive patients were analyzed by single cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape. RESULTS: Six major cell populations that included tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%) were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components, such as perforin and the granzymes GZMB, GNLY and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in CBG-treated samples. CONCLUSIONS: Our scRNAseq studies revealed key differences in the transcriptomic features of CBG-treated and untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time describe previously unknown activation of CD8+ T cells following CBG-treatment which may play a role in the tumoricidal actions of CBG.

Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis.

OBJECTIVES: The 22-question SinoNasal Outcome Test (SNOT-22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT-22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT-22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF). METHODS: Prospective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT-22 scores were obtained at baseline and after 3-6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution-based methods were used to assess internal consistency and calculate the MCID of the SNOT-22. RESULTS: A total of 184 PwCF participated with mean baseline SNOT-22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre- and post-HEMT data reported improvement in SNOT-22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT-22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02-1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14-18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39-20.11) were associated with greater SNOT-22 improvement. The mean MCID calculated via distribution-based methods was 8.5. CONCLUSION: Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT-22 in PwCF is 8.5 points, similar to non-CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT-22 has strong internal consistency in PwCF. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Comparison of patient-reported outcomes and clinical characteristics among patients with pituitary macroadenomas and giant adenomas.

KEY POINTS: Patients with giant adenomas are more likely to have tumor extension into the paranasal sinuses. Compared to macroadenomas, giant adenomas are not associated with worse preoperative SNOT-22 scores.

Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer.

BACKGROUND: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors. METHODS: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence. RESULTS: Among the eight treatment groups, APG-157 + anti-CTLA-4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti-PD-1 + anti-CTLA-4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG-157 + anti-CTLA-4 group compared to 4%-5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG-157 + anti-CTLA-4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG-157 + anti-CTLA-4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group. CONCLUSIONS: The results indicate that APG-157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control.

SNOT-22 subdomain outcomes following treatment for sinonasal malignancy: A prospective, multicenter study.

BACKGROUND: Patients with sinonasal malignancy (SNM) present with significant sinonasal quality of life (QOL) impairment. Global sinonasal QOL as measured by the 22-item Sinonasal Outcomes Test (SNOT-22) has been shown to improve with treatment. This study aims to characterize SNOT-22 subdomain outcomes in SNM. METHODS: Patients diagnosed with SNM were prospectively enrolled in a multi-center patient registry. SNOT-22 scores were collected at the time of diagnosis and through the post-treatment period for up to 5 years. Multivariable regression analysis was used to identify drivers of variation in SNOT-22 subdomains. RESULTS: Note that 234 patients were reviewed, with a mean follow-up of 22 months (3 months-64 months). Rhinologic, psychological, and sleep subdomains significantly improved versus baseline (all p < 0.05). Subanalysis of 40 patients with follow-up at all timepoints showed statistically significant improvement in rhinologic, extra-nasal, psychological, and sleep subdomains, with minimal clinically important difference met between 2 and 5 years in sleep and psychological subdomains. Adjuvant chemoradiation was associated with worse outcomes in rhinologic (adjusted odds ratio (5.22 [1.69-8.66])), extra-nasal (2.21 [0.22-4.17]) and ear/facial (5.53 [2.10-8.91]) subdomains. Pterygopalatine fossa involvement was associated with worse outcomes in rhinologic (3.22 [0.54-5.93]) and ear/facial (2.97 [0.32-5.65]) subdomains. Positive margins (5.74 [2.17-9.29]) and surgical approach-combined versus endoscopic (3.41 [0.78-6.05])-were associated with worse psychological outcomes. Adjuvant radiation (2.28 [0.18-4.40]) was associated with worse sleep outcomes. CONCLUSIONS: Sinonasal QOL improvements associated with treatment of SNM are driven by rhinologic, extra-nasal, psychological, and sleep subdomains.

Gigaxonin Suppresses Epithelial-to-Mesenchymal Transition of Human Cancer Through Downregulation of Snail.

Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail. SIGNIFICANCE: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer.

Patient perspectives on chronic rhinosinusitis in cystic fibrosis: Symptom prioritization in the era of highly effective modulator therapy.

BACKGROUND: Chronic rhinosinusitis (CRS) is common in people with cystic fibrosis (PwCF). Rhinologic symptom prioritization and areas that influence CRS treatment choices, including pursuing endoscopic sinus surgery (ESS), remain understudied. METHODS: Adult PwCF + CRS were enrolled at eight centers into a prospective, observational study (2019-2023). Participants were administered the 22-SinoNasal Outcome Test (SNOT-22) survey and a modified SNOT-22 instrument examining symptom importance. We determined importance rankings for individual symptoms and SNOT-22 symptom importance subdomains in two sets of subgroups-those pursuing ESS versus continuing medical management (CMT), and those on elexacaftor/tezacaftor/ivacaftor (ETI) versus not on ETI. RESULTS: Among 69 participants, the highest priorities were nasal congestion (n = 48, 69.6% important), post-nasal discharge (32, 46.4%), facial pain (29, 43.3%), waking up tired (27, 39.1%), and fatigue (26, 37.7%). Those electing surgery (n = 23) prioritized sleep and psychological dysfunction symptoms compared to those pursuing CMT (n = 49) (sleep median score = 19.0 [interquartile range: 12.0, 25.0] vs. 4.5 [0.0, 12.8]; p < 0.0001; psychological = 17.0 [7.0, 26.0] vs. 7.0 [0.0, 15.8]; p = 0.002). ETI users had comparable SNOT-22 total symptom importance scores to non-ETI users (p = 0.14). Non-ETI users (n = 34) showed a trend toward prioritizing sleep symptoms compared to ETI users (n = 35) (13.0 [2.8, 22.3] vs. 6.0 [2.0, 17.0]; p = 0.055). CONCLUSIONS: Nasal congestion and post-nasal discharge were top priorities reported by PwCF + CRS. Those electing surgery prioritized sleep and psychological symptoms, highlighting their importance in pre-operative discussions. Non-ETI users' prioritization of sleep improvement may highlight their unique disease impact and therapeutic needs; however, additional investigation is required.

Risk Factors Associated with Postoperative CSF Leak in Extrasellar Tumors.

Objective While postoperative cerebrospinal fluid (CSF) leak rates of pituitary tumors have been frequently studied, there are fewer studies examining postoperative CSF leak rates for extrasellar tumors. The purpose of this study was to identify risk factors for the development of postoperative CSF leak in patients undergoing endoscopic surgery for extrasellar tumors. Methods A retrospective chart review was done for patients who underwent endoscopic resection for extrasellar tumors between 2008 and 2020. Age, gender, tumor type, tumor location, tumor size, reconstruction technique, medical comorbidities, and other potential risk factors were identified. Data was analyzed to identify significant risk factors for development of postoperative CSF leak. Results There were 100 patients with extrasellar tumors who developed intraoperative CSF leaks. Seventeen patients (17%) developed postoperative CSF leaks. Leaks occurred at a median of 2 days following surgery (range 0-34 days). Clival tumors had a significantly higher incidence of postoperative leak than those in other sites ( p < 0.05). There were no significant differences in other locations, body mass index, tumor size, reconstruction technique, medical comorbidities, or other factors. There were nearly twice as many intraoperative grade III leaks in those who developed postoperative CSF leak, but this was not statistically significant ( p = 0.12). Conclusion Extrasellar tumors, particularly clival tumors, have a higher rate of postoperative CSF leak than pituitary tumors. Prophylactic lumbar drains can be considered for patients at high risk for developing postoperative CSF leak.

Predictive factors for decreased baseline quality of life in patients with sinonasal malignancies.

BACKGROUND: The impact of sinonasal malignancies (SNMs) on quality of life (QOL) at presentation is poorly understood. The Sinonasal Outcome Test (SNOT-22) and University of Washington Quality of Life (UWQOL) are validated QOL instruments with distinctive subdomains. This study aims to identify factors impacting pretreatment QOL in SNM patients to personalize multidisciplinary management and counseling. METHODS: Patients with previously untreated SNMs were prospectively enrolled (2015-2022) in a multicenter observational study. Baseline pretreatment QOL instruments (SNOT-22, UWQOL) were obtained along with demographics, comorbidities, histopathology/staging, tumor involvement, and symptoms. Multivariable regression models identified factors associated with reduced baseline QOL. RESULTS: Among 204 patients, presenting baseline QOL was significantly reduced. Multivariable regression showed worse total SNOT-22 QOL in patients with skull base erosion (p = 0.02). SNOT-rhinologic QOL was worse in women (p = 0.009), patients with epistaxis (p = 0.036), and industrial exposure (p = 0.005). SNOT extranasal QOL was worse in patients with industrial exposure (p = 0.016); worse SNOT ear/facial QOL if perineural invasion (PNI) (p = 0.027). Squamous cell carcinoma pathology (p = 0.037), palate involvement (p = 0.012), and pain (p = 0.017) were associated with worse SNOT sleep QOL scores. SNOT psychological subdomain scores were significantly worse in patients with palate lesions (p = 0.022), skull base erosion (p = 0.025), and T1 staging (p = 0.023). Low QOL was more likely in the presence of PNI on UW health (p = 0.019) and orbital erosion on UW overall (p = 0.03). UW social QOL was worse if palatal involvement (p = 0.023) or PNI (p = 0.005). CONCLUSIONS: Our findings demonstrate a negative impact on baseline QOL in patients with SNMs and suggest sex-specific and symptom-related lower QOL scores, with minimal histopathology association. Anatomical tumor involvement may be more reflective of QOL than T-staging, as orbital and skull base erosion, PNI, and palate lesions are significantly associated with reduced baseline QOL.

Fungal and Bacterial Microbiome in Sinus Mucosa of Patients with and without Chronic Rhinosinusitis.

OBJECTIVES: Dysbiosis of the sinonasal microbiome has been implicated in the pathogenesis of chronic rhinosinusitis (CRS). However, the mycobiome remains largely understudied, and microbial alterations associated with specific CRS subtypes have yet to be delineated. The objective of this study is to investigate the fungal and bacterial microbiome of sinus mucosa in CRS patients with and without nasal polyposis (CRSwNP and CRSsNP) versus healthy controls. METHODS: Sinus mucosa was obtained from 92 patients (31 CRSsNP, 31 CRSwNP, and 30 controls) undergoing endoscopic sinus/skull base surgery. Data regarding demographics, Lund-MacKay scores, and histopathology were collected. Fungal and bacterial microbiome analysis was performed utilizing internal transcribed spacer amplicon and 16S rRNA sequencing. RESULTS: Beta diversity of the sinonasal mycobiome differed significantly between CRS and controls (p = 0.001) and between CRSwNP and controls (p = 0.049), but not between CRSwNP and CRSsNP (p = 0.32) nor between CRSsNP and controls (p = 0.06). With respect to the bacterial microbiome, significantly lower alpha diversity was observed between CRS and controls (p < 0.001), CRSwNP versus controls (p < 0.001), and CRSsNP versus controls (p < 0.001). Beta diversity was also significantly different at the genus level between CRSwNP and CRSsNP (p = 0.019), CRSwNP and controls (p = 0.002)), and CRSsNP and controls (p < 0.001). However, alpha and beta diversity did not differ significantly between CRS patients with/without eosinophils or correlate with Lund-MacKay scores. CONCLUSIONS: Differences in mycobiota diversity in CRS patients in comparison with controls suggest that alterations in the mycobiome may contribute to disease pathogenesis. Our findings also confirmed that diminished diversity among bacterial communities is associated with CRS and that significant differences are present in microbial composition between CRSwNP and CRSsNP. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1054-1062, 2024.

Decreases in Rhinology Care Utilization by People with Cystic Fibrosis on Highly Effective Modulator Therapy.

BACKGROUND: Many people with cystic fibrosis (PwCF) have chronic rhinosinusitis (CRS). CRS requires additional management beyond that of pulmonary disease and leads to increased utilization of healthcare resources. Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy that has been shown to improve CRS in PwCF. However, the impact of ETI on rhinologic healthcare utilization is understudied. OBJECTIVE: To compare rates of rhinologic healthcare utilization and procedures among PwCF prior to and after initiating ETI therapy. METHODS: A single-center, cohort study investigating adult PwCF was performed in January 2023. Demographics, clinical characteristics, and data related to CF treatment were retrospectively abstracted. Characteristics of the cohort were compared over 2 periods: the 12-months prior to ETI initiation and the 12-months after ETI initiation. Post-ETI data were linearly extrapolated if a subject had not yet completed the full 12 months of ETI. Paired t-testing, Wilcoxon signed rank testing, and regression analysis were performed. RESULTS: Of 126 PwCF, 98 (77.8%) were on ETI therapy and 35 (27.7%) were both on ETI and concurrently followed by the rhinology service (ETI-ENT). Rhinology clinic visits (P = .007) and frequency of obtaining nasal cultures (P = .046) decreased for the ETI-ENT cohort after initiating ETI treatment. There were no significant changes in the number of endoscopic sinus surgeries (P = .452) performed. Beyond ETI use, regression analysis did not identify any factors associated with changes in utilization. CONCLUSION: Aspects of rhinology healthcare utilization by PwCF decreased after initiation of ETI therapy. Additional studies are needed to determine rhinologic healthcare requirements for PwCF who remain on ETI for the long-term and to evaluate larger cohorts of PwCF on ETI.

Factors that predict pursuing sinus surgery in the era of highly effective modulator therapy.

BACKGROUND: Comorbid chronic rhinosinusitis (CRS) remains unresolved for many people with cystic fibrosis (PwCF). While highly effective modulator therapy improves quality-of-life and symptom severity, the impact of this intervention and other factors associated with pursuing endoscopic sinus surgery (ESS) remains understudied. METHODS: Adult PwCF + CRS were enrolled into a prospective, observational, multi-institutional study. Participants completed validated outcome measures to evaluate respiratory symptom severity, depression, headache, and sleep quality, as well as nasal endoscopy, sinus computed tomography (CT), and olfactory testing. Bivariate comparisons and regression modeling evaluated treatment cofactors, disease characteristics, and outcome measures associated with pursuing ESS. RESULTS: Sixty PwCF were analyzed, including 24 (40%) who elected ESS. Pursuing ESS was associated with worse SinoNasal Outcome Test (SNOT-22) total, rhinologic, psychological, and sleep dysfunction domain scores; worse Patient Health Questionnaire-9-Revised depression scores; worse Pittsburgh Sleep Quality Index total scores; worse weight, role, emotion, and eating domain scores on the Cystic Fibrosis Questionnaire-Revised; more severe disease on nasal endoscopy; and lack of modulator therapy (all p < 0.050). Multivariable regression identified that worse SNOT-22 total score was associated with electing ESS (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.16, p = 0.015) and elexacaftor/tezacaftor/ivacaftor (ETI) treatment (OR 0.04, 95% CI 0.004-0.34, p = 0.004) was associated with pursing medical therapy. CONCLUSIONS: Worse sinonasal symptom burden, lack of ETI treatment, sleep quality, depression, and nasal endoscopy scores were associated with electing ESS, while lung disease severity and sinus CT scores were not. ETI use was associated with lower odds of pursuing ESS independent of sinonasal symptom burden.

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors.

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

Determining the minimal clinically important difference for the questionnaire of olfactory disorders in people with cystic fibrosis and factors associated with improvement after highly effective modulator therapy.

INTRODUCTION: Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF). The Questionnaire of Olfactory Disorders (QOD) is a validated instrument that evaluates olfactory-specific quality-of-life. The QOD minimal clinically important difference (MCID) and factors associated with olfactory improvement after elexacaftor/tezacaftor/ivacaftor have not been determined for PwCF. METHODS: Prospective observational data were pooled from three studies that enrolled adult PwCF with chronic rhinosinusitis (CRS). QOD scores and disease characteristics were assessed. To evaluate internal consistency and calculate the QOD MCID, Cronbach's alpha and four distribution-based methods were employed. For participants who enrolled prior to elexacaftor/tezacaftor/ivacaftor, QOD scores were obtained at baseline and after elexacaftor/tezacaftor/ivacaftor initiation. Multivariable regression was used to identify factors associated with QOD improvement. RESULTS: Of 129 PwCF included, 65 had QOD scores before and 3-6 months after starting elexacaftor/tezacaftor/ivacaftor. Mean baseline QOD score was 6.5 ± 7.9. Mean Cronbach's alpha was ≥0.85. The MCID estimates were as follows: Cohen's effect size = 1.6, standard error of measurement = 2.5, ½ baseline standard deviation = 4.0, and minimal detectable change = 6.9. Mean MCID was 3.7. Of those with pre/post elexacaftor/tezacaftor/ivacaftor QOD scores, the mean change in QOD was -1.3 ± 5.4. After elexacaftor/tezacaftor/ivacaftor, QOD improvement surpassed the MCID in 22% of participants (14/65). Worse baseline QOD scores and nasal polyps were associated with improved QOD scores after elexacaftor/tezacaftor/ivacaftor (both p < 0.04). CONCLUSION: The QOD MCID in PwCF was estimated to be 3.7. Elexacaftor/tezacaftor/ivacaftor led to qualitative but not clinically meaningful improvements in QOD score for most PwCF; PwCF with worse baseline QOD scores and nasal polyps improved in a clinically significant manner.

Anterior Skull Base Osteoradionecrosis in the Age of Intensity-Modulated Radiation Therapy: A Case Series.

Background Despites advances in radiation technology, skull base osteoradionecrosis (ORN) continues to be a rare, devastating, and hard to treat complication of radiotherapy. We present three cases of anterior skull base ORN in a cohort treated with intensity-modulated radiation therapy (IMRT). Case Series Three patients developed anterior skull base ORN after receiving at least one round of IMRT. ORN was diagnosed through either nasal endoscopy or imaging findings. The first was a 59-year-old woman with a sinonasal squamous cell carcinoma. Her chemoradiation history was notable for reirradiation and a high dose of radiation (143.3 Gy). The second was a 55-year-old man with recurrent nasopharyngeal carcinoma, whose history was notable for a high dose of radiation (∼140 Gy) and for being reirradiated. The final patient was a 37-year-old woman with an unremarkable history who received radiotherapy (65.0 Gy) for an esthesioneuroblastoma. One patient was asymptomatic and did not receive ORN-specific therapy. The other two were treated with a combination of medical and surgical intervention with successful short-term outcomes (no evidence of infection). Conclusion Anterior skull base ORN can be treated through conservative and surgical means to achieve successful short-term outcomes. Further investigation of long-term outcomes is warranted.

Laryngeal cancer treatment decision making: A conjoint analysis of general public attitudes and priorities.

Objective: Patients with advanced laryngeal cancer are typically presented with divergent treatment options, namely chemoradiation versus total laryngectomy. This study aims to understand general perspectives of the factors involved in this decision-making process. Methods: Surveys were constructed using specialized conjoint analysis software. Seven attributes integral to the decision-making process for advanced laryngeal cancer treatment were included. Results: Three hundred one healthy adult volunteers completed the decision-making program. The relative impact of each treatment attribute on decision making across all participants was scored with an average importance score (standard deviation) as follows: Lifespan 22.2% (±8.5), Voicing 21.4% (±5.9), Swallowing 19.1% (±7.3), Cancer Cure 14.9% (±6.2), Mode of Breathing 11.0% (±3.7), Self-Image 6.7% (±2.9), and Treatment Type 4.8% (±3.0). Conclusions: General public opinion ranked lifespan, voicing, and swallowing aspects as similarly important, and all were ranked more important than probability of cure. These data demonstrate a variety of priorities among participants and the need for tailored discussions when determining treatment choice for advanced laryngeal cancer. Level of Evidence: Level 4.

Residential Proximity to a Commercial Pesticide Application Site and Risk of Chronic Rhinosinusitis.

Importance: Environmental and occupational toxicants have been shown to be associated with an increased prevalence of chronic rhinosinusitis (CRS). However, few to no studies have evaluated patients for CRS using objective testing and workup protocols that fulfill guidelines for CRS diagnostic criteria. Furthermore, no study, to our knowledge, has investigated the risks of CRS in the context of residential exposure through proximity to a commercial pesticide application site. Objectives: To evaluate associations of residential proximity to a commercial pesticide application site and the prevalence of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSwoNP). Design, Setting, and Participants: This was a retrospective cohort study of patients who presented to a tertiary care institution for rhinology evaluation between March 1, 2018, and December 31, 2022. Main Outcomes and Measures: The outcome variable was the clinical diagnosis of CRS (CRSwNP, CRSwoNP, or non-CRS control). Patients' residential addresses were utilized to determine pesticide exposure status based on a validated computational geographic information algorithm based on data from the California Pesticide Use Report System. The dichotomous independent variable of exposure status (exposed or non-exposed) was determined by assessing reports of any pesticide applications within 2000 m of each participant's residence in 2017. Multivariable logistic regressions assessing CRS status and CRS subtypes were conducted with pesticide exposure as the primary covariate of interest. The primary study outcome and measurements as well as study hypothesis were all formulated before data collection. Results: Among a total of 310 patients (90 CRSwNP, 90 CRSwoNP, and 130 control), the mean (SD) age was 50 (17) years; 164 (53%) were female. Race and ethnicity information was not considered. Controlling for patient demographic information, smoking history, county of residence, and medical comorbidities, pesticide exposure was associated with an approximately 2.5-fold increase in odds of CRS (adjusted odds ratio, 2.41; 95% CI, 1.49-3.90). Pesticide exposure was associated with similar risks for CRSwNP (adjusted relative risk ratio [aRRR], 2.34; 95% CI, 1.31-4.18) and CRSwoNP (aRRR, 2.42; 95% CI, 1.37-4.30). Conclusions and Relevance: The findings of this retrospective cohort study and analysis revealed that residential exposure to commercial pesticide application within a 2000-m buffer was independently associated with an approximately 2.5-fold increase in odds of being diagnosed with CRS. If validated by additional research, this association would have substantial implications for public health.

Recurrence patterns among patients with sinonasal mucosal melanoma: A multi-institutional study.

OBJECTIVE: To evaluate recurrence patterns and survival after recurrence among patients with sinonasal mucosal melanoma (SNMM). METHODS: This was a multi-institutional retrospective review from seven U.S. institutions of patients with SNMM from 1991 to 2022. Recurrence was categorized as local, regional, distant, or multifocal. Kaplan-Meier tests were used to evaluate disease-free survival (DFS), overall survival (OS), and post-recurrence survival (PRS) reported with standard errors (SE) and log-rank testing used for comparison. Cox-regression was further used, with hazard ratios (HR) and 95% confidence intervals (CI) reported. RESULTS: Among 196 patients with SNMM, there were 146 patients with recurrence (74.5%). Among all patients, 60-month DFS (SE) was 15.5% (2.9%), 60-month OS (SE) was 44.7% (3.7%), mean age ± standard deviation at diagnosis was 69.7 ± 12.5 years, and 54.6% were female. In 26 patients who underwent primary treatment of the neck, 60-month DFS did not differ from no treatment (p > 0.05). Isolated distant recurrence was most common (42.8%), followed by local (28.3%), multifocal (20.7%), and regional recurrence (8.3%). Among patients with regional recurrence in the neck, there was no 60-month PRS benefit for patients undergoing salvage neck dissection or radiation (p > 0.05). Among patients with distant recurrence, only immunotherapy was associated with improved 12-month PRS (HR = 0.32, 95% CI = 0.11-0.92, p = 0.034), and no treatment group was associated with improved 24- or 60-month PRS (p > 0.05). CONCLUSION: SNMM is associated with a high recurrence rate and poor survival. Primary treatment of the neck was not associated with reduced recurrence, and immunotherapy for treatment of distant recurrence was associated with increased 12-month PRS.

Is lobectomy sufficient for multifocal papillary thyroid microcarcinoma?

IMPORTANCE: Multifocal papillary thyroid microcarcinoma (PTMC) has been associated with a higher incidence of lymph node involvement, bilateral involvement, and extrathyroidal extension compared to unifocal papillary thyroid cancer (PTC). OBJECTIVE: To describe the incidence and determinants of survival for patients with multifocal PTMC using the Surveillance, Epidemiology, and End Result (SEER) database. DESIGN, SETTING, PARTICIPANTS: The SEER registry was utilized to calculate survival trends for patients with PTMC between 2010 and 2015. Patient data was then analyzed with respect to age, sex, race, multifocality, and types of surgery rendered. MAIN OUTCOMES AND MEASURES: Overall Survival (OS) and Disease Specific Survival (DSS). RESULTS: 22,283 cases of papillary thyroid microcarcinoma (T1a N0 M0) were identified. The cohort was composed of 82.6 % females, and about 82 % of patients were of white race. The mean age at diagnosis was 51.9 years. Multifocal PTMC was present in 32.2 % of the tumors (n = 7186). 73.9 % of patients underwent total thyroidectomy and 23.0 % received lobectomy. OS at 2 and 5 years was 98 % and 95 %, respectively. Multivariate analysis revealed that age, sex, and multifocality were determinants of OS. Only age was a determinant of DSS. Kaplan-Meier survival analysis revealed that multifocal PTMC had similar mean OS between lobectomy and total thyroidectomy patients (69.59 months versus 69.82 months). CONCLUSIONS AND RELEVANCE: PTMC has a good prognosis. Our analysis revealed that age was a determinant of OS and DSS; sex and multifocality were also prognosticators for OS. The type of surgery, whether lobectomy or total thyroidectomy, was not a determinant of survival in multifocal PTMC.

An Algorithm for the Use of Free Tissue Graft Reconstruction in the Endoscopic Endonasal Approach for Pituitary Tumors.

OBJECTIVE: To identify factors associated with successful use of free tissue grafting versus vascularized reconstruction after resection of pituitary tumors. METHODS: A retrospective chart review of 2 tertiary academic medical centers over 3.5 years was conducted. Variables assessed included age, sex, body mass index, pathology, extent of surgical exposure, cavernous sinus or suprasellar extension, intraoperative cerebrospinal fluid (CSF) leak, grade of leak, previous radiation, and previous surgery. Reconstructive techniques were divided into no reconstruction, free tissue grafts, and vascularized flaps. RESULTS: A total of 485 patients were included. Free grafts were used in 299/485 cases (61.6%) and were more commonly used with smaller approaches (P < 0.001). Larger exposure size and CSF leak grades 2 and 3 were associated with vascularized flap use (P < 0.001 and P = 0.012, respectively). Using multivariate regression, type of reconstruction could be predicted by increasing extent of approach, intraoperative CSF leak grade, and suprasellar extension (odds ratio [OR], 2.014, P < 0.001, 95% confidence interval [CI], 1.335-3.039; OR, 1.636, P = 0.025, 95% CI, 1.064-2.517; OR, 1.975, P < 0.001, 95% CI, 1.554-2.510, respectively). Postoperative CSF leak occurred in 9 of 173 patients (5.2%) with intraoperative leak and was not associated with any factors on analysis. CONCLUSIONS: We propose an algorithm whereby grade 1 CSF leaks in sellar and parasellar resections can be successfully reconstructed with a free graft. Vascularized flaps may be reserved for grade 2 or 3 intraoperative CSF leaks, extended approaches, or tumors with suprasellar extension.