Lal, Devyani

ABSTRACT Objectives We evaluated the impact of teprotumumab therapy ( TT ) introduction on orbital decompression ( OD ) utilization for thyroid eye disease ( TED ) and compared rates of significant exophthalmos reduction ( SER ) and diplopia between TT and OD . Methods Newly diagnosed TED patients treated pre (2015–2020) and post teprotumumab (2020–2025) FDA approval were identified from the EHR . Utilization trends, diplopia rates, and immediate (≤ 6 weeks post‐intervention) and long‐term follow‐up SER (≥ 2 mm reduction) were studied. Results Of 406 TED patients, 53 (36.8%) underwent OD in the pre‐ TT cohort ( n = 144). Post‐teprotumumab approval ( n = 262), primary OD was performed in 29 (11.1%), of which 3 (10.3%) were subsequently placed on TT ; primary TT was used in 68/262 (25.9%) with subsequent OD performed in 9 (13.2%). The remaining patients used other treatments (corticosteroids, orbital radiation, rituximab, tocilizumab, etc.). In the overall cohort, immediate SER was achieved in 94.4% of OD versus 83.8% of TT patients ( p = 0.028), with greater median reduction in the OD group (5 vs. 4 mm; p = 0.001). At long‐term follow‐up (median 13 vs. 12 months), SER was sustained in 85.4% of OD and 62.9% of TT patients ( p = 0.042). Pre‐therapy diplopia was more prevalent in TT vs. OD patients (79.4% vs. 59.7%; p = 0.019). New‐onset posttreatment diplopia was higher in the OD group (20.7% vs. 5.9%; p = 0.008). Conclusions Rates of OD surgery declined following FDA approval of teprotumumab. OD achieved sustained and greater exophthalmos reduction but carried a higher risk of diplopia. Contemporaneous OD indications may have evolved to use in TT‐recalcitrant TED or those in need of urgent decompression. Level of Evidence 4.

Background Mepolizumab blocks IL-5, targeting eosinophilic type-2 inflammation. Due to existing phenotype driven patient selection, evidence of its effectiveness in primary diffuse CRS and CRS without nasal polyps (CRSsNP) and in real-world populations is limited. Our objective was to evaluate the real-world effectiveness of mepolizumab in patients with primary diffuse CRS, regardless of nasal polyp status, and to assess outcomes across CRS phenotypes and prior surgical history. Methods Adults with primary diffuse CRS treated with mepolizumab for ≥6 months were identified. Pre- and post-therapy outcomes included serum eosinophil counts, Lund-Mackay CT scores, Lund-Kennedy endoscopic scores, and SNOT-22 symptom scores. Subgroup analyses were performed by CRS phenotype (CRSwNP vs . CRSsNP) and prior endoscopic sinus surgery (ESS). Biologic switching and discontinuation were recorded. Results Among 277 patients (mean age 60.8 ± 14.7 years; 54.9% female), 93.5% had type-2 comorbidities, 29.6% had CRSsNP, and 27.8% were ESS-naïve. The median duration of mepolizumab therapy was 31 months. Mepolizumab therapy significantly reduced serum eosinophils (median 0.57 to 0.07 ×10 9 /L, p<0.001) and Lund-Mackay scores (median 14 to 10, p<0.001), which was consistent across all subgroups. Improvements in SNOT-22 and endoscopic scores were modest and not consistently significant. CRSwNP patients were more likely to undergo ESS during therapy, but time to first post-therapy ESS was longer than in CRSsNP. There were no differences in likelihood of undergoing ESS during therapy, time to subsequent ESS, or oral corticosteroid use between prior ESS and ESS-naïve patients. Biologic switching occurred in 24.9%, and discontinuation in 16.6%, primarily due to disease recalcitrance. Conclusion Mepolizumab effectively reduced systemic eosinophilia and radiographic disease burden in primary diffuse CRS, independent of phenotype or prior ESS. Symptom improvement was variable, highlighting the heterogeneity of clinical response. These findings support an endotype-driven approach to biologic therapy and suggest that IL-5 blockade may benefit selected CRSsNP patients.

Background: Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, high-grade, and aggressive tumor of the sinonasal tract. Due to the rarity of this malignancy, current treatment guidelines are based on small and often/mainly single-center retrospective datasets. In the absence of a universally accepted standard of care for SNUC, treatment approaches vary across countries and institutions, reflecting real-world clinical practice. The primary aim of this study was to describe real-world treatment and outcomes for patients with confirmed SNUC. Methods: This was an international, multi-center, retrospective, observational cohort study that pooled patients into the largest SNUC dataset to date. Fifteen centers were enrolled to contribute data, including seven from Europe, four from the United States, three from the United Kingdom, and one from Canada. In the absence of a universally accepted standard of care for SNUC, treatment approaches varied across countries and institutions, reflecting real-world clinical practice. Patients included were those with histologically confirmed SNUC who were treated between 1997 and 2021. Results: This study yielded 485 patients treated for SNUC. The median age at diagnosis was 55.6 years (IQR: 44.5–67.6), and 63.7% were male. Most cases presented at advanced stages, with 70.8% as T4a or T4b. Overall survival (OS) outcomes were available for 412 patients, with a median follow-up of 26.0 months. The 5- and 10-year OS were 47.2% (95% CI: 40.8–53.3%) and 39.6% (95% CI: 32.5–46.6%), respectively. Advanced age, dichotomized T-stage (T4a/b vs. T1–3), M-stage, and orbital involvement were significant poor prognostic factors on univariable analysis (p’s < 0.01). On multivariable analysis, orbital involvement (HR: 2.73, 95% CI: 1.42–5.27, p = 0.003) and distance metastasis stage (HR: 3.00, 95% CI: 1.25–7.21, p = 0.014) were both independently associated with worse OS. Conclusions: This observational study presents the largest multi-center cohort analysis of SNUC to date, providing new insights into prognostic factors for a rare cancer treated at global centers of excellence. Orbital involvement and the presence of metastases are candidate independent risk factors associated with poorer OS.

Purpose of review Increasing evidence suggests that epigenetic regulation plays a central role in chronic rhinosinusitis pathogenesis, heterogeneity, and treatment response. This review summarizes current knowledge of epigenetics in CRS pathogenesis, their role in endotype differentiation, and potential as diagnostic and therapeutic targets. Recent findings Distinct epigenetic signatures have been identified across CRS subtypes. Hypermethylation of TSLP and differential regulation of FZD5, IL8, and EMT-related genes distinguish eosinophilic CRSwNP from other phenotypes. Specific microRNAs (miR-941, miR-21, miR-125b, miR-155) correlate with disease severity, tissue eosinophilia, and corticosteroid responsiveness, highlighting their utility as noninvasive biomarkers. Experimental data suggest that targeting DNMTs or HDACs may reverse pathogenic remodeling. Emerging therapeutic approaches – such as biologics modulating epigenetically controlled cytokines (e.g. tezepelumab) and engineered extracellular vesicle-based miRNA delivery – illustrate translational promise. Summary Epigenetic mechanisms critically influence CRS pathogenesis and clinical variability. Their modulation offers novel opportunities for biomarker discovery, disease stratification, and personalized therapy. Future research should focus on standardizing epigenetic profiling methodologies, validating candidate biomarkers in diverse populations, and integrating multiomics and single-cell approaches to uncover cell-specific regulatory networks. These advances may enable precision medicine in CRS, bridging the gap between molecular mechanisms and targeted clinical management.