Pediatric Custom Tracheostomies: A Ten-Year Experience.

OBJECTIVES: To describe the use of customized and custom tracheostomies at our institution, and to identify trends in patient presentation and tracheostomy design. METHODS: A retrospective review was conducted for patients at our institution for whom a customized or custom tracheostomy tube was ordered between January 2011 and July 2021. Customized tracheostomy tubes allow for a small selection of alterations to trach design, such as cuff length and flange type. Custom tracheostomies have a unique design created by tracheostomy tube engineers in collaboration with the clinical provider, and are built specifically for a single patient. RESULTS: A total of 235 patients were included, of whom 220 (93%) received customized tracheostomies and 15 custom (7%). The most common indications for customized tracheostomy were tracheal or stomal breakdown on a standard tracheostomy (n = 73, 33%) and ventilation difficulties (n = 61, 27%). The most frequent customization was shaft length (n = 126, 57%). The most common indication for custom tracheostomies was a persistent air leak on a standard or customized trach (n = 9) and the most frequent designs were custom cuffs (n = 8), flanges (n = 4), and anteriorly curved shafts (n = 4). Patients treated with a customized tracheostomy had a 5-year overall survival of 75.3%, compared to 51.4% for custom. CONCLUSION: These are the first cohorts of pediatric patients with customized and custom tracheostomies to be described. Modifications to tracheostomies, in particular shaft length and cuff design, can address common complications of extended tracheostomy, and may help improve ventilation in the most challenging cases. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:452-458, 2024.

The Impact of Delay in Treatment on Survival in Surgically Managed Sinonasal Undifferentiated Carcinoma.

Background Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy with a poor prognosis, and multimodal therapy is the standard of care. We sought to characterize treatment delays in SNUC managed with surgery and adjuvant radiation and to determine the impact on survival using the National Cancer Database (NCDB). Methods This was a retrospective, population-based cohort study of patients with SNUC between 2004 and 2016 in the NCDB. The intervals of diagnosis to surgery (DTS), surgery to radiation (SRT), and radiation duration (RTD) were examined. Recursive partitioning analysis (RPA) was performed to identify the variables with the greatest impact on survival. The association between treatment delay and overall survival (OS) was then assessed using multivariate Cox proportional hazards regression. Results Of 173 patients who met inclusion criteria, 65.9% were male, average age at diagnosis was 56.6 years, and 5-year OS was 48.1%. Median durations of DTS, SRT, and RTD were 18, 43, and 46 days, respectively. Predictors of treatment delay included Black race, government insurance excluding Medicare/Medicaid, and positive margins. RPA-derived optimal thresholds were 29, 28, and 38 days for DTS, SRT and RTD, respectively. On multivariate analysis, positive margins (hazard ratio [HR]: 4.82; 95% confidence interval [CI]: 2.28-10.2) and DTS less than 29 days (HR: 2.41; 95% CI: 1.23-4.73) were associated with worse OS. Conclusion Our results likely reflect the aggressive nature of the disease with surgeons taking more invasive disease to the operating room more quickly. Median treatment intervals described may serve as relevant national benchmarks.

Carcinosarcoma of the nasal cavity and paranasal sinuses: Review of the national cancer database.

Background: Carcinosarcomas are rare, aggressive malignancies that can arise in the nasal cavity and paranasal sinuses. There are limited outcome data available. Accordingly, we sought to use the National Cancer Database (NCDB) to characterize patient demographics and outcomes. Method: A retrospective analysis of the NCDB from 2004 to 2016 for patients with sinonasal carcinosarcoma was conducted. Results: Thirty patients were included. The patients were predominantly male (n = 20), white (n = 23), and privately insured (n = 15), with an average age of 62.4 years. The nasal cavity was the most common subsite (n = 14), followed by the maxillary sinus (n = 8). Most patient were treated with surgery followed by radiation (n = 23), with the remaining undergoing surgery alone (n = 4), radiation alone (n = 2), or no treatment (n = 1). One-third (n = 10) received adjuvant chemotherapy. The 1- and 5-year overall survival (OS) in the cohort were 79.2% and 43.3%, respectively. Univariate log-rank testing showed OS varied based on intervention (P < 0.029), sex (P < 0.042), and age (P < 0.025), while on multivariate analysis none of these factors independently predicted OS. Conclusions: We describe the demographics and presenting features of a national cohort of sinonasal carcinosarcoma patients. Future research is needed to identify predictors of overall survival, and to assess the optimal roles for radiation and systemic chemotherapy.

Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.

Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation. When damaged proteins enter the proteasome, their attached PIs inhibit protease function, potentiating the parasiticidal action of ART and overcoming ART resistance. Binding of the PI moiety to the proteasome active site is enhanced by distal interactions of the extended attached peptides, providing a mechanism to overcome PI resistance. ATZs have an extra mode of action beyond that of each component, thereby overcoming resistance to both components, while avoiding transient monotherapy seen when individual agents have disparate pharmacokinetic profiles.

Interhemispheric gravity-assisted approach for microsurgical resection of a splenium arteriovenous malformation.

The parietal interhemispheric approach employing gravity retraction with skeletonization of bridging veins provides an excellent operative window for safe, curative resection of splenial arteriovenous malformations.

Multi-institutional review of sinonasal and skull base chondrosarcoma: 20-year experience.

BACKGROUND: Chondrosarcomas of the sinonasal cavity and skull base are uncommon malignancies. We sought to provide long-term outcomes at two tertiary care centers. METHODS: Patients with chondrosarcoma treated between 2000 and 2021 were included. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). RESULTS: Thirty-eight patients met inclusion criteria. Fourteen patients had sinonasal (36.8%), 7 petroclival (18.4%), and 17 other primary skull base lesions (44.7%). Twenty-eight patients (73.7%) underwent radiation with an average dose of 67.3 ± 15.1 Gy. Eighteen patients (47.4%) required revision surgery for recurrence. 1, 5, and 10-year OS were 97.3%, 93.1%, and 74.7%. DSS at 5- and 10-year survival was 95.7%. Adjuvant radiation was associated with improved OS (HR: 0.12; 95% CI: 0.02-0.75, p = 0.023). CONCLUSION: We present our experience over the last 20 years treating chondrosarcomas. Favorable survival outcomes can be achieved but recurrence requiring repeat resection is common.

Improvement of Asparagine Ethylenediamines as Anti-malarial Plasmodium-Selective Proteasome Inhibitors.

The Plasmodium proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors. Here, we report further a structure-activity relationship study of AsnEDAs for selective inhibition of Pf20S over human proteasomes. Additionally, we show new mutation that conferred resistance to AsnEDAs and collateral sensitivity to an inhibitor of the Pf20S ß2 subunit, the same as previously identified resistant mutation. This resistance could be overcome through the use of the structure-guided inhibitor design. Collateral sensitivity to inhibitors among respective proteasome subunits underscores the potential value of treating malaria with combinations of inhibitors of different proteasome subunits to minimize the emergence of drug resistance.