Citations

AbstractBackgroundIsolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.MethodsRetrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.ResultsA total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.ConclusionsTVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic add-back experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in NF1-mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells (SCs) has not been defined. We hypothesized that PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs). Methods We engineered NF1-deficient iHSCs with loss of function SUZ12 or EED mutations. RNA sequencing revealed 1327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis, we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways. Results We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog (SHH) signaling in PRC2-deficient iHSCs. Functional studies confirm that Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines. Conclusions We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

Background: Acute ischemic stroke (AIS) imposes a major healthcare burden. It is hypothesized that bacterial infection could influence atherosclerosis and thrombus formation, potentially contributing to AIS. Objectives: We aim to systematically review all studies that have investigated the presence of bacterial signatures within thrombi retrieved following mechanical thrombectomy (MT) procedures in patients with AIS. Design: This systematic review is designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist. Data sources and methods: A comprehensive search was conducted in the Web of Sciences, PubMed, Scopus, and Embase databases to identify relevant studies. Results: The literature search and screening included 11 studies involving 674 patients, with 414 (61.4%) being male and 260 (38.6%) females. Among all the patients, 393 (58.3%) were positive for bacterial presence in their retrieved thrombi. The most utilized technique for bacterial signature detection was bacterial DNA extraction followed by polymerase chain reaction amplification of the 16S rRNA gene sequence. Staphylococcus aureus was the most studied bacteria among the studies analyzed. Conclusion: Bacterial infections and the presence of bacteria within thrombi may significantly contribute to AIS by initiating or exacerbating atherosclerosis or thrombosis. Understanding the mechanisms by which bacteria affect vascular health is crucial for developing effective preventive and therapeutic strategies for stroke patients.

Abstract Purpose Excessive purchasing of influenza vaccine can lead to costly overages and waste of resources. Insufficient quantities, however, can jeopardize population health. Our project aimed to use predictive analytics to determine the influenza vaccine quantities that would be needed for the next influenza season while minimizing vaccine waste and meeting patient care demands. Methods Several data sources were evaluated to develop a predictive analytics model to better estimate future influenza vaccine orders during upcoming influenza seasons. A retrospective analysis of influenza vaccine administrations over the last 4 influenza seasons allowed the team to develop an algorithm to predict influenza vaccine needs. Two regions within Mayo Clinic were selected to determine the validity of our ordering process. These 2 regions, identified as regions 3 and 5, ordered influenza vaccines based on the algorithm, while the other 3 regions acted as control groups, ordering though traditional methods based on purchasing data. Results Predictive analysis for the 2 intervention regions resulted in a savings of over $1 million when compared to traditional ordering methods. The model predicted that the quantity of vaccine ordered should be 17,574.16 and 9,164.29 quadrivalent influenza vaccines for regions 3 and 5, respectively. On the basis of actual administration data, 15,902 vaccines for region 3 and 9,016 vaccines for region 5 will be administered by the end of the season, both of which are less than the predicted amount needed, demonstrating the accuracy of the analytics. Conclusion Compared to the traditional ordering method, ordering using predictive analytics allowed the team to more accurately determine future order volumes and spend, yielding significant cost savings.

Objectives To assess the impact of body mass index (BMI) on hypoglossal nerve stimulator (HNS) implantation outcomes in pediatric patients with Down syndrome (DS). We compare outcomes of HNS implantation when comparing children based on overweight or obese status. Methods Retrospective cohort study of patients at a single tertiary pediatric hospital who underwent HNS implantation between 2022 and 2024. Patients with DS under 21 years of age at time of implantation were included. One child with Wolf‐Hirschhorn syndrome was also included. The main outcome measured was reduction in apnea‐hypopnea index (AHI). Results Twenty patients were implanted with HNS during the study period. Eleven patients were implanted with a BMI considered overweight and 8 patients with a BMI considered obese. No significant correlation was found between BMI percentile and AHI reduction ( r = 0.06, p = 0.8). No significant differences were found between obese and non‐obese groups for preoperative AHI, postoperative AHI, or AHI reduction. Both groups responded favorably to HNS therapy with AHI reduction of 83.8% in obese patients and 81.9% in non‐obese patients. Conclusion We demonstrate no difference in postoperative AHI outcomes when comparing patients with obesity defined as BMI >95th percentile compared to those without. Level of Evidence 3 Laryngoscope , 135:1223–1226, 2025

Objective To identify primary care structures and processes that have the highest and lowest impact on chronic disease management and screening and prevention outcomes as well as to assess the feasibility of implementing these structures and processes into practice. Design A two-round Delphi study was conducted to establish consensus on the impact and feasibility of 258 primary care structures and processes. Participants 29 primary care providers, health system leaders and health services researchers in the USA. Outcomes Primary outcomes were (1) consensus on the impact of each structure and process on chronic disease management and screening and prevention outcomes, separately and (2) consensus on feasibility of implementation by primary care practices. Results Consensus on high impact and feasibility of implementation was reached on four items for chronic disease management: ‘Providers use motivational interviewing to help patients set goals’, ‘Practice has designated staff to manage patient panel’, ‘Practice has onsite providers or staff that speak the most dominant, non-English language spoken by patients’ and ‘Practice includes mental health providers and/or behavioural health specialists in care team’ and seven items for screening and prevention: ‘Practice utilizes standing protocols and orders’, ‘Practice generates reports to alert clinicians to missed targets and to identify gaps in care, such as overdue visits, needed vaccinations, screenings or other preventive services’, ‘Practice has designated staff to manage patient panel’, ‘Practice sets performance goals and uses benchmarking to track quality of care’, ‘Practice uses performance feedback to identify practice-specific areas of improvement’, ‘Practice builds quality improvement activities into practice operations’ and ‘Pre-visit planning data are reviewed during daily huddles’. Only ‘Practice has designated staff to manage patient panel’ appeared on both lists. Conclusion Findings suggest that practices need to focus on implementing mostly distinct, rather than common, structures and processes to optimise chronic disease and preventive care.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Abstract In patients with lunate fossa and proximal capitate degeneration, or failed scaphoid excision and partial wrist arthrodesis, double allograft interposition arthroplasty may allow patients to maintain wrist motion and improve pain. Following dorsal exposure of the carpus, a completion proximal row carpectomy is performed. Suture anchors are placed evenly along the perimeter of the distal radius and used to secure a precut sheet of allograft. Additional suture anchors are placed at the proximal aspect of the distal carpal row, securing a second piece of allograft to the proximal capitate and hamate. We present the case of a female with osteogenesis imperfecta who failed prior partial wrist fusion for treatment of scapholunate advanced collapse. She declined wrist arthrodesis and was not a candidate for total wrist arthroplasty. Proximal row carpectomy with double interposition arthroplasty provided resolution of her pain and preserved her wrist range of motion. Double interposition arthroplasty may provide reliable pain relief and wrist range of motion for patients with advanced wrist arthritis in whom traditional salvage procedures are contraindicated or have failed. Use of this technique offers benefits that may minimize complications and improve longevity compared with previously described allograft interposition techniques.