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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.

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.

Background and Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes, including HE. Androgen receptor agonists, androgen receptor agonists, can address these conditions through multimodal mechanisms of action; however, their safety and efficacy in patients with cirrhosis have not been well established. Approach and Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral Androgen Receptor Agonist LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary end point was the change from baseline to 24 weeks in skeletal muscle index measured by a CT scan of the L3 region, analyzed with a prespecified modified intent-to-treat population. The secondary end point was the number of overt HE events. Twenty-nine participants (mean age=59 y, MELD=17) received at least 1 dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary end point analysis demonstrated an increase in L3-skeletal muscle index measured by a CT scan of the L3 region in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm2/m2 (95% CI: 1.3–7.4 cm2/m2, p=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (Common Terminology Criteria for Adverse Events grade ≥2; p=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

Summary: The number of spinal reconstruction cases is growing, as are the accompanying complications. Wound complications after spinal reconstruction can be fatal and can affect up to 19% of patients undergoing major spine surgery. The discipline of spinoplastic surgery is characterized by the use of vascularized bone grafts to reconstruct spinal defects, which provide better results compared with nonvascularized and allogenic equivalents, owing to their superior blood supply. We present a 49-year-old man with spinal defect in the C3-C7 region treated with spinoplastic reconstruction. A 5 × 6 cm occipital VBG was designed with a centrally located muscular pedicle and successfully inset into the osseous defect. Radiographs taken 15 months postoperatively demonstrated overall excellent bony fusion, and the patient made an appropriate clinical recovery. In difficult spine procedures, the use of this occipital vascularized bone graft may lead to higher fusion rates without the need for free tissue transfer or allograft placement, which may not be available at all surgical centers around the world.

Abstract Background MASLD is a leading reason for liver transplant waitlisting. The relationship between cardiorespiratory fitness (CRF) and liver fibrosis in patients with MASLD remains unclear. This study aims to provide further evidence supporting the relationship between liver fibrosis and CRF. Methods Subjects with MASLD across various fibrosis stages, including those with cirrhosis awaiting liver transplantation from three U.S. transplant centers, underwent cardiopulmonary exercise testing (CPX). We compared participants based on fibrosis stage (F0-F1, F2-F3, and F4) and CPX parameters such as VO2peak, respiratory exchange ratio (RER), ventilatory efficiency (VE/VCO2), double product (DP) and chronotropic incompetence (CI). Multivariable models were then built to evaluate factors associated with these parameters. Results Sixty-one subjects underwent CPX testing across three centers. Subjects with F4 had lower VO2peak (11.8 mL/kg/min) compared to F0-F1 (22.2 mL/kg/min) and F2-F3 (22.9 mL/kg/min), p < 0.001. Subjects with F4 had higher RER (median 1.25) compared to F0-F1 (1.08) and F2-F3 (1.05), p = 0.001. Similarly, F4 subjects exhibited higher VE/VCO2 (median 36.5) compared to F0-F1 (31) and F2-F3 (30), p < 0.001. Additionally, F4 subjects had lower DP values (median 17,696) compared to F0-F1 (25,460) and F2-F3 (25,372), and higher prevalence of CI (90%) compared to F0-F1 (39%) and F2-F3 (25%), both p = < 0.001. Multivariable modeling confirmed advanced fibrosis (F > 3) as an independent predictor of low CRF. Conclusions In MASLD patients, advanced liver fibrosis, particularly cirrhosis, is associated with reduced CRF and poorer hemodynamic performance during CPX. Prioritizing exercise training for those in earlier stages (F3) may prevent fitness decline, which could hinder physical training and liver transplantation candidacy.

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown. Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) subjective form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity rating score. Patients were followed up for 6 years and asked to complete the identical set of outcome instruments. Regression analysis was used to control for baseline patient characteristics and surgical variables to assess the surgical risk factors for clinical outcomes 6 years after surgery. Results: A total of 1234 patients were enrolled (716 men, 58%; median age, 26 years), and 6-year follow-up was obtained on 79% of patients (980/1234). Using an interference screw for femoral fixation compared with a cross-pin resulted in significantly better outcomes in 6-year IKDC scores (odds ratio [OR], 2.2; 95% CI, 1.2-3.9; P = .008) and KOOS sports/recreation and quality of life subscale scores (OR range, 2.2-2.7; 95% CI, 1.2-4.8; P < .01). Use of an interference screw compared with a cross-pin resulted in a 2.6 times less likely chance of having a subsequent surgery within 6 years. Use of an interference screw for tibial fixation compared with any combination of tibial fixation techniques resulted in significantly improved scores for IKDC (OR, 1.96; 95% CI, 1.3-2.9; P = .001); KOOS pain, activities of daily living, and sports/recreation subscales (OR range, 1.5-1.6; 95% CI, 1.0-2.4; P < .05); and WOMAC pain and activities of daily living subscales (OR range, 1.5-1.8; 95% CI, 1.0-2.7; P < .05). Use of a transtibial surgical approach compared with an anteromedial portal approach resulted in significantly improved KOOS pain and quality of life subscale scores at 6 years (OR, 1.5; 95% CI, 1.02-2.2; P≤ .04). Conclusion: There are surgical variables at the time of ACL revision that can modify clinical outcomes at 6 years. Opting for a transtibial surgical approach and choosing an interference screw for femoral and tibial fixation improved patients’ odds of having a significantly better 6-year clinical outcome in this cohort.

Background Early detection of left and right ventricular systolic dysfunction (LVSD and RVSD respectively) in children can lead to intervention to reduce morbidity and death. Existing artificial intelligence algorithms can identify LVSD and RVSD in adults using a 12‐lead ECG; however, its efficacy in children is uncertain. We aimed to develop novel artificial intelligence–enabled ECG algorithms for LVSD and RVSD detection in pediatric patients. Methods and Results We identified 10 142 unique pediatric patients (age≤18) with a 10‐second, 12‐lead surface ECG within 14 days of a transthoracic echocardiogram, performed between 2002 and 2022. LVSD was defined quantitatively by left ventricular ejection fraction (LVEF). RVSD was defined semiquantitatively. Novel pediatric models for LVEF ≤35% and LVEF <50% achieved excellent test areas under the curve of 0.93 (95% CI, 0.89–0.98) and 0.88 (95% CI, 0.83–0.94) respectively. The model to detect LVEF <50% had a sensitivity of 0.85, specificity of 0.80, positive predictive value of 0.095, and negative predictive value of 0.995. In comparison, the previously validated adult data‐derived model for LVEF <35% achieved an area under the curve of 0.87 (95% CI, 0.84–0.90) for LVEF ≤35% in children. A novel pediatric model for any RVSD detection reached a test area under the curve of 0.90 (0.87–0.94). Conclusions An artificial intelligence–enabled ECG demonstrates accurate detection of both LVSD and RVSD in pediatric patients. While adult‐trained models offer good performance, improvements are seen when training pediatric‐specific models.

A subset of desmoplastic melanomas (DMs) can show extensive morphologic and immunohistochemical overlap with cutaneous diffuse-type neurofibroma. Neurofibroma-like desmoplastic melanoma (NFLDM) thus poses a significant diagnostic pitfall because the clinical implications of these 2 entities differ dramatically. A series of 17 DMs, including 5 cases of NFLDM, were compared with a cohort of 53 cutaneous diffuse-type neurofibromas to explore the utility of molecular testing in the differential diagnosis between NFLDM and neurofibroma and to determine potentially useful morphologic features in this differential diagnosis. Unlike NFLDM, cutaneous diffuse-type neurofibromas: (1) rarely feature intratumoral or peritumoral lymphoid aggregates, (2) consistently harbor an intrinsic stromal support vasculature composed of evenly spaced capillary-sized vessels, and (3) infiltrate adjacent adipose tissue in a dermatofibrosarcoma protuberans–like manner with a complete lack of chronic inflammation or fat necrosis at the leading edge of the tumor. Conversely, DMs, including NFLDM: (1) do not contain Wagner-Meissner bodies, (2) often induce fat necrosis and/or chronic inflammation at the interface with adjacent fibroadipose tissue, (3) lack the intrinsic capillary-sized stromal vasculature observed in most neurofibromas, and (4) may harbor foci of perineuriomatous differentiation, mimicking a hybrid nerve sheath tumor. Any deviation from the expected clinical or morphologic features of cutaneous diffuse-type neurofibroma should raise suspicion for NFLDM. Although not entirely sensitive or specific, molecular testing can help to support the diagnosis of NFLDM by demonstrating genetic abnormalities associated with melanoma, including a UV-light–induced mutational signature, high tumor mutational burden, and/or chromosomal copy number alterations typical of melanoma.