Citations

We aimed to review the molecular characteristics of metastatic melanoma and the role of surgery in metastasectomy for metastatic melanoma. We performed a systematic literature search on PubMed to identify relevant studies focusing on several mutations, including NRAS, BRAF, NF1, MITF, PTEN, TP53, CDKN2A, TERT, TMB, EGFR, and c-KIT. This was performed in the context of metastatic melanoma and the role of metastasectomy in the metastatic melanoma population. A comprehensive review of these molecular characteristics is presented with a focus on their prognosis and role in surgical metastasectomy.

Abstract Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer predisposition syndrome defined by germline deletion of one NF1 allele. Somatic loss of heterozygosity in the remaining NF1 allele in Schwann lineage cells gives rise to benign tumors known as plexiform neurofibromas. These tumors have a high risk of transforming into malignant peripheral nerve sheath tumors (MPNST) through the sequential deletion of CDKN2A/B followed by recurrent mutations in SUZ12 or EED, constituting the inactivation of polycomb repressor complex 2 (PRC2). PRC2 is a transcriptional repressor complex involved in the silencing of several development and differentiation genes. Loss of this complex leads to a depletion in trimethylation marks on Histone H3 Lysine 27 (H3K27me3) and the subsequent gain of acetylation marks on the same lysine residue (H3K27Ac). These molecular hallmarks are shared with diffuse intrinsic pontine gliomas (DIPG) harboring the H3K27M mutation which prevents effective deposition of H3K27me3, thus having similar molecular phenotypes to MPNST. However, the full range of epigenetic consequences of these events are currently not well characterized. Additionally, given that MPNSTs originate from cells of neural crest origin and DIPGs from cells of neural origin, it is not know to what degree epigenetic changes stemming from H3K27me3-loss are general across tumors or are context-dependent based on cell-of-origin. In order to contribute to this effort, the Largaespada lab has engineered Schwann cell lines to harbor deletions in NF1 and either SUZ12 or EED and assayed the H3K27ac landscape of these cells in addition to patient-derived MPNST cell lines. Utilizing the ranked ordering of super enhancers (ROSE) algorithm, we have identified common super enhancers within each MPNST cell line. These super enhancer elements are located nearby a variety of putative oncogenes responsible for the maintenance of cell identity. These elements were then compared to publicly available data from DIPG primary and patient-derived samples to understand common regulatory events driven by loss of H3K27me3 as well as molecular signatures present only in MPNST or in DIPG that may be a result of PRC2 or H3K27M alone. We further characterized these super enhancers by assessing the expression levels of their associated genes to understand their role in transcriptional activation. These efforts provide a roadmap of the super enhancer landscape of both MPNSTs and DIPGs to investigate novel mechanisms of H3K27me3-dependent tumorigenesis while also contributing to knowledge of potential effects of H3K27me3-loss that dependent on the cell-of-origin for each respective tumor. Citation Format: Christopher M. Stehn, Minu Bhunia, Kyle Williams, Alex T. Larsson, Ariel Caride, Jeong-Heon Lee, Tamas Ordog, David Largaespada. Characterizing the super enhancer landscape of H3K27me3 loss in MPNST and DIPG [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B009.

OBJECTIVE To determine the relative hazards of acute and chronic diabetes complications among people with diabetes across the U.S. rural-urban continuum. RESEARCH DESIGN AND METHODS This retrospective cohort study used the OptumLabs Data Warehouse, a deidentified data set of U.S. commercial and Medicare Advantage beneficiaries, to follow 2,901,563 adults (age ≥18 years) with diabetes between 1 January 2012 and 31 December 2021. We compared adjusted hazard ratios (HRs) of diabetes complications in remote areas (population <2,500), small towns (population 2,500–50,000), and cities (population >50,000). RESULTS Compared with residents of cities, residents of remote areas had greater hazards of myocardial infarction (HR 1.06 [95% CI 1.02–1.10]) and revascularization (HR 1.04 [1.02–1.06]) but lower hazards of hyperglycemia (HR 0.90 [0.83–0.98]) and stroke (HR 0.91 [0.88–0.95]). Compared with cities, residents of small towns had greater hazards of hyperglycemia (HR 1.06 [1.02–1.10]), hypoglycemia (HR 1.15 [1.12–1.18]), end-stage kidney disease (HR 1.04 [1.03–1.06]), myocardial infarction (HR 1.10 [1.08–1.12]), heart failure (HR 1.05 [1.03–1.06]), amputation (HR 1.05 [1.02–1.09]), other lower-extremity complications (HR 1.02 [1.01–1.03]), and revascularization (HR 1.05 [1.04–1.06]) but a smaller hazard of stroke (HR 0.95 [0.94–0.97]). Compared with small towns, residents of remote areas had lower hazards of hyperglycemia (HR 0.85 [0.78–0.93]), hypoglycemia (HR 0.92 [0.87–0.97]), and heart failure (HR 0.94 [0.91–0.97]). Hazards of retinopathy and atrial fibrillation/flutter did not vary geographically. CONCLUSIONS Adults in small towns are disproportionately impacted by complications of diabetes. Future studies should probe for the reasons underlying these disparities.

Abstract Introduction This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking. Methods Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan–Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0. Results A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort. Conclusion Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes.

Abstract Premortem clinical presentation of cancer‐associated non‐bacterial thrombotic endocarditis (Ca‐NBTE), therapy, and the clinal course is limited to case reports and small clinical series. An electronic search of Mayo Clinic records (03/31/2002–06/30/2022) with a subsequent manual review was performed to identify adult patients with echocardiographically detected NBTE and active malignancy, excluding those with infectious endocarditis or lupus anticoagulant/antiphospholipid antibodies. In this retrospective cohort study, we analyzed 115 Ca‐NBTE patients (mean age 63.2 ± 9.7 years, 66.1% female) involving 71 (61.7%) mitral, 58 (50.4%) aortic, 8 (6.9%) tricuspid, and 1 (0.9%) pulmonary valve. The most common cancer was lung ( n = 45 cases (39.1%), followed by pancreatic ( n = 19, 16.5%), gynecological (17, 14.8%), gastrointestinal ( n = 10, 8.7%), and 10 (8.7%) with hematologic malignancy; 6 patients had two active cancers. Embolic complications at presentation were frequent: 94 (81.7%) brain, 11 splenic, 10 renal, 6 coronary, and 4 to the extremities. Of 104 anticoagulated patients, 60 received low molecular weight heparin, 17 unfractionated heparin, 16 apixaban, 8 warfarin, and 3 rivaroxaban. There were 18 arterial thromboembolisms; the Kaplan–Meier estimates of the incidence at 2 years were consistent with a rate of 15.9% [95% Confidence Interval (CI) 9.9–23.3], including 14 strokes (12.4%, 95%CI, 7.1–19.2), and 8 other arterial emboli (10.5%, 95%CI, 4.7–18.9); there were 10 venous thromboembolisms (8.9%, 95%CI, 4.5–15.0). Fourteen major bleedings occurred (12.8%, 95%CI, 7.3–19.9) and 94 patients died during follow‐up (77.9%, 95%CI, 71.1–85.8). Ca‐NBTE predominantly affected women with lung adenocarcinoma or digestive tract cancers and manifested by stroke with high mortality and frequent embolic and bleeding complications during anticoagulation therapy.

Abstract Overgrowth of the fungus Wallemia mellicola in the intestines of mice enhances the severity of asthma. Wallemia mellicola interacts with the immune system through Dectin-2 expressed on the surface of myeloid and intestinal epithelial cells. Using Dectin-2-deficient mice, we show that the interaction of W. mellicola with Dectin-2 is essential for the gut-lung pathways, enhancing the severity of asthma in mice with W. mellicola intestinal dysbiosis. These findings offer better insight into dysbiosis-associated inflammation and highlight the role pattern recognition receptors have in immune recognition of commensal fungi in the gut, leading to alterations in immune function in the lungs.

Purpose To (1) review definitions and concepts necessary to interpret applications of deep learning (DL; a domain of artificial intelligence that leverages neural networks to make predictions on media inputs such as images) and (2) identify knowledge and translational gaps in the literature to provide insight into specific areas for improvement as adoption of this technology continues. Methods A comprehensive search of the literature was performed in December 2023 for articles regarding the use of DL in sports medicine. For each study, information regarding the joint of focus, specific anatomic structure/pathology to which DL was applied, imaging modality utilized, source of images used for model training and testing, data set size, model performance, and whether the DL model was externally validated was recorded. A numerical scale was used to rate each DL model’s clinical impact, with 1 corresponding to proof‐of‐concept studies with little to no direct clinical impact and 5 corresponding to practice‐changing clinical impact and ready for clinical deployment. Results Fifty‐five studies were identified, all of which were published within the past 5 years, while 82% were published within the past 3 years. Of the DL models identified, 84% were developed for classification tasks, 9% for automated measurements, and 7% for segmentation. A total of 62% of studies utilized magnetic resonance imaging as the imaging modality, 25% radiographs, and 7% ultrasound, while 1 study each used computed tomography, arthroscopic images, or arthroscopic video. Sixty‐five percent of studies focused on the detection of tears (anterior cruciate ligament [ACL], rotator cuff [RC], and meniscus). The diagnostic performance of ACL tears, as determined by the area under the receiver operator curve (AUROC), ranged from 0.81 to 0.99 for ACL tears (excellent to near perfect), 0.83 to 0.94 for RC tears (excellent), and from 0.75 to 0.96 for meniscus tears (acceptable to excellent). In addition, 3 studies focused on detection of cartilage lesions had AUROC ranging from 0.90 to 0.92 (excellent performance). However, only 4 (7%) studies externally validated their models, suggesting that they may not be generalizable or may not perform well when applied to populations other than that used to develop the model. Finally, the mean clinical impact score was 2 (range, 1‐3) on scale of 1 to 5, corresponding to limited clinical applicability. Conclusions DL models in orthopaedic sports medicine show generally excellent performance (high internal validity) but require external validation to facilitate clinical deployment. In addition, current models have low clinical applicability and fail to advance the field due to a focus on routine tasks and a narrow conceptual framework. Level of Evidence Level IV, scoping review of Level I to IV studies.

Background: Treatment of ulnar collateral ligament (UCL) tears with suture tape augmentation has gained interest given preliminary reports of favorable biomechanical characteristics. No study to date has quantitatively assessed the biomechanical effects of multiple augmentation techniques relative to the native UCL. Purpose: To perform a systematic review and meta-analysis of controlled laboratory studies to assess and comparatively rank biomechanical effects of UCL repair or reconstruction with or without augmentation. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: PubMed, OVID/Medline, and Cochrane databases were queried in January 2023. A frequentist network meta-analytic approach was used to perform mixed-treatment comparisons of UCL repair and reconstruction techniques with and without augmentation, with the native UCL as the reference condition. Pooled treatment estimates were quantified under the random-effects assumption. Competing treatments were ranked in the network meta-analysis by using point estimates and standard errors to calculate P scores (greater P score indicates superiority of treatment for given outcome). Results: Ten studies involving 206 elbow specimens in which a distal UCL tear was simulated were included. UCL reconstruction with suture tape augmentation (AugRecon) restored load to failure to a statistically noninferior magnitude (mean difference [MD], –1.99 N·m; 95% CI, –10.2 to 6.2 N·m; P = .63) compared with the native UCL. UCL reconstruction (Recon) (MD, –12.7 N·m; P < .001) and UCL repair with suture tape augmentation (AugRepair) (MD, –14.8 N·m; P < .001) were both statistically inferior to the native UCL. The AugRecon condition conferred greater load to failure compared with Recon ( P < .001) and AugRepair ( P = .002) conditions. AugRecon conferred greater torsional stiffness relative to all other conditions and was not statistically different from the native UCL (MD, 0.32 N·m/deg; 95% CI, –0.30 to 0.95 N·m/deg; P = .31). Medial ulnohumeral gapping was not statistically different for the AugRepair (MD, 0.30 mm; 95% CI, –1.22 to 1.82 mm; P = .70), AugRecon (MD, 0.57 mm; 95% CI, –0.70 to 1.84 mm; P = .38), or Recon (MD, 1.02 mm; 95% CI, –0.02 to 2.05 mm; P = .055) conditions compared with the native UCL. P-score analysis indicated that AugRecon was the most effective treatment for increasing ultimate load to failure and torsional stiffness, whereas AugRepair was the most effective for minimizing medial gapping. Conclusion: AugRecon restored load to failure and torsional stiffness most similar to the parameters of the native UCL, whereas Recon and AugRepair did not restore the same advantageous properties at time zero. Medial ulnohumeral gapping during a valgus load was minimized by all 3 treatments. Based on network interactions, AugRecon was the superior treatment approach for restoring important biomechanical features of the UCL at time zero that are jeopardized during a complete distal tear.

As the availability of extracorporeal membrane oxygenation (ECMO) expands, so has the need for interfacility transfer to ECMO centers. However, the impact of these transfers is unknown. We hypothesized that interfacility transfers would be associated with increased complications and mortality. This retrospective cohort study includes adult patients treated with venovenous (VV) ECMO at all four adult ECMO centers comprising our statewide registry. Complications, mortality, ECMO duration, length of stay, and disposition were compared based on cannulation at an ECMO center versus outside hospital and transferred by air versus ground after adjusting for baseline covariates/parameters. The study included 420 adult patients, 36% of whom were cannulated at an outside institution before transfer. Of these, 63% were transported by ground and the remainder by air. Risk adjusted logistic regression revealed similar odds of mortality between those cannulated at ECMO centers versus referring hospital and then transported (odds ratio [OR] = 0.77, confidence interval [CI] = 0.49–1.22). This study supports the practice of interfacility ECMO transfer.