Differential tractography and whole brain connectometry in primary motor area gliomas resection: A feasibility study.

OBJECTIVE: Establish the evolution of the connectome before and after resection of motor area glioma using a comparison of connectome maps and high-definition differential tractography (DifT). METHODS: DifT was done using normalized quantitative anisotropy (NQA) with DSI Studio. The quantitative analysis involved obtaining mean NQA and fractional anisotropy (FA) values for the disrupted pathways tracing the corticospinal tract (CST), and white fiber network changes over time. RESULTS: We described the baseline tractography, DifT, and white matter network changes from two patients who underwent resection of an oligodendroglioma (Case 1) and an IDH mutant astrocytoma, grade 4 (Case 2). CASE 1: There was a slight decrease in the diffusion signal of the compromised CST in the immediate postop. The NQA and FA values increased at the 1-year follow-up (0.18 vs. 0.32 and 0.35 vs. 0.44, respectively). CASE 2: There was an important decrease in the immediate postop, followed by an increase in the follow-up. In the 1-year follow-up, the patient presented with radiation necrosis and tumor recurrence, increasing NQA from 0.18 in the preop to 0.29. Fiber network analysis: whole-brain connectome comparison demonstrated no significant changes in the immediate postop. However, in the 1-year follow up there was a notorious reorganization of the fibers in both cases, showing the decreased density of connections. CONCLUSIONS: Connectome studies and DifT constitute new potential tools to predict early reorganization changes in a patient's networks, showing the brain plasticity capacity, and helping to establish timelines for the progression of the tumor and treatment-induced changes.

Impact of Hematopoietic Cell Transplantation on Myocardial Fibrosis in Young Patients with Sickle Cell Disease.

Serial cardiovascular magnetic resonance evaluation of children and young adults with sickle cell disease (SCD) who underwent hematopoietic cell transplantation (HCT) showed that the mean ECV, representing diffuse myocardial fibrosis, decreased by 3.4% from the baseline to 12-months post HCT. (NCT04362293).

Transseptal coronary artery-a pictorial review.

A transseptal coronary artery course, also known as a transconal course, is an anomalous course of the left main coronary artery (LMCA) or the left anterior descending artery (LAD) through the conal septal myocardium. The conal septal myocardium is the posterior wall of the right ventricular outflow tract (RVOT), acting as a dividing myocardial wall between the subaortic and subpulmonary outflow tracts. The initial segment of a transseptal coronary artery has an extraconal course between the aorta and the RVOT cranial to the true intramyocardial segment. The transseptal coronary artery then emerges out of the conal septal myocardium at the epicardial surface on the lateral aspect of the RVOT. Many consider the transseptal coronary artery to be a benign entity. However, there are few case reports of severe cardiac symptoms such as myocardial ischemia, arrhythmia, and even sudden cardiac deaths due to potential coronary artery compression in the systolic phase.​ In this article, we seek to describe the imaging findings of transseptal coronary artery course on coronary computed tomography angiography (CTA), discuss their clinical analysis, and briefly discuss the management of these lesions.

Faculty and Resident Perspectives on the Implementation of Entrustable Professional Activities in General Surgery Residency.

OBJECTIVE: This study aimed to identify what best practices facilitate implementation of Entrustable Professional Activities (EPAs) into surgical training programs. DESIGN: This is a mixed methods study utilizing both survey data as well as semi-structured interviews of faculty and residents involved in the American Board of Surgery (ABS) EPA pilot study. SETTING: From 2018 to 2020, the ABS conducted a pilot that introduced five EPAs across 28 general surgery training programs. PARTICIPANTS: All faculty members and residents at the 28 pilot programs were invited to participate in the study. RESULTS: About 117 faculty members and 79 residents responded to the survey. The majority of faculty (81%) and residents (66%) felt that EPAs were useful and were a valuable addition to training. While neither group felt that EPAs were overly time consuming to complete, residents did report difficulty incorporating them into their daily workflow (44%). Semi-structured interviews found that programs that focused on faculty and resident -development and utilized frequent reminders about the importance and necessity of EPAs tended to perform better. CONCLUSIONS: EPA implementation is feasible in general surgery training programs but requires significant effort and engagement from all levels of program personnel. As EPAs are implemented by the ABS nationally a focus on resident and faculty development will be critical to success.

Lessons from the Pandemic: Role of Percutaneous ECMO and Balloon Atrial Septostomy in Multi-System Inflammatory Syndrome in Children.

Multi-system inflammatory syndrome in children (MIS-C) in the setting of COVID-19 can be associated with severe cardiopulmonary dysfunction. This clinical deterioration may sometimes necessitate veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. We describe an algorithmic approach including the role of balloon atrial septostomy in this cohort. This is the first reported series of percutaneous VA-ECMO in pediatric patients with MIS-C for better outcomes. The lessons from this approach can be replicated in other pediatric clinical conditions and adds to the armament of multiple pediatric specialties.

Additive Value of MR Simulation Prior to Chemoradiation in Evaluating Treatment Response and Pseudoprogression in High-Grade Gliomas.

BACKGROUND: A dedicated MRI Simulation(MRsim) for radiation treatment(RT) planning in high-grade glioma(HGG) patients can detect early radiological changes, including tumor progression after surgery and before standard of care chemoradiation. This study aimed to determine the impact of using post-op MRI vs. MRsim as the baseline for response assessment and reporting pseudo-progression on follow-up imaging at one month(FU1) after chemoradiation. METHODS: Histologically confirmed HGG patients were planned for six weeks of RT in a prospective study for adaptive RT planning. All patients underwent post-op MRI, MRsim, and follow-up MRI scans every 2-3 months. Tumor response was assessed by three independent blinded reviewers using Response Assessment in Neuro-Oncology(RANO) criteria when baseline was either post-op MRI or MRsim. Interobserver agreement was calculated using light's kappa. RESULTS: 30 patients (median age 60.5 years; IQR 54.5-66.3) were included. Median interval between surgery and RT was 34 days (IQR 27-41). Response assessment at FU1 differed in 17 patients (57%) when the baseline was post-op MRI vs. MRsim, including true progression vs. partial response(PR) or stable disease(SD) in 11 (37%) and SD vs. PR in 6 (20%) patients. True progression was reported in 19 patients (63.3%) on FU1 when the baseline was post-op MRI vs 8 patients (26.7%) when the baseline was MRsim (p=.004). Pseudo-progression was observed at FU1 in 12 (40%) vs. 4 (13%) patients, when the baseline was post-op MRI vs. MRsim (p=.019). Interobserver agreement between observers was moderate (κ = 0.579; p<0.001). CONCLUSIONS: Our study demonstrates the value of acquiring an updated MR closer to RT in patients with HGG to improve response assessment, and accuracy in evaluation of pseudo-progression even at the early time point of first follow-up after RT. Earlier identification of patients with true progression would enable more timely salvage treatments including potential clinical trial enrolment to improve patient outcomes.

Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies.

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.

Modifiable Cardiometabolic Risk Factors in Survivors of Childhood Cancer: JACC: CardioOncology State-of-the-Art Review.

The growing community of childhood cancer survivors faces a heavy burden of late onset morbidities and mortality, with cardiovascular diseases being the leading noncancer cause. In addition to demographics and cancer treatment exposures, which cannot be altered, cardiometabolic risk factors (obesity, hypertension, diabetes, and dyslipidemia) and frailty potentiate the risk of morbidity and mortality associated with chronic health conditions. Important opportunities exist to target these risk factors and improve late health outcomes for survivors. Unfortunately, limited evidence exists on the optimal methods to prevent, screen, and treat cardiometabolic risk factors among survivors, resulting in significant underdiagnosis and undertreatment. In this review, we discuss the prevalence of, risk factors for, current survivor-specific recommendations, and gaps in knowledge to mitigate potentially modifiable cardiometabolic risk factors and frailty among survivors of childhood cancer.

Expert-centered Evaluation of Deep Learning Algorithms for Brain Tumor Segmentation.

Purpose To present results from a literature survey on practices in deep learning segmentation algorithm evaluation and perform a study on expert quality perception of brain tumor segmentation. Materials and Methods A total of 180 articles reporting on brain tumor segmentation algorithms were surveyed for the reported quality evaluation. Additionally, ratings of segmentation quality on a four-point scale were collected from medical professionals for 60 brain tumor segmentation cases. Results Of the surveyed articles, Dice score, sensitivity, and Hausdorff distance were the most popular metrics to report segmentation performance. Notably, only 2.8% of the articles included clinical experts' evaluation of segmentation quality. The experimental results revealed a low interrater agreement (Krippendorff α, 0.34) in experts' segmentation quality perception. Furthermore, the correlations between the ratings and commonly used quantitative quality metrics were low (Kendall tau between Dice score and mean rating, 0.23; Kendall tau between Hausdorff distance and mean rating, 0.51), with large variability among the experts. Conclusion The results demonstrate that quality ratings are prone to variability due to the ambiguity of tumor boundaries and individual perceptual differences, and existing metrics do not capture the clinical perception of segmentation quality. Keywords: Brain Tumor Segmentation, Deep Learning Algorithms, Glioblastoma, Cancer, Machine Learning Clinical trial registration nos. NCT00756106 and NCT00662506 Supplemental material is available for this article. © RSNA, 2023.

The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) account for up to 8% of deaths in men aged 65 years and over and 2.2% of women. Patients with AAAs often have atherosclerosis, and intimal atherosclerosis is generally present in AAAs. Accordingly, AAAs are considered a form of atherosclerosis and are frequently referred to as atherosclerotic aneurysms. Pathological observations advocate inflammatory cell infiltration alongside adverse extracellular matrix degradation as key contributing factors to the formation of human atherosclerotic AAAs. Therefore, macrophage production of proteolytic enzymes is deemed responsible for the damaging loss of ECM proteins, especially elastin and fibrillar collagens, which characterise AAA progression and rupture. Matrix metalloproteinases (MMPs) and their regulation by tissue inhibitors metalloproteinases (TIMPs) can orchestrate not only ECM remodelling, but also moderate the proliferation, migration, and apoptosis of resident aortic cells, alongside the recruitment and subsequent behaviour of inflammatory cells. Accordingly, MMPs are thought to play a central regulatory role in the development, progression, and eventual rupture of abdominal aortic aneurysms (AAAs). Together, clinical and animal studies have shed light on the complex and often diverse effects MMPs and TIMPs impart during the development of AAAs. This dichotomy is underlined from evidence utilising broad-spectrum MMP inhibition in animal models and clinical trials which have failed to provide consistent protection from AAA progression, although more encouraging results have been observed through deployment of selective inhibitors. This review provides a summary of the supporting evidence connecting the contribution of individual MMPs to AAA development, progression, and eventual rupture. Topics discussed include structural, functional, and cell-specific diversity of MMP members; evidence from animal models of AAA and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the advances in identifying aberrant MMP activity. As evidenced, our developing understanding of the multifaceted roles individual MMPs perform during the progression and rupture of AAAs, should motivate clinical trials assessing the therapeutic potential of selective MMP inhibitors, which could restrict AAA-related morbidity and mortality worldwide.

Preoperative tractography algorithm for safe resection of tumors located in the descending motor pathways zone.

Background: Diffusion tensor imaging (DTI) tractography facilitates maximal safe resection and optimizes planning to avoid injury during subcortical dissection along descending motor pathways (DMPs). We provide an affordable, safe, and timely algorithm for preoperative DTI motor reconstruction for gliomas adjacent to DMPs. Methods: Preoperative DTI reconstructions were extracted from a prospectively acquired registry of glioma resections adjacent to DMPs. The surgeries were performed over a 7-year period. Demographic, clinical, and radiographic data were extracted from patients' electronic medical records. Results: Nineteen patients (12 male) underwent preoperative tractography between January 1, 2013, and May 31, 2020. The average age was 44.5 years (range, 19-81 years). A complete radiological resection was achieved in nine patients, a subtotal resection in five, a partial resection in three, and a biopsy in two. Histopathological diagnoses included 10 patients with high-grade glioma and nine with low-grade glioma. A total of 16 perirolandic locations (10 frontal and six frontoparietal) were recorded, as well as two in the insula and one in the basal ganglia. In 9 patients (47.3%), the lesion was in the dominant hemisphere. The median preoperative and postoperative Karnofsky Performance Scores were 78 and 80, respectively. Motor function was unchanged or improved over time in 15 cases (78.9%). Conclusion: This protocol of DTI reconstruction for glioma removal near the DMP shows good results in low-term neurological functional outcomes.

Outcomes of Treatment With Neoadjuvant Cemiplimab for Patients With Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck: Secondary Analysis of a Phase 2 Clinical Trial.

This secondary analysis of a phase 2 clinical trial examines long-term survival for resectable cutaneous squamous cell carcinoma of the head and neck according to pathologic response.

Advances in the Radiological Evaluation of and Theranostics for Glioblastoma.

Imaging is essential for evaluating patients with glioblastoma. Traditionally a multimodality undertaking, CT, including CT cerebral blood profusion, PET/CT with traditional fluorine-18 fluorodeoxyglucose (18F-FDG), and MRI have been the mainstays for diagnosis and post-therapeutic assessment. However, recent advances in these modalities, in league with the emerging fields of radiomics and theranostics, may prove helpful in improving diagnostic accuracy and treating the disease.

Multidisciplinary Care of a Large Brain Metastasis in a Patient with Hormone-Receptor-Positive Breast Cancer with Ataxia-Telangiectasia Mutation.

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARP)i are emerging as standard oncology treatments in various tumor types. The indications will expand as PARPi are being investigated in various breast cancer subtypes. Currently, except for BRCA1/2 mutation carriers with human epidermal growth factor receptor 2 (HER2)-negative breast cancer, there is inadequate identification of predictive biomarkers of response. We present a 57-year-old woman with metastatic breast cancer, hormone-receptor-positive, HER2 negative with a germline ataxia-telangiectasia mutation with a large brain metastasis with clinical benefit to talazoparib. This case report exemplifies the importance of the multidisciplinary management of patients with brain metastases and personalized biomarker selected treatment.

Prognostic factors for pediatric, adolescent, and young adult patients with non-DIPG grade 4 gliomas: a contemporary pooled institutional experience.

PURPOSE: WHO grade 4 gliomas are rare in the pediatric and adolescent and young adult (AYA) population. We evaluated prognostic factors and outcomes in the pediatric versus AYA population. METHODS: This retrospective pooled study included patients less than 30 years old (yo) with grade 4 gliomas treated with modern surgery and radiotherapy. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis. RESULTS: Ninety-seven patients met criteria with median age 23.9 yo at diagnosis. Seventy-seven patients were ≥ 15 yo (79%) and 20 patients were < 15 yo (21%). Most had biopsy-proven glioblastoma (91%); the remainder had H3 K27M-altered diffuse midline glioma (DMG; 9%). All patients received surgery and radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection (GTR) was associated with better PFS in multivariate analysis [HR 2.00 (1.01-3.62), p = 0.023]. Age ≥ 15 yo was associated with improved OS [HR 0.36 (0.16-0.81), p = 0.014] while female gender [HR 2.12 (1.08-4.16), p = 0.03] and DMG histology [HR 2.79 (1.11-7.02), p = 0.029] were associated with worse OS. Only 7% of patients experienced grade 2 toxicity. 62% of patients experienced tumor progression (28% local, 34% distant). Analysis of salvage treatment found that second surgery and systemic therapy significantly improved survival. CONCLUSION: Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. DMG was associated with worse OS than glioblastoma. Reoperation and systemic therapy significantly increased survival after disease progression. Prospective studies in this population are warranted.

The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model.

The transmembrane protein 43 (TMEM43/LUMA) p.S358L mutation causes arrhythmogenic cardiomyopathy named as ARVC5, a fully penetrant disease with high risk of ventricular arrhythmias, sudden death, and heart failure. Male gender and vigorous exercise independently predicted deleterious outcome. Our systems genetics analysis revealed the importance of Tmem43 for cardiac and metabolic pathways associated with elevated lipid absorption from small intestine. This study sought to delineate gender-specific cardiac, intestinal, and metabolic phenotypes in vivo and investigate underlying pathophysiological mechanisms of S358L mutation. Serial echocardiography, surface electrocardiography (ECG), treadmill running, and body EchoMRI have been used in knock-in heterozygous (Tmem43WT/S358L), homozygous (Tmem43S358L), and wildtype (Tmem43WT) littermate mice. Electron microscopy, histology, immunohistochemistry, transcriptome, and protein analysis have been performed in cardiac and intestinal tissues. Systolic dysfunction was apparent in 3-mo-old Tmem43S358L and 6-mo-old Tmem43WT/S358L mutants. Both mutant lines displayed intolerance to acute stress at 6 mo of age, arrhythmias, fibro-fatty infiltration, and subcellular abnormalities in the myocardium. Microarray analysis found significantly differentially expressed genes between left ventricular (LV) and right ventricular (RV) myocardium. Mutants displayed diminished PPARG activities and significantly reduced TMEM43 and ß-catenin expression in the heart, whereas junctional plakoglobin (JUP) translocated into nuclei of mutant cardiomyocytes. Conversely, elongated villi, fatty infiltration, and overexpression of gut epithelial proliferation markers, ß-catenin and Ki-67, were evident in small intestine of mutants. We defined Tmem43 S358L-induced pathological effects on cardiac and intestinal homeostasis via distinctly disturbed WNT-ß-catenin and PPARG signaling thereby contributing to ARVC5 pathophysiology. Results suggest that cardiometabolic assessment in mutation carriers may be important for predictive and personalized care.NEW & NOTEWORTHY This manuscript describes the findings of our investigation of cardiac, small intestine, and metabolic features of Tmem43-S358L mouse model. By investigating interorgan pathologies, we uncovered multiple mechanisms of the S358L-induced disease, and these unique mechanisms likely appear to contribute to the disease pathogenesis. We hope our findings are important and novel and open new avenues in the hunting for additional diagnostic and therapeutic targets in subjects carrying TMEM43 mutation.

Phase II Clinical Trial of Axitinib and Avelumab in Patients With Recurrent/Metastatic Adenoid Cystic Carcinoma.

PURPOSE: We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC). PATIENTS AND METHODS: Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary end point was objective response rate (ORR) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Simon's optimal two-stage design tested the null hypothesis of ORR ≤5% versus ORR ≥20% at 6 months; ≥4 responses in 29 patients would reject the null hypothesis. RESULTS: Forty patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (six screen failures; six evaluable for safety only). The confirmed ORR was 18% (95% CI, 6.1 to 36.9); there was one unconfirmed partial response (PR). Two patients achieved PR after 6 months; thus, the ORR at 6 months was 14%. The median follow-up time for surviving patients was 22 months (95% CI, 16.6 to 39.1 months). The median PFS was 7.3 months (95% CI, 3.7 to 11.2 months), 6-month PFS rate was 57% (95% CI, 41 to 78), and median OS was 16.6 months (95% CI, 12.4 to not reached months). Most common treatment-related adverse events (TRAEs) included fatigue (62%), hypertension (32%), and diarrhea (32%). Ten (29%) patients had serious TRAEs, all grade 3; four patients (12%) discontinued avelumab, and nine patients (26%) underwent axitinib dose reduction. CONCLUSION: The study reached its primary end point with ≥4 PRs in 28 evaluable patients (confirmed ORR of 18%). The potential added benefit of avelumab to axitinib in ACC requires further investigation.

A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion.

AIMS: Endothelial erosion of plaques is responsible for ∼30% of acute coronary syndromes (ACS). Smoking is a risk factor for plaque erosion, which most frequently occurs on the upstream surface of plaques where the endothelium experiences elevated shear stress. We sought to recreate these conditions in vitro to identify potential pathological mechanisms that might be of relevance to plaque erosion. METHODS AND RESULTS: Culturing human coronary artery endothelial cells (HCAECs) under elevated flow (shear stress of 7.5 Pa) and chronically exposing them to cigarette smoke extract (CSE) and tumour necrosis factor-alpha (TNFα) recapitulated a defect in HCAEC adhesion, which corresponded with augmented Nrf2-regulated gene expression. Pharmacological activation or adenoviral overexpression of Nrf2 triggered endothelial detachment, identifying Nrf2 as a mediator of endothelial detachment. Growth/Differentiation Factor-15 (GDF15) expression was elevated in this model, with protein expression elevated in the plasma of patients experiencing plaque erosion compared with plaque rupture. The expression of two Nrf2-regulated genes, OSGIN1 and OSGIN2, was increased by CSE and TNFα under elevated flow and was also elevated in the aortas of mice exposed to cigarette smoke in vivo. Knockdown of OSGIN1&2 inhibited Nrf2-induced cell detachment. Overexpression of OSGIN1&2 induced endothelial detachment and resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and disturbed proteostasis mediated in part by HSP70, restoration of which reduced HCAEC detachment. In ACS patients who smoked, blood concentrations of HSP70 were elevated in plaque erosion compared with plaque rupture. CONCLUSION: We identified a novel Nrf2-OSGIN1&2-HSP70 axis that regulates endothelial adhesion, elevated GDF15 and HSP70 as biomarkers for plaque erosion in patients who smoke, and two therapeutic targets that offer the potential for reducing the risk of plaque erosion.