Tricuspid valve flow measurement using a deep learning framework for automated valve-tracking 2D phase contrast.

PURPOSE: Tricuspid valve flow velocities are challenging to measure with cardiovascular MR, as the rapidly moving valvular plane prohibits direct flow evaluation, but they are vitally important to diastolic function evaluation. We developed an automated valve-tracking 2D method for measuring flow through the dynamic tricuspid valve. METHODS: Nine healthy subjects and 2 patients were imaged. The approach uses a previously trained deep learning network, TVnet, to automatically track the tricuspid valve plane from long-axis cine images. Subsequently, the tracking information is used to acquire 2D phase contrast (PC) with a dynamic (moving) acquisition plane that tracks the valve. Direct diastolic net flows evaluated from the dynamic PC sequence were compared with flows from 2D-PC scans acquired in a static slice localized at the end-systolic valve position, and also ventricular stroke volumes (SVs) using both planimetry and 2D PC of the great vessels. RESULTS: The mean tricuspid valve systolic excursion was 17.8 ± 2.5 mm. The 2D valve-tracking PC net diastolic flow showed excellent correlation with SV by right-ventricle planimetry (bias ± 1.96 SD = -0.2 ± 10.4 mL, intraclass correlation coefficient [ICC] = 0.92) and aortic PC (-1.0 ± 13.8 mL, ICC = 0.87). In comparison, static tricuspid valve 2D PC also showed a strong correlation but had greater bias (p = 0.01) versus the right-ventricle SV (10.6 ± 16.1 mL, ICC = 0.61). In most (8 of 9) healthy subjects, trace regurgitation was measured at begin-systole. In one patient, valve-tracking PC displayed a high-velocity jet (380 cm/s) with maximal velocity agreeing with echocardiography. CONCLUSION: Automated valve-tracking 2D PC is a feasible route toward evaluation of tricuspid regurgitant velocities, potentially solving a major clinical challenge.

Practice Patterns of Cardiovascular Magnetic Resonance Use in the Diagnosis of Pediatric Myocarditis: A Survey-Based Study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is used to diagnose myocarditis in adults and children based on the original Lake Louise Criteria (LLC) and more recently the revised LLC. The major change included in the revised LLC was the incorporation of parametric mapping, which significantly increases the sensitivity and specificity of diagnosis. Subsequently, scientific statements have recommended the use of parametric mapping in the diagnosis of myocarditis in children. However, there are some challenges to parametric mapping that are unique to the pediatric population. Our goal is to characterize clinical CMR and parametric mapping practice patterns for diagnosis of myocarditis in pediatric centers. METHODS: The Cardiovascular Magnetic Resonance Evaluation in Return to Athletes for Myocarditis in COVID-19 and Immunization Consortium created a REDCap survey to evaluate clinical practice patterns for diagnosis of myocarditis in pediatrics. This survey was distributed to the Society for Cardiovascular Magnetic Resonance community. RESULTS: 59 responses from 51 centers were received, with only one response from each center being utilized. Only 35% of centers (37% of North America, 31% of international) reported using CMR routinely in all patients with a suspicion for myocarditis. Diagnostic uncertainty was noted as the most important reason for CMR, while cost was noted as the least important consideration. The majority of centers reported using the revised LLC (37/51, 72%) compared to original LLC (7/51, 14%) or a hybrid criteria (6/51, 12%). When looking at the use of parametric mapping, only 5/47 (11%) for T1 mapping and 11/49 (22%) for T2 mapping reported having scanner-specific pediatric normative data. CONCLUSION: Routine CMR imaging for diagnosis of myocarditis in pediatrics is infrequently performed at surveyed centers despite the focus on a group of non-invasive cardiac imagers. While the majority reported using parametric mapping, few centers reporting having pediatric scanner-specific normative data. This highlights an important gap in the utilization of CMR that may aid in the diagnosis of myocardial disease.

Longitudinal Evaluation of Atrial Function in Patients with Tetralogy of Fallot.

Atrial function provides insight into ventricular diastolic function. Invasive assessment of left ventricular (LV) diastolic function correlates with development of sustained ventricular tachyarrhythmias in patients with repaired tetralogy of Fallot (rTOF). Non-invasive assessment of atrial function may prove key towards assessment of diastolic function. We longitudinally evaluated the progression of biatrial function in patients with rTOF, regardless of pulmonary valve replacement (PVR). Patients with rTOF who had multiple CMR were identified. CMR examinations were retrospectively reviewed. Left (LA) and right (RA) atrial size and function were measured in the two and four-chamber views and assessed over time and after PVR. Left and right atrial reservoir, conduit, pump strain and strain rates were determined using tissue tracking. Thirty-six patients with rTOF were identified (64% male), ten (28%) had PVR during the study. Median age of PVR was 16.5 years. No improvement in RA or LA function was observed after PVR. A decline in RA reservoir strain rate (p < 0.05) and RA pump strain (p < 0.05) were observed despite improvements in right ventricular systolic function (p < 0.05). In patients who had multiple CMR without PVR, RA reservoir strain rate (p < 0.05) and pump strain rate (p < 0.05) worsened over time. LA pump strain decreased over time in all patients. There is progressive decline of several RA functional parameters over time. No significant improvement in LA or RA function after PVR was observed. Additional studies are needed to understand how these changes may relate to poor outcomes and potentially better guide timing of PVR.

Use of advanced cardiac imaging in congenital heart disease: growth, indications and innovations.

PURPOSE OF REVIEW: Significant improvements in the diagnosis and management of patients with congenital heart disease (CHD) have led to improved survival. These patients require life-long noninvasive evaluation. The use of advanced imaging such as cardiac magnetic resonance imaging (CMR) and cardiac computed tomography (CCT) has increased to support this need. The purpose of this review is to discuss the basics of advanced cardiac imaging, indications and review the recent innovations. RECENT FINDINGS: Recent literature has demonstrated the increasing reliance of advanced imaging for CHD patients. In addition, research is focusing on CMR techniques to shorten scan time and address previous limitations that made imaging younger and sicker patients more challenging. CCT research has involved demonstrating high-quality images with low radiation exposure. Advances in digital technology have impacted the interactivity of 3D imaging through the use of virtual and augmented reality platforms. With the increased reliance of advanced imaging, appropriate use criteria have been developed to address possible under or over utilization. SUMMARY: The utilization of advanced cardiac imaging continues to increase. As CMR and CCT continue to grow, increased knowledge of these modalities and their usage will be necessary for clinicians caring for CHD patients.

Myocardial involvement in children with post-COVID multisystem inflammatory syndrome: a cardiovascular magnetic resonance based multicenter international study-the CARDOVID registry.

BACKGROUND: Recent evidence shows an association between coronavirus disease 2019 (COVID-19) infection and a severe inflammatory syndrome in children. Cardiovascular magnetic resonance (CMR) data about myocardial injury in children are limited to small cohorts. The aim of this multicenter, international registry is to describe clinical and cardiac characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 using CMR so as to better understand the real extent of myocardial damage in this vulnerable cohort. METHODS AND RESULTS: Hundred-eleven patients meeting the World Health Organization criteria for MIS-C associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), having clinical cardiac involvement and having received CMR imaging scan were included from 17 centers. Median age at disease onset was 10.0 years (IQR 7.0-13.8). The majority of children had COVID-19 serology positive (98%) with 27% of children still having both, positive serology and polymerase chain reaction (PCR). CMR was performed at a median of 28 days (19-47) after onset of symptoms. Twenty out of 111 (18%) patients had CMR criteria for acute myocarditis (as defined by the Lake Louise Criteria) with 18/20 showing subepicardial late gadolinium enhancement (LGE). CMR myocarditis was significantly associated with New York Heart Association class IV (p = 0.005, OR 6.56 (95%-CI 1.87-23.00)) and the need for mechanical support (p = 0.039, OR 4.98 (95%-CI 1.18-21.02)). At discharge, 11/111 (10%) patients still had left ventricular systolic dysfunction. CONCLUSION: No CMR evidence of myocardial damage was found in most of our MIS-C cohort. Nevertheless, acute myocarditis is a possible manifestation of MIS-C associated with SARS-CoV-2 with CMR evidence of myocardial necrosis in 18% of our cohort. CMR may be an important diagnostic tool to identify a subset of patients at risk for cardiac sequelae and more prone to myocardial damage. CLINICAL TRIAL REGISTRATION: The study has been registered on ClinicalTrials.gov, Identifier NCT04455347, registered on 01/07/2020, retrospectively registered.

Left atrial strain and diastolic function abnormalities in obese and type 2 diabetic adolescents and young adults.

BACKGROUND: Adults with obesity and type 2 diabetes mellitus (T2DM) related to obesity are at increased risk of heart failure with preserved ejection fraction (HFpEF). Whether left ventricular (LV) diastolic function abnormalities related to obesity and T2DM start in adolescence and early adulthood is unknown. We non-invasively evaluated the differences seen in LV diastolic and left atrial (LA) function in adolescents and young adults with obesity and T2DM. METHODS: We analyzed echocardiographic measures of LV diastolic function in patients with structurally normal hearts which were divided into 3 groups (normal weight, obese, and T2DM). Spectral and tissue Doppler and 2-D speckle tracking measurements of diastolic function were obtained. Logistic regression was performed to compare the prevalence of abnormalities in diastolic function based on the worst 25th percentile for each measure to determine the prevalence of diastolic and LA function abnormalities in obese and T2DM patients. RESULTS: 331 teenagers and young adults (median age 22.1 years) were analyzed (101 normal weight, 114 obese, 116 T2DM). Obese and T2DM group had lower E/A and higher E/e'. Obese and T2DM patients had significantly lower atrial reservoir, conduit, and booster strain and worse reservoir and conduit strain rate compared to normal patients (p < 0.001 for all measures). All patients had normal LA volumes. On multivariable analysis, conduit strain and reservoir and conduit strain rate were independently associated with having below the 25th percentile e'. Conduit strain rate was independently associated with having below the 25th percentile for mitral E/A ratio on multivariable analysis. CONCLUSIONS: Abnormal indices of LV diastolic function are detected in adolescents and young adults with obesity and T2DM. LA function and strain analysis were able to detect evidence of decreased reservoir, conduit, and booster strain in these patients although LA volume was normal. The use of LA function strain may increase our ability to detect early diastolic function abnormalities in this population.

Atrial Function and Its Role in the Non-invasive Evaluation of Diastolic Function in Congenital Heart Disease.

Diastolic dysfunction has correlated with adverse outcomes in various forms of unrepaired and repaired or palliated congenital heart disease (CHD). The non-invasive assessment of diastolic function in pediatric and adult patients with CHD remains challenging. Atrial size has a pivotal role in the evaluation of diastolic function; however, a growing body of evidence supports the additional role of atrial function as a more sensitive parameter of ventricular diastolic dysfunction. While the importance of atrial function is becoming clearer in adult acquired heart disease, it remains ambiguous in those with CHD. In this review we set the stage with the current understanding of diastolic function assessment in CHD, followed by insight into atrial form and function including its non-invasive assessment, and conclude with the current knowledge of atrial function in CHD. A general pattern of decrease in reservoir and conduit function with compensatory increase followed by decompensatory decrease in contractile function seems to be the common pathway of atrial dysfunction in most forms of CHD.

Endocardial Coronary Artery: A Rare Congenital Coronary Anomaly.

Pediatric chest pain is a common reason for cardiology referral, and evaluation of exertional chest pain requires proper delineation of coronary anatomy. Congenital coronary anomalies are rare and often benign. However, certain anomalies such as intramural coronary arteries and myocardial bridges have been associated with angina, ventricular arrhythmias, and sudden cardiac death. We present a case of a 10-year-old male with exertional chest pain whose coronary anatomy could not be defined by echocardiography and further evaluation by computed tomography angiography revealed a rare congenital coronary anomaly.

Thoracic aortic aneurysm in an adolescent with intraoperative discovery of contained rupture: a case report.

Background: As surgical recommendations in adults based on size criteria of ascending aortic aneurysms become more refined, criteria for childhood/adolescence remains less clear. Multiple pathologic factors may predispose younger patients to thoracic aortic aortopathy and increase the risk of rupture. An evolving field of research is how to identify thoracic aortic dilation earlier in patients, risk stratify, and to obtain objective measures beyond size for proceeding with surgical intervention in order to prevent catastrophic thoracic aortic dissection. Case Description: We report an adolescent case of dilated ascending aortic aneurysm with a functionally unicuspid/bicuspid aortic valve. This patient was taken to surgery electively, given the gradual increasing size of the ascending aorta. Intraoperatively, there was an unexpected intraoperative finding of a contained aortic rupture. The patient underwent an aortic root replacement with mechanical valve composite graft and coronary artery reimplantation (modified Bentall) with ascending hemiarch replacement. The patient did well with no post-operative complications. Aortic pathology and genetic analysis were performed. The patient was discovered to have a heterozygous variant in PTPN11 which is typically associated with Noonan syndrome; however, this is not known to be associated with aortopathy. Conclusions: As criteria for surgical intervention in adult thoracic ascending aortic aneurysms continues to evolve, this case illustrates challenges when determining the optimal criteria for surgical intervention in adolescent patients.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.

Cardiac manifestations and outcomes of COVID-19 vaccine-associated myocarditis in the young in the USA: longitudinal results from the Myocarditis After COVID Vaccination (MACiV) multicenter study.

Background: We aimed to study the clinical characteristics, myocardial injury, and longitudinal outcomes of COVID-19 vaccine-associated myocarditis (C-VAM). Methods: In this longitudinal retrospective observational cohort multicenter study across 38 hospitals in the United States, 333 patients with C-VAM were compared with 100 patients with multisystem inflammatory syndrome in children (MIS-C). We included patients ≤30 years of age with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers and/or cardiovascular imaging findings. Demographics, past medical history, hospital course, biochemistry results, cardiovascular imaging, and follow-up information from April 2021 to November 2022 were collected. The primary outcome was presence of myocardial injury as evidenced by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. Findings: Patients with C-VAM were predominantly white (67%) adolescent males (91%, 15.7 ± 2.8 years). Their initial clinical course was more likely to be mild (80% vs. 23%, p < 0.001) and cardiac dysfunction was less common (17% vs. 68%, p < 0.0001), compared to MIS-C. In contrast, LGE on CMR was more prevalent in C-VAM (82% vs. 16%, p < 0.001). The probability of LGE was higher in males (OR 3.28 [95% CI: 0.99, 10.6, p = 0.052]), in older patients (>15 years, OR 2.74 [95% CI: 1.28, 5.83, p = 0.009]) and when C-VAM occurred after the first or second dose as compared to the third dose of mRNA vaccine. Mid-term clinical outcomes of C-VAM at a median follow-up of 178 days (IQR 114-285 days) were reassuring. No cardiac deaths or heart transplantations were reported until the time of submission of this report. LGE persisted in 60% of the patients at follow up. Interpretation: Myocardial injury at initial presentation and its persistence at follow up, despite a mild initial course and favorable mid-term clinical outcome, warrants continued clinical surveillance and long-term studies in affected patients with C-VAM. Funding: The U.S. Food and Drug Administration.

Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Computed Tomographic 3-Dimensional Virtual Dissection Aiding in Diagnosis and Surgical Planning of a Rare Form of Obstructed Supracardiac Total Anomalous Pulmonary Venous Connection With an Unusual Scimitar-Like Arrangement.

We present a case of a newborn with a rare presentation of obstructed supracardiac total anomalous pulmonary venous connection who required emergent cannulation to extracorporeal membrane oxygenation (ECMO). Computed tomographic angiography of the heart was performed and using novel virtual dissection techniques aided in surgical planning and guidance. Computed tomographic angiography can be successfully performed in neonates with complex congenital heart disease on ECMO without adjustment of flows to aid in surgical management and novel virtual dissection techniques aid in complex anatomical delineation and spatial orientation with noncardiac structures. The preoperative imaging in this case allowed for appropriate and detailed presurgical planning and contributed to the excellent outcome of this patient.

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma.

BACKGROUND: Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy. METHODS: Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic "hits" were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM. RESULTS: We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model. CONCLUSIONS: Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers.

Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome.

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3+ cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2+ CD163+ monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell-associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine--associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.

Thrombotic thrombocytopenic purpura in pediatric patients.

Although thrombotic thrombocytopenic purpura (TTP) is rarely seen in pediatric patients, failure to recognize this condition often leads to severe consequences and poor outcomes. Classic features of TTP include thrombocytopenia, microangiopathic hemolytic anemia, acute kidney injury, fever, and central nervous system involvement. However, patients suffering from this condition may not present with all of the symptoms simultaneously. Therefore, it is of utmost importance for healthcare providers to have a high index of suspicion. Laboratory investigations may reveal the presence of schistocytes on peripheral blood smear, negative Coombs test, high lactate dehydrogenase levels and severely low platelet counts. The etiology of TTP is mainly due to insufficient cleavage of the large multimers of von Willebrand factor (vWF) secondary to decreased activity of ADAMTS13 (a disintegrin and metalloprotease with Thrombospondin type 1 repeats, member 13). TTP can be broadly classified into familial TTP (Upshaw Schulman syndrome) and non-familial TTP. Familial TTP is due to a congenital deficiency of ADAMTS13. Its mainstay of therapy is initiation of plasmapheresis during the acute phase, followed by regular fresh frozen plasma (FFP) infusions. Alternatively, non-familial TTP is due to a decrease in ADAMTS13 activity secondary to the presence of anti-ADAMTS13 antibodies. Once again, the primary treatment is plasmapheresis; however, recent anecdotal data also supports the use of rituximab in select cases.

Challenges of Diagnosing Viral Myocarditis in Adolescents in the Era of COVID-19 and MIS-C.

Myocarditis has a wide array of clinical presentations ranging from asymptomatic to sudden cardiac death. Pediatric myocarditis is a rare disease, with an estimated annual incidence of 1 to 2 per 100,000 children though its true prevalence remains unknown due to its variable and often subclinical presentation. The diagnosis of myocarditis is challenging in the era of COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C), which can have overlapping clinical conundrum. Here, we present a case of a 17-year-old male presenting with chest tightness, shortness of breath, and electrocardiogram (EKG) findings concerning for myocardial injury along with elevated inflammatory markers such as D-dimer, ESR (Erythrocyte Sedimentation Rate), and CRP (C-Reactive Protein). We discuss the key elements of our clinical experience with this case and review the literature for pediatric myocarditis, with a focus on differentiating it from MIS-C in the current COVID-19 pandemic era.