Stool Protein Mass Spectrometry Identifies Biomarkers for Early Detection of Diffuse-type Gastric Cancer.

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of gastric cancer (GC) and individuals with hereditary diffuse gastric cancer (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of the stool of a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells [known as Triple Conditional (TCON) mice] identified differentially abundant proteins compared with littermate controls. Immunoblot assays validated a panel of proteins, including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP), as enriched in TCON stool compared with littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression compared with littermate controls. Proteomic mass spectrometry of stool obtained from patients with HDGC with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 relative to stool from healthy sex- and age-matched donors. Chemical inhibition of ASAH2 using C6 urea ceramide was toxic to GC cell lines and GC patient-derived organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, which suggested a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features that correlated with patient tumors. Herein, we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC. Prevention Relevance: This study highlights a novel panel of stool protein biomarkers that correlate with the presence of DGC and has potential use as early detection to improve clinical outcomes.

Advancing the care of individuals with cancer through innovation & technology: Proceedings from the cardiology oncology innovation summit 2020 and 2021.

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.

Worker and work-related factors influence on musculoskeletal symptoms among veterinary surgeons.

Worker and work-related musculoskeletal symptoms are prevalent among surgeons operating on human patients. Despite incidence rates for accidents among veterinarians and their staff being 2.9 times higher than that of general practitioners of human medicine, little is known about musculoskeletal symptoms among veterinary surgeons. In this study, 212 board-certified members of the American College of Veterinary Surgeons responded to a survey regarding various work-related activities and their experience with musculoskeletal symptoms in 10 different body regions. Across all body regions, reported pain increased from before to after a typical day of surgery (p <.01). Gender, weight, age, and years performing surgery were worker factors that were related to pain (p <.05), while number of procedures, practice focus, and proportion of minimally invasive surgery were work factors related to pain (p <.05). Our findings suggest that musculoskeletal symptoms are prevalent among veterinary surgeons and may help provide evidence for guidelines for minimising musculoskeletal injuries in veterinary surgery.Practitioner summary: Little is known about the risk factors for musculoskeletal symptoms (MSS) among veterinary surgeons. This cross-sectional survey of veterinary surgeons investigates worker and work factors related to MSS. We show that MSS are prevalent and identify key factors providing evidence that MSS are a concern in veterinary surgery.

Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes?

Transplantation-associated thrombotic microangiopathy (TA-TMA) can range from a self-limiting condition to a lethal transplantation complication. It is important to identify TA-TMA patients at risk for severe multiorgan endothelial injury to implement targeted therapies in a timely manner. Current therapeutic approaches with complement blockade have improved survival markedly in high-risk TA-TMA patients, yet one-third of these patients respond inadequately to eculizumab therapy. Poor response may indicate that substantial endothelial injury has already occurred and raises the possibility that earlier intervention may improve outcomes. The goal of this study was to identify additional TA-TMA patients who would benefit from early targeted intervention and update TA-TMA risk stratification methods to reflect these findings. We studied 130 HSCT recipients with a diagnosis of TA-TMA who were screened prospectively and stratified into 3 TA-TMA risk groups (high-risk, n = 64; moderate-risk, n = 48; 18 low-risk, n = 18). We specifically examined TA-TMA biomarkers and clinical outcomes in subjects who were not offered complement blocking therapy (moderate-risk and low-risk TA-TMA subjects) and compared them with those who received TA-TMA-targeted therapy (high-risk TA-TMA subjects). One-year post-HSCT survival for subjects with untreated moderate-risk TA-TMA was similar to those with high-risk TA-TMA receiving eculizumab therapy (71% versus 66%; P = .40), indicating that a subset of moderate-risk patients may benefit from therapy. A detailed analysis of moderate-risk subjects highlighted the importance of relative as well as absolute complement pathway activation in determining organ injury. We demonstrated that activated terminal complement (measured by elevated blood sC5b-9) alone is a valuable indicator of reduced survival. Moderate-risk TA-TMA subjects with elevated sC5b-9 levels had a nearly 3-fold higher risk of mortality that was statistically significant in multivariant analyses (P = .01). A "dose effect" also was observed, and higher sC5b-9 levels were associated with worse outcomes. Furthermore, all moderate-risk patients with sustained sC5b-9 elevation for >2 weeks ultimately developed multiorgan dysfunction syndrome (MODS). This indicates that scheduled sC5b-9 measurements could promptly identify patients at risk for poor outcomes and would facilitate early TA-TMA-directed therapy to prevent organ injury. Untreated low-risk TA-TMA patients had a 1-year post-HSCT survival of 94% and should be observed without targeted interventions. Routine TA-TMA screening and complement-blocking therapies have markedly improved the outcomes for high-risk TA-TMA patients, and our study suggests that additional patients may benefit from TA-TMA treatment. This study provides further support for prospective TA-TMA screening as an integral tool for identifying patients at greatest risk for organ injury and death from TA-TMA. An updated TA-TMA risk algorithm that incorporates relevant laboratory biomarkers, clinical findings, and comorbid conditions was generated using this study's findings, and we propose clinical implementation of this algorithm for the management of TA-TMA.

Heart-kidney listing is better than isolated heart listing for pediatric heart transplant candidates with significant renal insufficiency.

OBJECTIVES: Significant renal insufficiency is identified as a risk factor for post-transplantation mortality in pediatric heart transplant recipients. This study evaluates simultaneous heart-kidney transplantation listing outcomes compared with heart transplant for pediatric candidates with significant renal insufficiency. METHODS: The United Network for Organ Sharing registry was searched for patients (January 1987 to March 2020) who were simultaneously listed for a heart-kidney transplantation or for heart transplant with significant renal insufficiency at the time of listing. Significant renal insufficiency was defined as needing dialysis or having a low estimated glomerular filtration rate (<40 mL/min). Survival was calculated using Kaplan-Meier analysis. RESULTS: A total of 427 cases were identified; 109 were listed for heart-kidney transplantation, and 318 were listed for heart transplant alone. Median time on the waitlist was 101 days (interquartile range, 28-238) for heart-kidney transplantation listings compared with 39 days (14-86) and 23.5 days (6-51) for heart transplant recipients with a low estimated glomerular filtration rate (P = .002) or on dialysis (P < .001), respectively. Of all heart-kidney transplantation listings, 66% (n = 71) received a transplant compared with 54% (n = 173) of heart transplantation with significant renal insufficiency (P = .005) with a mean survival of 14.6 years (12.7-16.4 years) for heart transplant without significant renal insufficiency at transplantation and 7.6 years (5.4-9.9 years) for heart transplant with significant renal insufficiency at transplantation. At 1 year after listing, 69% of heart-kidney transplantation listed recipients were alive, compared with 51% of heart transplant listed recipients (P = .029). Heart-kidney transplantation recipients had better 1-year post-transplantation survival (86%) than heart transplantation with significant renal insufficiency at transplant (66%) (P = .001). There was no significant difference in the 1- and 5-year survivals of those undergoing heart transplantation listed with significant renal insufficiency but no significant renal insufficiency at the time of transplant (89% and 78%) and heart-kidney transplantation recipients (86% and 81%; P = .436). CONCLUSIONS: Pediatric candidates with significant renal insufficiency listed for heart-kidney transplantation have superior waitlist and post-transplantation outcomes compared with those listed for heart transplant alone. Patients with significant renal insufficiency should be listed for heart-kidney transplantation, however; if their renal function improves significantly, heart transplant alone appears judicious.

Current State of Pediatric Cardio-Oncology: A Review.

The landscape of pediatric oncology has dramatically changed over the course of the past several decades with five-year survival rates surpassing 80%. Anthracycline therapy has been the cornerstone of many chemotherapy regimens for pediatric patients since its introduction in the 1960s, and recent improved survival has been in large part due to advancements in chemotherapy, refinement of supportive care treatments, and development of novel therapeutics such as small molecule inhibitors, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors. Unfortunately, many cancer-targeted therapies can lead to acute and chronic cardiovascular pathologies. The range of cardiotoxicity can vary but includes symptomatic or asymptotic heart failure, arrhythmias, coronary artery disease, valvar disease, pericardial disease, hypertension, and peripheral vascular disease. There is lack of data guiding primary prevention and treatment strategies in the pediatric population, which leads to substantial practice variability. Several important future research directions have been identified, including as they relate to cardiac disease, prevention strategies, management of cardiovascular risk factors, risk prediction, early detection, and the role of genetic susceptibility in development of cardiotoxicity. Continued collaborative research will be key in advancing the field. The ideal model for pediatric cardio-oncology is a proactive partnership between pediatric cardiologists and oncologists in order to better understand, treat, and ideally prevent cardiac disease in pediatric oncology patients.

Abnormal Maximal and Submaximal Cardiopulmonary Exercise Capacity in Pediatric Stem Cell Transplant Recipients Despite Normal Standard Echocardiographic Parameters: A Pilot Study.

Left ventricular systolic dysfunction is a known complication of stem cell transplantation (SCT). There has been minimal research to determine whether subclinical cardiac dysfunction exists in SCT patients using tools other than standard echocardiography, such as maximal and submaximal effort cardiopulmonary exercise testing (CPET) and vascular function studies. The objective of this study was to determine the rate of subclinical cardiac dysfunction in patients with normal ejection fraction after SCT, identified by abnormal values by CPET, tissue-Doppler imaging, and arterial stiffness measurements and to further describe submaximal exercise test measures in this population. A prospective cohort study of SCT survivors who were at least 3 years after SCT without prior anthracycline or radiation exposure and with preserved systolic function (left ventricular ejection fraction > 50%) was performed to evaluate for abnormalities in exercise, vascular function, and diastolic function in an effort to detect subclinical dysfunction in SCT patients. Eleven patients (12.4 ± 3.8 years old) were included in the study. No patients had diastolic dysfunction. All patients completed a maximal effort exercise test, and 73% (8/11) had abnormal peak oxygen consumption (Vo2 peak), which is a measure of aerobic fitness. However, during submaximal effort CPET, 45% (5/11) had an abnormal Vo2 at anaerobic threshold (i.e., the point in exercise where aerobic transitions to anaerobic metabolism and fatigue starts), and 64% (7/11) had an abnormal oxygen uptake efficiency slope (a measure that relates Vo2 peak to total ventilation). Eighty-six percent (6/7) of the patients with an abnormal oxygen uptake efficiency slope ultimately had an abnormal Vo2 peak. There were no vascular function abnormalities. Pediatric survivors of SCT often have abnormal maximal and submaximal exercise capacity without vascular or cardiac dysfunction.

Comparative effectiveness of revascularization strategies for early coronary artery disease: A multicenter analysis.

OBJECTIVES: The goal of this analysis was to examine the comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention among patients aged less than 60 years. METHODS: We performed a multicenter, retrospective analysis of all cardiac revascularization procedures from 2005 to 2015 among 7 medical centers. Inclusion criteria were age less than 60 years and 70% stenosis or greater in 1 or more major coronary artery distribution. Exclusion criteria were left main 50% or greater, ST-elevation myocardial infarction, emergency status, and prior revascularization procedure. After applying inclusion and exclusion criteria, the final study cohort included 1945 patients who underwent cardiac surgery and 2938 patients who underwent percutaneous coronary intervention. The primary end point was all-cause mortality stratified by revascularization strategy. Secondary end points included stroke, repeat revascularization, and 30-day mortality. We used inverse probability weighting to balance differences among the groups. RESULTS: After adjustment, there was no significant difference in 30-day mortality (surgery: 0.8%; percutaneous coronary intervention: 0.7%, P = .86) for patients with multivessel disease. Patients undergoing surgery had a higher risk of stroke (1.3% [n = 25] vs 0.07% [n = 2], P < .001). Overall, surgery was associated with superior 10-year survival compared with percutaneous coronary intervention (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88; P = .002). Repeat procedures occurred in 13.4% (n = 270) of the surgery group and 36.4% (n = 1068) of the percutaneous coronary intervention group, with both groups mostly undergoing percutaneous coronary intervention as their second operation. Accounting for death as a competing risk, at 10 years, surgery resulted in a lower cumulative incidence of repeat revascularization compared with percutaneous coronary intervention (subdistribution hazard ratio, 0.34; 95% confidence interval, 0.28-0.40; P < .001). CONCLUSIONS: Among patients aged less than 60 years with 2-vessel disease that includes the left anterior descending or 3-vessel coronary artery disease, surgery was associated with greater long-term survival and decreased risk of repeat revascularization.

Jones Fracture Treatment: A Novel Surgical Technique and Case Series.

BACKGROUND: Jones fractures remain a challenging treatment entity in orthopaedics. Biomechanical stresses, including increased fifth metatarsal (5MT) lateral angle deviation (MLAD), are associated with increased fracture and refracture rates. Current fixation techniques produce good outcomes; however, they do not address metatarsal morphology, which can predispose to refracture. This study describes a novel surgical technique and case series utilizing intramedullary screw fixation and distal metatarsal corrective osteotomy for the management of Jones fractures. METHODS: A retrospective case series was undertaken, including 22 consecutive Jones fracture patients operated on by a single surgeon. Patient demographics, imaging, and operative information were obtained, with return to sport/previous function and radiological outcomes, including fracture union being the outcomes of interest. The surgical technique utilizes a distal osteotomy of the 5MT followed by retrograde guidewire and drilling utilizing the osteotomy. A cannulated screw is passed antegrade along the entire length of the 5MT with manual MLAD correction. Autograft or bone substitute (Augment) was then injected at the fracture site. RESULTS: Median age was 30 years (Q1, Q3: 18, 49 years). Median time from injury to operation was 13 weeks (Q1, Q3: 9, 30 weeks), and clinical follow-up period was 37 months (Q1, Q3: 14, 74 months). Radiological union was achieved at a median of 12 weeks (Q1, Q3: 8, 15 weeks) with clinical union at 11 weeks (Q1, Q3: 8, 14 weeks). All but one patient returned to preinjury functional levels, including 6 professional athletes who returned to preinjury national competition. No refractures were identified. CONCLUSION: The technique described in this study is a viable and safe means of managing Jones fractures. The technique may be particularly useful in patients with excessive MLAD. LEVELS OF EVIDENCE: Level IV: Retrospective case series.

Echocardiographic myocardial strain analysis describes subclinical cardiac dysfunction after craniospinal irradiation in pediatric and young adult patients with central nervous system tumors.

BACKGROUND: Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction. METHODS: Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (< 12 months) and late (≥ 12 months) time points after completion of CSI. RESULTS: Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was - 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was - 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was - 16.2 ± 5.4% vs. -21.6 ± 3.7% (p < 0.0001), GCS was - 20.9 ± 6.8% vs. -21.9 ± 3.5% (p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose (< 30 Gy vs. ≥ 30 Gy) did not impact any parameter, although numbers were small. CONCLUSIONS: Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.

Rapid cardiac MRI protocol for cardiac assessment in paediatric and young adult patients undergoing haematopoietic stem cell transplant: a feasibility study.

BACKGROUND: Haematopoietic stem cell transplantation is an important and effective treatment strategy for many malignancies, marrow failure syndromes, and immunodeficiencies in children, adolescents, and young adults. Despite advances in supportive care, patients undergoing transplant are at increased risk to develop cardiovascular co-morbidities. METHODS: This study was performed as a feasibility study of a rapid cardiac MRI protocol to substitute for echocardiography in the assessment of left ventricular size and function, pericardial effusion, and right ventricular hypertension. RESULTS: A total of 13 patients were enrolled for the study (age 17.5 ± 7.7 years, 77% male, 77% white). Mean study time was 13.2 ± 5.6 minutes for MRI and 18.8 ± 5.7 minutes for echocardiogram (p = 0.064). Correlation between left ventricular ejection fraction by MRI and echocardiogram was good (ICC 0.76; 95% CI 0.47, 0.92). None of the patients had documented right ventricular hypertension. Patients were given a survey regarding their experiences, with the majority both perceiving that the echocardiogram took longer (7/13) and indicating they would prefer the MRI if given a choice (10/13). CONCLUSION: A rapid cardiac MRI protocol was shown feasible to substitute for echocardiogram in the assessment of key factors prior to or in follow-up after haematopoietic stem cell transplantation.

The future is now! A supplemental webinar series to the First International Pediatric Cardio-Oncology Meeting.

Planning for the First International Pediatric Cardio-Oncology Meeting has been underway since early 2019, with the original date in October 2020 delayed due to the COVID-19 pandemic. But patients continue to need care, research carries on, and the ability to learn from our colleagues remains one of the most important tools in our collective ability to advance the field. Through collaboration with Heart University (www.heartuniversity.org), a free web-based global education resource and training tool with an emphasis on acquired and congenital heart disease, we are able to provide colleagues around the world with focused sessions similar to those that will be expanded at the in-person meeting. The first such two-hour webinar was presented live online on December 16, 2020, and moving forward similar webinars will be offered approximately every other month for the next year leading up to the in-person meeting in 2022, with all sessions available online afterward for on-demand viewing. Although we are excited to get together with our colleagues in person, why wait until then to share what we know? The future is now!

Live imaging of intra-lysosome pH in cell lines and primary neuronal culture using a novel genetically encoded biosensor.

Disorders of lysosomal physiology have increasingly been found to underlie the pathology of a rapidly growing cast of neurodevelopmental disorders and sporadic diseases of aging. One cardinal aspect of lysosomal (dys)function is lysosomal acidification in which defects trigger lysosomal stress signaling and defects in proteolytic capacity. We have developed a genetically encoded ratiometric probe to measure lysosomal pH coupled with a purification tag to efficiently purify lysosomes for both proteomic and in vitro evaluation of their function. Using our probe, we showed that lysosomal pH is remarkably stable over a period of days in a variety of cell types. Additionally, this probe can be used to determine that lysosomal stress signaling via TFEB is uncoupled from gross changes in lysosomal pH. Finally, we demonstrated that while overexpression of ARL8B GTPase causes striking alkalinization of peripheral lysosomes in HEK293 T cells, peripheral lysosomes per se are no less acidic than juxtanuclear lysosomes in our cell lines.Abbreviations: ARL8B: ADP ribosylation factor like GTPase 8B; ATP: adenosine triphosphate; ATP5F1B/ATPB: ATP synthase F1 subunit beta; ATP6V1A: ATPase H+ transporting V1 subunit A; Baf: bafilomycin A1; BLOC-1: biogenesis of lysosome-related organelles complex 1; BSA: bovine serum albumin; Cos7: African green monkey kidney fibroblast-like cell line; CQ: chloroquine; CTSB: cathepsin B; CYCS: cytochrome c, somatic; DAPI: 4',6-diamidino -2- phenylindole; DIC: differential interference contrast; DIV: days in vitro; DMEM: Dulbecco's modified Eagle's medium; E8: embryonic day 8; EEA1: early endosome antigen 1; EGTA: ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid; ER: endoplasmic reticulum; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GOLGA2/GM130: golgin A2; GTP: guanosine triphosphate; HEK293T: human embryonic kidney 293 cells, that expresses a mutant version of the SV40 large T antigen; HeLa: Henrietta Lacks-derived cell; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HRP: horseradish peroxidase; IGF2R/ciM6PR: insulin like growth factor 2 receptor; LAMP1/2: lysosomal associated membrane protein 1/2; LMAN2/VIP36: lectin, mannose binding 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PCR: polymerase chain reaction; PDL: poly-d-lysine; PGK1p: promotor from human phosphoglycerate kinase 1; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PPT1/CLN1: palmitoyl-protein thioesterase 1; RPS6KB1/p70: ribosomal protein S6 kinase B1; STAT3: signal transducer and activator of transcription 3; TAX1BP1: Tax1 binding protein 1; TFEB: transcription factor EB; TGN: trans-Golgi network; TGOLN2/TGN46: trans-Golgi network protein 2; TIRF: total internal reflection fluorescence; TMEM106B: transmembrane protein 106B; TOR: target of rapamycin; TRPM2: transient receptor potential cation channel subfamily M member 2; V-ATPase: vacuolar-type proton-translocating ATPase; VPS35: VPS35 retromer complex component.

Cardiovascular disease and its management in children and adults undergoing hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for many malignancies, hemoglobinopathies, metabolic diseases, bone marrow failure syndromes, and primary immune deficiencies. Despite the significant improvement in survival afforded by HSCT, the therapy is associated with major short and long-term morbidity and mortality. Cardiovascular complications such as cardiomyopathy, arrhythmias, pulmonary hypertension, and pericardial effusions are increasingly recognized as potential outcomes following HSCT. The incidence of cardiac complications is related to various factors such as age, co-morbid medical conditions, whether patients received cardiotoxic chemotherapy prior to HSCT, the type of HSCT (autologous versus allogeneic), and the specific conditioning regimen. Thus, the cardiovascular evaluation has become a core component of the pre-transplant assessment, however, the practice differs from center to center as national guidelines and contemporary high-quality studies are lacking. We review the incidence of cardiotoxicity in pediatric and adult HSCT, potential mechanisms of injury, and effects on long-term outcomes. We also discuss the possible therapeutic approaches when disease arises, as well as the indications and need for surveillance before, during, and after transplantation.

Cardiovascular disease and asymptomatic childhood cancer survivors: Current clinical practice.

BACKGROUND: It is poorly understood how cardiovascular screening in asymptomatic childhood cancer survivors (CCS) is applied to and impacts clinical care. OBJECTIVES: To describe the current role of cardiovascular screening in the clinical care of asymptomatic CCS. METHODS: At 50 pediatric academic medical centers, a childhood cancer survivorship clinic director, pediatric cardiologist, and adult cardiologist with a focus on CCS were identified and invited to participate in a survey. Surveys were managed electronically. Categorical data were analyzed using nonparametric methods. RESULTS: Of the 95 (63%) respondents, 39% were survivorship practitioners, and 61% were cardiologists. Eighty-eight percent of survivorship practitioners reported that greater than half of CCS received cardiovascular screening. CCS followed by adult cardiology were more likely to be seen by a cardio-oncologist. Those followed by pediatric cardiology were more likely to be seen by a heart failure/transplant specialist. Common reasons for referral to cardiology were abnormal cardiovascular imaging or concerns a CCS was at high risk for cardiovascular disease. Ninety-two percent of cardiologists initiated angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy for mild systolic dysfunction. Adult cardiologists initiated beta-blocker therapy for less severe systolic dysfunction compared to pediatric cardiologists (P < .001). Pediatric cardiologists initiated mineralocorticoid therapy for less severe systolic dysfunction compared to adult cardiologists (P = .025). Practitioners (93%) support a multi-institutional collaboration to standardize cardiovascular care for CCS. CONCLUSIONS: While there is much common ground in the clinical approach to CCS, heterogeneity is evident. This highlights the need for cohesive, multi-institutional, standardized approaches to cardiovascular management in CCS.

Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.