The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IGH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing (WGS) data from 1173 MM samples. Integrating molecular time and structural variants (SV) within early chromosomal duplications, we indeed identified pre-gain deletions in 9.4% of HY patients without IGH translocations, challenging HY as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSG) and/or oncogenes in 2.4% of HY patients without IGH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to post-gain deletions as novel driver mechanisms in MM. Using multi-omics approaches to investigate their biological impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both oncogene and TSG activity, despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans.

Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic MYC activation in the germinal center of genetically engineered Vk*MYC mice is sufficient to induce plasma cell tumors in which a variety of secondary mutations are spontaneously acquired and selected over time. Analysis of 119 Vk*MYC myeloma reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC. In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors.

Advanced Imaging Guidance for Ductus Venosus Stenting in Obstructed Total Anomalous Pulmonary Venous Return.

Obstructed infracardiac total anomalous pulmonary venous return is nearly always a surgical emergency in which infants present in severe cardiopulmonary distress. Ductal venosus stenting can provide a temporizing option for premature, low birth weight infants with high risk for surgical complications. In challenging anatomic cases, virtual reality, 3D-printed models, and fusion image guidance can aid in procedural planning and provide support for successful intervention.

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition.

Background: Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood. Methods: We identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated κAL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level. Results: Upon exposure to a cardiomyopathy-associated κAL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Conclusion: Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.

Arginine-NO metabolites are associated with morbidity in single ventricle infants undergoing stage 2 palliation.

BACKGROUND: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes. METHODS: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia. RESULTS: Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05). CONCLUSION: Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD. IMPACT: Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD.

Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.

SUMMARY: While the current approach to precursor hematologic conditions is to "watch and wait," this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.

Patient Screening for Self-Expanding Percutaneous Pulmonary Valves Using Virtual Reality.

BACKGROUND: In recent years, self-expanding technology to treat pulmonary regurgitation in the native right ventricular outflow tract became Food and Drug Administration approved in the United States and is now routinely used. The current practice for selection of patients who are candidates for these devices includes screening for "anatomic fit," performed by each of the manufacturing companies. Our study aims to validate the use of virtual reality (VR) as a tool for local physician-led screening of patients. METHODS AND RESULTS: This retrospective study from Children's Hospital Colorado included patients who underwent pulmonary valve replacement and had screening for a Harmony TPV or Alterra Prestent performed between September 2020 and January 2022. The data from the commercial companies' dedicated analysis for self-expanding transcatheter pulmonary valve frames evaluation with perimeter analysis were collected. VR simulation was performed blinded by 2 congenital interventional cardiologists using Elucis VR software and an Oculus Quest 2 headset. Among the 27 evaluated cases, the use of a self-expandable valve was recommended by companies' dedicated analysis in 23 cases (85.2%), by VR assessment in 26 cases (96.3), and finally implanted in 25 cases (92.6%). Regarding the level of agreement, both modalities (manufacturer and VR) were good at screening-in patients who received a self-expanding valve (100% versus 96.1%). When it came to screening-out the patients, VR presented good capacity to accurately classify nonsuitable patients (50% versus 100%). CONCLUSIONS: Our institutional experience with VR transcatheter pulmonary valve implantation planning accurately predicted clinical outcomes. This paves the way for routine use of VR in patient selection for self-expanding valve technologies.

Computed Tomography-Derived Normative Values of Right Ventricular Outflow Tract Structures in the Pediatric Population.

Recent advances in available percutaneous device technology require accurate measurements and quantification of relationships between right ventricular outflow tract (RVOT) structures in children with and without congenital heart disease to determine device suitability. To date, no population study has described normal reference ranges of these measurements by computed tomography (CT). We aimed to establish normative values for four CT-derived measurements between RVOT structures from a heterogeneous population without heart disease and develop z scores useful for clinical practice. Patients without heart disease who underwent cardiac CT between April 2014 and February 2021 at Children's Hospital Colorado were included. Distance between the right ventricular (RV) apex to pulmonary valve (PV), PV to pulmonary trunk bifurcation, and bifurcation to the right and left pulmonary artery was measured. Previously validated models were used to normalize the measurements and calculate Z scores. Each measurement was plotted against BSA and Z scores distributions were used as reference lines. Three-hundred and sixty-four healthy patients with a mean age of 8.8 years (range 1-21), 58% male, and BSA of 1 m2 (range 0.4-2.1) were analyzed. The Haycock formula was used to present data as predicted values for a given BSA and within equations relating each measurement to BSA. Predicted values and Z-score boundaries for all measurements are presented.We report CT-derived normative data for four measurements between RVOT structures from a heterogeneous cohort of healthy children. Knowledge of this normative data will be useful in both determining device fit and customizing future devices to accommodate the diverse pediatric size range.

Fusion imaging for guidance of pulmonary arteriovenous malformation embolisation with minimal radiation and contrast exposure.

Hereditary haemorrhagic telangiectasia is an inherited disorder characterised by vascular dysplasia that leads to the development of arteriovenous malformations. Pulmonary arteriovenous malformations occur in approximately 30% of patients with haemorrhagic telangiectasia. Given the complex characteristics of haemorrhagic telangiectasia lesions, the application of three-dimensional fusion imaging holds significant promise for procedural guidance and decrease in contrast and radiation dosing. We reviewed all patients who underwent transcatheter approach for pulmonary arteriovenous malformation occlusion with fusion image guidance from June 2018 to September 2023 from a single centre. A total of nine cases with haemorrhagic telangiectasia and transcatheter occlusion of pulmonary arteriovenous malformations using fusion imaging were identified. Five (56%) were male, mean age at procedure was 15.7 years (10-28 years) and mean number of pulmonary arteriovenous malformations intervened was three per patient (1-7). Two of the cases were complex repeat embolisations. The mean fluoroscopy time was 40.6 min (10.7-68.8 min), with mean contrast dose of 28.8 mL (11-60 mL; mean of 0.51 mL/kg) and mean radiation dose of 66.3 mGy (25.6-140 mGy; mean of 40.5 mGy/m2). There were no complications reported during the procedures, with no additional interventions necessary. Fusion imaging in pulmonary arteriovenous malformations embolisation for patients with haemorrhagic telangiectasia is feasible and has the potential to reduce contrast and radiation doses. To our knowledge, we describe the lowest radiation and contrast doses per patient using fusion imaging technology reported in the literature to date.

Use of Three-Dimensional Intracardiac Echocardiography Catheter in the Evaluation of Prosthetic Pulmonary Valves after Transcatheter Replacement.

Transcatheter pulmonary valve replacement (TPVR) is commonly performed in patients with congenital heart disease as a safe alternative to replacement via open heart surgery. Intracardiac echocardiography (ICE) is a useful technique for evaluating multiple structures that are difficult to assess by other echocardiographic techniques, particularly the pulmonary valve. To our knowledge, the use of three-dimensional (3D) ICE catheters to evaluate prosthetic valves after TPVR has not been reported. Three-dimensional ICE catheters offer a comprehensive evaluation of transcatheter-deployed pulmonary valves through 3D, 3D color, xPlane, and multiplane reconstruction. The aim of this study is to demonstrate the feasibility of using 3D ICE catheters, outline their role in evaluating post-TPVR deployment success and complications, consider their additive value to two-dimensional ICE, and present our institutional experience with it in 50 cases of TPVR.

Use of the Occlutech pmVSD Device for Hybrid Closure of a Large Mid-Muscular Ventricular Septal Defect in a Small Infant Born With Hypoplastic Aortic Arch.

We describe the perventricular device closure of a large mid-muscular ventricular septal defect (VSD) in a 2.9 kg infant born with hypoplastic aortic arch and VSD using an Occlutech perimembranous occluder. In this case, the anatomy required a short low-profile device and hence a perimembranous occluder was used. To our knowledge, this is the first described use of this device for hybrid closure of a muscular VSD and the application of this technique in a patient <3 kg.

Usefulness of PREDIC3T Case Type Risk Category in the CRISP Registry.

Procedural risk in Congenital Cardiac Catheterization (PREDIC3T) was recently reported as the contemporary procedure-type risk metric by the Congenital Cardiac Catheterization Project on Outcomes (C3PO) registry. The usefulness of this metric has not been evaluated elsewhere. The CRISP registry of Congenital Cardiovascular Interventional Study Consortium (CCISC) data set was analyzed. The study period was 14 years (2009 to 2022). The primary outcome was significant adverse event (SAE). Cases were assigned to the 6 PREDIC3T risk categories. Univariate and multivariable logistic regression models were used to evaluate the association between PREDIC3T and the primary outcome. The model discriminative performance was evaluated by the c-statistic. In a total of 64,419 enrolled cases, PREDIC3T case types were assigned in 59,822 cases (93%). The frequency for PREDIC3T category was 0 = 7,494 (12.5%), 1 = 16,932 (28.3%), 2 = 17,023 (28.5%), 3 = 9,885 (16.5%), 4 = 4,403 (7.4%), and 5 = 4,085 (6.8%). SAE was observed in 2,474 cases (4.1%). The SAE rates for category were 0 = 1.0%, 1 = 2.3%, 2 = 4.0%, 3 = 6.2%, 4 = 8.2%, and 5 = 9.0%. In a multivariable model, PREDIC3T case type risk category (odds ratios for category: 0 = 0.49, 1 = 1.00, 2 = 1.40, 3 = 2.06, 4 = 2.79, and 5 = 3.15; p <0.001) were significantly associated with SAE (c-statistic of 0.707) after adjusting for age, preprocedural inotropic support and systemic illness, low systemic saturation, high pulmonary vascular resistance, and the use of general anesthesia. The PREDIC3T case type risk category was associated with the risk of SAE in the CRISP registry data set and appeared to be a useful procedural risk classification tool.

Fontan Fenestration Reduction with an Occlutech Atrial Flow Regulator: Unique Views from Three-Dimensional Intracardiac Echocardiography.

Three-dimensional intracardiac echocardiography (3D ICE) has gained popularity in interventional cardiology given its improved spatial and temporal imaging in assessing intracardiac anatomy pre- and post-intervention. We describe the use of 3D ICE in the reduction of a Fontan fenestration with an Occlutech atrial flow regulator (AFR) device.

Kinetic evidence for multiple aggregation pathways in antibody light chain variable domains.

Aggregation of antibody light chain proteins is associated with the progressive disease light chain amyloidosis. Patient-derived amyloid fibrils are formed from light chain variable domain residues in non-native conformations, highlighting a requirement that light chains unfold from their native structures in order to aggregate. However, mechanistic studies of amyloid formation have primarily focused on the self-assembly of natively unstructured peptides, and the role of native state unfolding is less well understood. Using a well-studied light chain variable domain protein known as WIL, which readily aggregates in vitro under conditions where the native state predominates, we asked how the protein concentration and addition of pre-formed fibril "seeds" alter the kinetics of aggregation. Monitoring aggregation with thioflavin T fluorescence revealed a distinctly non-linear dependence on concentration, with a maximum aggregation rate observed at 8 µM protein. This behavior is consistent with formation of alternate aggregate structures in the early phases of amyloid formation. Addition of N- or C-terminal peptide tags, which did not greatly affect the folding or stability of the protein, altered the concentration dependence of aggregation. Aggregation rates increased in the presence of pre-formed seeds, but this effect did not eliminate the delay before aggregation and became saturated when the proportion of seeds added was greater than 1 in 1600. The complexity of aggregation observed in vitro highlights how multiple species may contribute to amyloid pathology in patients.

Percutaneous Stenting of a Stenotic Berlin Heart Outflow Cannula Graft in a 2 Year Old Child.

Left ventricular assist device (LVAD) outflow obstruction is a rare complication of long-term LVAD support. We present the first case of successful percutaneous stent implantation in a pediatric patient with LVAD outflow obstruction.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

Kinetic evidence for multiple aggregation pathways in antibody light chain variable domains.

Aggregation of antibody light chain proteins is associated with the progressive disease light chain amyloidosis. Patient-derived amyloid fibrils are formed from light chain variable domain residues in non-native conformations, highlighting a requirement that light chains unfold from their native structures in order to aggregate. However, mechanistic studies of amyloid formation have primarily focused on the self-assembly of natively unstructured peptides, and the role of native state unfolding is less well understood. Using a well-studied light chain variable domain protein known as WIL, which readily aggregates in vitro under conditions where the native state predominates, we asked how the protein concentration and addition of pre-formed fibril "seeds" alter the kinetics of aggregation. Monitoring aggregation with thioflavin T fluorescence revealed a distinctly non-linear dependence on concentration, with a maximum aggregation rate observed at 8 µM protein. This behavior is consistent with formation of alternate aggregate structures in the early phases of amyloid formation. Addition of N- or C-terminal peptide tags, which did not greatly affect the folding or stability of the protein, altered the concentration dependence of aggregation. Aggregation rates increased in the presence of pre-formed seeds, but this effect did not eliminate the delay before aggregation and became saturated when the proportion of seeds added was greater than 1 in 1600. The complexity of aggregation observed in vitro highlights how multiple species may contribute to amyloid pathology in patients.

Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease.

Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins-increased MMP 7 and decreased MMP 8-was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD.

Single-center review on safety of biodegradable airway stenting in pediatric population.

BACKGROUND: Tracheobronchomalacia (TBM) and airway stenosis are recognized etiologies of airway obstruction among children. Their management is often challenging, requiring multiple interventions and prolonged respiratory support with associated long-term morbidity. Metallic or silicone stents have been used with mixed success and high complication rates. More recently biodegradable Ella stents (BES) provided an attractive interventional option. OBJECTIVES: We report our experience in the treatment of TBM and vascular airway compression using BES. We deliberately downsized them to minimize intraluminal granulation tissue formation. MATERIALS AND METHODS: Retrospective study over an 8-year period between November 2012 and December 2020 of pediatric patients with severe airway obstruction requiring airway stenting for extubation failure, malacic death spells, recurrent chest infections, or lung collapse. RESULTS: Thirty-three patients (5 tracheal and 28 bronchial diseases) required 55 BES during the study period. The smallest patient weighed 1.8 kg. Median age of patient at first stent implantation was 13.1 months (IQR 4.9-58.3). The majority of the bronchial stents were in the left main bronchus (93%), of which 57% for vascular compression. Repeat stents were used in 19 patients (57.7%), with a range of two to four times. We did not experience erosion, infection, or obstructive granuloma needing removal by forceps or lasering. Three stent grid occluded with secretions needing bronchoscopic lavage. Stent migration occurred in three patients. CONCLUSIONS: BES holds promise as a treatment option with low rate of adverse effects for a specific subset of pediatric patients with airway malacia or vascular compression. Further studies are warranted.

Establishing Carotid Seldinger as Routine Access in Infants; Planning, Performance, and Follow-Up Protocols.

Percutaneous carotid access (PCA) in infants has been reported in small multicenter cohorts, case reports and wider studies over the last 20 years. Compare outcomes after implementation of a systematic approach to PCA in a single center including an imaging follow-up protocol. Retrospective case-control study of PCA at Children's Hospital Colorado was performed from January 2013 to December 2022. Seventy-four patients underwent 82 PCAs for cardiac catheterization. The median age (range) was 14 days (1-359), and weight was 3.25-kg (1.9-7.9). Median sheath size was 4-Fr (3.3-6). Seventy-seven interventions performed included PDA stenting, aortic valvoplasty, BTT shunt stenting, and coarctation stenting. Vascular access was performed using a modified 21 g butterfly needle. A protocolized approach was implemented in 2020 reversing the patient head-to-toe orientation on the catheterization table, maintaining intubation and sedation for 4-h during recovery and routine use of a specific vascular ultrasound protocol. Following these changes, time to access significantly improved with no major complications. Before 2020, two access related complications occurred. One requiring surgical vascular repair and one occlusive thrombus. A significant increase in sheath time in post-era was associated with increased case complexity. Longer sheath times were not associated with increased risk of vessel injury or thrombus. No neurological insults were reported. Our experience confirms that PCA is safe and achievable with preserved vessel patency regardless of patient weight or sheath size. A protocolized planning, recovery, and follow-up regimen is recommended to establish safe practice and identify and treat complications as necessary.