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

ABSTRACT: 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 data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers.

Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with enhancers, often called enhancer hijacking We analyzed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterized the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with hijacking of super-enhancers of other common oncogenes in B cell (MAF, MYC, and FGFR3/NSD2) and T cell malignancies (LMO2, TLX3, and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, in which the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.

Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial.

Prediction of individual patient benefit from lenalidomide (Len) maintenance after autologous stem cell transplant (ASCT) remains challenging. Here, we investigated extended molecular profiling for outcome prediction in patients in the National Cancer Research Institute Myeloma XI (MyXI) trial. Patients in the MyXI trial randomized to Len maintenance or observation after ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q), and del(17p) and co-occurrence of risk markers was computed. Progression-free survival (PFS), subsequent progression (PFS2), and overall survival (OS) were calculated from maintenance randomization, and groups were compared using Cox proportional hazards regression. Of 556 patients, 17% with double-hit multiple myeloma (MM) (≥2 risk markers), 32% with single-hit (1 risk marker), and 51% without risk markers were analyzed. Single-hit MM derived the highest PFS benefit from Len maintenance, specifically, isolated del(1p), del(17p), and t(4;14), with ∼40-fold, 10-fold, and sevenfold reduced risk of progression or death (PFS), respectively, compared with observation. This benefit translated into improved PFS2 and OS for this group of patients compared with observation; median PFS was 10.9 vs 57.3 months for observation vs Len maintenance. Patients with isolated gain(1q) derived no benefit, and double-hit MM limited benefit (regardless or risk lesions involved) from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway. This trial was registered at www.isrctn.com/ISRCTN49407852 as # ISRCTN49407852.

Chromothripsis as a pathogenic driver of multiple myeloma.

Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.

Anthropometric traits and risk of multiple myeloma: differences by race, sex and diagnostic clinical features.

BACKGROUND: Obesity is an established modifiable risk factor for multiple myeloma (MM). However, associations of obesity and MM risk in Black populations, for whom obesity and MM are more common, is less clear. METHODS: Using participants enrolled in the Integrative Molecular And Genetic Epidemiology study, we evaluated the association of anthropometric traits with MM risk overall, stratified by race and sex. Among cases, we assessed the association of BMI with the presence of myeloma-defining events. RESULTS: We observed an 18% increase in MM risk for every 5 kg/m2 increase in usual adult BMI. Participants with severe obesity (BMI ≥ 40 kg/m2) had the highest risk compared to those with a normal usual adult BMI (18.5-24.9 kg/m2; OR = 1.87, 95% CI 1.25-2.80), particularly among Black men (OR = 3.94, 95% CI 0.90-17.36). Furthermore, MM cases with overweight/obesity (BMI ≥ 25 kg/m2) were more likely to present at diagnosis with low renal function (OR = 1.62, 95% CI 1.09-2.40), deletion 13q (OR = 1.73, 95% CI 1.08-2.76) and lytic lesions or compression fractures (OR = 2.39, 95% CI 0.82-7.01) and less likely to present with severe diffuse osteopenia (OR = 0.51, 95% CI 0.31-0.81). CONCLUSIONS: Findings underscore the importance of obesity as a modifiable risk factor for MM, particularly in high-risk populations, and for the clinical presentation of disease.

Using a customized telescoped stent complex in the percutaneous treatment of a residual superior sinus venosus defect.

The management of superior sinus venosus defects (SVD) via transcatheter covered stent (CS) placement is becoming an acceptable alternative to open heart surgery. Though the medium-term success of this procedure has been described, residual shunting from damage to the covering of the implanted stents, use of stents which are too short and unanticipated shortening of stents may result in immediate or short-term procedural failure. In such cases, placement of a second CS may be required to address a residual defect. Preprocedural prediction of the length of stent required for residual leak treatment may not be as accurate as predicting the required stent length in a native defect, meaning that compassionate use applications to facilitate acquiring non-standard stent and balloon combinations may not be practical. We present a successful case of residual SVD closure using a novel sutured telescoping stent technique. Further collaboration with industry should encourage regulatory approval of longer CS, to mitigate the need for potentially unpredictable modifications such as this.

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.

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.

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.

The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial.

Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.

Abnormal flow conduction through pulmonary arteries is associated with right ventricular volume and function in patients with repaired tetralogy of Fallot: does flow quality affect afterload?

OBJECTIVES: Flow through the proximal pulmonary arteries (PAs) of patients with repaired Tetralogy of Fallot (TOF) is known to be highly disordered and associated with significant regurgitation. The purpose of this study was to evaluate 4D-Flow MRI-derived viscous energy loss [Formula: see text])-as a result of non-efficient flow propagation, and relate this parameter to standard right ventricular (RV) size and function markers in patients with repaired TOF. METHODS: Thirty-five patients with TOF and 14 controls underwent comprehensive 4D-Flow MRI evaluation for qualitative flow analysis and to calculate [Formula: see text] in the main and right pulmonary arteries. Sampled [Formula: see text] indices were correlated with the MRI-derived RV size and functional indices. RESULTS: All patients with TOF exhibited abnormal, supra-physiologic helical/vortical formations in the PAs. Patients with TOF had significantly increased peak systolic [Formula: see text] (8.0 vs 0.5 mW, p < 0.001), time-averaged [Formula: see text] (2.5 vs. 0.2 mW, p < 0.001), and peak systolic [Formula: see text] indexed to stroke volume (0.082 vs. 0.012 mW/mL, p < 0.001). [Formula: see text] indexed to stroke volume correlated with the RV end-diastolic volume (R = 0.68, p < 0.001), end-systolic volume (R = 0.62, p < 0.001), ejection fraction (R = -0.45, p = 0.002), and cardiac index (R = 0.45, p = 0.002). The mean estimated energy loss due to [Formula: see text] with regard to input RV mechanical power was 4.7%. CONCLUSION: This study demonstrates that patients with repaired TOF have highly abnormal flow conduction through the PAs which result into extensive viscous energy loss. This significant flow-mediated energy loss is associated with the RV volume and function, and might represent considerable loss of mechanical power generated by each cardiac cycle. Future studies are required to assess whether the abnormal flow conduction adds to the RV afterload and remodeling. KEY POINTS: • Abnormal flow patterns through proximal pulmonary arteries in patients with TOF are associated with excessive viscous energy loss. • Inefficient flow conduction is associated with the RV dilation and reduced function and might contribute to the RV adaptive remodeling.

Computed tomographic parenchymal lung findings in premature infants with pulmonary vein stenosis.

BACKGROUND: Developmental pulmonary vein pulmonary vein stenosis in the setting of prematurity is a rare and poorly understood condition. Diagnosis can be challenging in the setting of chronic lung disease of prematurity. High-resolution non-contrast chest computed tomography (CT) is the conventional method of evaluating neonates for potential structural changes contributing to severe lung dysfunction and pulmonary hypertension but may miss pulmonary venous stenosis due to the absence of contrast and potential overlap in findings between developmental pulmonary vein pulmonary vein stenosis and lung disease of prematurity. OBJECTIVE: To describe the parenchymal changes of pediatric patients with both prematurity and pulmonary vein stenosis, correlate them with venous disease and to describe the phenotypes associated with this disease. MATERIALS AND METHODS: A 5-year retrospective review of chest CT angiography (CTA) imaging in patients with catheterization-confirmed pulmonary vein stenosis was performed to identify pediatric patients (< 18 years) who had a history of prematurity (< 35 weeks gestation). Demographic and clinical data associated with each patient were collected, and the patients' CTAs were re-reviewed to evaluate pulmonary veins and parenchyma. Patients with post-operative pulmonary vein stenosis and those with congenital heart disease were excluded. Data was analyzed and correlated for descriptive purposes. RESULTS: A total of 17 patients met the inclusion criteria (12 female, 5 male). All had pulmonary hypertension. There was no correlation between mild, moderate, and severe grades of bronchopulmonary dysplasia and the degree of pulmonary vein stenosis. There was a median of 2 (range 1-4) diseased pulmonary veins per patient. In total, 41% of the diseased pulmonary veins were atretic. The right upper and left upper lobe pulmonary veins were the most frequently diseased (n = 13/17, 35%, n = 10/17, 27%, respectively). Focal ground glass opacification, interlobular septal thickening, and hilar soft tissue enlargement were always associated with the atresia of an ipsilateral vein. CONCLUSION: Recognition of the focal parenchymal changes that imply pulmonary vein stenosis, rather than chronic lung disease of prematurity changes, may improve the detection of a potentially treatable source of pulmonary hypertension, particularly where nonangiographic studies result in a limited direct venous assessment.

Radiofrequency Perforation of an Atretic Pulmonary Valve with a Modified Coronary Wire and Electrocautery Pencil.

Radiofrequency (RF) perforation of an atretic pulmonary valve is commonly performed in patients with pulmonary atresia with intact ventricular septum with specifically designed RF wires. In difficult anatomy or low-resource centers, this may instead be successfully performed with a modified coronary guide wire and an electrocautery surgical pencil.

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.

Percutaneous VA-ECMO from Cannulation to Decannulation: Novel Use of a Vascular Closure Device in Pediatrics.

VA-ECMO can be lifesaving in cardiogenic shock in children. While surgical vascular repair is the current standard of care for decannulation, it comes with notable risks. We present a series of eight patients who underwent decannulation with a collagen plug-based vascular closure device (MANTA) for the common femoral artery. Seven of the patients were successfully decannulated without access site-related vascular complications. One required conversion to surgical cut-down with arterial repair due to device failure. This series demonstrates the successful use of the MANTA device in percutaneous VA-ECMO decannulation in the pediatric population, while highlighting potential technical challenges for success.

Management of Complex Pulmonary Vein Stenosis at Altitude Combining Comprehensive Percutaneous Interventional Treatment with Sirolimus, Pulmonary Hypertension Medications and Intraluminal Imaging with Optical Coherence Tomography.

BACKGROUND: Pulmonary vein stenosis (PVS) is a growing problem for the pediatric congenital heart population. Sirolimus has previously been shown to improve survival and slow down the progression of in-stent stenosis in patients with PVS. We evaluated patients before and after initiation of sirolimus to evaluate its effects on re-intervention and vessel patency utilizing Optical Coherence Tomography (OCT). METHODS: We performed a retrospective study, reviewing the charts of patients with PVS, who had been prescribed sirolimus between October 2020 and December 2021. OCT was performed in the pulmonary vein of interest as per our published protocol. Angiographic and OCT imaging was retrospectively reviewed. Statistical analysis was performed using Chi square and Wilcoxon signed-rank test to compare pre-and post-sirolimus data. RESULTS: Ten patients had been started and followed on sirolimus. Median age at sirolimus initiation was 25 months with median weight of 10.6 kg and average follow-up of 1 year. Median total catheterizations were 7 for patients prior to starting sirolimus and 2 after starting treatment (p = 0.014). Comparing pre- and post-sirolimus, patients were catheterized every 3 months vs every 11 months (p = 0.011), median procedure time was 203 min vs 145 min (p = 0.036) and fluoroscopy time, 80 min vs 57.2 min (p = 0.036). 23 veins had severe in-stent tissue ingrowth prior to SST (luminal diameter < 30% of stent diameter). Post-sirolimus, 23 pulmonary veins had moderate to severe in-stent tissue ingrowth that responded to non-compliant balloon inflation only with stent luminal improvement of > 75%. CONCLUSION: Our study suggests that the addition of sirolimus in patients with moderate-severe PVS helps to decrease disease progression with decrease frequency of interventions. Reaching therapeutic levels for sirolimus is critical and medication interactions and side-effects need careful consideration. OCT continues to be important for evaluation and treatment guidance in this patient population.

The novel use of an advanced thrombectomy system to manage a complex pericardial effusion associated with kaposiform lymphangiomatosis.

A 4-year-old boy presented to our institution with pancytopenia, consumptive coagulopathy, hepatosplenomegaly and recurrent complex pericardial effusion secondary to kaposiform lymphagiomatosis. Due to extensive loculation, conventional drainage was minimally effective. As an adjunct to medical therapy, the Indigo™ aspiration system was used to remove thrombus within the pericardial space. Our patient had good medium-term results with complete resolution of his pericardial effusion at 4 months.

Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials.

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

A new FDA approved stent for congenital heart disease: First-in-man experiences with G-ARMORTM.

We present the first clinical experience with a new hybrid cell structure covered stent, designed for congenital heart disease applications. It represents a significant redesign of the Cheatham Platinum (CP) Stent (Numed Inc.), maintaining the traditional benefits of the covered CP whilst significantly decreasing shortening and allowing controlled flaring at the ends through its combination of larger and standard sized cells. We first implanted the stent in 2 patients with superior sinus venosus defects with anomalous drainage of the right upper and middle lobe pulmonary veins. The first was a 40 year male and the second a 36 year old female. The third case was a 60 year old patient with near atresia of the aorta, with pre and poststenotic aortic dilation. The clinical result in all cases was excellent with no obstruction to pulmonary venous return and no visible L-R shunt on the transthoracic echo on 24 h and 2 week follow-up for the patient with sinus venosus defects and uniform complete revascularization of the aorta without any vascular complications in the patient with coarctation. These are the first uses of this stent in human subjects. The design is specifically aimed toward procedures where stent shortening is undesirable. Hence, coarctation of the aorta as well as stent implantation in preparation for percutaneous pulmonary valve placement are obvious use areas, as well as the growing body of evidence supporting percutaneous treatment of sinus venosus defects.