Publications by authors named "Gareth Morgan"

610 Publications

Validating a risk assessment tool in United Kingdom and Irish paediatric cardiac catheterisation practice.

Cardiol Young 2021 Oct 14:1-8. Epub 2021 Oct 14.

The Heart Institute, Children's Hospital of Colorado, University of Colorado, Denver, CO, USA.

Background: No established risk prediction tool exists in United Kingdom and Irish Paediatric Cardiology practice for patients undergoing cardiac catheterisation. The Catheterisation RISk score for Paediatrics is used primarily in North American practice to assess risk prior to cardiac catheterisation. Validating the utility and transferability of such a tool in practice provides the opportunity to employ an already established risk assessment tool in everyday practice.

Aims: To ascertain whether the Catheterisation RISk score for Paediatrics assessment tool can accurately predict complications within United Kingdom and Irish congenital catheterisation practice.

Methods: Clinical and procedural data including National Institute for Cardiovascular Outcomes Research derived outcome data from 1500 patients across five large congenital cardiology centres in the United Kingdom and Ireland were retrospectively collected. Catheterisation RISk score for Paediatrics were then calculated for each case and compared with the observed procedural outcomes. Chi-square analysis was used to determine the relationship between observed and predicted events.

Results: Ninety-eight (6.6%) patients in this study experienced a significant complication as qualified by National Institute for Cardiovascular Outcomes Research classification. 4% experienced a moderate complication, 2.3% experienced a major complication and 0.3% experienced a catastrophic complication resulting in death. Calculated Catheterisation RISk score for Paediatrics scores correlated well with all observed adverse events for paediatric patients across all CRISP categories. The association was also transferable to adult congenital heart disease patients in lower Catheterisation RISk score for Paediatrics categories (CRISP 1-3).

Conclusion: The Catheterisation RISk score for Paediatrics score accurately predicts significant complications in congenital catheterisation practice in the United Kingdom and Ireland. Our data validated the Catheterisation RISk score for Paediatrics assessment tool in five congenital centres using National Institute for Cardiovascular Outcomes Research-derived outcome data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1047951121004170DOI Listing
October 2021

Baseline Values of the Compensatory Reserve Index in a Healthy Pediatric Population.

Pediatr Cardiol 2021 Sep 29. Epub 2021 Sep 29.

The Heart Institute, Children's Hospital Colorado, Box 100, 13123 East 16th Avenue, 80045, Aurora, CO, USA.

The objective of this study is to describe the compensatory reserve index (CRI) baseline values in a healthy cohort of healthy pediatric patients and evaluate the existing correlation with other physiological parameters that influence compensatory hemodynamic mechanisms. CRI is a computational algorithm that has been broadly applied to non-invasively estimate hemodynamic vascular adaptations during acute blood loss. So far, there is a lack of baseline values from healthy individuals, which complicates accurately estimating the severity of the hemodynamic compromise. Additionally, the application of this technology in pediatric populations is limited to a few reports, highlighting a marked variability by age, weight, and other physiological parameters. The CRI of 205 healthy subjects from 0 to 60 years of age were prospectively evaluated from January to February 2020 at several public outpatient clinics in El Salvador; vital signs and sociodemographic data were also collected during this period. After data collection, baseline values were classified for each age group. Multiple correlation models were tested between the CRI and the other physiological parameters. CRI value varies significantly for each age group, finding for patients under 18 years old a mean value lower than 0.6, which is currently considered the lower normal limit for adults. CRI presents strong correlations with other physiological variables such as age, weight, estimated blood volume, and heart rate (R > 0.8, R2 > 0.6, p < 0.0001). There is significant variability in the CRI normal values observed in healthy patients based on age, weight, estimated blood volume, and heart rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00246-021-02725-8DOI Listing
September 2021

Aspirin and cancer survival: a systematic review and meta-analyses of 118 observational studies of aspirin and 18 cancers.

Ecancermedicalscience 2021 2;15:1258. Epub 2021 Jul 2.

University Library Service, Cardiff University, Cardiff, UK.

Background: Despite the accumulation of research papers on aspirin and cancer, there is doubt as to whether or not aspirin is an acceptable and effective adjunct treatment of cancer. The results of several randomised trials are awaited, and these should give clear evidence on three common cancers: colon, breast and prostate. The biological effects of aspirin appear likely however to be of relevance to cancer generally, and to metastatic spread, rather than just to one or a few cancers, and there is already a lot of evidence, mainly from observational studies, on the association between aspirin and survival in a wide range of cancers.

Aims: In order to test the hypothesis that aspirin taking is associated with an increase in the survival of patients with cancer, we conducted a series of systematic literature searches to identify clinical studies of patients with cancer, some of whom took aspirin after having received a diagnosis of cancer.

Results: Three literature searches identified 118 published observational studies in patients with 18 different cancers. Eighty-one studies report on aspirin and cancer mortality and 63 studies report on all-cause mortality. Within a total of about a quarter of a million patients with cancer who reported taking aspirin, representing 20%-25% of the total cohort, we found aspirin to be associated with a reduction of about 20% in cancer deaths (pooled hazard ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84 in 70 reports and a pooled odds ratio (OR): 0.67; 0.45, 1.00 in 11 reports) with similar reductions in all-cause mortality (HR: 0.80; 0.74, 0.86 in 56 studies and OR: 0.57; 0.36, 0.89 in seven studies). The relative safety of aspirin taking was examined in the studies and the corresponding author of every paper was written to asking for additional information on bleeding. As expected, the frequency of bleeding increased in the patients taking aspirin, but fatal bleeding was rare and no author reported a significant excess in fatal bleeds associated with aspirin. No author mentioned cerebral bleeding in the patients they had followed.

Conclusions: There is a considerable body of evidence suggestive of about a 20% reduction in mortality in patients with cancer who take aspirin, and the benefit appears not to be restricted to one or a few cancers. Aspirin, therefore, appears to deserve serious consideration as an adjuvant treatment of cancer, and patients with cancer, and their carers, have a right to be informed of the available evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3332/ecancer.2021.1258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426031PMC
July 2021

Widespread Supplement Intake and Use of Poor Quality Information in Elite Adolescent Swiss Athletes.

Int J Sport Nutr Exerc Metab 2021 Sep 22:1-8. Epub 2021 Sep 22.

Department of Elite Sport, Swiss Federal Institute of Sport Magglingen, Magglingen,Switzerland.

Compared with adult athletes, rather little is known about supplementation behavior in adolescent athletes. This study's aim was to determine elite adolescent athletes' supplement use and sources of information relating thereto. A total of 430 (87%) of 496 questioned athletes returned the anonymized questionnaire. Thereof, 84% consumed at least one weekly supplement and 97% indicated some supplement intake during the previous 4 weeks. On average, 13.3 supplement servings were consumed per week. The 25th, 50th, and 75th percentile was 4.5, 10.5, and 20.0 servings per week, with a maximum of 67. The most prevalent supplements in use were multimineral products (41% of all athletes), multivitamins (34%), Vitamin C (34%), and Vitamin D (33%). Male athletes consumed significantly more Vitamin C and D, sports drinks, protein powder, and recovery products compared with female athletes; whereas, women consumed more iron supplements. The three most important motives for supplement use were recovery support (40%), health maintenance (39%), and performance enhancement (30%). The most frequent answers to the question "who recommended that you use supplements" were family/friends (36%), a physician (27%), and a trainer/coach (25%). The main three information sources about the supplements in use were the persons who recommended the supplementation (56%), the internet (25%), and information provided by supplement suppliers (11%). A positive doping attitude was associated with the consumption of performance enhancing supplements (p = .017). In conclusion, this study among elite adolescent Swiss athletes indicates a widespread and large-scale use of dietary supplements, which was associated with a low level of information quality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1123/ijsnem.2021-0043DOI Listing
September 2021

From Bench to Bedside: The Evolution of Genomics and Its Implications for the Current and Future Management of Multiple Myeloma.

Cancer J 2021 May-Jun 01;27(3):213-221

From the Perlmutter Cancer Center, NYU Langone Health, New York, NY.

Abstract: The summation of 20 years of biological studies and the comprehensive analysis of more than 1000 multiple myeloma genomes with data linked to clinical outcome has enabled an increased understanding of the pathogenesis of multiple myeloma in the context of normal plasma cell biology. This novel data have facilitated the identification of prognostic markers and targets suitable for therapeutic manipulation. The challenge moving forward is to translate this genetic and biological information into the clinic to improve patient care. This review discusses the key data required to achieve this and provides a framework within which to explore the use of response-adapted, biologically targeted, molecularly targeted, and risk-stratified therapeutic approaches to improve the management of patients with multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PPO.0000000000000523DOI Listing
October 2021

Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma.

Nat Commun 2021 08 27;12(1):5172. Epub 2021 Aug 27.

Myeloma Service, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.

Chromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-25469-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397708PMC
August 2021

Contrast-free percutaneous pulmonary valve replacement: a safe approach for valve-in-valve procedures.

Postepy Kardiol Interwencyjnej 2021 Jun 9;17(2):200-209. Epub 2021 Jul 9.

The Heart Institute, Children's Hospital Colorado, Aurora, USA.

Introduction: Percutaneous pulmonary valve replacement (PPVI) continues to gather pace in pediatric and adult congenital practice. This is fueled by an expanding repertoire of devices, techniques and equipment to suit the heterogenous anatomical landscape of patients with lesions of the right ventricular outflow tract (RVOT). Contrast-induced nephropathy is a real risk for teenagers and adults with congenital heart disease (CHD).

Aim: To present a series of patients who underwent PPVI without formal RVOT angiography and propose case selection criteria for patients who may safely benefit from this approach.

Material And Methods: We retrospectively collected PPVI data from the preceding 2 years at our institution identifying patients who had been listed as suitable for consideration for contrast-free PPVI from our multidisciplinary team (MDT) meeting based on predefined criteria. Demographic, clinical, imaging and hemodynamic data were collected. Data were analyzed using SPSS.

Results: Twenty-one patients were identified. All patients had a technically successful implantation with improvements seen in invasive and echocardiographic hemodynamic measurements. 90% of patients had a bio-prosthetic valve (BPV) prior to PPVI. One patient had a complication which may have been recognized earlier with post-intervention RVOT contrast injection.

Conclusions: Zero-contrast PPVI is technically feasible and the suitability criteria for those who might benefit are potentially straightforward. The advent of fusion and 3D imaging in cardiac catheterization laboratories is likely to expand our capacity to perform more procedures with less contrast. Patients with bio-prosthetic valves in the pulmonary position may benefit from contrast-free percutaneous pulmonary valve implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5114/aic.2021.107500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356834PMC
June 2021

Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups.

Leukemia 2021 Aug 7. Epub 2021 Aug 7.

Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA.

Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01379-yDOI Listing
August 2021

The Unusual Journey of a Pericardial Drainage Catheter in Pentalogy of Cantrell.

Case Rep Pediatr 2021 8;2021:2109934. Epub 2021 Jul 8.

Department of Pediatric Cardiology, Children's Hospital Colorado, Aurora, CO, USA.

A 4-month-old male infant diagnosed with Pentalogy of Cantrell presented to the cardiac catheterization laboratory with a large pericardial effusion. During an urgent pericardial drain placement, the patient, whose prior hemodynamics and clinical findings had suggested a noncritical cardiac lesion, had a profound desaturation, with echocardiography suggesting minimal or no flow across the right ventricular outflow tract (RVOT). The position of the drainage catheter on fluoroscopy and echocardiography suggested that the spell was being caused by obstruction of the main pulmonary artery (MPA) by the pericardial drain. After partially withdrawing the drain to reposition it, there was immediate resolution of the hypoxemia, and echocardiography once again showed adequate flow across the outflow tract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/2109934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282392PMC
July 2021

Implementation of virtual reality for patient distraction during diagnostic cardiac catheterisation.

Cardiol Young 2021 Jul 26:1-5. Epub 2021 Jul 26.

The Heart Institute, Children's Hospital Colorado, Aurora, CO, USA.

Until now, the application of virtual reality as a distraction model has been widely described in the medical field, showing different benefits offered on patient's perception, particularly related to pain and anxiety. Previous clinical experience of virtual reality applications on surgical intervention has shown how during procedures with local anaesthesia, this modality improves patients' experience without changing times, costs, and clinical outcomes. Herein, we report our experience with three patients during diagnostic cardiac catheterisation, showing the effect of this technology on patients' perception and metrics during the procedure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1047951121002845DOI Listing
July 2021

Coronary Artery Reimplantation and Berlin Heart EXCOR Rescue for Left Coronary Artery Atresia With Severe Ischemic Cardiomyopathy.

World J Pediatr Congenit Heart Surg 2021 Jul 15:21501351211024662. Epub 2021 Jul 15.

Section of Congenital Cardiac Surgery, Department of Surgery, Children's Hospital Colorado, University of Colorado, Aurora, CO, USA.

We describe a successful bridge to recovery by coronary reimplantation and Berlin Heart EXCOR left ventricular assist device in a child with left main coronary artery ostial atresia and severe ischemic cardiomyopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/21501351211024662DOI Listing
July 2021

Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis.

Authors:
Gareth J Morgan

Molecules 2021 Jun 11;26(12). Epub 2021 Jun 11.

Section of Hematology and Medical Oncology, Amyloidosis Center, Department of Medicine, School of Medicine, Boston University, Boston, MA 02118, USA.

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26123571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230685PMC
June 2021

Baseline intracardiac echocardiography predicts haemodynamic changes and Doppler velocity patterns during follow-up after percutaneous pulmonary valve implantation.

Cardiol Young 2021 Jun 18:1-7. Epub 2021 Jun 18.

The Heart Institute, Children's Hospital Colorado, Aurora, Colorado, USA.

Background: Intracardiac echocardiography Doppler-derived gradients have previously been shown to correlate with post-procedure echocardiographic evaluations when compared with invasive gradients measured during percutaneous pulmonary valve implantation, suggesting that intracardiac echocardiography could offer an accurate and predictable starting point to estimate valve function after percutaneous pulmonary valve implantation.

Methods: We performed a retrospective chart review of 51 patients who underwent percutaneous pulmonary valve implantation between September 2018 and December 2019 in whom intracardiac echocardiography was performed immediately after valve implantation. We evaluated the correlation between intracardiac echocardiography gradients and post-procedural Doppler-derived gradients. Among the parameters assessed, those which demonstrated the strongest correlation were used to create a predictive model of expected echo-derived gradients after percutaneous pulmonary valve implantation. The equation was validated on the same sample data along with a subsequent cohort of 25 consecutive patients collected between January 2020 and July 2020.

Results: All the assessed correlation models between intracardiac echocardiography evaluation and post-procedure transthoracic echocardiographic assessments were statistically significant, presenting moderate to strong correlations. The strongest relationship was found between intracardiac echocardiography mean gradients and post-procedural transthoracic echocardiographic mean gradients. Therefore, an equation was created based on the intracardiac echocardiography-derived mean gradient, to allow prediction of the post-procedural and follow-up transthoracic echocardiographic-derived mean gradients within a range of ±5 mmHg from the observed value in more than 80% of cases.

Conclusions: There is a strong correlation between intracardiac echocardiography and post-procedure transthoracic echocardiographic. This allowed us to derive a predictive equation that defines the expected transthoracic echocardiographic Doppler-derived gradient following the procedure and at out-patient follow-up after percutaneous pulmonary valve implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1047951121002365DOI Listing
June 2021

Metalloproteinases and their inhibitors are associated with pulmonary arterial stiffness and ventricular function in pediatric pulmonary hypertension.

Am J Physiol Heart Circ Physiol 2021 07 4;321(1):H242-H252. Epub 2021 Jun 4.

Linda Crnic Institute for Down Syndrome, University of Colorado Denver, Aurora, Colorado.

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH ( = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and ) standard PAH indices from catheterization, ) cardiac MRI hemodynamics, and ) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume ( = 0.45, = 0.04). MMP-9 levels were significantly associated with stroke volume ( = -0.49, = 0.03) and pulmonary vascular resistance ( = 0.49, = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change ( = -0.79, < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity ( = 0.51, = 0.03) and backward compression wave ( = 0.52, = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices. Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00750.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424580PMC
July 2021

Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial.

Clin Lymphoma Myeloma Leuk 2021 Oct 24;21(10):667-675. Epub 2021 Apr 24.

The Institute of Cancer Research, London; The Royal Marsden Hospital, London. Electronic address:

Background: Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored.

Patients And Methods: We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated.

Results: Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population.

Conclusion: Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2021.04.013DOI Listing
October 2021

The mutagenic impact of melphalan in multiple myeloma.

Leukemia 2021 08 19;35(8):2145-2150. Epub 2021 May 19.

Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.

The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called "SBS-MM1") directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10-20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01293-3DOI Listing
August 2021

Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US.

Ann Hematol 2021 Sep 10;100(9):2325-2337. Epub 2021 May 10.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04534-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357697PMC
September 2021

Chromothripsis as a pathogenic driver of multiple myeloma.

Semin Cell Dev Biol 2021 May 3. Epub 2021 May 3.

Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcdb.2021.04.014DOI Listing
May 2021

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.

J Med Chem 2021 05 3;64(9):6273-6299. Epub 2021 May 3.

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.

In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-π stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.1c00339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428256PMC
May 2021

Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multicenter, phase II, randomized, controlled trial (MUK).

Haematologica 2021 10 1;106(10):2694-2706. Epub 2021 Oct 1.

Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds.

The proteasome inhibitors, carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these proteasome inhibitors in combination with cyclophosphamide and dexamethasone (KCd vs. VCd) in second-line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomized patients (2:1) to KCd (n=201) or VCd (n=99); responding patients on carfilzomib were randomized to maintenance carfilzomib (n=69) or no further treatment (n=72). Primary endpoints were: (i) very good partial response (non-inferiority, odds ratio [OR] 0.8) at 24 weeks, and (ii) progression-free survival. More participants achieved a very good partial response or better with carfilzomib than with bortezomib (40.2% vs. 31.9%, OR=1.48, 90% confidence interval [CI]: 0.95, 2.31; non-inferior), with a trend for particular benefit in patients with adverse-risk disease. KCd was associated with higher overall response (partial response or better, 84.0% vs. 68.1%, OR=2.72, 90% CI: 1.62, 4.55, P=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, P<0.0001), while grade ≥3 cardiac events and hypertension were only reported in the KCd arm (3.6% each). The median progression-free survival in the KCd arm was 11.7 months vs. 10.2 months in the VCd arm (hazard ratio [HR]=0.95, 80% CI: 0.77, 1.18). Carfilzomib maintenance was associated with longer progression-free survival, median 11.9 months vs. 5.6 months for no maintenance (HR 0.59, 80% CI: 0.46-0.77, P=0.0086). When used as fixed duration therapy in first relapase, KCd is at least as effective as VCd, and carfilzomib is an effective maintenance agent. This trial was registered with International Standard Randomised Controlled Trial Number (ISRCTN) identifier: ISRCTN17354232.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2021.278399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485692PMC
October 2021

Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.

Blood Adv 2021 04;5(8):2196-2215

Department of Hematology, Cancer Center Amsterdam, Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands.

Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095149PMC
April 2021

Short-Term Effects of Inhaled Nitric Oxide on Right Ventricular Flow Hemodynamics by 4-Dimensional-Flow Magnetic Resonance Imaging in Children With Pulmonary Arterial Hypertension.

J Am Heart Assoc 2021 04 6;10(8):e020548. Epub 2021 Apr 6.

Division of Cardiology Heart Institute Children's Hospital ColoradoUniversity of Colorado DenverAnschutz Medical Campus Aurora CO USA.

Background Pulmonary arterial hypertension (PAH) manifests with progressive right ventricular (RV) dysfunction, which eventually impairs the left ventricular function. We hypothesized that 4-dimensional-flow magnetic resonance imaging can detect flow hemodynamic changes associated with efficient intracardiac flow during noninvasive inhaled nitric oxide (iNO) challenge in children with PAH. Methods and Results Children with PAH (n=10) underwent 2 same-day separate iNO challenge tests using: (1) 4-dimensional-flow magnetic resonance imaging and (2) standard catheterization hemodynamics. Intracardiac flow was evaluated using the particle tracking 4-flow component analysis technique evaluating the , , , and . Respective flow hemodynamic changes were compared with the corresponding catheterization iNO challenge results. The RV analysis revealed decreased direct flow in patients with PAH when compared with controls (<0.001) and increase in residual volume (<0.001). Similarly, the left ventricular analysis revealed decreased direct flow in patients with PAH when compared with controls (=0.004) and increased proportion of the residual volume (=0.014). There was an increase in the RV direct flow during iNO delivery (=0.009), with parallel decrease in the residual volume (=0.008). Conclusions Children with PAH have abnormal biventricular flow associated with impaired diastolic filling. The flow efficiency is significantly improved in the RV on iNO administration with no change in the left ventricle. The changes in the RV flow have occurred despite the minimal change in catheterization hemodynamics, suggesting that flow hemodynamic evaluation might provide more quantitative insights into vasoreactivity testing in PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.020548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174179PMC
April 2021

A proof-of-concept study for the pathogenetic role of enhancer hypomethylation of MYBPHL in multiple myeloma.

Sci Rep 2021 03 26;11(1):7009. Epub 2021 Mar 26.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.

Enhancer DNA methylation and expression of MYBPHL was studied in multiple myeloma (MM). By bisulfite genomic sequencing, among the three CpGs inside the MYBPHL enhancer, CpG1 was significantly hypomethylated in MM cell lines (6.7-50.0%) than normal plasma cells (37.5-75.0%) (P = 0.007), which was negatively correlated with qPCR-measured MYBPHL expression. In RPMI-8226 and WL-2 cells, bearing the highest CpG1 methylation, 5-azadC caused enhancer demethylation and expression of MYBPHL. In primary samples, higher CpG1 methylation was associated with lower MYBPHL expression. By luciferase assay, luciferase activity was enhanced by MYBPHL enhancer compared with empty vector control, but reduced by site-directed mutagenesis of each CpG. RNA-seq data of newly diagnosed MM patients showed that MYBPHL expression was associated with t(11;14). MOLP-8 cells carrying t(11;14) express the highest levels of MYBPHL, and its knockdown reduced cellular proliferation and increased cell death. Herein, as a proof-of-concept, our data demonstrated that the MYBPHL enhancer, particularly CpG1, was hypomethylated and associated with increased MYBPHL expression in MM, which was implicated in myelomagenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-86473-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997988PMC
March 2021

Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities.

Nat Commun 2021 03 25;12(1):1861. Epub 2021 Mar 25.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22140-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994386PMC
March 2021

Case Report: Two Cases of Cryptosporidiosis in Heavily Pretreated Patients With Myeloma.

Clin Lymphoma Myeloma Leuk 2021 06 2;21(6):e545-e547. Epub 2021 Feb 2.

Department of Haematology Lille University Hospital, Lille, France; Myeloma Research Program, Perlmutter Cancer Center, NYU Langone, New York, NY. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2021.01.019DOI Listing
June 2021
-->