Faculty Bibliography

INTRODUCTION/BACKGROUND:Creation of a fenestration during completion of a total cavopulmonary connection (TCPC) has been associated with a reduction in early mortality and morbidity. However, the long-term benefits are negated by an associated limitation in exercise tolerance and the potential risks of thrombo-embolic complications. We sought to describe the safety and efficacy of an Amplatzer Duct Occluder II (ADO II) for transcatheter fenestration closure following TCPC. MATERIAL AND METHODS/METHODS:Between January 2000 and July 2014, 102 patients underwent percutaneous closure of extra-cardiac TCPC fenestrations with a range of devices. Patients in whom fenestration closure was performed with an ADO II and who had at least 6 months of follow-up were included in this study. RESULTS:< 0.001). Eight patients developed heart failure symptoms, managed by optimization of medical therapy, with 1 patient requiring device removal to reopen the fenestration. Color Doppler transthoracic echocardiography demonstrated residual flow across the device in 18 (38%), 10 (22%), 5 (11%) and 4 (9%) patients before discharge, at 1 and 6 months, and at the latest outpatient visit, respectively. CONCLUSIONS:The ADO II can be safely and effectively used to close fenestrations in extra-cardiac type Fontan completions. Many of the design features of this device confer potential benefit in this population.

Hyperhaploid clones (24-34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58-68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.

The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10^-9) with opposing effects between CLL (P = 1.97 × 10^-8) and HL (P = 3.31 × 10^-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10^-12) was associated with increased CLL and HL risk (P = 4.68 × 10^-12), and reduced MM risk (P = 1.12 × 10^-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10^-10) showed opposing effects between CLL (P = 3.52 × 10^-3) and HL (P = 3.41 × 10^-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Using advances in genetic analysis to segment and direct treatment of multiple myeloma (MM) represents a way of maintaining therapeutic progress. Recent genetic analyses have opened the possibility of enhancing risk stratification approaches and of using different risk and biologic strata as part of clinical trials. The Myeloma Genome Project is a collaborative project that has compiled the largest set of cases with sequencing and have outcome data that are available for stratification purposes. Mutation-targeted treatment of the Ras pathway has been shown to be active in MM, but is compromised by the presence of the subclonal genetic variation typical of myeloma. Going forward, risk and biologically stratified therapy for MM looks to be a promising way of maintaining therapeutic progress, as does precision immunotherapy directed by the cellular context of the bone marrow.