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Key Points We conducted the first exome-wide association study between germ line variant genotype and survival outcomes after unrelated-donor BMT. A number of novel genes were found to significantly affect survival outcomes.

AbstractBackgroundPublished guidelines mandate complete device removal in cases of cardiovascular implantable electronic device (CIED) infection. Clinical predictors of successful salvage of infected CIEDs have not been defined.MethodsData from the Multicenter Electrophysiologic Device Infection Collaboration, a prospective, observational, multinational cohort study of CIED infection, were used to investigate whether clinical predictors of successful salvage of infected devices could be identified.ResultsOf 433 adult patients with CIED infections, 306 (71%) underwent immediate device explantation. Medical management with device retention and antimicrobial therapy was initially attempted in 127 patients (29%). “Early failure” of attempted salvage occurred in 74 patients (58%) who subsequently underwent device explantation during the index hospitalization. The remaining 53 patients (42%) in the attempted salvage group retained their CIED. Twenty‐six (49%) had resolution of CIED infection (successful salvage group) whereas 27 patients (51%) experienced “late” salvage failure. Upon comparing the salvage failure group, early and late (N = 101), to the group experiencing successful salvage of an infected CIED (N = 26), no clinical or laboratory predictors of successful salvage were identified. However, by univariate analysis, coagulase‐negative staphylococci as infecting pathogens (P = 0.0439) and the presence of a lead vegetation (P = 0.024) were associated with overall failed salvage.ConclusionsIn patients with definite CIED infections, clinical and laboratory variables cannot predict successful device salvage. Until new data are forthcoming, device explantation should remain a mandatory and early management intervention in patients with CIED infection in keeping with existing expert guidelines unless medical contraindications exist or patients refuse device removal.

Abstract Introduction:Pathogenic and/or founder germline variants in the ataxia-telangiectasia mutated (ATM) gene confer an increased breast cancer (BC) risk. The protein kinase ATM plays a central role inDNA double-strand break-repair and in the activation of downstream targets such as p53 and BRCA1. We sought to define the repertoire of somatic genetic alterations of BCs from patients with pathogenic germline ATM mutations and whether somatic loss of heterozygosity (LOH) of ATM would be present in these cancers. Methods: 21 BCs from ATM germline mutation carriers were microdissected. Tumor and normal DNA samples were subjected to whole-exome sequencing (WES, n=12) or massively parallel sequencing targeting all coding regions and selected intronic and regulatory regions of 410 key cancer genes (n=9). Somatic mutations, copy number alterations, cancer cell fractions, large-scale state transitions (LSTs) and mutational signatures were defined using state-of-the-art bioinformatics algorithms. ABSOLUTE and FACETS were employed to assess LOH of the wild-type allele of ATM. Results: Of the patients included in this study, 71%, 24% and 5% of cases harbored ATM missense (all but one p.V2424G), frame-shift and nonsense germline mutations, respectively. All tumors were ER-positive and four (19%) were HER2-positive. The median age of the patients was 46 years (32–79 years). Our analyses revealed biallelic inactivation of ATM through LOH of the wild-type allele in 16 of 21 cases (76%), and second somatic ATM mutations were not found. The median number of non-synonymous somatic mutations was 38 (range 15-113) and 2 (range 0-8)in tumors subjected to WES and targeted sequencing, respectively. The repertoire of somatic genetic alterations of ATM-associated BCs was found to be heterogeneous, including clonal PIK3CA mutations (24%), GATA3 mutations (19%), FANCI amplifications (19%) and CCND1 amplifications (14%). Importantly, however, no somatic mutations affecting TP53 were found. Analysis of the WES data revealed that 5 (42%) ATM-associated BCs displayed high LST scores, all of which harbored bi-allelic ATM inactivation. In contrast to BRCA1- and BRCA2-associated BCs, which frequently display the mutational signature 3 associated with defective homologous recombination DNA repair, the ATM-associated BCs studied displayed the ageing mutational signature (i.e. signature 1). Comparison of the mutational profiles of the ATM--associated BCs subjected to WES (n=12) with those of BRCA1- (n=11) and BRCA2-associated (n=10) BCs from The Cancer Genome Atlas revealed that TP53 was more frequently mutated in BCs from BRCA1 germline mutation carriers (0% vs 72%, P<0.001), while no differences with BRCA2-associated BCs were found. Conclusion: ATM-associated BCs frequently display bi-allelic ATM inactivation through LOH of the wild-type allele and a subset of these cases displayed high levels of LSTs. These findings suggest that at least in a subset of ATM-associated BCs, biallelic inactivation of ATM rather than a dominant negative effect of the germline mutation may be the mechanism of inactivation of this tumor suppressor gene. The repertoire of somatic genetic alterations of ATM-associated BCs is heterogeneous, with a noticeable lack of TP53 somatic mutations. Citation Format: Weigelt B, Bi R, Kumar R, James PA, Thorne H, Couch FJ, Eccles DM, Blows F, Geyer FC, Li A, Selenica P, Lim RS, Blecua P, Shen R, Wen H, Robson ME, Reis-Filho JS, Chenevix-Trench G. The landscape of somatic genetic alterations in breast cancers from ATM germline mutation carriers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-15.

Although brain natriuretic peptide (BNP) of myocardial origin is important in cardiovascular and renal function and as a marker of cardiac dysfunction, the expression of BNP in atrial and ventricular myocardium remains controversial both under normal conditions and in heart failure. We therefore determined left atrial and left ventricular (LV) gene expression and tissue concentration as well as circulating BNP during the evolution of rapid ventricular pacing-induced congestive heart failure (CHF) in the dog. Early LV dysfunction after 10 days of pacing was characterized by impaired LV function but maintained arterial pressure, and overt CHF after 38 days of pacing was characterized by further impaired LV function and decreased systemic arterial pressure. Under normal conditions, cardiac BNP mRNA and cardiac tissue BNP were of atrial origin. In early LV dysfunction, BNP mRNA and tissue BNP were markedly increased in the left atrium in association with an increase in circulating BNP but remained below or at the limit of detection in the LV. In overt CHF, BNP mRNA was further increased in the left atrium and first increased in the LV, together with an increase in LV tissue BNP and a further increase in circulating BNP. In the progression of CHF, early LV dysfunction is characterized by a selective increase in atrial BNP expression in association with increased circulating BNP. Overt CHF is characterized by an additional recruitment of ventricular BNP expression and a further increase in circulating BNP. These studies provide important new insight into the local and temporal regulation of cardiac BNP gene expression during the progression of heart failure and underscore the predominant endocrine role of atrial myocardium under normal conditions and in early LV dysfunction.

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP‐AP4B1), is due to bi‐allelic loss‐of‐function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP‐4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1‐associated SPG47, the majority born to non‐consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP‐4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non‐consanguineous populations, we believe that AP‐4 deficiency may be more common than previously appreciated.