Detecting the "undetectable" alterations: Use of NGS to uncover high-risk alterations.

Copy number variants are common in patients with myeloid malignancies and may confer diagnostic, prognostic or therapeutic relevance. However, detection of these variants may require multiple testing modalities, which may not be available or ordered on all cases. We present a case that highlights the efficacy of copy number analysis by next generation sequencing to identify clinically relevant variants that may otherwise be missed by conventional cytogenetics and typical florescent in situ hybridization panels.

Diagnosing heparin-induced thrombocytopenia in mechanical circulatory support device patients.

BACKGROUND: Mechanical circulatory support device (MCSD) patients with positive heparin-induced thrombocytopenia (HIT) screening pose a unique challenge, as clinicians must make rapid decisions about their anticoagulation and whether they can safely undergo cardiopulmonary bypass. We identified screening practices at our institution and other institutions nationwide that differed from American Society of Hematology (ASH) guidelines. This discovery prompted a data review to confirm the applicability of guidelines to this unique population and to highlight complications of "gestalt" screening. METHODS: Our study included MCSD patients with HIT testing from April 2014 to August 2020. We evaluated 510 PF4 IgG ELISA results. RESULTS: HIT was confirmed in 4.2% of patients. There was an increased prevalence of HIT in patients with nondurable (5.3%) vs durable devices (2.9%) or those in the preimplantation setting (1.3%), however this difference was not statistically significant (p = 0.26). None of the patients with a low probability 4T Score had HIT. All patients with a high probability 4T Score and PF4 immunoassay OD >2.0 had HIT. False positive results occurred in 22% of assays ordered for patients with a low probability 4T Score. Twelve patients with a low probability 4T Score and a false positive immunoassay were switched to a direct thrombin inhibitor (DTI) while awaiting confirmatory results. Two patients experienced clinically significant bleeding after conversion to a DTI. An organ was refused in one patient with false positive HIT screening. CONCLUSIONS: Our findings demonstrate that an opportunity exists to improve clinical outcomes by re-emphasizing the utility of established guidelines and highlighting their safe use in the MCSD patient population.

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Altered type 1 interferon responses in alloimmunized and nonalloimmunized patients with sickle cell disease.

Patients with sickle cell disease (SCD) have a high prevalence of RBC alloimmunization. However, underlying mechanisms are poorly understood. Given that proinflammatory type 1 interferons (IFNα/ß) and interferon stimulated genes (ISGs) promote alloimmunization in mice, we hypothesized that IFNα/ß may contribute to the increased frequency of alloimmunization in patients with SCD. To investigate this, expression of ISGs in blood leukocytes and peripheral blood mononuclear cells (PBMCs) of previously transfused SCD patients with or without alloimmunization and race-matched healthy controls were quantified, and IFNα/ß gene scores were calculated. IFNα/ß gene scores of SCD leukocytes and plasma cytokines were elevated, compared to controls (gene score, p < 0.01). Upon stimulation with IFNß, isolated PBMCs from patients with SCD had elevated ISGs and IFNα/ß gene scores (p < 0.05), compared to stimulated PBMCs from controls. However, IFNß-stimulated and unstimulated ISG expression did not significantly differ between alloimmunized and non-alloimmunized patients. These findings indicate that patients with SCD express an IFNα/ß gene signature, and larger studies are needed to fully determine its role in alloimmunization. Further, illustration of altered IFNα/ß responses in SCD has potential implications for IFNα/ß-mediated viral immunity, responses to IFNα/ß-based therapies, and other sequelae of SCD.

Core needle biopsy is a safe and accurate initial diagnostic procedure for suspected lymphoma.

BACKGROUND: Excisional biopsy is currently recommended for the analysis of lymphadenopathy suspicious for lymphoma. This study aims to evaluate the efficacy and safety of image-guided core needle biopsy (IGCNB) for the diagnosis of lymphoma using a standard protocol for tissue acquisition and analysis. METHODS: All IGCNBs from 2008 to 2014 performed under the study protocol were included in analysis. Demographics, pathology results, additional studies, and follow-up information were recorded. RESULTS: Seventy-three IGCNBs were performed in 71 consecutive patients. Lymphoma was diagnosed in 37 patients (51%). All 37 patients (100%) were subtyped and treated based on IGCNB results. The remaining 36 IGCNBs in 34 patients did not have subsequent diagnosis of lymphoma in a mean follow-up of 15 months (range, 0 to 54 months). There were no complications. CONCLUSIONS: IGCNB performed under a standard protocol is effective and safe and should be considered as an initial diagnostic tool for the evaluation of lymphadenopathy suspicious for lymphoma.