The seasonal distribution of immune thrombotic thrombocytopenic purpura is influenced by geography: Epidemiologic findings from a multi-center analysis of 719 disease episodes.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

Challenges in the diagnosis of thrombotic thrombocytopenic purpura.

INTRODUCTION: Immune-mediated TTP (iTTP) is a rare condition without pathognomonic signs and symptoms. For this reason, the diagnosis of iTTP may be delayed or even missed, with potentially catastrophic consequences. AREAS COVERED: The authors performed an extensive literature review on the diagnosis of iTTP and its challenges combined with their own experience in a referral center for patients with iTTP. EXPERT OPINION: Although a definitive diagnosis of iTTP depends on the ADAMTS13 activity result, timely testing is rarely available at many centers to which patients present. If less complex tests were to become available, they would decrease the chances of late and/or missed diagnoses of iTTP throughout the world. While clinical scores to estimate the likelihood of iTTP exist, they are not well known, and can be misleading if used in the wrong context. Furthermore, the three scoring systems (PLASMIC, Bentley, and French) only moderately correlate with each other, which further complicates the landscape. The existence of these scores and how they should be used in practice is but one opportunity that can be seized through more robust programs to educate nonspecialist clinicians on how to recognize and treat patients with iTTP.

Effects of Improved DNA Integrity by Punch From Tissue Blocks as Compared to Pinpoint Extraction From Unstained Slides on Next-Generation Sequencing Quality Metrics.

OBJECTIVES: To compare the effects of two methods of formalin-fixed paraffin-embedded (FFPE) tissue harvesting on DNA quality and next-generation sequencing (NGS) quality metrics. METHODS: DNA integrity number (DIN) and NGS quality metrics resulting from DNA extraction and sequencing of 199 sequential samples harvested via the Pinpoint Slide DNA Isolation System and the punch method were compared. RESULTS: DNA extracted from FFPE tissue punches had higher DIN than that extracted from Pinpoint samples (mean ± SD, 6.18 ± 0.83 vs 5.09 ± 0.91; P < .0001), indicating less degradation. Lower DIN correlated with lower-quality metrics of NGS, that is lower percentage of unique on-target reads, average depth of coverage, and percentage of positions with coverage depth greater than or equal to 100×, 400×, and 1,000×. CONCLUSIONS: Our study demonstrated methods to harvest tissue from FFPE blocks may affect quality of DNA, which in turn has an effect on other NGS quality metrics.

Immunogenomics: using genomics to personalize cancer immunotherapy.

While the use of genomic data has the potential to revolutionize patient care, there is still much work to be done with regard to the transformation of host-tumor interactions into favorable clinical outcomes for our patients. High-throughput technologies, such as next-generation sequencing (NGS), have rapidly advanced our understanding of oncology, and we are learning that most tumors do not simply possess consistently mutated genes that are responsible for tumorigenesis, facilitating the need for personalized cancer therapy. A T cell-dependent mechanism of cancer progression was discovered in 2012, providing a potential link to cancer immunotherapy. Since then, an antibody against cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), ipilimumab, and three programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq), were approved by the Food and Drug Administration (FDA) in the USA. In this review article, based on evidence that has been emerging in the literature over the last decade, we will discuss the basis for including genomic data in immunotherapy regimens, the current progress in identifying biomarkers targetable by immune checkpoint blockade, and the application of these therapies in modern oncology programs. Going forward, the clinical application of NGS in personalized oncology programs could include dose monitoring and adjustment or the development of individualized vaccines or other personalized therapies based on the mutational landscape. The continued identification of new neoantigens and the efficient mobilization of tumor-reactive lymphocytes in patients with cancer will promote the advancement of immunotherapy using personalized NGS-guided technologies.

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura is primarily caused by the deficiency of plasma ADAMTS13 activity resulting from autoantibodies against ADAMTS13. However, ADAMTS13 deficiency alone is often not sufficient to cause acute thrombotic thrombocytopenic purpura. Infections or systemic inflammation may precede acute bursts of the disease, but the underlying mechanisms are not fully understood. Herein, 52 patients with acquired autoimmune thrombotic thrombocytopenic purpura and 30 blood donor controls were recruited for the study. The plasma levels of human neutrophil peptides 1-3 and complement activation fragments (i.e. Bb, iC3b, C4d, and sC5b-9) were determined by enzyme-linked immunosorbent assays. Univariate analyses were performed to determine the correlation between each biomarker and clinical outcomes. We found that the plasma levels of human neutrophil peptides 1-3 and Bb in patients with acute thrombotic thrombocytopenic purpura were significantly higher than those in the control (P<0.0001). The plasma levels of HNP1-3 correlated with the levels of plasma complement fragment Bb (rho=0.48, P=0.0004) and serum lactate dehydrogenase (rho=0.28, P=0.04); in addition, the plasma levels of Bb correlated with iC3b (rho=0.55, P<0.0001), sC5b-9 (rho=0.63, P<0.0001), serum creatinine (rho=0.42, p=0.0011), and lactate dehydrogenase (rho=0.40, P=0.0034), respectively. Moreover, the plasma levels of iC3b and sC5b-9 were correlated (rho=0.72, P<0.0001), despite no statistically significant difference of the two markers between thrombotic thrombocytopenic purpura patients and the control. We conclude that innate immunity, i.e. neutrophil and complement activation via the alternative pathway, may play a role in the pathogenesis of acute autoimmune thrombotic thrombocytopenic purpura, and a therapy targeted at these pathways may be considered in a subset of these patients.