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Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum., (© 2023 The Authors.)

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR, or MPL in >80% of the cases. PMF that lacks these canonical alterations is termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared with those of conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aimed to identify clinicopathologic and molecular genetic differences between patients with TN-PMF (n = 56) and DM-PMF (n = 89), all of whom fulfilled the 2016 World Health Organization diagnostic criteria for PMF. Compared with the control group, patients in the TN-PMF group were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow in patients with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted next-generation sequencing revealed a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 comutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Developments in genomics are profoundly influencing medical practice. With increasing use of genetic and genomic testing across every aspect of the health care continuum, patients and their families are increasingly turning to primary care physicians (PCPs) for discussion and advice regarding tests, implications, and results. Yet, with the rapid growth of information, technology, and applications, PCPs are finding it challenging to fill the gaps in knowledge and support the growing needs of their patients. A critical component in expanding PCP genomic literacy lies in the education of physicians in training and in practice. Although a framework for developing physician competencies in genomics has already been developed, the Association for Molecular Pathology is uniquely situated to actively utilize the skills of its members to engage and support PCPs in this effort. This report provides an overview and a suggested basic teaching framework, which can be used by molecular professionals in their individual institutions as a starting point for educational outreach., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In this review of megaloblastic anemia (MA), an overview of vitamin B 12 and folate body requirements, biochemical pathways, and laboratory testing strategies will be provided. However, the focus of this review is the classic and unique features of MA in blood and bone marrow. Acquired MA is a benign disorder for many, but can be detrimental for some. The clinical presentation can vary considerably, and the spectrum of symptoms and signs is diverse and quite broad. Prompt recognition and therapy are critical to prevent potential irreversible damage and clinical sequelae, especially in patients with vitamin B 12 deficiency. A delay in diagnosis of vitamin B 12 deficiency can result in significant neurologic sequelae that may not fully resolve with treatment, including in neonates and young infants. The blood and bone marrow features in MA can closely mimic thrombocytopenic purpura, myelodysplasia, and other myeloid neoplasms. Both pancytopenia and normal MCV at presentation are common in MA and raise unique challenges for the diagnostician. Partially treated MA is also a significant diagnostic "trap". MA is highly responsive to treatment, and patients tend to improve rapidly upon treatment initiation. However, the broad range of clinical and hematologic features makes the rapid, successful diagnosis of MA a unique challenge for the hematopathologist. Even in the era of state-of-the-art laboratory testing, a high suspicion is required., (© 2022 John Wiley & Sons Ltd.)

Background: Liquid based cytology (LBC) specimens are increasingly utilized for molecular analysis, as results are comparable to molecular analysis performed on traditional specimens (biopsy or cell block). However, there are few studies demonstrating the long-term viability of DNA in LBC samples., Methods: In this study, a 50-gene next generation sequencing (NGS) panel was performed on DNA isolated from post-centrifuged supernatant LBC samples of cases of non-small-cell lung carcinoma. Comparison was made to results of an identical NGS panel performed on a concurrent clinical sample (biopsy or cell block). Quality parameters including DNA concentration, total reads, amplicons with reads under 450 and 350, and variant allele fraction were also compared. For a subset of LBC samples, DNA was isolated after being held for varying extended lengths of time after collection (up to 41 days) at 5°C and results compared., Results: Results of NGS mutation analysis were concordant between LBC samples and clinical samples. DNA concentration was on average higher in the LBC samples compared to the clinical samples. The remaining metrics were more variable, but illustrated the adequacy of LBC samples for NGS testing. DNA isolated from LBC samples held for longer periods of time was of good concentration. NGS analysis was successfully performed on all samples, with concordance with results of clinical samples., Conclusion: DNA isolated directly from LBC fluid is suitable for NGS analysis. DNA is also stable in LBC preservative for extended periods of time before isolation and NGS analysis can subsequently be successfully performed., (© 2021 Wiley Periodicals LLC.)

Pathogenic New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS), a severe immunopathogenic disease in humans manifested by pulmonary edema and respiratory distress, with case fatality rates approaching 40%. High levels of inflammatory mediators are present in the lungs and systemic circulation of HCPS patients. Previous studies have provided insights into the pathophysiology of HCPS. However, the longitudinal correlations of innate and adaptive immune responses and disease outcomes remain unresolved. This study analyzed serial immune responses in 13 HCPS cases due to Sin Nombre orthohantavirus (SNV), with 11 severe cases requiring extracorporeal membrane oxygenation (ECMO) treatment and two mild cases. We measured viral load, levels of various cytokines, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1). We found significantly elevated levels of proinflammatory cytokines and PAI-1 in five end-stage cases. There was no difference between the expression of active uPA in survivors' and decedents' cases. However, total uPA in decedents' cases was significantly higher compared to survivors'. In some end-stage cases, uPA was refractory to PAI-1 inhibition as measured by zymography, where uPA and PAI-1 were strongly correlated to lymphocyte counts and IFN-γ. We also found bacterial co-infection influencing the etiology and outcome of immune response in two cases. Unsupervised Principal Component Analysis and hierarchical cluster analyses resolved separate waves of correlated immune mediators expressed in one case patient due to a sequential co-infection of bacteria and SNV. Overall, a robust proinflammatory immune response, characterized by an imbalance in T helper 17 (Th17) and regulatory T-cells (Treg) subsets, was correlated with dysregulated inflammation and mortality. Our sample size is small; however, the core differences correlated to survivors and end-stage HCPS are instructive.

The human leukocyte antigen (HLA) system is a highly polymorphic family of genes involved in immunity and responsible for identifying self versus non-self. HLA typing is essential for solid organ and bone marrow transplantation as well as in non-transplant settings such as disease association and pharmacogenomics. Typing of HLA genes differs from most molecular testing as, rather than evaluating differences from an accepted "wild-type" gene, it must distinguish between thousands of similar, but distinct alleles. This article will describe the HLA system and nomenclature. We will then discuss clinical uses of HLA typing including solid organ transplantation, hematopoietic stem cell transplantation, evaluation of platelet refractory patients, disease association, and pharmacogenetics. Finally, we describe common molecular methods of HLA typing.

Objectives: We report on the validity of a fully quantitative technology to determine tumor cells' PD-L1 expression compared with a standard immunohistochemical (IHC) assay in non-small cell lung cancer., Methods: Nineteen fresh tissue specimens were processed into single-cell suspensions using the IncellPREP Kit. Cells were treated with the OncoTect iO Lung Assay, which quantitatively assessed tumor-infiltrating lymphocytes (TILs), DNA content, and PD-L1 expression on diploid and aneuploid tumor populations., Results: Comparison of the OncoTect iO Lung Assay with IHC revealed a concordance of 95% overall (negative percent agreement, 97%; positive percent agreement, 89%). PD-L1 expression varied depending on the DNA content. The number of TILs and antigen-presenting cells (APCs) was significantly decreased in tumor compared with normal lung tissue., Conclusions: The nonsubjective OncoTect iO Lung Assay has been shown to be at least as accurate and sensitive as IHC for the detection of PD-L1 expression while providing additional information to guide treatment.

Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) largely defined morphologically. It is, unclear, however, whether aCML-associated features are distinctive enough to allow its separation from unclassifiable MDS/MPN (MDS/MPN-U). To study these 2 rare entities, 134 patient archives were collected from 7 large medical centers, of which 65 (49%) cases were further classified as aCML and the remaining 69 (51%) as MDS/MPN-U. Distinctively, aCML was associated with many adverse features and an inferior overall survival (12.4 vs 21.8 months, P = .004) and AML-free survival (11.2 vs 18.9 months, P = .003). The aCML defining features of leukocytosis and circulating myeloid precursors, but not dysgranulopoiesis, were independent negative predictors. Other factors, such as lactate dehydrogenase, circulating myeloblasts, platelets, and cytogenetics could further stratify MDS/MPN-U but not aCML patient risks. aCML appeared to have more mutated RAS (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]), but was not statistically significant. Somatic CSF3R T618I (0/54) and CALR (0/30) mutations were not detected either in aCML or MDS/MPN-U. In conclusion, within MDS/MPN, the World Health Organization 2008 criteria for aCML identify a subgroup of patients with features clearly distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters.