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Amy M Trottier, Sonia Cerquozzi, Carolyn J Owen Division of Hematology and Hematological Malignancies, University of Calgary, Foothills Medical Centre, Calgary, AB, Canada Abstract: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare CD4+ CD56+ myeloid malignancy that is challenging to diagnose and treat. BPDCN typically presents with nonspecific cutaneous lesions with or without extra-cutaneous manifestations before progressing to leukemia. Currently, there is no standard of care for the treatment of BPDCN and various approaches have been used including acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma-based regimens with or without stem cell transplantation. Despite these treatment approaches, the prognosis of BPDCN remains poor and there is a lack of prospective data upon which to base treatment decisions. Recent work examining the mutational landscape and gene expression profiles of BPDCN has identified a number of potential therapeutic targets. One such target is CD123, the α subunit of the human interleukin-3 receptor, which is the subject of intervention studies using the novel agent SL-401. Other investigational therapies include UCART123, T-cell immunotherapy, and venetoclax. Prospective trials are needed to determine the best treatment for this uncommon and aggressive neoplasm. Keywords: BPDCN, myeloid, neoplasm, cutaneous, dendritic cell

Background and Objectives: To investigate in a cross-sectional study the determinants of oral human papillomavirus infection in 287 individuals who are sexually active.Goal: To assess prevalence as well as risk factors for oral human papillomavirus infection.Study Design: One hundred seventy-eight human immunodeficiency virus-seropositive (158 men and 20 women) and 109 human immunodeficiency virus-negative (73 men and 36 women) individuals were recruited consecutively from sexually transmitted disease-human immunodeficiency virus clinics and gastrointestinal endoscopy clinics. Oral brushings were tested with the L1 consensus polymerase chain reaction assay for human papillomavirus detection.Results: Human papillomavirus DNA was detected in 32 (11.2%) of 287 individuals. Associated with oral human papillomavirus infection on univariate analyses were human immunodeficiency virus infection (odds ratio, 6.9; 95% confidence interval, 2.0-23.2), homosexuality (odds ratio, 3.7; 95% confidence interval, 1.5-9.4), unprotected oral sex (odds ratio, 5.5; 95% confidence interval, 1.6-18.4), syphilis (odds ratio, 2.5; 95% confidence interval, 1.1-6.3), gonorrhea (odds ratio, 4.2; 95% confidence interval, 1.9-9.1), Chlamydia trachomatis (odds ratio, 4.4; 95% confidence interval, 1.8-10.6), and genital herpes (odds ratio, 2.9; 95% confidence interval, 1.3-6.5). Human immunodeficiency virus infection and C. trachomatis were independently predictive of human papillomavirus infection in multivariate stepwise logistic regression. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDSs) treatment focuses on improving quality of life (QOL), affected by anemia and transfusion dependence (TD). Using the MDS-CAN registry, we studied how changes in transfusion status - TD to transfusion independence (TI) (group A), or vice versa (group B), and maintaining TD (group C) or TI (group D) - affected OS and QOL in 1120 MDS patients. Analysis showed superior OS for those remaining TI, poorer for those remaining TD, and intermediate for those with changes. Among 656 treated patients, group A ( n  = 54) showed improved QOL, with trends toward improved physical and social function scores. Group B ( n  = 151) experienced declines in global QOL measures after switching to TD, particularly in fatigue and physical, role, and social functioning. Group C had notable fatigue worsening, while group D showed milder declines across multiple QOL aspects. Achieving TI in MDS correlates with improved QOL, whereas reverting to TD more significantly worsens overall QOL and function scores.

Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Acute myeloid leukemia with germline CEBPA mutation is a subtype of acute myeloid leukemia that is associated with a favorable prognosis. Most of the reported cases of acute myeloid leukemia with CEBPA germline variants involve a germline variant in the N-terminus and a somatic variant in the C-terminus. There are only a few reported cases where the CEBPA germline variant has been identified in the C-terminus and the somatic variant in the N-terminus. This case report and review of the literature illustrates that, although acute myeloid leukemia with CEBPA N- or C-terminal germline variants have certain similarities such as atypically young age at diagnosis, frequent relapse, and favourable overall prognosis, there are also significant differences such as lower life-time penetrance of acute myeloid leukemia and shorter time to relapse for germline C-terminal cases. These findings add important information on the natural history and clinical outcomes of acute myeloid leukemia with germline CEBPA C-terminal variants and these findings should be considered in the management of patients and their family members., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis., (© 2022 by The American Society of Hematology.)

Inherited predisposition to haematopoietic malignancies, due to deleterious germline variants in a variety of genes, is an important clinical entity with implications for the health and management of patients and their family members. Unfortunately, there remain several common misconceptions in this field that can result in patients going unrecognised and/or having incomplete or improper testing including: the impression that inherited haematological malignancy syndromes are rare, that myeloid and lymphoid malignancy predisposition syndromes are mutually exclusive, and that solid tumour predisposition syndromes are unique and distinct from haematopoietic malignancy predisposition syndromes. In the present review, we challenge these ideas with our insights into germline genetic testing for these conditions with the hope that increased awareness and knowledge will overcome barriers and lead to improved diagnosis and management., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Colony-stimulating factor 3 receptor (CSF3R) encodes the receptor for granulocyte colony-stimulating factor (G-CSF), a cytokine vital for granulocyte proliferation and differentiation. Acquired activating heterozygous variants in CSF3R are the main cause of chronic neutrophilic leukemia, a hyperproliferative disorder. In contrast, biallelic germ line hypomorphic variants in CSF3R are a rare cause of severe congenital neutropenia, a hypoproliferative condition. The impact of heterozygous germ line CSF3R variants, however, is unknown. We identified CSF3R as a new germ line hematologic malignancy predisposition gene through analysis of 832 next-generation sequencing tests conducted in 632 patients with hematologic malignancies. Among germ line CSF3R variants, 3 were abnormal in functional testing, indicating their deleterious nature. p.Trp547* was identified in 2 unrelated men with myelodysplastic syndromes diagnosed at 76 and 33 years of age, respectively. p.Trp547* is a loss-of-function nonsense variant in the extracellular domain that results in decreased CSF3R messenger RNA expression and abrogation of CSF3R surface expression and proliferative responses to G-CSF. p.Ala119Thr is a missense variant found in 2 patients with multiple myeloma and acute lymphoblastic leukemia, respectively. This variant is located between the extracellular immunoglobulin-like and cytokine receptor homology domains and results in decreased G-CSF sensitivity. p.Pro784Thr was identified in a 67-year-old man with multiple myeloma. p.Pro784Thr is a missense variant in the cytoplasmic domain that inhibits CSF3R internalization, producing a gain-of-function phenotype and G-CSF hypersensitivity. Our findings identify germ line heterozygous CSF3R variants as risk factors for development of myeloid and lymphoid malignancies., (© 2020 by The American Society of Hematology.)

With improvements in DNA sequencing technologies and the consequent reduction in costs, next generation sequencing is being utilized increasingly in panel-based testing to perform molecular profiling of tumors. Such tumor-based panels are often referred to as 'somatic' panels, but this term is misleading and should not be used, since not all DNA variants within a tumor are somatic in nature. Every cell in a person's body contains that person's germline DNA, including tumor cells. Moreover, tumor samples are invariably contaminated with blood, a tissue that can contain somatic mutations itself in a process now called clonal hematopoiesis. Differentiating between germline variants or tumor-associated somatic mutations versus clonal hematopoiesis can be challenging. In this review, we address how to interpret the results of somatic mutation panels, how to differentiate between germline and truly somatic events, and discuss the importance of this distinction., (Copyright © 2019. Published by Elsevier Inc.)

The presence of human papillomavirus (HPV) DNA in esophageal brushings from human immunodeficiency virus (HIV)-seropositive hosts was investigated in a cross-sectional study. Oral and esophageal brushings from individuals scheduled for esophagogastroscopy (53 HIV-positive and 61 age-matched HIV-negative patients) were tested for the presence of HPV DNA by a consensus L1 polymerase chain reaction assay. HPV DNA was detected in esophageal brushings of 9 (17%) of the 53 HIV-seropositive patients and 0 of the 61 HIV-negative individuals. HPV-16 DNA was the most frequently detected. No proliferative mucosal lesion was noted in individuals with HPV-positive esophageal brushings. Cytological smears were done for 6 of the 9 patients with HPV-positive esophageal brushings, and epithelial atypia was recorded for 1. HIV infection and a history of genital herpes were strong independent predictors of HPV, suggesting that HPV is transmitted sexually in the esophagus.

The role of human papillomaviruses (HPVs) in ovarian epithelium (either normal or neoplastic) remains controversial. We have investigated by PCR the presence of HPV DNA in fresh tissue from ovarian neoplasms and in primary cell cultures established from either normal, benign or malignant ovarian surface epithelia. None of the fresh samples and primary ovarian cultures contained HPV DNA sequences.