The new lymphotropic herpesviruses (HHV-6, HHV-7, HHV-8) and hepatitis C virus (HCV) in human lymphoproliferative diseases: An overview

Considerable evidence has been accumulating in favor of a possible involvement of viral agents in the pathogenesis of human lymphomas. The most recent proposal for a lymphoma classification, the Revised European-American Classification, emphasized for the first time the pathogenetic importance of two viruses, namely Epstein-Barr virus (EBV) and human T lymphotropic virus I (HTLV-I) in the development of certain lymphoid neoplasias. However, in the last ten years new viral agents possibly related to lymphoproliferative activity have been discovered: three herpesviruses [human herpesvirus-6 (HHV-6), -7 (HHV-7) and -8 (HHV-8)] and a flavivirus, HCV. HHV-6 was isolated from the peripheral blood of patients with lymphomas and a possible role for this beta-herpesvirus in Hodgkin's disease and in angioimmunoblastic lymphadenopathy (AILD) has emerged from serological and molecular studies. HHV-7, a beta-herpesvirus genetically close to HHV-6, has not yet been found in a human disease but it utilizes CD4 as a receptor on the lymphocyte surface. Only partial HHV-8 genomic sequences have been identified so far, suggesting a genetic homology with members of the gamma-herpesvirus family, including EBV. HHV-8 sequences have been identified for the first time in all forms of Kaposi's sarcoma as well as in a variety of lymphoid disorders, including body-cavity-based non Hodgkin's lymphomas, Castleman's disease, AILD and a type of HIV-negative reactive lymphadenopathy with peculiar histologic features. Finally, after its identification as the major cause of post-transfusion and sporadic non-A, non-B hepatitis, HCV has revealed a lymphotropism both in vitro and in vivo. A strong association between HCV infection and a benign lymphoproliferative disease, essential mixed cryoglobulinemia type II, has clearly emerged both from serological and molecular studies. A possible role for this viral infection in B-cell non Hodgkin's lymphomas not associated with cryoglobulinemia has also been proposed recently. The present work offers an overview of the huge amount of experimental and clinical observations supporting the possible involvement of these new lymphotropic viruses in human lymphoproliferative diseases

From gating to computational flow cytometry: Exploiting artificial intelligence for MRD diagnostics

The era of AI-based methods to improve flow cytometry diagnostics in haematology is now at the beginning. The study by Nguyen and colleagues explored an emerging machine learning approach to assess phenotypic MRD in chronic lymphocytic leukaemia patients, showing that such AI-driven computational analysis may represent a robust and feasible tool for advanced diagnostics of haematological malignancies.Commentary on: Nguyen et al. Computational flow cytometry provides accurate assessment of measurable residual disease in chronic lymphocytic leukaemia. Br J Haematol 2023 (Online ahead of print). doi

Philadelphia chromosome-positive acute lymphoblastic leukemia

Philadelphia chromosome-positive Acute Lymphoblastic Leukemi

Words hurt: common and distinct neural substrates underlying nociceptive and semantic pain

Introduction: Recent studies have shown that processing semantic pain, such as words associated with physical pain, modulates pain perception and enhances activity in regions of the pain matrix. A direct comparison between activations due to noxious stimulation and processing of words conveying physical pain may clarify whether and to what extent the neural substrates of nociceptive pain are shared by semantic pain. Pain is triggered also by experiences of social exclusion, rejection or loss of significant others (the so-called social pain), therefore words expressing social pain may modulate pain perception similarly to what happens with words associated with physical pain. This event-related fMRI study aims to compare the brain activity related to perceiving nociceptive pain and that emerging from processing semantic pain, i.e., words related to either physical or social pain, in order to identify common and distinct neural substrates. Methods: Thirty-four healthy women underwent two fMRI sessions each. In the Semantic session, participants were presented with positive words, negative pain-unrelated words, physical pain-related words, and social pain-related words. In the Nociceptive session, participants received cutaneous mechanical stimulations that could be either painful or not. During both sessions, participants were asked to rate the unpleasantness of each stimulus. Linguistic stimuli were also rated in terms of valence, arousal, pain relatedness, and pain intensity, immediately after the Semantic session. Results: In the Nociceptive session, the 'nociceptive stimuli' vs. 'non-nociceptive stimuli' contrast revealed extensive activations in SI, SII, insula, cingulate cortex, thalamus, and dorsolateral prefrontal cortex. In the Semantic session, words associated with social pain, compared to negative pain-unrelated words, showed increased activity in most of the same areas, whereas words associated with physical pain, compared to negative pain-unrelated words, only activated the left supramarginal gyrus and partly the postcentral gyrus. Discussion: Our results confirm that semantic pain partly shares the neural substrates of nociceptive pain. Specifically, social pain-related words activate a wide network of regions, mostly overlapping with those pertaining to the affective-motivational aspects of nociception, whereas physical pain-related words overlap with a small cluster including regions related to the sensory-discriminative aspects of nociception. However, most regions of overlap are differentially activated in different conditions

Lymphoproliferative syndromes associated with human herpesvirus-6A and human herpesvirus-6B

Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) have been noted since their discovery for their T-lymphotropism. Although it has proven difficult to determine the extent to which HHV-6A and HHV-6B are involved in the pathogenesis of many diseases, evidence suggests that primary infection and reactivation of both viruses may induce or contribute to the progression of several lymphoproliferative disorders, ranging from benign to malignant and including infectious mononucleosis-like illness, drug induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), and nodular sclerosis Hodgkin's lymphoma. Herein, we discuss the conditions associated with the lymphoproliferative capacity of HHV-6, as well as the potential mechanisms behind them. Continued exploration on this topic may add to our understanding of the interactions between HHV-6 and the immune system and may open the doors to more accurate diagnosis and treatment of certain lymphoproliferative disorders

Cytarabine-related lung infiltrates on high resolution computerized tomography: a possible complication with benign outcome in leukemic patients.

Potentially fatal lung toxicity occurs in 12-20% of leukemic patients treated with cytarabine especially at intermediate to high doses, usually presenting as noncardiogenic pulmonary edema (NCPE). Anecdotally the association between cytarabine and the onset of bronchiolitis obliterans organizing pneumonia (BOOP) has been reported. We describe here three cases of patients affected by acute myeloid leukemia (AML) treated with chemotherapeutic regimens including high dose cytarabine, who developed early onset of fever, mild dyspnea, moderate hypoxemia on arterial blood gas analysis and lung infiltrates documented by high-resolution computerized tomography (HRCT), with a more indolent behaviour and a benign clinical outcome, compared with similar cases previously reported in the literature. Our cases widen the spectrum of clinical features of cytarabine-related toxicity in leukemic patients

A typical atypical chronic myeloid leukemia

Key Clinical MessageIn the context of leukocytosis due to increased number of neutrophils and their precursors, with significant dysgranulopoiesis and no or minimal basophilia and no or minimal monocytosis, the typical feature of "clumped" chromatin, in irregularly coarse compacted nuclei, should lead to suspect the diagnosis of atypical chronic myeloid leukemia

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients

Novel agents for acute myeloid leukemia

Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is \u201c3 + 7\u201d regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors\u2019 opinion