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Epstein-Barr virus (EBV) is associated with hematologic and solid tumors. In this study, we utilized a hybridization capture-based next generation sequencing (NGS) platform that targets 400 genes associated with hematological malignancies to detect and quantify non-targeted viral-derived EBV reads that aligned to the EBV reference contig (NC_007605). We evaluated 5,234 samples from 3,636 unique patients with hematological neoplasms and found that 100 samples (1.9%) in 93 unique patients had ≥ 6 EBV reads (range, 6-32,325; mean, 827.5; median, 54). The majority (n=73, 73%) represented known EBV-associated conditions, and the most common was post-transplant lymphoproliferative disorders (n=21, 29%). Documented EBV viremia accounted for a moderate quantity of EBV reads in 4/27 samples corresponding to conditions not known to be EBV-associated, while suspected viremia or low-level activation was likely the etiology in the remaining 23 samples. A good correlation (Spearman r=0.8, 95% CI 0.74-0.85) was found between EBV reads by NGS and systematic semi-quantitative EBER ISH assessment in 162 available samples, particularly at higher level of EBV-involvement. An optimal threshold for significant morphologic EBV-involvement was found to be ≥10 reads by the receiver operating characteristic (ROC) analysis (AUC 0.990 and 95% CI 0.9974-1.000%). Thus, in addition to mutational analysis, hybrid-capture-based NGS panels can be used to detect and quantitate off-target EBV-derived viral DNA, which correlates well with morphology.

Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross-sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies. Resumo As neoplasias hematológicas e de células hematopoiéticas dos genes e as células hematopoiéticas estão associadas à mutação genética, geralmente em nível cromossômico. O estudo citogenético padrão é amplamente aceito como um dos principais determinantes diagnósticos e prognósticos em pacientes. Portanto, o presente estudo descritivo e transversal buscou determinar a análise citogenética de neoplasias hematológicas frequentes no Paquistão. Um total de 202 amostras de medula óssea periférica ou sangue de pacientes com malignidade hematológica benigna e maligna foi coletado usando uma técnica convencional de banda G. Entre os pacientes inscritos, a média de idade foi de 21,5 anos ± 23,4, e a distribuição por gênero mostrou uma marcada predominância da população masculina de 147 (73%) em comparação com a feminina de 55 (27%). Pacientes na faixa etária (2-10 anos) tiveram a maior frequência, 48 (24%), de neoplasias hematológicas, seguida da idade (11-20 anos) com 40 (20%). Cariótipos normais (46, XX / 46, XY) foram encontrados em 51% (n = 103) dos pacientes. Além disso, a frequência de cariótipo complexo foi de 30 (15%), enquanto normal foi observada em 171 (85%) pacientes. Leucemia linfoblástica aguda pré-B (LLA Pré-B) foi a doença maligna mais prevalente de 66 (33%), seguida por leucemia mieloide crônica (LMC) de 41 (20%) e leucemia linfocítica aguda de 29 (14%). A translocação foi o 50 mais prevalente (25%), seguido por hipotriploidia 14 (7%) e monossomia 8 (4%) na análise de aberração cromossômica. Além disso, a translocação t (9:22) encontrada foi de 20 (10%) na LMC, com a maioria na faixa etária (31-40 anos). Este estudo recomenda que o cariótipo deve ser testado com frequência em condições hematológicas porque pode fornecer informações sobre as alterações cromossômicas relativas associadas a doenças malignas específicas.

Key Points Comparison of the mutation frequencies and numbers of 122 genes in 3096 cases enables identification of “mutation-driven” entities.Differences in mutation patterns in cases with or without CHIP-associated mutations across entities suggest differences in pathophysiology., Visual Abstract, Acquired somatic mutations are crucial for the development of most cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation with CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases of 28 different hematological malignancies. Differences were observed regarding (1) the median number of mutations (highest, median n = 4; lowest, n = 0); (2) specificity of certain mutations (high frequencies in atypical chronic myeloid leukemia [aCML; ASXL1, 86%], follicular lymphoma [FL; KMT2D, 87%; CREBBP, 73%], hairy cell lymphoma [BRAF, 100%], lymphoplasmacytic lymphoma [MYD88, 98%; CXCR4, 51%], myeloproliferative neoplasm [MPN; AK2, 68%]); (3) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage for TET2, ASXL1, DNMT3A, TP53, BCOR, and ETV6); (4) correlation of mutations with patient’s age (correlated with older age across entities: TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, and IDH2; younger age: KIT, POT1, RAD21, U2AF2, and WT1); (5) correlation of mutation number per patient with age. Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, and EZH2 in cases comprising at least 1 DTA (DNMT3A, TET2, ASXL1) mutation, whereas in cases without DTA mutations, TP53, KRAS, WT1, and SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (myelodysplastic syndrome/MPN overlap; secondary acute myeloid) in comparison with entities defined by chromosomal fusions (chronic myeloid leukemia; myeloid/lymphoid neoplasm with eosinophilia).

Background Multiple myeloma (MM) is one of the most common hematological neoplasms and accounts for approximately 1% of human cancers. Objectives Description of current diagnostics and classification of MM and related plasma cell neoplasms from the pathology viewpoint. Materials and methods Current knowledge regarding pathology and genetics of MM is summarized and tissue-based diagnostics following international consensus classifications and the current S3 guideline are described. Results MM and related neoplasms are composed of malignant plasma cells that secrete a monoclonal immunoglobulin, which is an important parameter of disease activity. MM shows a multistage development. Almost all cases are preceded by a clinically inapparent precursor lesion, monoclonal gammopathy of undetermined significance (MGUS), which can progress to smoldering myeloma with a higher tumor burden, but absence of organ damage. Systemic MM needs to be discerned from the localized forms, solitary osseous and primary extramedullary plasmacytoma. MM is genetically very heterogeneous and can be broadly subdivided into two cytogenetic groups, cases with primary IGH translocations and cases with hyperdiploidy. Intratumoral genetic heterogeneity is frequently pronounced and correlates with the size of focal lesions in imaging. Conclusions Diagnosis of plasma cell neoplasms is done according to the criteria of the International Myeloma Working Group (IWMG) and requires interdisciplinary evaluation of clinical, serological, pathological and radiological features. In addition to clinical parameters, molecular markers, especially cytogenetic aberrations, are of great prognostic relevance.

Pediatric HIV is a significant contributor to childhood morbidity and mortality. As HIV infects bone marrow CD34-positive progenitor cells, the hematological abnormalities are well-expected. The viral load is much higher in children predisposing them to opportunistic infections and hematopoietic malignancies. The present study aimed to determine the spectrum of hematological abnormalities that may yield clinically useful information in HIV-infected children. This was a retrospective study of 19 HIV-infected children who underwent bone marrow examination. Overall, 20 peripheral blood and bone marrow samples were analyzed for morphological changes in all hematopoietic lineages. Immunohistochemistry was performed on trephine biopsy sections for evaluation of B and T cells and cytomegalovirus inclusions. Anemia was the most common cytopenia (95%), followed by thrombocytopenia (45%) and leukopenia (40%). Myelodysplasia was noted in 70% of cases. Dysmegakaryopoiesis was predominant in 65% of cases, while dyserythropoiesis was noted in 25% of cases. Hemophagocytosis and reactive cellular changes were noted in 20% of cases each. Benign lymphoid aggregates and granulomatous inflammation were observed in 15% and 10% of cases, respectively. Significant myelofibrosis was found in 35% of cases. One case showed infiltration by Burkitt lymphoma. Parvoviral inclusions were identified in 1 case. An interstitial increase and aggregates of CD8 + T cells and reduced CD4 + T cells were noted. CD20 + B cells were normal to mildly increased in the bone marrow. Bone marrow examination provides clinically significant information in pediatric HIV revealing the underlying cause of hematopoietic abnormalities and allows the exclusion of major hematological neoplasms.

El Síndrome Mielodisplásico (SMD) es un grupo de neoplasias hematológicas cuyo diagnóstico se basa en la presencia de citopenia inexplicada, displasia de alguna de las líneas mieloides y anormalidades citogenéticas típicas. Los estudios moleculares han permitido avanzar en el estudio de la fisiopatología y se han incorporado también al abordaje diagnóstico, permitiendo la clasificación en subtipos específicos, así como la predicción de respuesta a terapias específicas y el pronóstico. A pesar de esto, el diagnóstico aún recae en una adecuada historia clínica, en el análisis morfológico, en la exclusión de otras entidades que cursan con displasia y en los estudios de citogenética. La citometría de flujo no hace parte de los criterios diagnósticos, pero puede ser de utilidad en casos dudosos. El pronóstico es variable en función del subtipo pero, en general, es pobre y además del IPSS-R, se han identificado otras variables que inciden en el pronóstico, sobre todo en los casos asociados a terapia.

This study aimed to compare the detection performance of [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the patients with various oncological and non-oncological lesions. A total of 123 patients underwent contemporaneous [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT were included in this prospective study. The maximum standard uptake value (SUVmax) was measured to compare oncological and non-oncological lesion uptake. The sensitivity, specificity, predictive values, and accuracy of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT for detecting primary, metastatic, and non-oncological lesions were calculated and compared to evaluate the detection efficacy. The study subjects consisted of 123 patients (69 men and 54 women; mean age 56.11 ± 11.94 years). Among the 102 patients with either newly diagnosed (82 patients) or previously treated solid tumor (20 patients), a total of 88 solid primary malignant tumors in 84/102 patients were detected. Two patients had two primary tumors each and 1 patient had three primary tumors. Among them, 58/102 and 43/102 patients had nodal (376 lesions) and distant metastases (406 lesions), respectively. Eight patients had hematological neoplasm. No malignant oncological diseases were detected in the remaining 13 patients. A total of 145 non-oncological lesions and benign tumors in 52/123 patients were detected incidentally. [68 Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a significantly higher uptake and detection rate for the primary (SUVmax 10.98 ± 5.83 vs. 8.36 ± 6.43, p

In recent years, genome-based classifications for hematological neoplasms have been proposed successively and proved to be more accurate than histologic classifications. However, some previous studies have reported the racial differences of genetic landscape in persons with hematological neoplasms including myelodysplastic syndromes (MDS), which may cause a genomic classification based on a particular ethnic group does not operate in other races. To determine whether race plays an important role in the genomic-based classification, we validated a newly proposed genomic classification of MDS (J Clin Oncol.2021; JCO2001659), which was based on a large European database, in Chinese patients from our center. Our results showed significant differences between Chinese and European patients including proportion of each group to overall cohort when applying this novel genomic classification. Our data indicate that a genomic classification of hematological neoplasms probably should be revised according to specific genetic features in different races.

Background Myeloid sarcoma (MS) is a very rare condition, develops both in patients with other hematological neoplasms, and as isolated tumor. MS of the gynecologic tract is extremely rare. An available literature data about diagnosis and management of MS is summarized in the article. The role of chemotherapy, radiation therapy, surgery and bone marrow transplantation in the treatment is discussed. Polychemotherapy and allogeneic bone marrow transplantation were suggested to be the optimal treatment strategy of MS of the gynecological tract. The use of new targeted agents results in promising clinical data. Case presentation We are presenting a rare clinical case of a MS of the uterine cervix with concomitant bone marrow involvement and describe all the peculiarities of the clinical course, diagnosis, and treatment. The patient received chemotherapy followed by allogeneic bone marrow transplantation. The pre-transplant therapy allowed us to perform allogeneic bone marrow transplantation with the deepest response possible: complete PET-negative and MRD-negative remission of the disease. Conclusions MS remains a subject of discussion regarding its diagnostic and therapeutic aspects. The use of novel targeting agents can be perspective option for patient with extramedullary disease.

The tumors that induce autoimmune hemolytic anemia (AIHA) are usually hematological neoplasms such as malignant lymphoma and chronic lymphocytic leukemia. AIHA associated with germ cell tumors is very rare with literature limited to case reports with most of them reported with ovarian dermoid, which abated with the removal of the tumor. We report an unusual presentation of AIHA with malignant sacrococcygeal germ cell tumor in a 3-year-old child, which rapidly disappeared after the excision of a sacrococcygeal teratoma.

Lymphatic filariasis is a vector borne infection classified under the WHO category of Neglected Tropical Disease (NTD). It is a major public health concern globally. This study describes this vector-borne infection in a young pregnant lady, a known case of chronic myeloid leukemia (CML) on chemotherapy. Such an association is hitherto unreported.

Acute panmyelosis with myelofibrosis (APMF) is a subtype of acute myeloid leukemia (AML) classified among the category of “AML, not otherwise specified” in the WHO 2016 classification of hematopoietic tumors. It is a rare, fatal hematological neoplasm that is characterized by acute onset of cytopenias and bone marrow fibrosis in the absence of splenomegaly or fibrosis related morphological changes in the red blood cells. The difficulty of diagnosis and management explains why APMF is rarely reported in Africa. We report here the case of a 30-year-old man who presented with dizziness, palpitations and dyspnea. Diagnosis of APMF was retained on bone marrow histology and immunohistochemistry which showed bone marrow fibrosis and high cellularity with majority of myeloid blast cells. The patient was treated by low dose cytarabine monotherapy 30 mg/m2 per week. At 3 months of treatment, the patient was transfusion-independent, with normalization of hemoglobin and platelets counts. However, the death occurred after 8 months. This case highlights the diagnosis specificity and management of AMPF, knowing the number of potential differential diagnoses and difficulties of its therapeutic management.

Immunotherapies, such as monoclonal antibody therapy and checkpoint inhibitor therapy, have shown inspiring clinical effects for the treatment of cancer. Chimeric antigen receptor T (CAR-T) cells therapy was an efficacious therapeutic approach treating hematological malignancies and encouraging results have been achieved. Three kinds of CAR-T cell therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), were approved for clinical application in 2017 and Tecartus (brexucabtagene autoleucel) was approved in 2020. Despite some progress have been made in treating multiple hematologic tumors, threats still remain for the application of CAR-T cell therapy considering its toxicities and gaps in knowledge. To further comprehend present research status and trends, the review concentrates on CAR-T technologies, applications, adverse effects and safety measures about CAR-T cell therapy in hematological neoplasms. We believe that CAR-T cell therapy will exhibit superior safety and efficacy in the future and have potential to be a mainstream therapeutic choice for the elimination of hematologic tumor.

Blood cell morphological identification on the peripheral blood and bone marrow films remains a cornerstone for the diagnosis of hematological neoplasms to be integrated with immunophenotyping, molecular genetics, and histopathology. Although standardization is still far from being achieved, with high interobserver variability, in recent years, several classification approaches, from the 1976 FAB to the 2016 WHO classification, have provided hematologists with detailed morphological descriptions for a large number of diseases. Counting blasts and detecting dysplastic specimens are two cornerstones of morphological diagnosis. This review deals with identifying difficult cells, with particular reference of those with relevant diagnostic implications.

In the era of precision medicine, liquid biopsy is becoming increasingly important in oncology. It consists in the isolation and analysis of tumor-derived biomarkers, including extracellular vesicles (EVs), in body fluids. EVs are lipid bilayer-enclosed particles, heterogeneous in size and molecular composition, released from both normal and neoplastic cells. In tumor context, EVs are valuable carriers of cancer information; in fact, their amount, phenotype and molecular cargo, including proteins, lipids, metabolites and nucleic acids, mirror nature and origin of parental cells rendering EVs appealing candidates as novel biomarkers. Translation of these new potential diagnostic tools into clinical practice could deeply revolutionize the cancer field mainly for solid tumors but for hematological neoplasms, too.

Propósito de la revisión: el objetivo de la revisión es delinear la fisiopatología de los linfomas de estirpe B. Buscamos reportes en donde se incluye la descripción del origen de los Linfomas B para una mejor comprensión de esta patología, a la luz de los avances en las diferentes áreas. Recientes hallazgos: El Grupo Euroflow ha publicado una lista de paneles de Expresión de Antígenos de Superficie en Linfoma no Hodgkin, cuya lista se presenta en este artículo. Extracto: Las neoplasias hematológicas han tenido grandes avances en los últimos años en varios campos, evolucionando desde la identificación citológica, pasando por su caracterización inmunofenotípica por medio de la Citometría de Flujo e Inmunohistoquímica y llegando a la caracterización molecular, iniciando por Técnicas de Cariotipo Convencional, continuando por técnicas de Inmunohibridación in situ y actualmente con la identificación molecular por medio de la Secuenciación de Nueva Generación. Esta es la razón por la que los sistemas de estadificación han ido evolucionando también, siendo el que está al momento en vigencia el propuesto por la Organización Mundial de la Salud en el año 2016. Los linfomas constituyen un grupo heterogéneo de neoplasias hematológicas con un amplio espectro de presentación clínica, cuyo origen se encuentra en los precursores de linfoides y que afectan a los diversos órganos linfoides. De estos, los linfomas de la línea B son los más comunes, motivo de esta revisión.

Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KITD816V. Prognostically-significant pathogenic KIT mutations also occur in 30–40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KITD816V-mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN (n = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases (n = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KITD816V, only eight (44%) showed evidence of SM at any point in their disease course (p = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance (n = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n = 7; AML, not otherwise specified, n = 2; AML-MRC, n = 1; acute promyelocytic leukemia, n = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort (n = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KITD816V mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.

Systemic mastocytosis (SM) is a rare clonal disorder with multi-organ involvements and shortened life expectancy. To date, no curative treatment for SM exists. Cladribine (2-CdA) is a purine analogue showing activity against neoplastic mast cells and its use was found to be effective in some patients with SM. Nine patients (six males and three females) with advanced SM at median age of 63 years (range 33–67) who received at least one course of 2-CdA were included in a retrospective analysis. Study patients were classified as having aggressive SM (ASM; n = 7) and SM with an associated hematological neoplasm (SM-AHN; n = 2). The “C” findings were as follows: (1) absolute neutrophil count (ANC) 9/l (n = 1) and/or hemoglobin level n = 4) and/or platelet count 9/l (n = 4); (2) hepatomegaly with ascites (n = 4); (3) skeletal involvement (n = 2); (4) palpable splenomegaly with hypersplenism (n = 3) and (5) malabsorption with weight loss (n = 5). Treatment consisted of 2-CdA at dose 0.14 mg/kg/day intravenously over a 2-h infusion for 5 consecutive days. Median dose per cycle was 45 mg (range 35–60). Median number of cycles was 6 (range 1–7). Overall response rate (ORR) was 66% (6/9 pts) including three partial responses and three clinical improvements. ORR was 100% and 66% for SM-AHN and ASM, respectively. Median duration of response was 1.98 years (range 0.2–11.2). At the last contact, five patients died, four have little disease activity, but remain treatment- free. 2-CdA seems to be beneficial in some patients with SM, however the response is incomplete.

Hodgkin’s lymphoma (HL) is a hematological neoplasm generally related to a favorable prognosis, since approximately 80% of patients will be cured with actual regimen treatment. However, 10 to 30% o...

Bone marrow (BM) is a highly complex tissue that provides important regulatory signals to orchestrate hematopoiesis. Resident and transient cells occupy and interact with some well characterized niches to produce molecular and cellular mechanisms that interfere with differentiation, migration, survival, and proliferation in this microenvironment. The acute myeloid leukemia (AML), the most common and severe hematological neoplasm in adults, arises and develop in the BM. The osteoblastic, vascular, and reticular niches provide surface co-receptors, soluble factors, cytokines, and chemokines that mediate important functions on hematopoietic cells and leukemic blasts. There are some evidences of how AML modify the architecture and function of these three BM niches, but it has been still unclear how essential those modifications are to maintain AML development. Basic studies and clinical trials have been suggesting that disturbing specific cells and molecules into the BM niches might be able to impair leukemia competencies. Either through niche-specific molecule inhibition alone or in combination with more traditional drugs, the bone marrow microenvironment is currently considered the potential target for new strategies to treat AML patients. This review describes the cellular and molecular constitution of the BM niches under healthy and AML conditions, presenting this anatomical compartment by a new perspective: as a prospective target for current and next generation therapies.

Systemic mastocytosis (SM) is a rare neoplasm resulting from extracutaneous infiltration of clonal mast cells (MC). The clinical features of SM are very heterogenous and treatment should be highly individualized. Up to 40% of all SM cases can be associated with another hematological neoplasm, most frequently myeloproliferative neoplasms. Here, we present a patient with indolent SM who subsequently developed a myeloid neoplasm with PDGFRA rearrangement with complete response to low-dose imatinib. The 63-year-old patient presented with eosinophilia and elevated serum tryptase level. Bone marrow analysis revealed aberrant MCs in aggregates co-expressing CD2/CD25 and KIT D816V mutation (0.01%), and the FIP1L1-PDGFRA fusion gene was not identified. In the absence of ‘B’ and ‘C’ findings, we diagnosed an indolent form of SM. For 2 years after the diagnosis, the absolute eosinophil count progressively increased. Bone marrow evaluation showed myeloid hyperplasia and the FIP1L1-PDGFRA fusion gene was detected. Thus, the diagnosis of myeloid neoplasm with PDGFRA rearrangement was established. The patient was treated with imatinib 100 mg daily and rapidly obtained a complete molecular remission. The clinical, biological, and therapeutic aspects of SM might be challenging, especially when another associated hematological disease is diagnosed. Little is known about the underlying molecular and immunological mechanisms that can promote one entity prevailing over the other one. Currently, the preferred concept of SM pathogenesis is a multimutated neoplasm in which KIT mutations represent a “phenotype modifier” toward SM. Our patient showed an evolution from KIT mutated indolent SM to a myeloid neoplasm with PDGFRA rearrangement; when the eosinophilic component expanded, a regression of the MC counterpart was observed. In conclusion, extensive clinical monitoring associated with molecular testing is essential to better define these rare diseases and consequently their prognosis and treatment.

Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.

Systemic mastocytosis is a rare hematologic disorder characterized by the clonal proliferation of mast cells in extra-cutaneous organs. This disease can be further subdivided into five different phenotypes: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL). The tyrosine kinase inhibitor (and also potent KIT D816V inhibitor) avapritinib, initially approved for the treatment of gastrointestinal stromal tumors (GISTs) bearing a PDGFRA exon 18 mutation, also showed great promise in patients with systemic mastocytosis, a disease known to be driven by a mutation in KIT (D816V). We present an overview of this rare disorder, including a review of the current understanding of the genetic mechanisms which lead to the disease state, the action of the tyrosine kinase inhibitors, as well as the latest clinical trial data which led to the current recommendations for the use of avapritinib.

SARS-COV2 pandemic has caused profound challenges in health care systems worldwide. Patients affected by hematological neoplasms appear to be particularly at risk of developing COVID-19 complications, with unfavorable outcomes. Here, we present the case of a 57-years-old woman diagnosed with severe COVID-19 pneumonia and concurrent acute myeloid leukemia (AML). At the time of diagnosis, it was decided to postpone leukemia therapy to enable adequate COVID-19 pneumonia treatment. When her conditions related to pneumonia improved, the combination of Azacitidine-Venetoclax was used as first-line treatment, instead of conventional intensive chemotherapy. At the end of the first two cycles, the patient showed complete remission, and a post-remission consolidation with allogeneic hematopoietic stem cell transplantation has been planned. This case suggests that Azacytidine-Venetoclax induction may represent a valid and safe alternative to intensive chemotherapy in the challenging setting of patients with a concomitant diagnosis of AML and severe COVID-19 infection.

Telomeres compose the end portions of human chromosomes, and their main function is to protect the genome. In hematological disorders, telomeres are shortened, predisposing to genetic instability that may cause DNA damage and chromosomal rearrangements, inducing a poor clinical outcome. Studies from 2010 to 2019 were compiled and experimental studies using samples of patients diagnosed with hematological malignancies that reported the size of the telomeres were described. Abnormal telomere shortening is described in cancer, but in hematological neoplasms, telomeres are still shortened even after telomerase reactivation. In this study, we compared the sizes of telomeres in leukemias, myelodysplastic syndrome and lymphomas, identifying that the smallest telomeres are present in patients at relapse. In conclusion, the experimental and clinical data analyzed in this review demonstrate that excessive telomere shortening is present in major hematological malignancies and its analysis and measurement is a crucial step in determining patient prognosis, predicting disease risk and assisting in the decision for targeted therapeutic strategies.

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematological neoplasm with features of both myeloproliferation and myelodysplasia with an incidence 0.4 per lakh population. A number of prognostic risks scoring systems have attempted to predict survival and risk of CMML patients, like International Prognostic Scoring System (IPSS), the Spanish Score, the modified Bournemouth Score, the Dusseldorf Score and the MDAP Score. But no prognostic system has been widely accepted. More data from different regions are required to create a widely accepted working prognostic system for CMML. No case series on CMML has been published in literature from India in our knowledge. This article attempts to put to light the various clinicopathological parameters of CMML cases from India and the impact of these parameters on final outcome. Methods: All admitted patients in a tertiary center in western India, with a diagnosis of either a chronic myeloproliferative disease or a myelodysplastic disease over a period of 3 years (2015-2018) were evaluated, out of which nine(n=9) cases fulfilled the diagnostic criteria of CMML. All patients underwent peripheral blood examination, bone marrow aspirate, bone marrow biopsy and cytogenetic studies. Result: All patients (n=9) were between 50 and 80 years and most were males (n=8). Five patients presented with hepatosplenomegaly. Renal and liver function of one patient was deranged who had pleural effusion, ascites. Most patients (n=8) had total leukocyte count above 13000/cumm, while three had low platelet counts. Two out of three patients classified as CMML-II with increased blasts in peripheral blood and bone marrow had fatal outcomes. Patients whose karyotypes were available had normal karyotypes without any additional cytogenetic abnormalities. All were negative for JAK2 and BCR-ABL1. Conclusion: The study concluded that altered biochemical tests (LDH, LFT), blast percentage, CMML II, relative lymphocytosis and transformation to AML were associated with poor outcome.

The coexistence of dual hematological neoplasms is very rare. Sequential or synchronous neoplasms in hematology are an uncommon and complex clinical situation. The aim of the Hemo2 study was to describe the clinical characteristics and analyze the outcome of these patients. We performed a retrospective review of all patients diagnosed with sequential or synchronous hematological malignancies in the university hospital of Tours, between 2007 and 2018. We identified 49 patients in our study, with a prevalence of 0.89%. Sequential and synchronous combinations were found in 36 (73%) and 13 (27%) patients, respectively. One patient presented three sequential neoplasms. The median cumulative incidence was 6 years (95% CI 3–7). Among all neoplasms diagnosed (n = 99), we found 79 lymphoid neoplasms (LNs) (80%) and 20 myeloid neoplasms (MNs) (20%). Sex ratio was 1.88 with 65% of males and 35% of females. The most common LNs were Hodgkin lymphoma (n = 16; 16%) and multiple myeloma (n = 11; 11%). The most frequent MN was essential thrombocythemia (n = 5; 5%). The most common combination was Hodgkin lymphoma and follicular lymphoma in five (10%) patients. The overall survival from the first diagnosis (OS1) at 5 years was 82.4% (95% CI 72.1–94.3). The median overall survival from the second diagnosis (OS2) was 98 months (95% CI 44–NR) and 5-year OS2 was 58.7% (95% CI 45.5–75.7). Median progression-free survival from the second diagnosis (PFS) was 47 months (95% CI 27–NR) with 5-year PFS of 49% (95% CI 35.9–67). OS and PFS did not statistically differ between synchronous and sequential dual neoplasms. In this cohort, that the death relative risk (RR) was significantly lower if the second neoplasm appeared after more than 4 years following the first diagnosis (OR 0.37 (95% CI 0.16–0.90)). The Hemo2study confirmed the rarity of dual hematological neoplasms. In this cohort, HL and FL were the most frequent combinations. Our results may support that synchronous and sequential dual neoplasms bear the same prognosis. Further studies are needed to better characterize these uncommon clinical situations.

Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) is a rare diagnosis commonly associated with myeloid disorders. Herein, we describe the case of a 53-year-old female diagnosed with systemic mastocytosis (SM) in conjunction with renal light chain amyloidosis (AL) and smoldering myeloma. Although cytokines such as IL-6 may play a role in the proliferation of plasma cells, delays in the diagnosis of SM and paucity of relevant studies cast uncertainty on whether the associated disease is secondary to the mast cells or etiologically independent. To our knowledge, this is the first case of confirmed renal AL disease in conjunction with SM. We review and summarize the available literature describing SM in association with plasma cell disorders.

Acute megakaryoblastic leukemia (AMegL) is a rare hematological neoplasm most often diagnosed in children and is commonly associated with Down's syndrome (DS). Although AMegLs are specifically characterized and typically diagnosed by megakaryoblastic expansion, recent advancements in molecular analysis have highlighted the heterogeneity of this disease, with specific cytogenic and genetic alterations characterizing different disease subtypes. Areas covered: This review will focus on describing recurrent molecular variations in both DS and non-DS pediatric AMegL, their role in promoting leukemogenesis, their association with different clinical aspects and prognosis, and finally, their influence on future treatment strategies with a number of specific drugs beyond conventional chemotherapy already under development. Expert opinion: Deep understanding of the genetic and molecular landscape of AMegL will lead to better and more precise disease classification in terms of diagnosis, prognosis, and possible targeted therapies. Development of new therapeutic approaches based on these molecular characteristics will hopefully improve AMegL patient outcomes.

Systemic mastocytosis (SM) is a hematological malignancy characterized by extracutaneous infiltration by atypical mast cells. Together with indolent SM, aggressive SM, and mast cell leukemia, the World Health Organization (WHO) recognizes another major disease subgroup: SM with an associated hematological neoplasm, which is characterized by the presence of a concurrent neoplasm, more commonly, a chronic myelomonocytic leukemia. While KIT D816V is commonly regarded as the driver mutation, the clinical presentation of SM is extremely varied. Treatment of SM might not be simple, but now more specific therapies tailored toward prognostic subgroups of patients have been developed. Here, we report a detailed description of clinical management and biological features of a systemic mastocytocis case associated with multiple hematologic non-mast cell lineage diseases.

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamon Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counselling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms. This article is protected by copyright. All rights reserved.

Systemic Mastocytosis is a clonal proliferation of mast cells; in a significant fraction of cases it is associated with another concurrent hematological neoplasm. Molecular analysis of KIT mutations and other associated genetic alterations suggest a common origin in the stem cell compartment. Mast cell infiltration patterns in bone marrow biopsy may be subtle in cases associated with t (8;21) AML. Here we report three cases of clonally related SM-AHN, two cases with SM-CMML and one case with SM- t (8;21) AML. We describe in detail the bone marrow infiltration pattern at diagnosis and during the course of treatment with allogeneic stem cell transplant and novel TK inhibitors, showing the unique dynamics of mast cell clearance after therapy.

Pediatric cerebral venous sinus thrombosis (CVST) is rare but a potentially fatal disease requiring its understanding in local setting. In this study, we observed the clinical course, management, and outcome of pediatric patients with sinus thrombosis in a tertiary care center at Pakistan. Patients between age 0 to 18 years of both genders diagnosed with sinus thrombosis during 2011 to 2020 were included. Data was collected through in-house computerized system and SPSS version 19 was used for analysis. Of 143492 pediatric admissions, 32 (21 males and 11 females) patients with a median (IQR) age of 4.5 years (0-16) had CVST. This is equivalent to 18.5 CVST events per million pediatric admissions. Adolescents were mostly affected, and the overall mortality was 7%. Primary underlying disorders were infections (59%), hematological neoplasms (12.5%), thrombotic thrombocytopenic purpura (3%) and antiphospholipid syndrome (3%). Activated protein C resistance (44%) was the most common inherited thrombophilia. Twenty-one (66%) patients were anemic with a mean (±SD) hemoglobin of 9.0 g/dL (±2.3). Regression analysis showed a positive association of anemia with multiple sinus involvement ( P-value 0.009) but not with duration of symptoms ( P-value 0.344), hospital stay ( P-value 0.466), age ( P-value 0.863) or gender ( P-value 0.542) of the patients. SARS-COV2 was negative in patients during 2020. Adolescents were primarily affected by sinus thrombosis and infections was the predominant risk factor for all age groups, with a low all-cause mortality. A high index of clinical suspicion is required for prompt diagnosis and intervention.

Haematopoietic stem cell transplantation (HSCT) may dramatically alter the immunity of a recipient. Transient immunodeficiency that occurs before and after HSCT could be associated with the development of sudden sensorineural hearing loss (SSNHL), which is presumed to be often due to viral aetiology. We found an incidence of SSNHL of 29.4 per 10,000 person-years in patients receiving HSCT, 12-fold higher than reported for background population incidence. Development of SSNHL tended to cluster early after diagnosis of haematological malignancies, rather than around date of treatment with HSCT. Increased risk of unilateral SSNHL in patients with haematological malignancy may relate to underlying disease rather than treatment.

Introduction Pancytopenia is a clinical entity encountered in pediatric practice as a feature of various benign and malignant disorders. It describes the simultaneous presence of anemia, leucopenia and thrombocytopenia. Attempts to identify the correct etiology and gauging the severity of pancytopenia will help to determine the management and prognosis of the patients. Objectives To study etio-hematological profile, clinical correlates and outcome of pancytopenia in Indian children Methods This prospective observational study of children with pancytopenia was conducted at a tertiary care center from August 2015 to July 2016. Clinical, hematological and bone marrow studies were performed and patients were followed for one year. The collected data were statistically analyzed. Results Out of 84 cases, the mean age at diagnosis was 70 (70.77±4.8) months. Bone marrows showed aplastic changes in 37% and hyperplasia in 14% of patients. In our study, most common causes were aplastic anemia, acute leukemia and nutritional anemia. During the first year of follow-up, 67% pancytopenics survived and 12% succumbed (rest discontinued treatment) with ~26% of aplastic anemia (7/27 cases) and 9% of acute leukemia (2/22 cases) not surviving. Anthropometric status of patients and severity in aplastic anemia were significantly associated (p < 0.05) with outcome. Conclusion The data gathered support a complex picture for pancytopenia in our study population since both benign nutritional deficiencies and malignant hematological neoplasms were common. Bone marrow studies seem to be of salient use in delineating etiology. As the outcome is multifactorial, factors like anthropometry, hematological parameters have a bearing on prognosis.

Conventional cytogenetics are the gold standard for the identification of chromosomal alterations recurrent in myeloid neoplasms. Some next-generation sequencing (NGS) panels are designed for the detection of copy number variations (CNV) or translocations, however, their use is far from being widespread. Here we report on the results of a commercial panel including frequent mutations, CNVs and translocations in myeloid neoplasms. Frequent chromosomal alterations were analyzed by NGS in 135 patients with myeloid neoplasms and three with acute lymphoblastic leukemia. NGS analysis was performed using the enrichment-capture Myeloid Neoplasm-GeneSGKit (Sistemas Genómicos, Spain) gene panel including 35 genes for mutational analysis and frequent CNVs and translocations. NGS results were validated with cytogenetics and/or MLPA when possible. A total of 66 frequent alterations included in NGS panel were detected, 48 of them detected by NGS and cytogenetics. Ten of them were observed only by cytogenetics (mainly trisomy 8), and another eight only by NGS (mainly deletion of 12p). Aside from this, 38 secondary CNVs were detected in any of the genes included mainly for mutational analysis. NGS represents a reliable complementary source of information for the analysis of CNVs and translocations. Moreover, NGS could be a useful tool for the detection of alterations not observed by conventional cytogenetics.

Objective To determine the prevalence of Latent Tuberculosis in patients with hematological neoplasms at the Instituto Nacional de Cancerología in Mexico City using the Tuberculin skin test (TST). Methods This retrospective study included all patients with a recent diagnosis of hematological neoplasms who were admitted for treatment from 2017 to 2018 and who were screened for latent tuberculosis with the TST. The prevalence of latent tuberculosis in this group, tolerance and therapeutic adherence in treated patients are described. Results The files of 446 patients with hematological malignancy who had a TST were reviewed. The prevalence of latent tuberculosis was 31.2% (n = 139). Ninety-three patients received isoniazid, 15.1% had some adverse reactions, but only 4 (4.3%) had to discontinue treatment. Two patients with latent tuberculosis under treatment with Isoniazid reactivated tuberculosis infection. Conclusions The prevalence in our study was within the range of other similar Mexican populations. Isoniazid treatment had an adequate tolerance and adherence. Longer follow-up could offer more information on the risk of reactivation in both groups.

Simple Summary Benzene is produced by diverse petroleum transformation processes and it is widely employed in industry despite its oncogenic effects. In fact, occupational exposure to benzene may cause hematopoietic malignancy. The leukemogenic action of benzene is particularly complex. Possible processes of onset of hematological malignancies have been recognized as a genotoxic action and the provocation of immunosuppression. However, benzene can induce modifications that do not involve alterations in the DNA sequence, the so-called epigenetics changes. Acquired epigenetic modification may also induce leukemogenesis, as benzene may alter nuclear receptors, and cause changes at the protein level, thereby modifying the function of regulatory proteins, including oncoproteins and tumor suppressor proteins. Abstract Benzene carcinogenic ability has been reported, and chronic exposure to benzene can be one of the risk elements for solid cancers and hematological neoplasms. Benzene is acknowledged as a myelotoxin, and it is able to augment the risk for the onset of acute myeloid leukemia, myelodysplastic syndromes, aplastic anemia, and lymphomas. Possible mechanisms of benzene initiation of hematological tumors have been identified, as a genotoxic effect, an action on oxidative stress and inflammation and the provocation of immunosuppression. However, it is becoming evident that genetic alterations and the other causes are insufficient to fully justify several phenomena that influence the onset of hematologic malignancies. Acquired epigenetic alterations may participate with benzene leukemogenesis, as benzene may affect nuclear receptors, and provoke post-translational alterations at the protein level, thereby touching the function of regulatory proteins, comprising oncoproteins and tumor suppressor proteins. DNA hypomethylation correlates with stimulation of oncogenes, while the hypermethylation of CpG islands in promoter regions of specific tumor suppressor genes inhibits their transcription and stimulates the onset of tumors. The discovery of the systems of epigenetic induction of benzene-caused hematological tumors has allowed the possibility to operate with pharmacological interventions able of stopping or overturning the negative effects of benzene.

Objectives: to describe epidemiological characteristics and deaths in children with cancer and COVID-19 at a reference hospital in Recife, Brazil. Methods: cohort involving children under the age of 19 underwent cancer treatment during April to July 2020. During the pandemic, real-time reverse transcriptase polymerase chain reaction assay (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS -CoV-2) in nasal / oropharyngeal swab were collected in symptomatic patients or before hospitalization. Those with detectable results were included in this cohort study. The outcomes were delayed on cancer treatment and death. Descriptive analysis was performed and presented in preliminary results. Results: 48 children participated in the cohort, mostly with hematological neoplasms (66.6%.),69% were male, median age was 5.5 years. The most frequent symptoms were fever (58.3%) and coughing (27.7%);72.9% required hospitalization, 20% had support in ICU and 10.5% on invasive ventilatory assistance.66.6% of the patients had their oncological treatment postponed, 16.6% died within 60 days after confirmation of SARS-CoV-2 infection. Conclusions: COVID-19 led a delay in the oncological treatment for children with cancer and a higher mortality frequency when compared to the historical series of the service. It would be important to analyze the risk factors to determine the survival impact.

Comprehensive characterization of somatic genomic alterations has led to fundamental shifts in our understanding of tumor biology. In clinical practice, these studies can lead to modifications of diagnosis and/or specific treatment implications, fulfilling the promise of personalized medicine. Herein, we describe a 78-yr-old woman under surveillance for long-standing untreated chronic lymphocytic leukemia (CLL). Molecular studies from a peripheral blood specimen revealed a TP53 p.V157F mutation, whereas karyotype and fluorescence in situ hybridization (FISH) identified a 17p deletion, trisomy 12, and no evidence of IGH-CCND1 rearrangement. Positron emission tomography-computed tomography scan identified multistation intra-abdominal lymphadenopathy and a pulmonary nodule, and subsequent pulmonary wedge resection confirmed the presence of a concurrent lung adenocarcinoma. Targeted next-generation sequencing of the lung tumor identified an EGFR in-frame exon 19 deletion, two TP53 mutations (p.P152Q, p.V157F), and, unexpectedly, a IGH-CCND1 rearrangement. Follow-up immunohistochemistry (IHC) studies demonstrated a cyclin D1–positive lymphoid aggregate within the lung adenocarcinoma. The presence of the TP53 p.V157F mutation in the lung resection, detection of an IGH-CCND1 rearrangement, and cyclin D1 positivity by IHC led to revision of the patient's hematologic diagnosis and confirmed the extranodal presence of mantle cell lymphoma within the lung mass, thus representing a “tumor in tumor.” Manual review of the sequencing data suggested the IGH-CCND1 rearrangement occurred via an insertional event, whose size precluded detection by original FISH studies. Thus, routine imaging for this patient's known hematologic malignancy led to detection of an unexpected solid tumor, whose subsequent precision medicine studies in the solid tumor redefined the original hematological diagnosis.

Objective: Hypocholesterolemia is a metabolism disorder that may be seen in chronic diseases and malignancies. Various dyslipidemia profiles have been shown in adult and pediatric hematological malignancies. We aimed to evaluate the lipid profile properties in patients diagnosed with a hematological malignancy compared to a healthy control group. Method: Out of 1213 patients diagnosed with hematologic malignancy, the data of 98 patients whose pretreatment lipid profiles had already been studied, were reviewed. Forty healthy individuals were selected as the control group. The levels of total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were compared. Results: Triglyceride values were significantly higher (p=0.02), and the total cholesterol, LDL and HDL levels were lower in the study group compared to the control group. Triglyceride values were higher (p=0.013), and HDL levels were lower (p=0.022) in parallel with increases in uric acid levels. There was a significant correlation between the International Prognostic Index (IPI) score and TG (p=0.003) in those diagnosed with non-Hodgkin lymphoma (NHL). Whereas no significant correlation was found between TG, total cholesterol, and LDL values in the limited (early) and advanced stage NHL, while a significant negative correlation was found with HDL (p=0.027). Conclusion: Hypertriglyceridemia, as well as low LDL and HDL values may be seen in hematological malignancies. It should be kept in mind that there may be chronic diseases and malignancies in the etiology of incidental hypocholesterolemia and hypertriglyceridemia. Further studies are needed on this subject to determine the effects of dyslipidemia on the pathogenesis and prognosis of the disease in hematological malignancies.

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g., Matutes ≤ 3) are also encountered, and for these diseases, biology and prognostic impact are less clear. Here we report the genomic characterization of a case of atypical B-CLL in a 70-yr-old male patient; B-CLL cells showed a Matutes score of 3, chromosomal translocation t(14;18)(q32;q21) (BCL2/IGH), mutated IGHV, deletion 17p, and mutations in BCL2, NOTCH1 (subclonal), and TP53 (subclonal). Quite strikingly, a novel PAX5 mutation that was predicted to be loss of function was also seen. Exome sequencing identified, in addition, a potentially actionable BRAF mutation, together with novel somatic mutations affecting the homeobox transcription factor NKX2-3, known to control B-lymphocyte development and homing, and the epigenetic regulator LRIF1, which is implicated in chromatin compaction and gene silencing. Neither NKX2-3 nor LRIF1 mutations, predicted to be loss of function, have previously been reported in B-CLL. Sequencing confirmed the presence of these mutations together with BCL2, NOTCH1, and BRAF mutations, with the t(14;18)(q32;q21) translocation, in the initial diagnostic sample obtained 12 yr prior. This is suggestive of a role for these novel mutations in B-CLL initiation and stable clonal evolution, including upon treatment withdrawal. This case extends the spectrum of atypical B-CLL with t(14;18)(q32;q21) and highlights the value of more global precision genomics for patient follow-up and treatment in these patients.

Mastocytosis is a rare hematologic disorder characterized by abnormal proliferation and accumulation of neoplastic mast cells in various body sites. Isolated skin involvement is termed cutaneous mastocytosis (CM) and the term systemic mastocytosis (SM) refers to multi-organ involvement, most commonly of the bone marrow, skin, liver, and spleen. A subset of patients with SM have an associated clonal hematologic neoplasm which is most commonly myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myelogenous leukemia and this entity is termed SM with associated hematological neoplasm (AHN). Bone marrow involvement is present in all patients regardless of the subtype of SM. The genetic hallmark of SM is a somatic gain-of-function point mutation within the KIT gene. Other molecular aberrations that have been reported include somatic mutations in TET2, SRSF2, ASXL1, CBL, RUNX1, and RAS and these are common in SM-AHN. The clinical presentation of SM can range from indolent to advanced depending on extent of mast cell burden and genetic profile. In the case of indolent SM, the goal of treatment is to control mediator release-related effects as well as to reduce mast cell burden. In the case of SM-AHN, therapy is primarily that of the AHN and allogeneic hematopoietic stem cell transplantation is the preferred therapy in suitable candidates.

Simple Summary YES-associated protein (YAP) is a co-transcriptional activator that binds to transcriptional factors to increase the rate of transcription of a set of genes, and it can intervene in the onset and progression of different tumors. Most of the data in the literature refer to the effects of the YAP system in solid neoplasms. In this review, we analyze the possibility that YAP can also intervene in hematological neoplasms such as lymphomas, multiple myeloma, and acute and chronic leukemias, modifying the phenomena of cell proliferation and cell death. The possibilities of pharmacological intervention related to the YAP system in an attempt to use its modulation therapeutically are also discussed. Abstract The Hippo/YES-associated protein (YAP) signaling pathway is a cell survival and proliferation-control system with its main activity that of regulating cell growth and organ volume. YAP operates as a transcriptional coactivator in regulating the onset, progression, and treatment response in numerous human tumors. Moreover, there is evidence suggesting the involvement of YAP in the control of the hematopoietic system, in physiological conditions rather than in hematological diseases. Nevertheless, several reports have proposed that the effects of YAP in tumor cells are cell-dependent and cell-type-determined, even if YAP usually interrelates with extracellular signaling to stimulate the onset and progression of tumors. In the present review, we report the most recent findings in the literature on the relationship between the YAP system and hematological neoplasms. Moreover, we evaluate the possible therapeutic use of the modulation of the YAP system in the treatment of malignancies. Given the effects of the YAP system in immunosurveillance, tumorigenesis, and chemoresistance, further studies on interactions between the YAP system and hematological malignancies will offer very relevant information for the targeting of these diseases employing YAP modifiers alone or in combination with chemotherapy drugs.

Myelodysplastic syndrome (MDS) is a heterogeneous hematological neoplasm with a wide range of clinical presentations from isolated anemia to pancytopenia and propensity to transform to acute myeloid leukemia. MDS is characterized by morphologic bone marrow dysplasia and ineffective hematopoiesis resulting from a range of cytogenetic abnormalities and somatic gene mutations. Disease management varies from observation alone for low-risk disease to hypomethylating agents and hematopoietic cell transplantation (HCT) for higher risk disease. In this chapter, we review the classification, risk stratification, and optimal management of patients with MDS.

Extremely low frequency (ELF) magnetic fields (MF) have been classified as possibly carcinogenic. This classification was mainly based on studies indicating increased risk of leukemia in children living near power lines. Increased risks of adult hematological malignancies and brain tumors have also been reported, but the results are mixed. We assessed incidence of adult hematological malignancies and brain tumors associated with residential MF exposure. All cohort members had lived in buildings with indoor transformer stations (TS). MF exposure was assessed based on apartment location. Out of the 256,372 individuals, 9,636 (165,000 person-years of follow-up) living in apartments next to TSs were considered as exposed. Associations between MF exposure and neoplasms were examined using Cox proportional hazard models. The hazard ratio (HR) for MF exposure ≥ 1 month was below one for most hematological neoplasms (HR for any hematological neoplasm: 0.75; 95% CI: 0.54–1.03), and decreased with increasing duration of exposure (HR for exposure ≥ 10 years: 0.47; 95% CI: 0.22–0.99). However, the HR for acute lymphocytic leukemia (ALL) was 2.86 (95% CI: 1.00–8.15), based on 4 exposed cases; the risk increased with duration of exposure (HR for exposure ≥3 years: 3.61; 95% CI: 1.05–12.4) and was particularly associated with childhood exposure (2 exposed cases, HR for exposure during the first two years of life: 11.5; 95% CI: 1.92–68.9). The HR for meningioma was 0.46 (95% CI: 0.19–1.11), with no evidence of exposure-response gradient with increasing duration of exposure. The HR for glioma was 1.47 (95% CI: 0.84–2.57). The hypothesis of a positive association between ELF MFs and adult hematological malignancies was supported only for ALL. The results suggested decreased rather than increased risk of most hematological neoplasms. publishedVersion

Background: Febrile neutropenia (FN) is a frequent complication of chemotherapy treatment in children with oncological diseases. It can cause serious complications due to infections (SIC), such as severe sepsis and septic shock. In order to identify the predictors of severity for diminished survival in these patients, it is important to have a better treatment strategy, so as to reduce the rate of mortality. Procedure: Retrospective, descriptive and analytical study conducted through a review of medical records of cancer patients from 0 to 18 years old with FN episodes admitted to the Pediatric Intensive Care Unit in Brazil, from June/2013 to January/2018. Epidemiological, clinical and laboratory variables were analyzed for survival outcome. The rates of severe sepsis, septic shock, and mortality were also investigated. Results: Data from 140 FN episodes were analyzed. Most of the children had hematological diseases (80.8%), the average age was 8.5 years old, and the main microorganisms identified in cultures were Gram negative bacteria. The predictors of severity for diminished survival utilizing multivariate analyses were hematological neoplasms in relapse, abnormal capillary filling, and a serum calcium value

CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent “don’t eat me” signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.

The ubiquitin proteasome system (UPS) is the main cellular degradation machinery designed for controlling turnover of critical proteins involved in cancer pathogenesis, including hematological malignancies. UPS plays a functional role in regulating turnover of key proteins involved in cell cycle arrest, apoptosis and terminal differentiation. When deregulated, it leads to several disorders, including cancer. Several studies indicate that, in some subtypes of human hematological neoplasms such as multiple myeloma and Burkitt’s lymphoma, abnormalities in the UPS made it an attractive therapeutic target due to pro-cancer activity. In this review, we discuss the aberrant role of UPS evaluating its impact in hematological malignancies. Finally, we also review the most promising therapeutic approaches to target UPS as powerful strategies to improve treatment of blood cancers.

Acute lymphoid leukemia (ALL) is a type of hematological neoplasm that affects the precursor cells of strains B, T and NK, with a higher incidence in the pediatric range. The pathophysiology of ALL is characterized by chromosomal abnormalities and genetic alterations involved in the differentiation and proliferation of lymphoid precursor cells. Despite the lack of information in the literature, it is believed that leukemogenesis originates from a complex interaction between environmental and genetic factors, which combined lead to cellular modifications. Environmental factors have been evaluated as possible predisposing factors in the development of ALL but there are still conflicting results in the world literature. In this context, the aim of the present review is to discuss the major exogenous factors regarding ALL.