Unraveling the Immune Microenvironment in Diffuse Large B-Cell Lymphoma: Prognostic and Potential Therapeutic Implications.

Diffuse large B cell lymphoma (DLBCL) is a multifaceted condition characterized by significant diversity in its molecular and pathological subtypes and clinical manifestation. Despite the progress made in the treatment of DLBCL through the development of novel drugs, an estimated one-third of patients encounter relapse or acquire refractory disease. The tumor microenvironment (TME) of DLBCL, a complex network consisting of cellular and noncellular components that engage in interactions with the tumor, is a parameter that is gaining increasing attention. The TME comprises both the immune and nonimmune microenvironments. The immune microenvironment comprises natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), neutrophils, myeloid-derived suppressor cells (MDSCs), and T and B lymphocytes. The nonimmune microenvironment consists of the extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells, and other molecules that are secreted. Despite ongoing research, the exact impact of these components and their interaction on the progression of the disease remains elusive. A comprehensive review of significant discoveries concerning the cellular and noncellular constituents, molecular characteristics, and treatment response and prognosis of the TME in DLBCL, as well as the potential targeting of the TME with novel therapeutic approaches, is provided in this article.

Expression Patterns of GATA3 in Classical Hodgkin Lymphoma: A Clinico-Pathological Study.

GATA3 is a transcription factor involved in T-cell maturation and has been previously shown to be aberrantly overexpressed in malignant Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). However, the immunophenotypes of the cell types expressing GATA3 have not been precisely characterized so far in cHL tissues. In this single-center retrospective cohort study we analyzed the expression patterns of GATA3 alone and in combination with B, T, NK or macrophage-associated markers in 73 cases with newly diagnosed cHL and investigated for a possible correlation with clinical and laboratory parameters. Immunohistochemistry (single and double) was performed using GATA3 alone and in combination with CD20, CD3, CD56, CD68, CD30 or CD15. Clinical and laboratory parameters were collected and correlated with the expression of GATA 3. GATA3 nuclear expression was found in HRS cells in 39/73 (54%) cases of cHL. The Nodular Sclerosis (NS) subtype showed the highest positivity rate (35/56, 63%), followed by mixed cellularity (MC; 4/14, 29%) and lymphocyte rich (LR; 0/3). Double immunostainings showed that GATA3 was expressed by CD30+ or CD15+ HRS cells and a few CD3+ T-cells, whereas GATA3 expression was not detected in CD20, CD56 or CD68+ cells. GATA3-negative cHL was significantly associated with unfavorable prognostic factors such as older age at diagnosis and increased levels of serum ß2-microglobulin. The heterogenous expression patterns of GATA3 in HRS cells that were observed in a substantial proportion of cHL, mainly in the NS subtype, further support the biological heterogeneity of cHL.

The Role of Non-Coding RNAs in Myelodysplastic Neoplasms.

Myelodysplastic syndromes or neoplasms (MDS) are a heterogeneous group of myeloid clonal disorders characterized by peripheral blood cytopenias, blood and marrow cell dysplasia, and increased risk of evolution to acute myeloid leukemia (AML). Non-coding RNAs, especially microRNAs and long non-coding RNAs, serve as regulators of normal and malignant hematopoiesis and have been implicated in carcinogenesis. This review presents a comprehensive summary of the biology and role of non-coding RNAs, including the less studied circRNA, siRNA, piRNA, and snoRNA as potential prognostic and/or predictive biomarkers or therapeutic targets in MDS.

Central Diabetes Insipidus in a Patient With Lymphoma: A Case Report.

Primary central nervous system (CNS) lymphoma or systemic non-Hodgkin lymphoma that infiltrates the CNS can cause central diabetes insipidus (CDI). Polyuria and polydipsia should raise the suspicion of CDI development in patients with lymphoma that infiltrates the CNS. CDI is effectively treated with desmopressin. However, careful monitoring of the patient's serum sodium, fluid intake, urine output, and weight is necessary because patients receiving desmopressin may develop hyponatremia, so they should be alert to recognize this side effect promptly. Moreover, CDI due to lymphoma can occasionally be reversible. Therefore, the dosage of desmopressin should be adapted during or after the treatment of lymphoma.

Luspatercept: A New Tool for the Treatment of Anemia Related to ß-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis.

Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (ß-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-ß (TGF-ß) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta ß-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with ß-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in ß-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders.

CD56 expression in multiple myeloma: Correlation with poor prognostic markers but no effect on outcome.

CD56 or neural cell adhesion molecule (NCAM) is a membrane glycoprotein expressed on neural cells, muscle tissues and myeloma cells. Expression of CD56 has been studied in patients with multiple myeloma (MM) with controversial results. The scope of this study was to examine the expression of CD56 in MM patients at diagnosis and investigate its association with clinicopathologic parameters. We retrospectively collected and analyzed data from 109 patients with MM diagnosed over the last decade (January 2010 to June 2020). Expression of CD56 was assessed by immunohistochemistry in bone marrow biopsies and investigated its association with a variety of clinicopathological parameters. For the statistical analysis χ2 test and Mann-Whitney U tests were used to compare categorical and continuous variables in CD56+ and CD56- patients, respectively. Statistical analysis was performed using SPSS 21.0 for Windows (SPSS, Chicago, IL). Based on the expression of CD56 the patient population was divided to CD56+ patients and CD56- patients; Sixty-eight patients were CD56 + and 41 patients were CD56-. Absence of CD56 expression was associated with unfavorable prognostic parameters such as elevated lactate dehydrogenase (LDH) and ß2-microglobulin levels, advanced stage according to the International Staging System (ISS) and clonal bone marrow plasma cell infiltration ≥ 60%, but no effect on outcome, while the expression of CD56 was associated with well differentiated neoplastic plasma cells. Our study confirmed that lack of CD56 expression is a possible marker of poor prognosis in patients with MM. The detection of CD56 expression by either immunohistochemistry or flow cytometry is simple and cheap, and it could be incorporated in future prognostic or predictive scores. Prospective studies are needed in order to evaluate the role of expression of CD56 as a predictive biomarker in the era of novel regimens.

Paraneoplastic Intrahepatic Cholestasis in Supradiaphragmatic Classical Hodgkin Lymphoma Successfully Treated With Brentuximab Vedotin: A Case Report and Review of the Literature.

BACKGROUND: Hepatic dysfunction in patients with classical Hodgkin lymphoma (cHL) is of multifactorial aetiology. Prompt evaluation with laboratory tests and imaging methods is sufficient for diagnosis in most cases. Intrahepatic cholestasis and vanishing bile duct syndrome (VBDS) may complicate cHL as rare paraneoplastic phenomena. Liver biopsy provides crucial evidence of cholestasis, and ductopenia, if present, confirms the diagnosis of VBDS. CASE REPORT: We report on a cHL patient that presented with jaundice and bulky mediastinal disease and unfold the therapeutic dilemmas we confronted. Marked hyperbilirubinemia was successfully reversed with brentuximab vedotin (BV) at a dose of 1.2 mg/kg and the patient was subsequently treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) at full doses, achieving complete metabolic response. A literature review of intrahepatic cholestasis in cHL is also presented based on currently available data with focus on treatment options and clinicopathologic associations. CONCLUSION: VBDS and intrahepatic cholestasis are rare and potentially fatal complications of cHL. Their prompt recognition and appropriate treatment can dramatically affect cHL patients' outcome. BV, used at a reduced dose as a bridging therapy, should be considered as a high-priority treatment plan in these challenging cases.

Hyponatremia in Patients with Hematologic Diseases.

Hyponatremia is the most common electrolyte disorder in clinical practice and is associated with increased morbidity and mortality. It is frequently encountered in hematologic patients with either benign or malignant diseases. Several underlying mechanisms, such as hypovolemia, infections, toxins, renal, endocrine, cardiac, and liver disorders, as well as the use of certain drugs appear to be involved in the development or the persistence of hyponatremia. This review describes the pathophysiology of hyponatremia and discusses thoroughly the contributing factors and mechanisms that may be encountered specifically in patients with hematologic disorders. The involvement of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and renal salt wasting syndrome (RSWS) in the development of hyponatremia in such patients, as well as their differential diagnosis and management, are also presented. Furthermore, the distinction between true hyponatremia and pseudohyponatremia is explained. Finally, a practical algorithm for the evaluation of hyponatremia in hematologic patients, as well as the principles of hyponatremia management, are included in this review.

Hematological manifestations of SARS-CoV-2 in children.

Infection from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), though mainly a respiratory disease, can impair many systems, including causing hematological complications. Lymphopenia and hypercoagulability have been reported in adults with coronavirus disease 2019 (COVID-19) and are considered markers of poor prognosis. This review summarizes the hematological findings in children with SARS-CoV-2 infection. The majority of infected children had a normal leukocyte count, while the most common white blood cell abnormality was leukopenia. Lymphopenia, which may be a marker of severe disease, was rarer in children than in adults, possibly due to their immature immune system or due to the less severe manifestation of COVID-19 in this age group. Age may have an impact, and in neonates and infants the most common abnormality was lymphocytosis. Abnormalities of red blood cells and platelets were uncommon. Anemia and hypercoagulability were reported mainly in children presenting the novel multisystem inflammatory syndrome (MIS) associated with SARS-CoV-2.

Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) possesses distinct biology and peculiar natural history, in which the roles of the winged and hedgehog signalling pathways are unclear. MATERIALS AND METHODS: We constructed tissue microarrays and studied the immunohistochemical (IHC) expression of ß-catenin, smoothened (SMO) and the transcription factors TCF, LEF, GLI1 in 87 CUP cases for prognostic significance. RESULTS: A low rate of IHC expression of proteins was seen, the cut-off used being any expression in ≥ 1% of tumour cells. At univariate analysis, only nuclear IHC SMO expression displayed a statistically significant association with favourable outcome [median Overall survival (OS) of 19 months in SMO-positive vs. 12 months in SMO-negative cases, P = 0·01]. An activated Wnt pathway, defined as IHC expression of any of nuclear ß-catenin, TCF and LEF, was significantly associated with favourable progression free survival (median 9 vs. 5 months, P = 0·037) and OS (median 19 vs. 13 months, P = 0·04). This prognostic impact on OS was mainly driven by nuclear expression of TCF and/or LEF (P = 0·03). No prognostic significance of the hedgehog pathway activation status, defined as IHC expression of SMO or nuclear GLI1, could be established. A favourable prognostic impact of the concurrent activation of both pathways was observed. A trend for association of activated Wnt with response to chemotherapy (responders 67% among activated Wnt cases vs. 35% among nonactivated Wnt cases, P = 0·07) was observed in CUP adenocarcinomas. CONCLUSIONS: Activation of the Wnt pathway was a positive prognostic factor in a small CUP series, possibly via enhanced chemosensitivity. Independent validation is warranted.