Role of the STING pathway in myeloid neoplasms: a prospero-registered systematic review of principal hurdles of STING on the road to the clinical practice.

Myeloid neoplasms are a group of bone marrow diseases distinguished by disruptions in the molecular pathways that regulate the balance between hematopoietic stem cell (HSC) self-renewal and the generation of specialized cells. Cytokines and chemokines, two important components of the inflammatory process, also influence hematological differentiation. In this scenario, immunological dysregulation plays a pivotal role in the pathogenesis of bone marrow neoplasms. The STING pathway recognizes DNA fragments in the cell cytoplasm and triggers an immune response by type I interferons. The role of STING in cancer has not yet been established; however, both actions, as an oncogene or tumor suppressor, have been documented in other types of cancer. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42023407512) to discuss the role of STING pathway in the advancement of pathogenesis and/or prognosis for different myeloid neoplasms. In brief, scientific evidence supports investigations that primarily use cell lines from myeloid neoplasms, such as leukemia. More high-quality research and clinical trials are needed to understand the role of the STING pathway in the pathology of hematological malignancies. Finally, the STING pathway suggests being a promising therapeutic molecular target, particularly when combined with current drug therapies.

CD38 as a pan-hematologic target for chimeric antigen receptor T cells.

Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat 3 different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38 mediated the rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant because it expands the potential for this novel therapy to affect diverse patient populations.

Apoptotic events induced by a natural plastoquinone from the marine alga Desmarestia menziesii in lymphoid neoplasms.

There exists an urgent need for the development of new drugs for the treatment of lymphoid neoplasms. The aim of this study was to evaluate the cytotoxic effect of the marine plastoquinone 9'-hydroxysargaquinone (9'-HSQ), focusing on investigation of the mechanism by which it causes death in lymphoid neoplastic cells. This particular plastoquinone reduced the cell viability of different hematological tumor cell lines in a time-dependent and concentration-dependent manner. Intrinsic apoptosis occurred with time-dependent reduction of mitochondrial membrane potential (42.3 ± 1.1% of Daudi cells and 18.6 ± 5.6% of Jurkat cells maintained mitochondrial membrane integrity) and apoptosis-inducing factor release (Daudi: 133.3 ± 8.1%, Jurkat: 125.7 ± 6.9%). Extrinsic apoptosis also occurred, as reflected by increased FasR expression (Daudi: 139.5 ± 7.1%, Jurkat: 126.0 ± 1.0%). Decreases were observed in the expression of Ki-67 proliferation marker (Daudi: 67.5 ± 2.5%, Jurkat: 84.3 ± 3.8%), survivin (Daudi: 66.0 ± 9.9%, Jurkat: 63.1 ± 6.0%), and NF-κB (0.7 ± 0.04% in Jurkat cells). Finally, 9'-HSQ was cytotoxic to neoplastic cells from patients with different lymphoid neoplasms (IC50: 4.9 ± 0.6 to 34.2 ± 0.4 µmol/L). These results provide new information on the apoptotic mechanisms of 9'-HSQ and suggest that it might be a promising alternative for the treatment of lymphoid neoplasms.

Cortactin Expression in Hematopoietic Cells: Implications for Hematological Malignancies.

Cortactin is an actin-binding protein expressed in virtually all cell types. It regulates several cell functions, including adhesion and migration. Cortactin overexpression is associated with increased metastasis formation and worse outcome in different types of solid tumors, thus highlighting a critical role of cortactin in cancer progression. Mechanistically, this is due to increased invadopodia formation and matrix metalloproteinase secretion. Cortactin has been until recently considered absent in hematopoietic cells because these cells express the cortactin homolog hematopoietic cell-specific lyn substrate-1. However, many recent reports describe functional expression of cortactin in different hematopoietic cells, such as macrophages, dendritic cells, and lymphocytes. Of note, cortactin is strongly overexpressed in leukemic cell lines and primary patient-derived leukemic cells. In B-cell chronic lymphocytic leukemia, this is associated with poor prognosis and increased chemotaxis; in B-cell acute lymphoblastic leukemia, high cortactin levels correlate with treatment failure and relapse. Moreover, cortactin has been proposed as a diagnostic marker for non-Hodgkin B-cell lymphomas. This review summarizes current knowledge on cortactin expression in hematopoietic cells and discusses the functional implications for different hematological malignancies.

Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells.

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy.

Epigenetics in Hematological Malignancies.

Acute leukemias are hematologic malignancies with aggressive behavior especially in adult population. With the introduction of new gene expression and sequencing technologies there have been advances in the knowledge of the genetic landscape of acute leukemias. A more detailed analysis allows for the identification of additional alterations in epigenetic regulators that have a profound impact in cellular biology without changes in DNA sequence. These epigenetic alterations disturb the physiological balance between gene activation and gene repression and contribute to aberrant gene expression, contributing significantly to the leukemic pathogenesis and maintenance. We review epigenetic changes in acute leukemia in relation to what is known about their mechanism of action, their prognostic role and their potential use as therapeutic targets, with important implications for precision medicine.

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

Hippo pathway deregulation: implications in the pathogenesis of haematological malignancies.

The Hippo pathway participates in the regulation of cell proliferation, differentiation and apoptosis. It is composed by a large array of proteins whose deregulation has been associated with pro-oncogenic and antioncogenic processes. The present review focuses on the Hippo pathway signalling network and discusses its dual role in oncogenesis, particularly in haematological malignancies.

Telomere protein complexes and their role in lymphoid malignancies.

Telomeres are highly regulated and dynamic complexes that protect the genomic DNA and prevent the end of linear chromosomes from being misrecognized as a broken DNA. Due to the end replication problem, telomeres of somatic cells shorten with each cell division, inducing cell senescence. Telomerase is a reverse transcriptase capable of compensating telomere attrition by adding telomere repeats to the ends of chromosomes. Human telomeres are associated with the shelterin complex which consists of six telomere-associated proteins that specifically bind to telomeric DNA. Alterations or removal of individual shelterin components would lead to telomere uncapping and telomere dysfunction, resulting in cellular senescence and transformation to a malignant state. Another complex of multifunctional proteins, named non-shelterin complex, is thought to prevent telomere degradation and facilitate telomerase-based telomere elongation. As telomerase is highly expressed in most human tumor cells, it is considered an attractive target for new therapeutic strategies. In this review, we will summarize the characteristics of telomeres and telomerase in lymphoid malignancies and discuss the role of telomere-associated proteins in these entities.

Twist as a new prognostic marker in hematological malignancies.

Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies.

Differential profile of PIP4K2A expression in hematological malignancies.

PIP4K2A is a lipid kinase that phosphorylates PtdIns5P, generating PtdIns4,5P2. Recently, PIP4K2A was identified as a potential target in acute myeloid leukemia cells. The objective of the present study was to investigate the PIP4K2A expression in hematological malignancies and verify the effects of PIP4K2A silencing on proliferation and survival of leukemia cell lines. PIP4K2A was found to be a cytoplasmic and nuclear protein with reduced levels in leukemia cell lines compared to normal leukocytes. PIP4K2A mRNA levels were significantly reduced in bone marrow cells from acute lymphoid leukemia (ALL) patients compared with healthy donors and in myelodysplastic syndromes (MDS) with ≥5% compared with <5% bone marrow blasts. Low PIP4K2A expression (lowest tertile versus 2 higher tertiles) negatively impacted overall survival of MDS patients by univariate analysis. PIP4K2A silencing did not modulate cell proliferation, clonogenicity and apoptosis of HEL and Namalwa leukemia cells. In summary, we characterized the expression of PIP4K2A in a cohort of patients with hematological malignancies and we found that PIP4K2A mRNA expression is downregulated in RAEB-1/RAEB-2 MDS and ALL cells, and PIP4K2A silencing does not modulate cell survival in HEL and Namalwa leukemia cells.

Foreign Bodies in the Ear, Nose and Throat: An Experience in a Tertiary Care Hospital in Central Nepal

Introduction A foreign body (FB) is an object or substance foreign to the location where it is found. FBs in the ear, nose, and throat are a common problem frequently encountered in both children and adults. Objective To analyze FBs in terms of type, site, age, and gender distribution and method of removal. Methods A retrospective study was performed in a tertiary care hospital in the central part of Nepal. The study period was from June 2013 to May 2014. The information was obtained from hospital record books. Results A total of 134 patients had FBs in the ear, nose, or throat; 94 were males and 40 were females. Of the 134 patients, 70 (52.23% ) had FB in the ear, 28 (20.89% ) in the nose, and 36 (26.86% ) in the throat. The FB was animate (living) in 28 (40% ) patients with FB in the ear and 1 (3.5% ) patient with FB in the nose, but the FB was inanimate (nonliving) in any patient with FB in the throat, in 42 (60% ) patients with FB in the ear FB, and in 27 (96.4% ) patients with FB of the nose. The FB was removed with or without local anaesthesia (LA) in 98 (73.13% ) patients, and only 36 patients (26.86% ) required general anaesthesia (GA). The most common age group affected was <10 years. Conclusion FBs in the ear and nose were found more frequently in children, and the throat was the most common site of FB in adults and elderly people. Most of the FBs can be easily removed in emergency room or outpatient department. .

Individuals with hematological malignancies before undergoing chemotherapy present oxidative stress parameters and acute phase proteins correlated with nutritional status.

Hematological malignancies present abnormal blood cells that may have altered functions. This study aimed to evaluate nutritional status, acute phase proteins, parameters of cell's functionality, and oxidative stress of patients with hematological malignancies, providing a representation of these variables at diagnosis, comparisons between leukemias and lymphomas and establishing correlations. Nutritional status, C-reactive protein (CRP), albumin, phagocytic capacity and superoxide anion production of mononuclear cells, lipid peroxidation and catalase activity in plasma were evaluated in 16 untreated subjects. Main diagnosis was acute leukemia (n = 9) and median body mass index (BMI) indicated overweight (25.6 kg/m(2)). Median albumin was below (3.2 g/dL) and CRP above (37.45 mg/L) the reference values. Albumin was inversely correlated with BMI (r = -0.53). Most patients were overweight before the beginning of treatment and had a high CRP/albumin ratio, which may indicate a nutrition inflammatory risk. BMI values correlated positively with lipid peroxidation and catalase activity. A strong correlation between catalase activity and lipid peroxidation was found (r = 0.75). Besides the elevated BMI, these patients also have elevated CRP values and unexpected relations between nutritional status and albumin, reinforcing the need for nutritional counseling during the course of chemotherapy, especially considering the correlations between oxidative stress parameters and nutritional status evidenced here.

Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2.

The transcription factor signal STAT5 is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematologic malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacologic bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small-molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain subfamily of proteins, it seems that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T-cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knockdown or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors (TKI) in inducing apoptosis in leukemia cells. In contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and TKIs may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.

Pharmacokinetics of piperacillin/tazobactam in cancer patients with hematological malignancies and febrile neutropenia after chemotherapy.

INTRODUCTION: Patients with febrile neutropenia (FN) exhibit changes in extracellular fluid that may alter the plasma concentrations of beta-lactams and result in therapeutic failure or toxicity. We evaluated the pharmacokinetics of piperacillin/tazobactam in patients with hematological malignancies and FN after receiving chemotherapy at a primary public cancer center. METHODS: This was an open, nonrandomized, observational, descriptive, and prospective study. Samples from 15 patients with hematological malignancies and FN were evaluated after the administration of chemotherapy. Five blood samples were taken from each patient when the antibiotic level was at steady-state 10, 60, 120, 180, and 350 min after each dose. Antibiotic concentrations were measured using gel diffusion with Bacillus subtilis. All study participants provided written informed consent. RESULTS: We investigated the pharmacokinetics of piperacillin in 14 patients between the ages of 18 years and 59 years and with a mean absolute neutrophil count of 208 cells per mm³ (standard deviation (SD) ± 603.2). The following pharmacokinetic measurements were obtained: maximum concentration, 94.1-1133 mg/L; minimum concentration, 0.47-37.65 mg/L; volume of distribution, 0.08-0.65 L/kg (mean, 0.34 L/kg); drug clearance (CL), 4.42-27.25 L/h (mean, 9.93 L/h); half-life (t(1/2)), 0.55-2.65 h (mean, 1.38 h); and area under the curve, 115.12-827.16 mg · h/L. CONCLUSION: Patients with FN after receiving chemotherapy exhibited significant variations in the pharmacokinetic parameters of piperacillin compared with healthy individuals; specifically, FN patients demonstrated an increase in t1(/2) and decreased CL.

Galectins in hematological malignancies.

PURPOSE OF REVIEW: Galectins are a family of lectin molecules that have emerged as key players in inflammation and tumor progresssion by displaying intracellular and extracellular activities. This review describes the recent advances on the role of galectins in hematological neoplasms. RECENT FINDINGS: Galectin-1 and galectin-3 are the best studied galectins in oncohematology. Increased expression of galectin-1 has been associated with tumor progression in Hodgkin's lymphoma and chronic lymphocytic leukemia, whereas galectin-3 plays a supporting role in chronic myelogenous leukemia and multiple myeloma. Functional studies have assigned a key role for galectin-1 as a negative regulator of T-cell immunity in Hodgkin's lymphoma and cutaneous T-cell lymphoma. Of therapeutic interest is the development of agents with the capacity to interfere with galectin functions. SUMMARY: Current knowledge indicates a key role for galectins in hematological neoplasms by favoring the growth and survival of tumor cells and facilitating tumor immune escape. Intervention using specific galectin inhibitors is emerging as an attractive therapeutic option to alter the course of these malignancies.

Efeito bifidogênico do frutooligossacarídeo na microbiota intestinal de pacientes com neoplasia hematológica / Bifidogenic effect of fructooligosaccharides in the intestinal flora of patients with hematological neoplasia

OBJETIVO: Verificar o efeito bifidogênico do frutooligossacarídeo nos pacientes com neoplasias hematológicas submetidos a quimioterapia. MÉTODOS: Trata-se de um estudo clínico randomizado duplo cego, desenvolvido na Unidade de Transplante de Medula Óssea do Centro de Pesquisas Oncológicas de Florianópolis, o qual envolve 25 pacientes divididos em 2 grupos que receberam, por 15 dias, 12g de frutooligossacarídeo (n=14) ou placebo (maltodextrina) (n=11). Foram avaliados a quantidade de bifidobactérias e os valores de pH fecal antes e após a suplementação. RESULTADOS: Observou-se na população estudada o predomínio do sexo masculino (72 por cento) e a idade média de 34 anos. O grupo suplementado apresentou um aumento significante na quantidade de bifidobactérias (p<0,05) e o pH fecal não foi alterado em nenhum dos grupos. CONCLUSÃO: Verificou-se que a suplementação aumentou a quantidade de bifidobactérias, interferindo na composição da microbiota intestinal, e que não houve alteração do pH fecal.

OBJECTIVE: To verify the bifidogenic effect of fructooligosaccharides in patients with hematological neoplasia submitted to chemotherapy. METHODS: This is a clinical, randomized, double-blind study done in the Bone Marrow Transplant Unit of the Oncology Research Center of Florianopolis. It involved 25 patients divided into 2 groups who received 12g of fructooligosaccharides (n=14) for 15 days or placebo (maltodextrin) (n=11). The amount of bifidobacteria and the values of fecal pH before and after supplementation were investigated. RESULTS: Most of the studied population was male (72 percent) and the mean age was 34 years. The group that received supplementation presented a significant increase in the amount of bifidobacteria (p<0.05) and fecal pH remained unchanged in both groups. CONCLUSION: Supplementation increased the amount of bifidobacteria, interfering in the composition of the intestinal flora, but fecal pH was not affected.

Detection of BCR-ABL transcripts by multiplex and nested PCR in different haematological disorders.

Single-step Multiplex RT-PCR was used as a rapid and highly sensitive method for screening patients with myeloproliferative conditions and ALL for the presence of underlying BCR-ABL gene fusions. Positive and negative results obtained with the multiplex assay were subsequently confirmed by nested PCR. We studied 21 patients for detecting the presence of b3a2, b2a2 and e1a2 BCR-ABL transcripts at diagnosis and following treatment with different therapeutical procedures. These studies allowed the molecular characterisation of patients with different haematological disorders and for demonstrating BCR-ABL transcripts in Ph-CML. In a Ph+ CML patient, a switch of isoforms was detected after bone marrow transplantation and infusion with donor lymphocytes, implying substitution of e1a2 for b3a2 coexisting with a myeloid/lymphoid biphenotypic profile. In ALL, one Ph+ patient showed coexpression of e1a2 and b2a2 at diagnosis followed by persistence of e1a2 after bone marrow transplantation. Our results were compared to previous findings in the literature on molecular diagnosis of leukaemias.