Pub Date : 2024-09-01Epub Date: 2024-08-27DOI: 10.3390/hemato5030024
Alexandria P Eiken, Elizabeth Schmitz, Erin M Drengler, Audrey L Smith, Sydney A Skupa, Kabhilan Mohan, Sandeep Rana, Sarbjit Singh, Jayapal Reddy Mallareddy, Grinu Mathew, Amarnath Natarajan, Dalia El-Gamal
Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells.
Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells.
Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics.
Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.
{"title":"The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax.","authors":"Alexandria P Eiken, Elizabeth Schmitz, Erin M Drengler, Audrey L Smith, Sydney A Skupa, Kabhilan Mohan, Sandeep Rana, Sarbjit Singh, Jayapal Reddy Mallareddy, Grinu Mathew, Amarnath Natarajan, Dalia El-Gamal","doi":"10.3390/hemato5030024","DOIUrl":"https://doi.org/10.3390/hemato5030024","url":null,"abstract":"<p><strong>Background: </strong>B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells.</p><p><strong>Methods: </strong>We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells.</p><p><strong>Results: </strong>The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics.</p><p><strong>Conclusions: </strong>Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.</p>","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"5 3","pages":"321-339"},"PeriodicalIF":0.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute lymphoblastic leukemia (ALL), a remarkable cancer that mainly affects children, has seen commendable advances in its treatment. However, the occurrence of relapses after initial treatments poses a major threat and is one of the leading causes of cancer-related mortality in pediatric patients. To address this problem, innovative therapeutic approaches for ALL need to be continuously developed and refined. Synthetic lethality, an interaction between genes in which alteration of only one allows survival, but simultaneous alteration of both leads to inviability, is emerging as a promising therapeutic approach against ALL and other cancers. In this regard, the review aims to examine the documented cases of synthetic lethality in ALL reported to date (2023) and to elucidate the molecular mechanisms underlying this phenomenon. Furthermore, this review explores possible targets that have so far gone unnoticed, justifying their importance in this context.
急性淋巴细胞白血病（ALL）是一种主要影响儿童的常见癌症，在治疗方面取得了令人称道的进展。然而，初次治疗后复发是一个重大威胁，也是导致儿童患者癌症相关死亡的主要原因之一。为解决这一问题，需要不断开发和完善针对 ALL 的创新治疗方法。合成致死性是基因之间的相互作用，其中只有一个基因发生改变才能存活，但两个基因同时发生改变则会导致死亡。为此，本综述旨在研究迄今（2023 年）报道的 ALL 合成致死性病例，并阐明这一现象的分子机制。此外，本综述还探讨了迄今为止尚未引起人们注意的可能靶点，以证明它们在这方面的重要性。
{"title":"Synthetic Lethality Approaches in Acute Lymphoblastic Leukemia","authors":"F. A. Lagunas-Rangel, V. Chávez-Valencia","doi":"10.3390/hemato5010002","DOIUrl":"https://doi.org/10.3390/hemato5010002","url":null,"abstract":"Acute lymphoblastic leukemia (ALL), a remarkable cancer that mainly affects children, has seen commendable advances in its treatment. However, the occurrence of relapses after initial treatments poses a major threat and is one of the leading causes of cancer-related mortality in pediatric patients. To address this problem, innovative therapeutic approaches for ALL need to be continuously developed and refined. Synthetic lethality, an interaction between genes in which alteration of only one allows survival, but simultaneous alteration of both leads to inviability, is emerging as a promising therapeutic approach against ALL and other cancers. In this regard, the review aims to examine the documented cases of synthetic lethality in ALL reported to date (2023) and to elucidate the molecular mechanisms underlying this phenomenon. Furthermore, this review explores possible targets that have so far gone unnoticed, justifying their importance in this context.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"21 47","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139156064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hemato (ISSN 2673-6357) is an open access, peer-reviewed journal that publishes original articles and reviews highlighting important advances in the fundamental areas of Hematology [...]
{"title":"Hemato Keeps You Updated on the Research in Hematology","authors":"Antonino Carbone","doi":"10.3390/hemato5010001","DOIUrl":"https://doi.org/10.3390/hemato5010001","url":null,"abstract":"Hemato (ISSN 2673-6357) is an open access, peer-reviewed journal that publishes original articles and reviews highlighting important advances in the fundamental areas of Hematology [...]","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"28 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139158938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lívia de Oliveira Sales, L. L. B. de Oliveira, Jean Breno Silveira da Silva, M. O. de Moraes Filho, M. E. D. de Moraes, R. Montenegro, C. Moreira-Nunes
The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China and is responsible for Coronavirus disease (COVID-19). Despite being well tolerated by most patients, a fraction of cases evolve into a potentially fatal condition requiring intensive care. In addition to respiratory complications, several studies have reported cases of patients who developed intense thrombosis, including acute myocardial infarction and ischemic stroke, as well as the presence of elevated coagulation markers. Evidence has shown that the virus can interact directly with platelets and modulate their thrombotic and inflammatory functions, with significant prognostic implications. It is important to highlight that the emerging literature shows that when hyperactive these cells can act as pro-viral infections both in transporting their particles and in increasing inflammation, leading to a hyperinflammatory state and consequent clinical worsening. In this review, we searched for studies available in public databases and discussed the interaction of platelet biomarkers in the pathogenesis of COVID-19. In this context, understanding the mechanism of SARS-CoV-2 and these cells in different clinical conditions could help us to understand the coagulation and inflammation profiles of critically ill patients with the disease, guiding faster clinical management and enabling the reuse and targeting of more efficient therapies.
{"title":"The Role of Platelet Molecules in Risk Stratification of Patients with COVID-19","authors":"Lívia de Oliveira Sales, L. L. B. de Oliveira, Jean Breno Silveira da Silva, M. O. de Moraes Filho, M. E. D. de Moraes, R. Montenegro, C. Moreira-Nunes","doi":"10.3390/hemato4040029","DOIUrl":"https://doi.org/10.3390/hemato4040029","url":null,"abstract":"The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China and is responsible for Coronavirus disease (COVID-19). Despite being well tolerated by most patients, a fraction of cases evolve into a potentially fatal condition requiring intensive care. In addition to respiratory complications, several studies have reported cases of patients who developed intense thrombosis, including acute myocardial infarction and ischemic stroke, as well as the presence of elevated coagulation markers. Evidence has shown that the virus can interact directly with platelets and modulate their thrombotic and inflammatory functions, with significant prognostic implications. It is important to highlight that the emerging literature shows that when hyperactive these cells can act as pro-viral infections both in transporting their particles and in increasing inflammation, leading to a hyperinflammatory state and consequent clinical worsening. In this review, we searched for studies available in public databases and discussed the interaction of platelet biomarkers in the pathogenesis of COVID-19. In this context, understanding the mechanism of SARS-CoV-2 and these cells in different clinical conditions could help us to understand the coagulation and inflammation profiles of critically ill patients with the disease, guiding faster clinical management and enabling the reuse and targeting of more efficient therapies.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"190 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139206412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guillermo A. Herrera, J. Teng, Chun Zeng, L. Del Pozo-Yauner, Bing Liu, E. Turbat-Herrera
The process of light-chain-associated amyloid (AL-Am) fibril formation in unique organelles (fibril-forming organelles) with lysosomal features has been documented in vitro in renal mesangial cells incubated with amyloidogenic light chains using electron microscopy and lysosomal gradient centrifugation to visualize intricate interactions between monoclonal light chains and endosomes/lysosomes. It is important to determine whether this process also occurs in vivo in the human renal mesangium. The present study analyzes 13 renal biopsies from patients with renal AL-amyloidosis and utilizes ultrastructural labeling techniques to define the nature and function of these organelles. Organelles were labeled for lysosomal-associated membrane protein (LAMP) and CD-68 (a macrophage marker). Furthermore, lambda was also localized inside these structures in transformed mesangial cells with a macrophage phenotype. These 11 cases from renal biopsies with a diagnosis of AL-amyloidosis (5 kappa and 8 lambda light-chain-associated) were examined ultrastructurally. All of the cases exhibited numerous fibrils forming organelles in approximately 40–50% of the remaining mesangial cells. All of the cases revealed mesangial cells engaged in active amyloidogenesis. Fibril-forming organelles are organelles with morphological/immunohistochemical and biochemical characteristics of lysosomes but with a unique, peculiar morphology. Five cases of other glomerular disorders used as controls were also carefully scrutinized for fibril-forming organelles and failed to show any. In the AL-amyloid renal cases, there was an intricate interaction between the fibril-forming organelles and lambda-/kappa-containing amyloid fibrils, supporting the notion that the monoclonal light chains participated in their formation.
{"title":"Fibril-Forming Organelles in Mesangial Cells in Renal Biopsies from Patients with Light-Chain-Associated Amyloidosis","authors":"Guillermo A. Herrera, J. Teng, Chun Zeng, L. Del Pozo-Yauner, Bing Liu, E. Turbat-Herrera","doi":"10.3390/hemato4040028","DOIUrl":"https://doi.org/10.3390/hemato4040028","url":null,"abstract":"The process of light-chain-associated amyloid (AL-Am) fibril formation in unique organelles (fibril-forming organelles) with lysosomal features has been documented in vitro in renal mesangial cells incubated with amyloidogenic light chains using electron microscopy and lysosomal gradient centrifugation to visualize intricate interactions between monoclonal light chains and endosomes/lysosomes. It is important to determine whether this process also occurs in vivo in the human renal mesangium. The present study analyzes 13 renal biopsies from patients with renal AL-amyloidosis and utilizes ultrastructural labeling techniques to define the nature and function of these organelles. Organelles were labeled for lysosomal-associated membrane protein (LAMP) and CD-68 (a macrophage marker). Furthermore, lambda was also localized inside these structures in transformed mesangial cells with a macrophage phenotype. These 11 cases from renal biopsies with a diagnosis of AL-amyloidosis (5 kappa and 8 lambda light-chain-associated) were examined ultrastructurally. All of the cases exhibited numerous fibrils forming organelles in approximately 40–50% of the remaining mesangial cells. All of the cases revealed mesangial cells engaged in active amyloidogenesis. Fibril-forming organelles are organelles with morphological/immunohistochemical and biochemical characteristics of lysosomes but with a unique, peculiar morphology. Five cases of other glomerular disorders used as controls were also carefully scrutinized for fibril-forming organelles and failed to show any. In the AL-amyloid renal cases, there was an intricate interaction between the fibril-forming organelles and lambda-/kappa-containing amyloid fibrils, supporting the notion that the monoclonal light chains participated in their formation.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"53 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139245623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karina P. Verma, Rebecca Steuer, Camille V. Edwards
Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.
未确定意义单克隆γ病(MGUS)是一种病因尚不完全清楚的恶性前浆细胞疾病。可改变的风险因素和遗传倾向可能相互作用，增加特定个体和人群的MGUS风险。确定地理流行模式和可改变的危险因素对于了解MGUS的病因至关重要。本综述的目的是概述跨地理位置的MGUS患病率和可改变的危险因素的原始研究。我们对来自PubMed®、Embase®和Web of Science®的39项符合条件的研究进行了系统评价，这些研究以英文撰写，并于2023年2月前发表。我们的协议是按照普洛斯彼罗指南注册的。研究使用研究电子数据采集进行综合，并使用国家心脏、肺和血液研究所的研究质量评估工具进行评估。不同地理位置的MGUS患病率从0.24%到9%不等。可改变的MGUS危险因素包括感染、自身免疫性疾病、慢性炎症、生活方式因素、环境暴露和电离辐射。因此，MGUS的发生可能与促进浆细胞克隆增殖的慢性抗原刺激和遗传畸变有关。评估基因-环境相互作用的前瞻性研究需要进一步确定MGUS的危险因素，并为筛查和预防策略提供信息。
{"title":"Geographic Prevalence Patterns and Modifiable Risk Factors for Monoclonal Gammopathy of Undetermined Significance","authors":"Karina P. Verma, Rebecca Steuer, Camille V. Edwards","doi":"10.3390/hemato4040027","DOIUrl":"https://doi.org/10.3390/hemato4040027","url":null,"abstract":"Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"60 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135221535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chiara Marvisi, Elena Galli, Caterina Ricordi, Rexhep Durmo, Massimo Roncali, Francesco Muratore, Carlo Salvarani, Annibale Versari
The role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (18F-FDG PET) in the diagnosis of large vessel vasculitis (LVV) is well established. It permits us to assess the extent and the grade of vascular involvement and to rule out the other causes in clinical scenarios characterized by less specific symptoms. The advantages of 18F-FDG PET are far less clear in monitoring disease activity over time. Studies looking for the role of 18F-FDG PET as a potential biomarker had conflicting results and whether and when to repeat it during follow-up is based on clinical experience. A comprehensive assessment, including clinical, laboratory and morphological imaging is still required to monitor patients with large-vessel vasculitis over time. The aim of this review is to present more recent data about the utility of 18 F-FDG PET in the diagnosis and follow-up of LVV.
{"title":"The Role of PET in the Diagnosis and Disease Activity Assessment in Large Vessel Vasculitis","authors":"Chiara Marvisi, Elena Galli, Caterina Ricordi, Rexhep Durmo, Massimo Roncali, Francesco Muratore, Carlo Salvarani, Annibale Versari","doi":"10.3390/hemato4040026","DOIUrl":"https://doi.org/10.3390/hemato4040026","url":null,"abstract":"The role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (18F-FDG PET) in the diagnosis of large vessel vasculitis (LVV) is well established. It permits us to assess the extent and the grade of vascular involvement and to rule out the other causes in clinical scenarios characterized by less specific symptoms. The advantages of 18F-FDG PET are far less clear in monitoring disease activity over time. Studies looking for the role of 18F-FDG PET as a potential biomarker had conflicting results and whether and when to repeat it during follow-up is based on clinical experience. A comprehensive assessment, including clinical, laboratory and morphological imaging is still required to monitor patients with large-vessel vasculitis over time. The aim of this review is to present more recent data about the utility of 18 F-FDG PET in the diagnosis and follow-up of LVV.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"64 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136102788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Bared Dukenik, Deborah Soong, Wenhui Li, Ellen Madarang, Justin Watts, Justin Taylor
We describe a case of a female patient with acute lymphoblastic leukemia treated with high-dose systemic methotrexate and intrathecal methotrexate for leukemic relapse of the central nervous system. She developed complete bilateral lower-limb paralysis that was not attributable to any other cause. She was treated with folic acid, vitamin B12, methionine, S-adenosylmethionine, leucovorin, and dextromethorphan. After a 3-month period of paraplegia, she began to slowly recover motor function. She can now ambulate with assistance and continues to improve. There is a paucity of literature on methotrexate-induced subacute combined degeneration, which is typically described as irreversible. In addition to reporting our unique case, we review the published literature and call for more awareness and research in this area.
{"title":"Methotrexate-Induced Subacute Combined Degeneration in Acute Lymphoblastic Leukemia with CNS Relapse May Be Reversible","authors":"David Bared Dukenik, Deborah Soong, Wenhui Li, Ellen Madarang, Justin Watts, Justin Taylor","doi":"10.3390/hemato4040025","DOIUrl":"https://doi.org/10.3390/hemato4040025","url":null,"abstract":"We describe a case of a female patient with acute lymphoblastic leukemia treated with high-dose systemic methotrexate and intrathecal methotrexate for leukemic relapse of the central nervous system. She developed complete bilateral lower-limb paralysis that was not attributable to any other cause. She was treated with folic acid, vitamin B12, methionine, S-adenosylmethionine, leucovorin, and dextromethorphan. After a 3-month period of paraplegia, she began to slowly recover motor function. She can now ambulate with assistance and continues to improve. There is a paucity of literature on methotrexate-induced subacute combined degeneration, which is typically described as irreversible. In addition to reporting our unique case, we review the published literature and call for more awareness and research in this area.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136114417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leigh A. Madden, Rebecca V. Vince, Victoria C. Edwards, Vivienne M. Lee, Desmond M. Connolly
The blood coagulation response to decompression stress in humans has yet to be fully investigated. Here we utilised calibrated automated thrombogram (CAT) on samples from healthy volunteers exposed to decompression stress to investigate real-time thrombin generation. To induce decompression stress, fifteen apparently healthy males (age 20–50 yr) were exposed to two consecutive ascents to 25,000 ft for 60 min (1st ascent) and then 90 min (2nd ascent) while breathing 100% oxygen. Citrated blood samples were taken prior to exposure (T0), following the 2nd ascent (T8) and at 24 h (T24). Thrombin generation curves were obtained using ThrombinoscopeTM. Parameters determined were lag time (LAG), time to peak (TTP), peak thrombin (PEAK), endogenous thrombin potential (ETP) and velocity index (VEL). Of the 15 subjects, 12 had validated coagulation profiles. TTP and ETP showed no significant differences. However, there was a significant increase in VEL from T0 to T8 (p = 0.025) and from T8 to T24 (p = 0.043). A non-significant trend of an overall increase in PEAK was also observed from T0 to T8 (p = 0.069) and from T8 to T24 (p = 0.098). PEAK and VEL were found to be correlated. Taken together, these two parameters suggest an overall shift towards a more procoagulant profile following hypobaric stress.
{"title":"Coagulation Profiles in Humans Exposed to Exertional Hypobaric Decompression Stress Determined by Calibrated Automated Thrombogram","authors":"Leigh A. Madden, Rebecca V. Vince, Victoria C. Edwards, Vivienne M. Lee, Desmond M. Connolly","doi":"10.3390/hemato4040024","DOIUrl":"https://doi.org/10.3390/hemato4040024","url":null,"abstract":"The blood coagulation response to decompression stress in humans has yet to be fully investigated. Here we utilised calibrated automated thrombogram (CAT) on samples from healthy volunteers exposed to decompression stress to investigate real-time thrombin generation. To induce decompression stress, fifteen apparently healthy males (age 20–50 yr) were exposed to two consecutive ascents to 25,000 ft for 60 min (1st ascent) and then 90 min (2nd ascent) while breathing 100% oxygen. Citrated blood samples were taken prior to exposure (T0), following the 2nd ascent (T8) and at 24 h (T24). Thrombin generation curves were obtained using ThrombinoscopeTM. Parameters determined were lag time (LAG), time to peak (TTP), peak thrombin (PEAK), endogenous thrombin potential (ETP) and velocity index (VEL). Of the 15 subjects, 12 had validated coagulation profiles. TTP and ETP showed no significant differences. However, there was a significant increase in VEL from T0 to T8 (p = 0.025) and from T8 to T24 (p = 0.043). A non-significant trend of an overall increase in PEAK was also observed from T0 to T8 (p = 0.069) and from T8 to T24 (p = 0.098). PEAK and VEL were found to be correlated. Taken together, these two parameters suggest an overall shift towards a more procoagulant profile following hypobaric stress.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135459353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ringo Manta, Chiara Lauri, Maurizio Taurino, Alberto Signore
Diagnosis of vascular graft/endograft infection (VGEI) is a challenge for clinicians due to the heterogeneity of clinical presentation and the complexity of its management. Microbiological culture is the gold standard, but it often fails to isolate the causative microorganism. A non-invasive imaging approach is therefore needed to assess VGEI. CTA is currently the first-choice imaging modality. Nuclear medicine techniques are recommended in case of negative or doubtful CTA results with persisting clinical suspicion. This review aims to summarize data from original studies published in the last decades regarding the role of both white blood cell (WBC) scans and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT), their respective diagnostic performances, and their integration into the diagnostic approach for patients with a suspicion of VGEI.
{"title":"Imaging of Vascular Graft/Endograft Infection with Radiolabeled White Blood Cell Scan and [18F]FDG PET/CT","authors":"Ringo Manta, Chiara Lauri, Maurizio Taurino, Alberto Signore","doi":"10.3390/hemato4040023","DOIUrl":"https://doi.org/10.3390/hemato4040023","url":null,"abstract":"Diagnosis of vascular graft/endograft infection (VGEI) is a challenge for clinicians due to the heterogeneity of clinical presentation and the complexity of its management. Microbiological culture is the gold standard, but it often fails to isolate the causative microorganism. A non-invasive imaging approach is therefore needed to assess VGEI. CTA is currently the first-choice imaging modality. Nuclear medicine techniques are recommended in case of negative or doubtful CTA results with persisting clinical suspicion. This review aims to summarize data from original studies published in the last decades regarding the role of both white blood cell (WBC) scans and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT), their respective diagnostic performances, and their integration into the diagnostic approach for patients with a suspicion of VGEI.","PeriodicalId":93705,"journal":{"name":"Hemato","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136098863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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