Pub Date : 2023-03-17DOI: 10.3389/frhem.2023.1127322
A. Tridente, Nina C Dempsey, M. Khalifa, Jacklyn Goddard, K. Shuker, J. Hall, Y. Sorour, J. Wright, S. Webber, G. Mills, J. Snowden
Background Critical care (CC) admission has traditionally been viewed as likely to result in a poor outcome for hematological malignancy (HM) patients. Such a view can have implications for decisions surrounding CC admission. Recent studies have challenged this poor prognostication, however, there still remains limited data to support CC admission and escalation decisions and to elucidate risk factors which independently predict short- and longer-term survival outcomes. Methods We retrospectively analyzed a large cohort of adult HM patients (n=437) admitted to CC over a sixteen-year period, with the specific aim of identifying risk factors present at CC unit admission that could help to predict outcome. We assessed all-cause mortality at CC discharge (CC mortality, primary outcome) and at further time points (hospital discharge and 12-months post-discharge from CC). Single variable and multivariate analyses were performed to identify independent predictors of outcome. Results CC unit and hospital mortality rates were 33.4% (146 patients) and 46.2% (202 patients) respectively. At six-month and one-year follow-up, mortality increased to 59.5% and 67.9% respectively. At single variable adjusted regression analysis, eight factors were associated with CC mortality: APACHE II score, the number of organs supported, requirement for continuous renal replacement therapy (CRRT), cardiovascular support, or respiratory support (invasive and non-invasive), the ratio between arterial partial pressure of oxygen (PaO2) and the inspired oxygen concentration (FiO2) (P/F ratio) on CC admission, and the lowest P/F ratio during CC admission. However, only three factors showed independent predictive capacity for CC outcome at multivariate logistic regression analysis; APACHE II score on admission, requirement for ventilation and lowest P/F ratio. Conclusion One third of HM patients admitted to CC died on the unit and, following admission to CC, approximately one-third of HM patients survived over 1 year. Our data show that, while a diagnosis of HM should not preclude admission of patients who might otherwise benefit from CC support, the prognosis of those with a high APACHE II score upon admission, or those requiring IMV remains poor, despite considerable advances in IMV techniques.
{"title":"Predicting outcomes of hematological malignancy patients admitted to critical care","authors":"A. Tridente, Nina C Dempsey, M. Khalifa, Jacklyn Goddard, K. Shuker, J. Hall, Y. Sorour, J. Wright, S. Webber, G. Mills, J. Snowden","doi":"10.3389/frhem.2023.1127322","DOIUrl":"https://doi.org/10.3389/frhem.2023.1127322","url":null,"abstract":"Background Critical care (CC) admission has traditionally been viewed as likely to result in a poor outcome for hematological malignancy (HM) patients. Such a view can have implications for decisions surrounding CC admission. Recent studies have challenged this poor prognostication, however, there still remains limited data to support CC admission and escalation decisions and to elucidate risk factors which independently predict short- and longer-term survival outcomes. Methods We retrospectively analyzed a large cohort of adult HM patients (n=437) admitted to CC over a sixteen-year period, with the specific aim of identifying risk factors present at CC unit admission that could help to predict outcome. We assessed all-cause mortality at CC discharge (CC mortality, primary outcome) and at further time points (hospital discharge and 12-months post-discharge from CC). Single variable and multivariate analyses were performed to identify independent predictors of outcome. Results CC unit and hospital mortality rates were 33.4% (146 patients) and 46.2% (202 patients) respectively. At six-month and one-year follow-up, mortality increased to 59.5% and 67.9% respectively. At single variable adjusted regression analysis, eight factors were associated with CC mortality: APACHE II score, the number of organs supported, requirement for continuous renal replacement therapy (CRRT), cardiovascular support, or respiratory support (invasive and non-invasive), the ratio between arterial partial pressure of oxygen (PaO2) and the inspired oxygen concentration (FiO2) (P/F ratio) on CC admission, and the lowest P/F ratio during CC admission. However, only three factors showed independent predictive capacity for CC outcome at multivariate logistic regression analysis; APACHE II score on admission, requirement for ventilation and lowest P/F ratio. Conclusion One third of HM patients admitted to CC died on the unit and, following admission to CC, approximately one-third of HM patients survived over 1 year. Our data show that, while a diagnosis of HM should not preclude admission of patients who might otherwise benefit from CC support, the prognosis of those with a high APACHE II score upon admission, or those requiring IMV remains poor, despite considerable advances in IMV techniques.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"175 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134104954","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}
Pub Date : 2023-03-10DOI: 10.3389/frhem.2023.1134837
Kieran D Sahasrabudhe, Weiqiang Zhao, Miriam Berg, B. Bhatnagar
Older patients with acute lymphoblastic leukemia (ALL) have a poor prognosis, with a 5-year overall survival rate of only 10%–20%. This is attributable to patient comorbidities, poor performance status, and high-risk disease biology. The prognosis for patients with relapsed/refractory (R/R) disease remains poor, particularly for patients who are not candidates for therapies targeting CD19 or CD22. Additional treatment options are needed for these patient populations. The patient presented here is a 76-year-old man diagnosed with precursor B-cell ALL with aberrant expression of myeloid markers and lacking significant CD19 or CD22 expression. A 3-year remission was achieved with one cycle of CVP (cyclophosphamide, vincristine, and prednisone) followed by 22 months of maintenance DOMP (dexamethasone, vincristine, methotrexate, and 6-mercaptopurine) prior to relapse. He was then treated with one cycle of salvage CVP, which was complicated by a stroke resulting in hemiparesis. Next-generation sequencing (NGS) was performed on the relapsed bone marrow, which revealed the presence of an R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. He was subsequently treated with the IDH1 inhibitor ivosidenib and remained in a second remission for nearly 1 year. IDH1 mutations are present in up to 14% of acute myeloid leukemia (AML) cases but are also seen more rarely in ALL, particularly in cases involving aberrant expression of myeloid markers. Ivosidenib has demonstrated efficacy in patients with IDH1-mutated AML but has not been extensively studied in other hematologic malignancies. This case demonstrates the role of NGS in revealing treatment options in patients with otherwise limited available therapies.
{"title":"Case report: Sustained complete remission with ivosidenib in a patient with relapsed, IDH1-mutated acute leukemia","authors":"Kieran D Sahasrabudhe, Weiqiang Zhao, Miriam Berg, B. Bhatnagar","doi":"10.3389/frhem.2023.1134837","DOIUrl":"https://doi.org/10.3389/frhem.2023.1134837","url":null,"abstract":"Older patients with acute lymphoblastic leukemia (ALL) have a poor prognosis, with a 5-year overall survival rate of only 10%–20%. This is attributable to patient comorbidities, poor performance status, and high-risk disease biology. The prognosis for patients with relapsed/refractory (R/R) disease remains poor, particularly for patients who are not candidates for therapies targeting CD19 or CD22. Additional treatment options are needed for these patient populations. The patient presented here is a 76-year-old man diagnosed with precursor B-cell ALL with aberrant expression of myeloid markers and lacking significant CD19 or CD22 expression. A 3-year remission was achieved with one cycle of CVP (cyclophosphamide, vincristine, and prednisone) followed by 22 months of maintenance DOMP (dexamethasone, vincristine, methotrexate, and 6-mercaptopurine) prior to relapse. He was then treated with one cycle of salvage CVP, which was complicated by a stroke resulting in hemiparesis. Next-generation sequencing (NGS) was performed on the relapsed bone marrow, which revealed the presence of an R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. He was subsequently treated with the IDH1 inhibitor ivosidenib and remained in a second remission for nearly 1 year. IDH1 mutations are present in up to 14% of acute myeloid leukemia (AML) cases but are also seen more rarely in ALL, particularly in cases involving aberrant expression of myeloid markers. Ivosidenib has demonstrated efficacy in patients with IDH1-mutated AML but has not been extensively studied in other hematologic malignancies. This case demonstrates the role of NGS in revealing treatment options in patients with otherwise limited available therapies.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"34 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131335576","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}
Pub Date : 2023-03-07DOI: 10.3389/frhem.2023.1135261
Kunapa Iam-arunthai, Supat Chamnanchanunt, Pravinwan Thungthong, Chajchawan Nakhahes, T. Suwanban, P. Rojnuckarin
Purpose Recent studies suggested that adding other agents to corticosteroids as a first-line treatment for immune thrombocytopenia (ITP) could improve outcomes. However, combination regimens may increase side effects and costs. To determine clinical factors associated with responses to the first-line steroid at 1 month. Materials and methods We retrospectively reviewed the medical records of patients with ITP aged ≥ 18 years, who were treated at Rajavithi Hospital between 2012 and 2020. Clinical data, laboratory results, treatment regimens, and responses to therapy were analyzed. Results Of the 226 patients, 76.6% were female. The mean age was 46.5 ± 18.1 years, and the median follow-up duration was 40 months. The proportion of chronic ITP was 97.3%. The complete response and response rates to first-line therapy were 65.5% and 88.9%, respectively. The age over 26 years, presentation clinically non-significant bleeding and a difference in platelet count of >50 x 109/L between days 1 and 7 after initial treatment were associated with the response to first-line treatment (adjusted odds ratio [OR] 5.09, 95% confidence interval [CI] 1.50-17.28, p = 0.009); OR 5.87, 95%CI 1.19-28.91, p = 0.029, and OR 3.60, 95%CI 1.10-11.73, p = 0.034, respectively. Younger patients and a difference in platelet count between day 1 and 7 ≤ 50 x 109/L were more likely to require second-line treatments. There were significant increases in the median platelet counts after prescribing azathioprine (baseline vs. 3 months, p = 0.001), cyclophosphamide (baseline vs. 6 months, p = 0.021), or danazol (baseline vs. 12 months, p = 0.039). Conclusion Adult, severity of bleeding at presentation, and rapid platelet increases within 1 week were related to excellent corticosteroid responses in ITP patients. These patients may not need combination regimens.
最近的研究表明，在皮质类固醇的基础上添加其他药物作为治疗免疫性血小板减少症(ITP)的一线治疗可以改善预后。然而，联合用药可能会增加副作用和费用。确定与一线类固醇治疗1个月反应相关的临床因素。材料和方法回顾性分析2012年至2020年在Rajavithi医院治疗的年龄≥18岁的ITP患者的医疗记录。分析了临床资料、实验室结果、治疗方案和对治疗的反应。结果226例患者中，女性占76.6%。平均年龄46.5±18.1岁，中位随访时间40个月。慢性ITP占97.3%。一线治疗的完全缓解率和有效率分别为65.5%和88.9%。年龄大于26岁、出现临床无显著性出血以及初始治疗后第1天至第7天血小板计数>50 × 109/L的差异与一线治疗的疗效相关(校正优势比[OR] 5.09, 95%可信区间[CI] 1.50-17.28, p = 0.009);OR分别为5.87,95%CI 1.19-28.91, p = 0.029; OR为3.60,95%CI 1.10-11.73, p = 0.034。年轻患者和第1天和第7天血小板计数差异≤50 × 109/L的患者更有可能需要二线治疗。在处方硫唑嘌呤(基线vs. 3个月，p = 0.001)、环磷酰胺(基线vs. 6个月，p = 0.021)或那那唑(基线vs. 12个月，p = 0.039)后，血小板计数中位数显著增加。结论成人、就诊时出血严重程度和1周内血小板快速升高与ITP患者良好的皮质类固醇反应有关。这些患者可能不需要联合治疗。
{"title":"Identification factors to adjust early combination regimens in adult primary immune thrombocytopenia: An 8-year data analysis","authors":"Kunapa Iam-arunthai, Supat Chamnanchanunt, Pravinwan Thungthong, Chajchawan Nakhahes, T. Suwanban, P. Rojnuckarin","doi":"10.3389/frhem.2023.1135261","DOIUrl":"https://doi.org/10.3389/frhem.2023.1135261","url":null,"abstract":"Purpose Recent studies suggested that adding other agents to corticosteroids as a first-line treatment for immune thrombocytopenia (ITP) could improve outcomes. However, combination regimens may increase side effects and costs. To determine clinical factors associated with responses to the first-line steroid at 1 month. Materials and methods We retrospectively reviewed the medical records of patients with ITP aged ≥ 18 years, who were treated at Rajavithi Hospital between 2012 and 2020. Clinical data, laboratory results, treatment regimens, and responses to therapy were analyzed. Results Of the 226 patients, 76.6% were female. The mean age was 46.5 ± 18.1 years, and the median follow-up duration was 40 months. The proportion of chronic ITP was 97.3%. The complete response and response rates to first-line therapy were 65.5% and 88.9%, respectively. The age over 26 years, presentation clinically non-significant bleeding and a difference in platelet count of >50 x 109/L between days 1 and 7 after initial treatment were associated with the response to first-line treatment (adjusted odds ratio [OR] 5.09, 95% confidence interval [CI] 1.50-17.28, p = 0.009); OR 5.87, 95%CI 1.19-28.91, p = 0.029, and OR 3.60, 95%CI 1.10-11.73, p = 0.034, respectively. Younger patients and a difference in platelet count between day 1 and 7 ≤ 50 x 109/L were more likely to require second-line treatments. There were significant increases in the median platelet counts after prescribing azathioprine (baseline vs. 3 months, p = 0.001), cyclophosphamide (baseline vs. 6 months, p = 0.021), or danazol (baseline vs. 12 months, p = 0.039). Conclusion Adult, severity of bleeding at presentation, and rapid platelet increases within 1 week were related to excellent corticosteroid responses in ITP patients. These patients may not need combination regimens.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114776987","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}
Pub Date : 2023-03-07DOI: 10.3389/frhem.2023.1055086
Anne-Sophie Cloos, M. Rab, P. van der Smissen, B. V. van Oirschot, E. Mignolet, J. B. van der Net, A. Koster, Kelly Kleinen, Y. Larondelle, Romano Terrasi, G. Muccioli, R. van Wijk, D. Tyteca
Sitosterolemia is a metabolic disorder leading to excessive accumulation of phytosterols. Hemolytic stomatocytosis and macrothrombocytopenia are part of the clinical picture. However, the impact of phytosterols on red blood cell (RBC) deformability, membrane lipid composition and distribution and the efficiency of the reference treatment, Ezetimibe, are largely unknown. This study addresses these issues using RBCs from three patients with sitosterolemia and healthy RBCs exposed to β-sitosterol. Patients presented an increased proportion of stomatocytes, decreased RBC deformability and increased RBC hydration and osmotic fragility compared to healthy donors. At the membrane level, patient RBCs showed (i) very high content in β-sitosterols, (ii) increased proportions of saturated fatty acids and polyunsaturated fatty acid species with long and unsaturated carbon chains, and (iii) decreased content in phosphatidylethanolamine species. These lipid changes were accompanied by an almost complete abrogation of cholesterol-enriched domains, which could result from: (i) the reduced phosphatidylethanolamine content which positively correlated with domain abundance; and (ii) the fatty acid modifications and increased phytosterol content, both compatible with higher membrane stiffness. The role of β-sitosterol was supported by comparable changes in RBC morphology and cholesterol-enriched domains upon β-sitosterol integration at the healthy RBC membrane. Finally, Ezetimibe treatment combined with a sterol restricted diet lowered phytosterols and improved anemia and RBC deformability and hydration. However, this treatment had no or limited effect on RBC morphology and cholesterol-enriched domain abundance. This study reveals for the first time that phytosterols affect RBC membrane lipid composition and distribution but also RBC morphology, hydration, deformability and fragility.
{"title":"Red blood cells from patients with sitosterolemia exhibit impaired membrane lipid composition and distribution and decreased deformability","authors":"Anne-Sophie Cloos, M. Rab, P. van der Smissen, B. V. van Oirschot, E. Mignolet, J. B. van der Net, A. Koster, Kelly Kleinen, Y. Larondelle, Romano Terrasi, G. Muccioli, R. van Wijk, D. Tyteca","doi":"10.3389/frhem.2023.1055086","DOIUrl":"https://doi.org/10.3389/frhem.2023.1055086","url":null,"abstract":"Sitosterolemia is a metabolic disorder leading to excessive accumulation of phytosterols. Hemolytic stomatocytosis and macrothrombocytopenia are part of the clinical picture. However, the impact of phytosterols on red blood cell (RBC) deformability, membrane lipid composition and distribution and the efficiency of the reference treatment, Ezetimibe, are largely unknown. This study addresses these issues using RBCs from three patients with sitosterolemia and healthy RBCs exposed to β-sitosterol. Patients presented an increased proportion of stomatocytes, decreased RBC deformability and increased RBC hydration and osmotic fragility compared to healthy donors. At the membrane level, patient RBCs showed (i) very high content in β-sitosterols, (ii) increased proportions of saturated fatty acids and polyunsaturated fatty acid species with long and unsaturated carbon chains, and (iii) decreased content in phosphatidylethanolamine species. These lipid changes were accompanied by an almost complete abrogation of cholesterol-enriched domains, which could result from: (i) the reduced phosphatidylethanolamine content which positively correlated with domain abundance; and (ii) the fatty acid modifications and increased phytosterol content, both compatible with higher membrane stiffness. The role of β-sitosterol was supported by comparable changes in RBC morphology and cholesterol-enriched domains upon β-sitosterol integration at the healthy RBC membrane. Finally, Ezetimibe treatment combined with a sterol restricted diet lowered phytosterols and improved anemia and RBC deformability and hydration. However, this treatment had no or limited effect on RBC morphology and cholesterol-enriched domain abundance. This study reveals for the first time that phytosterols affect RBC membrane lipid composition and distribution but also RBC morphology, hydration, deformability and fragility.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"57 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126963034","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}
Pub Date : 2023-02-06DOI: 10.3389/frhem.2023.1055484
A. K. Haugaard, H. Madsen, T. Masmas, K. Vettenranta, J. Buechner, K. Mellgren, D. Turkiewicz, S. Rosthøj, H. Marquart, C. Heilmann, Klaus Gottlob Müller, M. Ifversen
Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. Real time quantitative PCR (RQ-PCR) chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. In a prospective multicenter study, we analyzed increasing mixed chimerism (IMC) in blood samples following transplantation for leukemia in 64 children. IMC was defined as a minimum increase of either 0.1% or 0.05% recipient DNA between two samples or a ≥10-fold increase. Samples closer than 30 days to diagnosis of relapse were omitted. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (27.8 (95% CI 4.4-175.8; P<.001), and 18.4 (95% CI 2.8-120.5; P=0.002), respectively). From the date of IMC, the 3-year CI of relapse or MRD-positivity was 26.7% (CI 9.4-47.0) and 18.5% (6.4-35.3) for IMC ≥ 0.1% (n=27) and ≥ 0.05% (n= 40), respectively. In the subset of children without an IMC ≥ 0.1% or ≥ 0.05%, CI of relapse or molecular relapse were 16.7% (5.0 -34.1) and 10.8% (3.4 -23.3), respectively. In all cases with a relapse undetectable by IMC, MRD remained undetectable prior to relapse and standard chimerism negative. In a landmark analysis, neither an IMC ≥ 0.1% nor ≥ 0.05% prior to 90 days post‐HCT was significantly associated with an increased relapse incidence. These results indicate that the serial monitoring of RQ‐PCR chimerism in peripheral blood post-HCT may be a valuable supplement to the minimal residual disease analysis for an early detection of relapse in acute childhood leukemia.
{"title":"Highly-sensitive chimerism analysis in blood after allogeneic hematopoietic cell transplantation in childhood leukemia: Results from the Nordic Microchimerism Study","authors":"A. K. Haugaard, H. Madsen, T. Masmas, K. Vettenranta, J. Buechner, K. Mellgren, D. Turkiewicz, S. Rosthøj, H. Marquart, C. Heilmann, Klaus Gottlob Müller, M. Ifversen","doi":"10.3389/frhem.2023.1055484","DOIUrl":"https://doi.org/10.3389/frhem.2023.1055484","url":null,"abstract":"Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. Real time quantitative PCR (RQ-PCR) chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. In a prospective multicenter study, we analyzed increasing mixed chimerism (IMC) in blood samples following transplantation for leukemia in 64 children. IMC was defined as a minimum increase of either 0.1% or 0.05% recipient DNA between two samples or a ≥10-fold increase. Samples closer than 30 days to diagnosis of relapse were omitted. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (27.8 (95% CI 4.4-175.8; P<.001), and 18.4 (95% CI 2.8-120.5; P=0.002), respectively). From the date of IMC, the 3-year CI of relapse or MRD-positivity was 26.7% (CI 9.4-47.0) and 18.5% (6.4-35.3) for IMC ≥ 0.1% (n=27) and ≥ 0.05% (n= 40), respectively. In the subset of children without an IMC ≥ 0.1% or ≥ 0.05%, CI of relapse or molecular relapse were 16.7% (5.0 -34.1) and 10.8% (3.4 -23.3), respectively. In all cases with a relapse undetectable by IMC, MRD remained undetectable prior to relapse and standard chimerism negative. In a landmark analysis, neither an IMC ≥ 0.1% nor ≥ 0.05% prior to 90 days post‐HCT was significantly associated with an increased relapse incidence. These results indicate that the serial monitoring of RQ‐PCR chimerism in peripheral blood post-HCT may be a valuable supplement to the minimal residual disease analysis for an early detection of relapse in acute childhood leukemia.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124786031","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}
Pub Date : 2023-01-16DOI: 10.3389/frhem.2022.1062705
Bing Chen, Haochuan Liu, Zhengang Liu, Fan Yang
Humanized mouse models with functional human genes, cells, and tissues are typically used for in vivo studies of diseases. Decades of studies on humanized mouse models have improved our understanding of hematopoiesis, infectious diseases, cancer biology, innate and adaptive immunity, and regenerative medicine. This review discusses the establishment and development of humanized mouse models and how they are used to model red blood cell-related diseases facilitating research in several biomedical disciplines. Furthermore, we provide approaches to overcome the limitations of these models.
{"title":"Benefits and limitations of humanized mouse models for human red blood cell-related disease research","authors":"Bing Chen, Haochuan Liu, Zhengang Liu, Fan Yang","doi":"10.3389/frhem.2022.1062705","DOIUrl":"https://doi.org/10.3389/frhem.2022.1062705","url":null,"abstract":"Humanized mouse models with functional human genes, cells, and tissues are typically used for in vivo studies of diseases. Decades of studies on humanized mouse models have improved our understanding of hematopoiesis, infectious diseases, cancer biology, innate and adaptive immunity, and regenerative medicine. This review discusses the establishment and development of humanized mouse models and how they are used to model red blood cell-related diseases facilitating research in several biomedical disciplines. Furthermore, we provide approaches to overcome the limitations of these models.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"21 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128154513","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}
Pub Date : 2023-01-04DOI: 10.3389/frhem.2022.1085952
Mihaiescu Dan, Bianca-Ioana Gutu, E. Severin, Vlad Tanase
Beta-thalassemia is a well-known blood genetic disorder inherited in an autosomal recessive manner. Beta-thalassemia is found everywhere in the world as a rare, relatively rare, or common disease depending on the ethnic population. Affected individuals have chronic anemia associated with delayed growth, pale skin, weakness, fatigue, and more serious complications resulting in early death. Those with the severe form need frequent lifelong transfusions and depend on blood donations to survive. This literature mini-review highlights the healthcare needs that are not optimally met by people living with beta-thalassemia. The needs-led research can help to improve clinical outcomes through more appropriate management of the disease, increase provider satisfaction, and reduce the cost of care.
{"title":"Innovative and Needs-led research on β-thalassemia treatment methods","authors":"Mihaiescu Dan, Bianca-Ioana Gutu, E. Severin, Vlad Tanase","doi":"10.3389/frhem.2022.1085952","DOIUrl":"https://doi.org/10.3389/frhem.2022.1085952","url":null,"abstract":"Beta-thalassemia is a well-known blood genetic disorder inherited in an autosomal recessive manner. Beta-thalassemia is found everywhere in the world as a rare, relatively rare, or common disease depending on the ethnic population. Affected individuals have chronic anemia associated with delayed growth, pale skin, weakness, fatigue, and more serious complications resulting in early death. Those with the severe form need frequent lifelong transfusions and depend on blood donations to survive. This literature mini-review highlights the healthcare needs that are not optimally met by people living with beta-thalassemia. The needs-led research can help to improve clinical outcomes through more appropriate management of the disease, increase provider satisfaction, and reduce the cost of care.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"224 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133301122","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}
Pub Date : 2023-01-01Epub Date: 2023-09-14DOI: 10.3389/frhem.2023.1235170
Yaseswini Neelamraju, Evisa Gjini, Sagar Chhangawala, Hao Fan, Shuning He, Chang-Bin Jing, Ashley T Nguyen, Subhash Prajapati, Caroline Sheridan, Yariv Houvras, Ari Melnick, A Thomas Look, Francine E Garrett-Bakelman
Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and dysplasia. The gene encoding ten-eleven translocation 2 (tet2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the tet2 gene. The tet2m/m-mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia, but normal circulating blood counts by 11 months of age and accompanying anemia, signifying the onset of MDS, by 24 months of age.
Methods: In the current study, we collected progenitor cells from the kidney marrows of the adult tet2m/m and tet2wt/wt fish at 4 and 15 months of age and conducted enhanced reduced representation of bisulfite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of hematopoietic stem and progenitor cells (HSPCs).
Results and discussion: A global increase in DNA methylation of gene promoter regions and CpG islands was observed in tet2m/m HSPCs at 4 months of age when compared with the wild type. Furthermore, hypermethylated genes were significantly enriched for targets of SUZ12 and the metal-response-element-binding transcription factor 2 (MTF2)-involved in the polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, we observed a paradoxical global decrease in DNA methylation in tet2m/m HSPCs. Gene expression analyses identified upregulation of genes associated with mTORC1 signaling and interferon gamma and alpha responses in tet2m/m HSPCs at 4 months of age when compared with the wild type. Downregulated genes in HSPCs of tet2-mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and interleukin 2 (IL2)/signal transducer and activator of transcription 5 (STAT5) signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with tet2 loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.
{"title":"Depletion of <i>tet2</i> results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome.","authors":"Yaseswini Neelamraju, Evisa Gjini, Sagar Chhangawala, Hao Fan, Shuning He, Chang-Bin Jing, Ashley T Nguyen, Subhash Prajapati, Caroline Sheridan, Yariv Houvras, Ari Melnick, A Thomas Look, Francine E Garrett-Bakelman","doi":"10.3389/frhem.2023.1235170","DOIUrl":"10.3389/frhem.2023.1235170","url":null,"abstract":"<p><strong>Introduction: </strong>Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and dysplasia. The gene encoding ten-eleven translocation 2 (<i>tet</i>2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the <i>tet2</i> gene. The <i>tet2</i><sup><i>m/m</i></sup>-mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia, but normal circulating blood counts by 11 months of age and accompanying anemia, signifying the onset of MDS, by 24 months of age.</p><p><strong>Methods: </strong>In the current study, we collected progenitor cells from the kidney marrows of the adult <i>tet2</i><sup><i>m/m</i></sup> and <i>tet2</i><sup><i>wt/wt</i></sup> fish at 4 and 15 months of age and conducted enhanced reduced representation of bisulfite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of hematopoietic stem and progenitor cells (HSPCs).</p><p><strong>Results and discussion: </strong>A global increase in DNA methylation of gene promoter regions and CpG islands was observed in <i>tet2</i><sup><i>m/m</i></sup> HSPCs at 4 months of age when compared with the wild type. Furthermore, hypermethylated genes were significantly enriched for targets of SUZ12 and the metal-response-element-binding transcription factor 2 (MTF2)-involved in the polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, we observed a paradoxical global decrease in DNA methylation in <i>tet2</i><sup><i>m/m</i></sup> HSPCs. Gene expression analyses identified upregulation of genes associated with mTORC1 signaling and interferon gamma and alpha responses in <i>tet2</i><sup><i>m/m</i></sup> HSPCs at 4 months of age when compared with the wild type. Downregulated genes in HSPCs of <i>tet2</i>-mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and interleukin 2 (IL2)/signal transducer and activator of transcription 5 (STAT5) signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with <i>tet2</i> loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.</p>","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71490973","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}
Pub Date : 2022-12-19DOI: 10.3389/frhem.2022.1039821
S. Hlaing, Christine J. Kurian, J. Tan, E. Behling, A. Hussein
Hemophagocytic lymphohistiocytosis (HLH) is a highly detrimental syndrome that can progress to multiorgan failure, necessitating the resources of an intensive care unit, with a mortality rate as high as 40%. Secondary HLH is usually triggered by infection, most often from a viral infection or malignancy. Management of HLH in adults is challenging as treatment algorithms targeting hyperinflammation are based on pediatric protocols, such as HLH-94 and HLH-2004. To our knowledge, there are only a few reported cases of HLH secondary to ehrlichiosis infection and none in elderly patients with multiple comorbidities. Here, we present a unique case of HLH secondary to ehrlichiosis infection in an 82-year-old female successfully treated with antibiotics and steroids.
{"title":"Case Report: A unique case of secondary hemophagocytic lymphohistiocytosis from ehrlichiosis infection","authors":"S. Hlaing, Christine J. Kurian, J. Tan, E. Behling, A. Hussein","doi":"10.3389/frhem.2022.1039821","DOIUrl":"https://doi.org/10.3389/frhem.2022.1039821","url":null,"abstract":"Hemophagocytic lymphohistiocytosis (HLH) is a highly detrimental syndrome that can progress to multiorgan failure, necessitating the resources of an intensive care unit, with a mortality rate as high as 40%. Secondary HLH is usually triggered by infection, most often from a viral infection or malignancy. Management of HLH in adults is challenging as treatment algorithms targeting hyperinflammation are based on pediatric protocols, such as HLH-94 and HLH-2004. To our knowledge, there are only a few reported cases of HLH secondary to ehrlichiosis infection and none in elderly patients with multiple comorbidities. Here, we present a unique case of HLH secondary to ehrlichiosis infection in an 82-year-old female successfully treated with antibiotics and steroids.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123533033","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}
Pub Date : 2022-12-15DOI: 10.3389/frhem.2022.1060029
M. Mahmoud, L. Al Mahmasani, M. Charafeddine, A. Zahreddine, N. Moukalled, J. El Cheikh, A. Bazarbachi, I. Abou Dalle
Purpose Numerous factors may affect the survival outcomes of patients with acute myeloid leukemia (AML), mainly disease-related and treatment-related factors. The impact of other factors, such as the insurance status and the distance to healthcare facilities, are still unclear and may differ between different healthcare systems. We investigated the effects of insurance status and distance to the treatment center on the survival of AML patients. Materials and methods This is a single-center, observational, retrospective study of patients diagnosed with AML (2015–2020) and treated at the American University of Beirut Medical Center in Lebanon. Data regarding patient baseline characteristics, disease-related factors, insurance status, and area of residence were collected. Multivariate Cox regression analysis was used to identify main independent predictors of overall survival (OS). Results We identified 142 AML patients with a median age of 52 years (range 18–86). Of them, 91 (64%) were males, 77 (54%) had ELN intermediate risk, and 88 (62%) patients received intensive chemotherapy. After a median follow-up of 22.4 months, the median RFS and OS were 37.4 months and not reached, respectively. A Cox regression model for OS was done using the following variables: age, gender, body mass index, comorbidities, smoking status, insurance status, distance from the center, ELN classification, treatment used, and allotransplant. A higher risk of death was seen among the uninsured patients and those living beyond 40 km from the treatment center compared with fully insured patients and those living in proximity to the center (hazard ratio [HR]: 3.65; 95% CI [1.79, 7.45], p-value <0.0001; HR: 4.38; 95% CI [1.75, 10.95], p-value 0.002, respectively). Conclusions The outcome of patients with AML does not depend only on disease-related factors, as the insurance status and the distance from the area of residence to the treatment center were found to be independent predictors of survival in AML patients.
影响急性髓系白血病(AML)患者生存结局的因素很多，主要是疾病相关因素和治疗相关因素。其他因素的影响，如保险状况和与医疗机构的距离，仍然不清楚，并且在不同的医疗保健系统之间可能有所不同。我们调查了保险状况和到治疗中心的距离对AML患者生存的影响。材料与方法本研究是一项单中心、观察性、回顾性研究，研究对象为在黎巴嫩贝鲁特美国大学医学中心接受治疗的AML患者(2015-2020)。收集有关患者基线特征、疾病相关因素、保险状况和居住地区的数据。采用多变量Cox回归分析确定总生存期(OS)的主要独立预测因子。结果142例AML患者，中位年龄52岁(范围18-86岁)。其中男性91例(64%)，ELN中度风险77例(54%)，88例(62%)接受强化化疗。中位随访22.4个月后，中位RFS和OS分别为37.4个月和未达到。采用以下变量:年龄、性别、体重指数、合并症、吸烟状况、保险状况、离中心距离、ELN分类、使用的治疗方法和同种异体移植，建立OS的Cox回归模型。无保险患者和居住在距离治疗中心40公里以外的患者的死亡风险高于完全保险患者和居住在中心附近的患者(风险比[HR]: 3.65;95% CI [1.79, 7.45]， p值<0.0001;人力资源:4.38;95% CI [1.75, 10.95]， p值分别为0.002)。结论AML患者的预后不仅仅取决于疾病相关因素，保险状况和居住地到治疗中心的距离是AML患者生存的独立预测因素。
{"title":"Impact of insurance status and distance from residence to treatment center on the outcomes of patients diagnosed with acute myeloid leukemia","authors":"M. Mahmoud, L. Al Mahmasani, M. Charafeddine, A. Zahreddine, N. Moukalled, J. El Cheikh, A. Bazarbachi, I. Abou Dalle","doi":"10.3389/frhem.2022.1060029","DOIUrl":"https://doi.org/10.3389/frhem.2022.1060029","url":null,"abstract":"Purpose Numerous factors may affect the survival outcomes of patients with acute myeloid leukemia (AML), mainly disease-related and treatment-related factors. The impact of other factors, such as the insurance status and the distance to healthcare facilities, are still unclear and may differ between different healthcare systems. We investigated the effects of insurance status and distance to the treatment center on the survival of AML patients. Materials and methods This is a single-center, observational, retrospective study of patients diagnosed with AML (2015–2020) and treated at the American University of Beirut Medical Center in Lebanon. Data regarding patient baseline characteristics, disease-related factors, insurance status, and area of residence were collected. Multivariate Cox regression analysis was used to identify main independent predictors of overall survival (OS). Results We identified 142 AML patients with a median age of 52 years (range 18–86). Of them, 91 (64%) were males, 77 (54%) had ELN intermediate risk, and 88 (62%) patients received intensive chemotherapy. After a median follow-up of 22.4 months, the median RFS and OS were 37.4 months and not reached, respectively. A Cox regression model for OS was done using the following variables: age, gender, body mass index, comorbidities, smoking status, insurance status, distance from the center, ELN classification, treatment used, and allotransplant. A higher risk of death was seen among the uninsured patients and those living beyond 40 km from the treatment center compared with fully insured patients and those living in proximity to the center (hazard ratio [HR]: 3.65; 95% CI [1.79, 7.45], p-value <0.0001; HR: 4.38; 95% CI [1.75, 10.95], p-value 0.002, respectively). Conclusions The outcome of patients with AML does not depend only on disease-related factors, as the insurance status and the distance from the area of residence to the treatment center were found to be independent predictors of survival in AML patients.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"45 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115012230","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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