Association of PARP1 Expression Levels and Clinical Parameters in Different Leukemic Subtypes With BCR::ABL1 p190+ Translocation.

Background/Aim: Although the reciprocal translocation t(9;22)(q34;q11) is a hallmark of chronic myeloid leukemia (CML), it is also present in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Depending on the gene's breakpoint, it is possible to obtain three isoforms, among which p190 stands out for the poor prognosis it induces whenever it appears. Due to the genomic instability induced by BCR::ABL1, it is proposed to expand the applicability of poly-ADP-ribose polymerase-1 (PARP1) and its inhibitors in hematological neoplasms. Materials and Methods: We measured the expression levels of PARP1 by quantitative real-time PCR (qPCR) using TaqMan®, correlating its expression with BCR::ABL1 p190+, to evaluate its influence in the clinic of adult patients. Results: We found that PARP1 is expressed differently in ALL, AML and CML and that p190 transcripts do not follow a linear pattern in these populations. We also found that PARP1 expression is not correlated with age, white blood cell and the amount of p190 transcripts. Conclusion: Despite the lack of statistical correlation between the variables analyzed, the role of PARP1 in BCR::ABL1 leukemia cannot be ruled out, given the instability profile promoted by this translocation. Finally, further studies involving a larger sample of patients are needed, as well as investigations into other molecular pathways that may impact on the pathogenesis of different BCR::ABL1 leukemic subtypes.

Cognitive performance and brain volume among survivors of pediatric hematological malignancies: a case-control study.

BACKGROUND: Cognitive dysfunction may be one of the hazardous late effects among survivors of pediatric hematological malignancies. Our study aimed to explore cognitive performance and assess the global and regional brain volume changes in survivors of hematological malignancies. METHODS: This case-control study was conducted on 68 survivors of hematological malignancies, with a median follow-up period of 2 years (ranging from 1 to 6.2 years). Stanford-Binet Test was used for cognitive assessment. A quantitative volumetric assessment of the brain was done using the NeuroQuant Brain Magnetic Resonance. Age and sex-matched 68 children were selected as a comparison group. RESULTS: Cancer survivors showed significantly lower levels of IQ and their subtests than the control group. Global brain atrophy was observed in the majority of the survivors. Many risk factors significantly affected different IQ subtests, such as radiotherapy (RTH), high cumulative doses of methotrexate (MTX), and prednisone. At the same time, low white matter volume (WMV) was observed with higher cumulative doses of MTX and anthracyclines. CONCLUSIONS: Hematological malignancies have a negative impact on cognition. Neurocognitive impairment and related brain changes were evident in those who received RTH, HDMTX, or high cumulative doses of steroids.

Metformin as a therapeutic tool for resistant hematological malignancies: a literature review.

BACKGROUND AND OBJECTIVE: Hematological malignancies (HMs) are a group of neoplasms with hematopoietic origin, currently divided into leukemias, lymphomas and multiple myeloma (MM). Although the advances in the management of HMs, the rate of drug resistance, relapse and refractory disease has been increasing, requiring new therapeutic strategies. In this review, we aim to summarize metformin's antitumoral mechanisms of action and present the latest studies of metformin action in HMs, including in resistant ones. METHODS: For this review of literature, studies published between 1996 and 2023 from PubMed and clinical trials submitted to clinicaltrials.gov were considered. KEY CONTENT AND FINDINGS: Throughout this review we demonstrated the capacity of metformin to act as an anti-HMs drug, being able to re-sensitize HMs to classical anti-HMs agents and to overcome relapse and refractory HMs, as shown in vitro and in vivo studies. Associated with the potential anti-HM effect of metformin, some clinical trials are in progress, including in the view of reducing resistance and recurrence rate of HMs, which requires further exploration. The relationship among HMs cancer stem cells (HMs CSCs), drug resistance, cancer recurrence, and the effect of metformin in inhibiting CSCs were also discussed, despite this field needing more attention. CONCLUSIONS: In summary, metformin is a promising anti-HMs drug that can enhance patients' survival and prognosis through its action in the improvement of HMs response.

Fungal-associated pneumonia in patients with hematological malignancies.

PURPOSE: Patients with hematologic malignancies (HM) are at high risk of invasive lung fungal infections (ILFI). To describe the main characteristics, treatment, and outcomes for five years in adult patients with HM and fungal pneumonia. METHODS: We conducted a retrospective study at Instituto Nacional de Cancerología (INCan), a referral tertiary care oncology hospital with 135 beds in Mexico City, Mexico. We included all cases of fungal pneumonia in patients with HM from January 1, 2017, to December 31, 2022. Cases were classified as proven, probable, and possible according to EORTC/MSG criteria 2021. RESULTS: Two hundred ten patients were included; the mean age was 40 years. The most frequent HM was acute lymphoblastic leukemia (n = 74) and acute myeloid leukemia (n = 68). One hundred forty patients (66.7%) had severe neutropenia for a median of 16 days. All patients had a CT thorax scan; in 132 (62.9%), multiple nodules were documented. Serum galactomannan (GM) was positive in 21/192 (10.9%) and bronchoalveolar lavage in 9/36 (25%). Fifty-three patients (25.2%) died in the first month. In the multivariate analysis for mortality in the first 30 days, hypoalbuminemia, shock, possible ILFI, and inappropriate antifungal treatment were statistically associated. CONCLUSIONS: In high-risk HM patients, CT thorax scan and GM help diagnose ILFI. An appropriate antifungal improves mortality.

Fibrinogen contribution to clot strength in patients with sepsis and hematologic malignancies and thrombocytopenia-a prospective, single-center, analytical, cross-sectional study.

Background: Patients with hematological malignancies (HM) frequently present thrombocytopenia and higher risk of bleeding. Although transfusion is associated with higher risk of adverse events and poor outcomes, prophylactic transfusion of platelets is a common practice to prevent hemorrhagic complications. Thromboelastometry has been considered a better predictor for bleeding than isolated platelet counts in different settings. In early stages of sepsis, hypercoagulability may occur due to higher fibrinogen levels. Objectives: To evaluate the behavior of coagulation in patients with HM who develop sepsis and to verify whether a higher concentration of fibrinogen is associated with a proportional increase in maximum clot firmness (MCF) even in the presence of severe thrombocytopenia. Methods: We performed a unicentric analytical cross-sectional study with 60 adult patients with HM and severe thrombocytopenia, of whom 30 had sepsis (sepsis group) and 30 had no infections (control group). Coagulation conventional tests and specific coagulation tests, including thromboelastometry, were performed. The main outcome evaluated was MCF. Results: Higher levels of fibrinogen and MCF were found in sepsis group. Both fibrinogen and platelets contributed to MCF. The relative contribution of fibrin was significantly higher (60.5 ± 12.8% vs 43.6 ± 9.7%; P < .001) and that of platelets was significantly lower (39.5 ± 12.8% vs 56.4 ± 9.7%; P < .001) in the sepsis group compared with the control group. Conclusion: Patients with sepsis and HM presented higher concentrations of fibrinogen than uninfected patients, resulting in greater MCF amplitudes even in the presence of thrombocytopenia.

Fertility preservation in hematological cancer patients.

Among adolescents and young adults, hematological malignancies are the most common malignancies. Although the survival rate of hematological malignancies in young patients has been dramatically improved, due to the continuous improvement and development of tumor diagnosis and treatment options, cytotoxic therapies can significantly reduce a patient's reproductive capacity and cause irreversible infertility. The most two established solutions are embryo cryopreservation and oocyte cryopreservation which can be considered in single female. Sperm or testicular tissue cryopreservation in adult male are feasible approaches that must be considered before gonadotoxic therapy. A comprehensive consultation with reproductive specialists when once diagnosed is a significantly issue which would help those survivors who want to have children. In this article, we review germ cell toxicity, which happens during the treatment of hematological malignancies, and aims to propose safety, efficacy fertility preservation methods in younger patients with hematological malignancies.

Six-year experience with GM test in hematological patients in a public Brazilian tertiary hospital.

Invasive fungal infection (IFI) is frequent in patients with hematologic malignancies or submitted hematopoietic stem cell transplantation (HSCT). OBJECTIVES: To evaluate the role of the GM (galactomannan) test in prescribing therapeutic antifungals; to determine invasive aspergillosis (IA) frequency, the factors associated with positive GM test, and the in-hospital mortality. METHODS: We conducted a retrospective observational study including patients aged 18 or over with hematological malignancy or submitted to HSCT. GM test was measured twice weekly. The hypothesis of IFI was considered in patients with neutropenia and persistent fever despite broad-spectrum antibiotics. RESULTS: A total of 496 patients were evaluated; the mean of GM tests performed per patient was 4.2 (+3.1), and 86 (17.3 %) had positive results. IFI was diagnosed in 166 (33.5 %) and IA in 22 (24.6 %) patients. Positive GM test was more frequent in patients with IFI (72.2 % and 25.1 %; OR 8.1; 95 % CI 4.8 - 13.8), and was associated with therapeutic antifungals prescription (52, 9 % and 20.5 %; OR 4.3, 95CI% 2.0 - 9.4), as well as lung abnormalities on HRCT (45.3% vs. 21.5 %; OR 3.0, 95 %CI 1.4 - 6.5). Mortality was 31.6 %. In the multivariate analysis, the variables associated with mortality were the hypothesis of IFI (OR 6.35; 95 % CI 3.63-11.12.0), lung abnormalities on HRCT (57.9 % and 26.9 %; OR 2 0.6; 95 % CI 1.5 - 4.4), and positive GM test (57.9 % and 26.9 %; OR 2.7 95 % CI 1.6 - 4.5). CONCLUSIONS: Positive GM test was associated with lung abnormalities on HRCT and with the introduction of therapeutic antifungals. If adequate anti-mold prophylaxis is available, the GM test should not be used as screening, but to investigate IFI in high-risk patients. The diagnosis of IFI, positive GM test and lung abnormalities on HRCT were predictors of hospital mortality in patients with hematological malignancies or undergoing HSCT.

Six-year experience with GM test in hematological patients in a public Brazilian tertiary hospital

Abstract Invasive fungal infection (IFI) is frequent in patients with hematologic malignancies or submitted hematopoietic stem cell transplantation (HSCT). Objectives To evaluate the role of the GM (galactomannan) test in prescribing therapeutic antifungals; to determine invasive aspergillosis (IA) frequency, the factors associated with positive GM test, and the in-hospital mortality. Methods We conducted a retrospective observational study including patients aged 18 or over with hematological malignancy or submitted to HSCT. GM test was measured twice weekly. The hypothesis of IFI was considered in patients with neutropenia and persistent fever despite broad-spectrum antibiotics. Results A total of 496 patients were evaluated; the mean of GM tests performed per patient was 4.2 (+3.1), and 86 (17.3 %) had positive results. IFI was diagnosed in 166 (33.5 %) and IA in 22 (24.6 %) patients. Positive GM test was more frequent in patients with IFI (72.2 % and 25.1 %; OR 8.1; 95 % CI 4.8 - 13.8), and was associated with therapeutic antifungals prescription (52, 9 % and 20.5 %; OR 4.3, 95CI% 2.0 - 9.4), as well as lung abnormalities on HRCT (45.3% vs. 21.5 %; OR 3.0, 95 %CI 1.4 - 6.5). Mortality was 31.6 %. In the multivariate analysis, the variables associated with mortality were the hypothesis of IFI (OR 6.35; 95 % CI 3.63-11.12.0), lung abnormalities on HRCT (57.9 % and 26.9 %; OR 2 0.6; 95 % CI 1.5 - 4.4), and positive GM test (57.9 % and 26.9 %; OR 2.7 95 % CI 1.6 - 4.5). Conclusions Positive GM test was associated with lung abnormalities on HRCT and with the introduction of therapeutic antifungals. If adequate anti-mold prophylaxis is available, the GM test should not be used as screening, but to investigate IFI in high-risk patients. The diagnosis of IFI, positive GM test and lung abnormalities on HRCT were predictors of hospital mortality in patients with hematological malignancies or undergoing HSCT.

A population-based analysis of hematological malignancies from a French-West-Indies cancer registry's data (2009-2018).

BACKGROUND: A worldwide increased incidence of HM has been marked in recent decades. Therefore, to update epidemiological characteristics of HM in a French West Indies territory, we have performed analysis through Martinique's population-based cancer registry database. METHODS: We included cancer case data, from 2009-2018, coded in strict compliance with international standards set by International Agency for Research on Cancer. We calculated standardized incidence rates, cumulative rate (ages 0-74), and temporal trends for cases and deaths using the global population standard, by sex and five age group. Mortality rates were obtained from the French Epidemiology Center on Medical Causes of Death (CépiDc). RESULTS: One thousand forty seven new cases and 674 deaths from HM were recorded, of which 501 MM (47.8%), 377 LMNH (36%), 123 LAM (11.8%), and 46 LH (4.4%) were reported in both sexes. MM is one of the hematological malignancies with the highest incidence in Martinique among men. Temporal trends of incidence rates for all HM decreased overall in both sexes, except for MM in men. There is significant variability in mortality rates for both sexes. In addition, over the period, the temporal trends of mortality rates for all HMs has decreased overall. Gender-specific rates, between 2009 and 2018, showed that all lymphoid HM have a multimodal distribution curve that increased with age. CONCLUSIONS: Characteristics of HM in Martinique over the reporting periods differ from mainland France. Higher incidences have been observed, particularly for MM, and non-significant sub-mortality is observed compared to mainland France. Moreover, temporal distribution of mortality and incidence trends had decreased over the reporting periods except for MM. Our results showed similarities with African-Americans groups in United States and in particular an equivalence in the frequency distribution of diagnosed HM. However, SMR remains lower compared to US black ethnic groups. Our results contributed to expanding knowledge on the epidemiology of HM with Caribbean data.

Etiología, clínica y evolución de infecciones fúngicas invasoras en pacientes con neoplasias hematológicas en un hospital universitario de Argentina / Etiology, clinical characteristics and outcomes of invasive fungal infection in patients with hematological malignancies in a university hospital in Argentina

INTRODUCCIÓN: Las infecciones fúngicas invasoras (IFI) en pacientes con neoplasias hematológicas (NH) representan un desafío diagnóstico y terapéutico. OBJETIVOS: Describir la etiología, características clínicas, diagnóstico y evolución de los episodios de IFI probadas y probables en pacientes con NH y trasplante de progenitores hematopoyéticos (TPH). PACIENTES Y MÉTODOS: Estudio descriptivo, retrospectivo y de cohorte que incluyó IFI probadas y probables en pacientes adultos con NH y TPH. Se realizó seguimiento hasta el día 90. RESULTADOS: Se incluyeron 80 episodios de IFI: 49% probadas y 51% probables, 67,5% por hongos filamentosos (HF), 30% por hongos levaduriformes (HL) y 2,5% por hongos dimorfos. Los tipos de IFI más frecuentes fueron aspergilosis invasoras pulmonares (AP) y candidiasis invasoras (CI), en su mayoría por Candida spp. no albicans. Todos los casos de AP se diagnosticaron por detección de galactomanano en sangre y/o lavado broncoalveolar, y solamente 22,2% presentaban nódulos con halo en la tomografía computada (TC) de tórax, siendo los infiltrados inespecíficos los hallazgos más frecuentes. Tuvieron coinfección bacteriana y viral el 30 y 17,5%, respectivamente. El 50% fueron IFI de brecha, y la mortalidad global y mortalidad relacionada a la IFI fue 51 y 24%, respectivamente. CONCLUSIÓN: Los HF fueron la principal causa de IFI, con una gran proporción de IFI de brecha, y presentaron elevada mortalidad. Para el diagnóstico, resulta importante la utilización de biomarcadores y jerarquizar cualquier imagen patológica en la TC.

BACKGROUND: Invasive fungal infections (IFI) in patients with hematological malignancies (HM) represent a diagnostic and therapeutic challenge. AIM: To describe the etiology, clinical characteristics, diagnosis and evolution of proven and probable IFI episodes in patients with HM and hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective, descriptive, cohort study performed in adult patients with HM and HSCT, who developed proven and probable IFI. Follow-up was carried out until day 90. RESULTS: A total of 80 IFI episodes were included: 49% proven and 51% probable, 67,5% due to mold (M), 30% to yeast-like fungi (Y) and 2,5% to dimorphic fungi. The most frequent causes were probable pulmonary aspergillosis (PA) and invasive candidiasis (IC), mainly due to non-albicans Candida species. PA were all diagnosed by detection of galactomannan (GM) in blood and bronchoalveolar lavage, and only 22,2% presented halo sign on chest CT. Bacterial and viral coinfections were reported in 30% and 17,5% respectively. Breakthrough IFI occurred in 50%, and global and IFI-related mortality were 51% and 24% respectively. CONCLUSION: Mold was the main cause of IFI, with a large proportion of breakthrough IFI, presenting high mortality. The use of biomarkers and the classification of any pathological image on CT contribute to the diagnosis.

Tumor lysis syndrome in hematological inpatients, experience from a university hospital in Brazil: A retrospective cohort study.

INTRODUCTION: The tumor lysis syndrome is a medical emergency. Its presentation can be spontaneous or secondary, as a consequence of the established treatment. The diagnosis and treatment of the tumor lysis syndrome (TLS) has become a crucial goal to the evolution and improvement of treatments and targeted therapies. METHODS: Between January 2014 and December 2019, we retrospectively reviewed inpatients aged over 18 years with hematological neoplasms from a tertiary hospital in Brazil. We identified 112 episodes of TLS in 97 patients. The incidence was 10.5% and the median OS was 13.0 months (95%CI 6.2 - 19.7). The median age was 56 years (IQR 39.5 - 64). The most frequent diagnoses were multiple myeloma (18.6%), acute myeloid leukemia (17.5%) and diffuse large B-cell lymphoma (17.5%). All patients received intravenous (IV) hydration. The management also included the administration of allopurinol in 76% of the cases and rasburicase in eight patients. Renal replacement therapy was necessary in 37% of the cases. In the multivariate analysis, age, HIV status and ICU treatment were significantly associated with OS. CONCLUSION: The TLS is a serious complication in the setting of hematological malignancies. The use of scores for risk stratification, as well as the inclusion of prophylactic measures and prompt treatment with frequent laboratory monitoring, is essential to reduce morbidity and mortality in the comprehensive treatment of these patients.

Performance of Clostridioides difficile infection severity scores and risk factors related to 30-day all-cause mortality in patients with cancer.

PURPOSE: There are currently no standard definitions for assessing the severity of Clostridioides difficile infection (CDI) in cancer patients. We evaluated the performance of scoring systems for severity and analyzed risk factors for mortality in a cancer cohort. METHODS: We conducted an observational study in patients with cancer and CDI. We calculated the incidence of hospital-onset (HO-CDI) and community-onset health-care facility associated (CO-HCFA-CDI) episodes. We classified severity using five prognostic scales and calculated sensitivity, specificity, positive (PPV), and negative predictive values (NPV) for mortality and intensive care unit (ICU) admission. In addition, multivariate regression was performed to assess variables associated with mortality. RESULTS: The HO-CDI and CO-HCFA-CDI incidence rates were 3.7 cases/10,000 patient-days and 1.9 cases/1,000 admissions, respectively. ESCMID criteria showed the higher sensitivity (97%, 95% CI; 85-100%) and NPV (98%, 95% CI; 85-100%), while ATLAS (≥ 6 points) had the highest specificity (95%, 95% CI; 90-98%) for 30-day all-cause mortality; similar performance was observed for ICU admission. Characteristics associated with fatal outcome were neutropenia (≤ 100 cells/ml) (aOR; 3.03, 95% CI; 1.05-8.74, p = 0.040), male gender (aOR; 2.90, 95% CI; 1.08-7.80, p = 0.034), high serum creatinine (aOR; 1.71, 95% CI; 1.09-2.70, p = 0.020), and albumin (aOR; 0.17, 95% CI; 0.07-0.42, p < 0.001). CONCLUSIONS: Some of the current scales may not be appropriate to discriminate severity in patients with cancer. The variables in this study associated with unfavorable outcomes could be evaluated in prospective studies to develop prognostic scores that identify susceptible patients, especially in immunocompromised populations.

Cytogenetic abnormalities in patients with hematological malignancies in Lahore city, Pakistan / Anormalidades citogenéticas em pacientes com neoplasias hematológicas na cidade de Lahore, Paquistão

Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies.(AU)

As neoplasias hematológicas e de células hematopoiéticas dos genes e as células hematopoiéticas estão associadas à mutação genética, geralmente em nível cromossômico. O estudo citogenético padrão é amplamente aceito como um dos principais determinantes diagnósticos e prognósticos em pacientes. Portanto, o presente estudo descritivo e transversal buscou determinar a análise citogenética de neoplasias hematológicas frequentes no Paquistão. Um total de 202 amostras de medula óssea periférica ou sangue de pacientes com malignidade hematológica benigna e maligna foi coletado usando uma técnica convencional de banda G. Entre os pacientes inscritos, a média de idade foi de 21,5 anos ± 23,4, e a distribuição por gênero mostrou uma marcada predominância da população masculina de 147 (73%) em comparação com a feminina de 55 (27%). Pacientes na faixa etária (2-10 anos) tiveram a maior frequência, 48 (24%), de neoplasias hematológicas, seguida da idade (11-20 anos) com 40 (20%). Cariótipos normais (46, XX / 46, XY) foram encontrados em 51% (n = 103) dos pacientes. Além disso, a frequência de cariótipo complexo foi de 30 (15%), enquanto normal foi observada em 171 (85%) pacientes. Leucemia linfoblástica aguda pré-B (LLA Pré-B) foi a doença maligna mais prevalente de 66 (33%), seguida por leucemia mieloide crônica (LMC) de 41 (20%) e leucemia linfocítica aguda de 29 (14%). A translocação foi o 50 mais prevalente (25%), seguido por hipotriploidia 14 (7%) e monossomia 8 (4%) na análise de aberração cromossômica. Além disso, a translocação t (9:22) encontrada foi de 20 (10%) na LMC, com a maioria na faixa etária (31-40 anos). Este estudo recomenda que o cariótipo deve ser testado com frequência em condições hematológicas porque pode fornecer informações sobre as alterações cromossômicas relativas associadas a doenças malignas específicas.(AU)

Application of mass cytometry to characterize hematopoietic stem cells in apheresis products of patients with hematological malignancies.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is a widely used therapy, but its success largely depends on the number and quality of stem cells collected. Current evidence shows the complexity of the hematopoietic system, which implies that, in the quality assurance of the apheresis product, the hematopoietic stem cells are adequately characterized and quantified, in which mass cytometry (MC) can provide its advantages in high-dimensional analysis. OBJECTIVE: This research aimed to characterize and enumerate CD45dim/CD34+ stem cells using the MC in apheresis product yields from patients with chronic lymphoid malignant diseases undergoing autologous transplantation at the Abu Dhabi Stem Cells Center. METHODS: An analytical and cross-sectional study was performed on 31 apheresis products from 15 patients diagnosed with multiple myeloma (n = 9) and non-Hodgkin lymphomas (n = 6) eligible for HSCT. The MC was employed using the MaxPar Kit for stem cell immunophenotyping. The analysis was performed manually in the Kaluza and unsupervised by machine learning in Cytobank Premium. RESULTS: An excellent agreement was found between mass and flow cytometry for the relative and absolute counts of CD45dim/CD34+ cells (Bland-Altman bias: -0.029 and -64, respectively), seven subpopulations were phenotyped and no lineage bias was detected for any of the methods used in the pool of collected cells. A CD34+/CD38+/CD138+ population was seen in the analyses performed on four patients with multiple myeloma. CONCLUSIONS: The MC helps to characterize subpopulations of stem cells in apheresis products. It also allows cell quantification by double platform. Unsupervised analysis allows results completion and validation of the manual strategy. The proposed methodology can be extended to apheresis products for purposes other than HSCT.

Cytogenetic abnormalities in patients with hematological malignancies in Lahore city, Pakistan / Anormalidades citogenéticas em pacientes com neoplasias hematológicas na cidade de Lahore, Paquistão

Abstract Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross-sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies.

Resumo As neoplasias hematológicas e de células hematopoiéticas dos genes e as células hematopoiéticas estão associadas à mutação genética, geralmente em nível cromossômico. O estudo citogenético padrão é amplamente aceito como um dos principais determinantes diagnósticos e prognósticos em pacientes. Portanto, o presente estudo descritivo e transversal buscou determinar a análise citogenética de neoplasias hematológicas frequentes no Paquistão. Um total de 202 amostras de medula óssea periférica ou sangue de pacientes com malignidade hematológica benigna e maligna foi coletado usando uma técnica convencional de banda G. Entre os pacientes inscritos, a média de idade foi de 21,5 anos ± 23,4, e a distribuição por gênero mostrou uma marcada predominância da população masculina de 147 (73%) em comparação com a feminina de 55 (27%). Pacientes na faixa etária (2-10 anos) tiveram a maior frequência, 48 (24%), de neoplasias hematológicas, seguida da idade (11-20 anos) com 40 (20%). Cariótipos normais (46, XX / 46, XY) foram encontrados em 51% (n = 103) dos pacientes. Além disso, a frequência de cariótipo complexo foi de 30 (15%), enquanto normal foi observada em 171 (85%) pacientes. Leucemia linfoblástica aguda pré-B (LLA Pré-B) foi a doença maligna mais prevalente de 66 (33%), seguida por leucemia mieloide crônica (LMC) de 41 (20%) e leucemia linfocítica aguda de 29 (14%). A translocação foi o 50 mais prevalente (25%), seguido por hipotriploidia 14 (7%) e monossomia 8 (4%) na análise de aberração cromossômica. Além disso, a translocação t (9:22) encontrada foi de 20 (10%) na LMC, com a maioria na faixa etária (31-40 anos). Este estudo recomenda que o cariótipo deve ser testado com frequência em condições hematológicas porque pode fornecer informações sobre as alterações cromossômicas relativas associadas a doenças malignas específicas.

Cytogenetic abnormalities in patients with hematological malignancies in Lahore city, Pakistan / Anormalidades citogenéticas em pacientes com neoplasias hematológicas na cidade de Lahore, Paquistão

Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies.

As neoplasias hematológicas e de células hematopoiéticas dos genes e as células hematopoiéticas estão associadas à mutação genética, geralmente em nível cromossômico. O estudo citogenético padrão é amplamente aceito como um dos principais determinantes diagnósticos e prognósticos em pacientes. Portanto, o presente estudo descritivo e transversal buscou determinar a análise citogenética de neoplasias hematológicas frequentes no Paquistão. Um total de 202 amostras de medula óssea periférica ou sangue de pacientes com malignidade hematológica benigna e maligna foi coletado usando uma técnica convencional de banda G. Entre os pacientes inscritos, a média de idade foi de 21,5 anos ± 23,4, e a distribuição por gênero mostrou uma marcada predominância da população masculina de 147 (73%) em comparação com a feminina de 55 (27%). Pacientes na faixa etária (2-10 anos) tiveram a maior frequência, 48 (24%), de neoplasias hematológicas, seguida da idade (11-20 anos) com 40 (20%). Cariótipos normais (46, XX / 46, XY) foram encontrados em 51% (n = 103) dos pacientes. Além disso, a frequência de cariótipo complexo foi de 30 (15%), enquanto normal foi observada em 171 (85%) pacientes. Leucemia linfoblástica aguda pré-B (LLA Pré-B) foi a doença maligna mais prevalente de 66 (33%), seguida por leucemia mieloide crônica (LMC) de 41 (20%) e leucemia linfocítica aguda de 29 (14%). A translocação foi o 50 mais prevalente (25%), seguido por hipotriploidia 14 (7%) e monossomia 8 (4%) na análise de aberração cromossômica. Além disso, a translocação t (9:22) encontrada foi de 20 (10%) na LMC, com a maioria na faixa etária (31-40 anos). Este estudo recomenda que o cariótipo deve ser testado com frequência em condições hematológicas porque pode fornecer informações sobre as alterações cromossômicas relativas associadas a doenças malignas específicas.

Cytogenetic abnormalities in patients with hematological malignancies in Lahore city, Pakistan

Abstract Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross-sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies.

Resumo As neoplasias hematológicas e de células hematopoiéticas dos genes e as células hematopoiéticas estão associadas à mutação genética, geralmente em nível cromossômico. O estudo citogenético padrão é amplamente aceito como um dos principais determinantes diagnósticos e prognósticos em pacientes. Portanto, o presente estudo descritivo e transversal buscou determinar a análise citogenética de neoplasias hematológicas frequentes no Paquistão. Um total de 202 amostras de medula óssea periférica ou sangue de pacientes com malignidade hematológica benigna e maligna foi coletado usando uma técnica convencional de banda G. Entre os pacientes inscritos, a média de idade foi de 21,5 anos ± 23,4, e a distribuição por gênero mostrou uma marcada predominância da população masculina de 147 (73%) em comparação com a feminina de 55 (27%). Pacientes na faixa etária (2-10 anos) tiveram a maior frequência, 48 (24%), de neoplasias hematológicas, seguida da idade (11-20 anos) com 40 (20%). Cariótipos normais (46, XX / 46, XY) foram encontrados em 51% (n = 103) dos pacientes. Além disso, a frequência de cariótipo complexo foi de 30 (15%), enquanto normal foi observada em 171 (85%) pacientes. Leucemia linfoblástica aguda pré-B (LLA Pré-B) foi a doença maligna mais prevalente de 66 (33%), seguida por leucemia mieloide crônica (LMC) de 41 (20%) e leucemia linfocítica aguda de 29 (14%). A translocação foi o 50 mais prevalente (25%), seguido por hipotriploidia 14 (7%) e monossomia 8 (4%) na análise de aberração cromossômica. Além disso, a translocação t (9:22) encontrada foi de 20 (10%) na LMC, com a maioria na faixa etária (31-40 anos). Este estudo recomenda que o cariótipo deve ser testado com frequência em condições hematológicas porque pode fornecer informações sobre as alterações cromossômicas relativas associadas a doenças malignas específicas.

Modeling Patient-Specific CAR-T Cell Dynamics: Multiphasic Kinetics via Phenotypic Differentiation.

Chimeric Antigen Receptor (CAR)-T cell immunotherapy revolutionized cancer treatment and consists of the genetic modification of T lymphocytes with a CAR gene, aiming to increase their ability to recognize and kill antigen-specific tumor cells. The dynamics of CAR-T cell responses in patients present multiphasic kinetics with distribution, expansion, contraction, and persistence phases. The characteristics and duration of each phase depend on the tumor type, the infused product, and patient-specific characteristics. We present a mathematical model that describes the multiphasic CAR-T cell dynamics resulting from the interplay between CAR-T and tumor cells, considering patient and product heterogeneities. The CAR-T cell population is divided into functional (distributed and effector), memory, and exhausted CAR-T cell phenotypes. The model is able to describe the diversity of CAR-T cell dynamical behaviors in different patients and hematological cancers as well as their therapy outcomes. Our results indicate that the joint assessment of the area under the concentration-time curve in the first 28 days and the corresponding fraction of non-exhausted CAR-T cells may be considered a potential marker to classify therapy responses. Overall, the analysis of different CAR-T cell phenotypes can be a key aspect for a better understanding of the whole CAR-T cell dynamics.

End of life decisions in immunocompromised patients with acute respiratory failure.

PURPOSE: To identify patient, disease and organizational factors associated with decisions to forgo life-sustaining therapies (DFLSTs) in critically ill immunocompromised patients admitted to the intensive care unit (ICU) for acute respiratory failure. MATERIAL AND METHODS: We performed a secondary analysis of the international EFRAIM prospective study, which enrolled 1611 immunocompromised patients with acute respiratory failure admitted to 68 ICUs in 16 countries between October 2015 and June 2016. Multivariate logistic analysis was performed to identify independent predictors of DFLSTs. RESULTS: The main causes of immunosuppression were hematological malignancies (50%) and solid tumor (38%). Patients had a median age of 63 yo (54-71). A pulmonologist was involved in the patient management in 38% of cases. DFLSTs had been implemented in 28% of the patients. The following variables were independently associated with DFLSTs: 1) patient-related: older age (OR 1.02 per one year increase, 95% confidence interval(CI) 1.01-1.03,P < 0.001), poor performance status (OR 2.79, 95% CI 1.98-3.93, P < 0.001); 2) disease-related: shock (OR 2.00, 95% CI 1.45-2.75, P < 0.001), liver failure (OR 1.59, 95% CI 1.14-2.21, P = 0.006), invasive mechanical ventilation (OR 1.79, 95% CI 1.31-2.46, P < 0.001); 3) organizational: having a pulmonologist involved in patient management (OR 1.85, 95% CI 1.36-2.52, P < 0.001), and the presence of a critical care outreach services (OR 1.63, 95% CI 1.11-2.38, P = 0.012). CONCLUSIONS: A DFLST is made in one in four immunocompromised patient admitted to the ICU for acute respiratory failure. Involving a pulmonologist in patient's management is associated with less non beneficial care.

CAR-T cell therapy for patients with hematological malignancies. A systematic review.

Hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, particularly considering patients who manifest multiple refractory diseases. Recently, chimeric antigen receptor (CAR)-T cell therapy has emerged as a potential treatment option for relapsed/refractory B cell malignancies, which have motivated the Food and Drug Administration approval of a series of products based on this technique. The objective of this systematic review was to assess the efficacy and safety of CAR-T cell therapy for patients with hematological malignancies. A comprehensive literature search was conducted in the electronic databases (CENTRAL, Embase, LILACS, and MEDLINE), clinical trials register platforms (Clinicaltrials.gov and WHO-ICTRP), and grey literature (OpenGrey). The Cochrane Handbook for Reviews of Interventions was used for developing the review and the PRISMA Statement for manuscript reporting. The protocol was prospectively published in PROSPERO database (CRD42020181047). After the selection process, seven RCTs were included, three of which with available outcome results. The available results are from studies assessing axicabtagene, lisocabtagene, and tisagenlecleucel for patients with B cell lymphoma, and the certainty of evidence ranged from very low to low for survival and progression-related outcome and for safety outcomes. Additionally, four randomized controlled trials comparing CAR-T cell therapy to the standard treatment for various types of relapsed/refractory B cell non-Hodgkin lymphomas and multiple myeloma included in this systematic review still did not have available outcome data. The results of this review may be used to guide clinical practice but evidence concerning the safety and efficacy of CAR-T Cell therapy for hematological malignancies is still immature to recommend its application outside of clinical trials or compassionate use context for advanced and terminal cases. It is expected the results of the referred comparative studies will provide further elements to subsidize the broader application of this immunotherapy.