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Integrated genomic analyses identify high-risk factors and actionable targets in T-cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy often associated with poor outcomes. To identify high-risk factors and potential actionable targets for T-ALL, we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients, of whom 85% have outcome information. The genomic mutation landscape of this Chinese cohort is very similar to the Western cohort published previously, except that the rate of

WBC-based segmentation and classification on microscopic images a minor improvement.

Introduction White blood cells (WBCs) are immunity cells which fight against viruses and bacteria in the human body. Microscope images of captured WBCs for processing and analysis are important to interpret the body condition. At present, there is no robust automated method to segment and classify WBCs images with high accuracy. This paper aims to improve on WBCs image segmentation and classification method. Methods A triple thresholding method was proposed to segment the WBCs meanwhile, a convolutional neural network (CNN)-based binary classification model that adopts transfer learning technique was proposed to detect and classify WBCs as a healthy or a malignant. The input dataset of this research work is the Acute Lymphoblastic Leukemia Image Database (ALL-IDB). The process first converts the captured microscope images into HSV format for obtaining the H component. Otsu thresholding is applied to segment the WBC area. A 13 × 13 kernel with two iterations was used to apply morphological opening on image to ameliorate output results. Collected cell masks were used to detect the contour of each cell on the original image. To classify WBCs into a healthy or a malignant category, characteristics and conditions of WBCs are to be examined. A transfer learning technique and pre-trained InceptionV3 model were employed to extract the features from the images for classification. Results The proposed WBCs segmentation method yields 90.45% accuracy, 83.81% of the structural similarity index, 76.25% of the dice similarity coefficient, and is computationally efficient. The accuracy of fine-tuned classifier model for training, validation and test sets are 93.27%, 92.31% and 96.15% respectively. The obtained results are high in accuracy and precision are over 96% and with lower loss value. Discussion Triple thresholding outperforms K-means clustering in segmenting smaller dataset. Pre-trained InceptionV3 model and transfer learning improve the flexibility and ability of classifier.

A challenging case of an adolescent and young adult patient with high-risk acute lymphoblastic leukemia the need for a multidisciplinary approach a case report.

Adolescents and young adults diagnosed with acute lymphoblastic leukemia are treated according to pediatric-based regimens to achieve better results. However, implementation of intensive chemotherapy protocols in this age group is associated with increased treatment-related toxicities, affecting almost every organ and system. In this case, the focus of our interest was on rather rare entities steroid-induced psychosis that seldom develops in children and adolescents, and choroid plexus hemosiderosis, infrequently identified as a first sign of iron overload. The aim of this paper is to present a challenging case of a 15-year-old Caucasian male patient treated for high-risk acute lymphoblastic leukemia and who experienced various adverse incidents during intensive chemotherapy, thus necessitating a high-quality multidisciplinary approach. Slow minimal residual disease clearance was an additional concerning issue. Induction and re-induction were complicated by steroid-induced hyperglycemia that required multiple-week insulin. During consolidation, acute kidney injury on the basis of chronic kidney disease was verified, demanding subsequent drug dose modifications. By the end of re-induction, after dexamethasone cessation, infrequent steroid-induced psychosis, presented as incoherent speech, aggressive behavior, and mood swings, required intensive psychiatric support. Neurological evaluation of seizures revealed uncommon choroid plexus hemosiderosis by brain magnetic resonance imaging, warranting appropriate selection of iron chelation therapy in the context of preexisting nephropathy. Ultimately, iron deposits of moderate intensity were verified by liver magnetic resonance imaging, while heart tissue remained intact. The early diagnosis and adequate treatment of aforementioned difficult toxicities resulted in complete recovery of the patient. Treating adolescents with high-risk acute leukemia and multiple therapy-related morbidities remains a challenge, even in the era of extensive and effective supportive therapy. Superior survival rates might be achieved by prompt recognition of both frequent and rarely encountered adverse episodes, as well as well-timed and appropriate management by a well-coordinated multidisciplinary team.

Taste Alteration in Children With Acute Lymphoblastic Leukemia Undergoing Maintenance Treatment.

The purpose of the present study is to examine taste alteration in children with acute lymphoblastic leukemia (ALL) undergoing maintenance treatment. The population of the study was comprised of children with ALL between the ages of 7 and 18 who received maintenance treatment. The study sample was included 72 children (children with ALL36 and healthy children 36) determined by power analysis. This was a cross-sectional study. The children in both groups were applied to the taste test by the researcher. It was determined that there is a statistically significant difference ( P <0.05) between sweet (sucrose), salty (sodium chloride), sour (citric acid), and bitter (quinine hydrochloride) taste test score averages of the children with ALL and healthy children and that the 4 taste test score averages are lower in the experiment group. The taste alterations were determined in the present study for children with ALL undergoing maintenance treatment. Problems of children with cancer such as loss of appetite, negative attitude toward food or weight loss can be reduced or prevented when taste alteration is determined in children with cancer thereby improving the feeding of the children thereby increasing their quality of life.

Mutational Analysis of the VPREB1 Gene of Pre-BCR Complex in a Cohort of Sporadic Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia.

During bone marrow B-cell development, the pre-B-cell receptor is formed by the association of the immunoglobulin heavy chain with a surrogate light chain, which is encoded by the VPREB1, and λ5 genes. It is known that pre-BCR signaling signifies a critical checkpoint at the pre-B-cell stage. Thus, failure pre-BCR signaling is proposed as a critical factor for the development of B-cell acute lymphoblastic leukemia (B-ALL). B‑ALL is the most common pediatric cancer and is one of the leading causes of death in children. Until now, several molecular analyses were performed for genomic alterations in B-ALL, but for genomic analysis of the VPREB1 gene and its rare variations, limited studies have been conducted. In this study, using polymerase chain reaction and direct sequencing of 88 pediatric patients with B-ALL, we investigated the genomic region of the VPREB1 gene to find sequence variations of this gene. Our study presented ten homozygous and heterozygous point mutations and heterozygous nucleotide deletions, in the VPREB1 gene in 36 boys and 32 girls patients. Our Bioinformatics assay results presented that these variations may alter the RNA folding, protein structure, and therefore probable effect on the protein function. These results propose that nucleotide changes probably contribute to B-ALL pathogenesis.

SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies.

SYK and ZAP70 nonreceptor tyrosine kinases serve essential roles in initiating B-cell receptor (BCR) and T-cell receptor (TCR) signaling in B- and T-lymphocytes, respectively. Despite their structural and functional similarity, expression of SYK and ZAP70 is strictly separated during B- and T-lymphocyte development, the reason for which was not known. Aberrant co-expression of ZAP70 with SYK was first identified in B-cell chronic lymphocytic leukemia (CLL) and is considered a biomarker of aggressive disease and poor clinical outcomes. We recently found that aberrant ZAP70 co-expression not only functions as an oncogenic driver in CLL but also in various other B-cell malignancies, including acute lymphoblastic leukemia (B-ALL) and mantle cell lymphoma. Thereby, aberrantly expressed ZAP70 redirects SYK and BCR-downstream signaling from NFAT towards activation of the PI3K-pathway. In the sole presence of SYK, pathological BCR-signaling in autoreactive or premalignant cells induces NFAT-activation and NFAT-dependent anergy and negative selection. In contrast, negative selection of pathological B-cells is subverted when ZAP70 diverts SYK from activation of NFAT towards tonic PI3K-signaling, which promotes survival instead of cell death. We discuss here how both B-cell malignancies and autoimmune diseases frequently evolve to harness this mechanism, highlighting the importance of developmental separation of the two kinases as an essential safeguard.

Poricoic acid A (PAA) inhibits T-cell acute lymphoblastic leukemia through inducing autophagic cell death and ferroptosis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with poor clinical outcome. Poricoic acid A (PAA) is the main chemical constituent on the surface layer of the mushroom Poria cocos, and exerts protective effects against various diseases. In the study, its effects on T-ALL progression were investigated both in vitro and in vivo. Our results showed that PAA strongly reduced the cell viability of T-ALL cell lines, and induced cell G2 cycle arrest and apoptosis in vitro. Mitochondrial dysfunction was also elevated by PAA, along with enhanced cellular reactive oxygen species (ROS) production. Importantly, PAA-suppressed cell viability and -triggered apoptosis were ROS-dependent. Additionally, autophagy was significantly induced by PAA in T-ALL cells through regulating AMP-activated protein kinase (AMPK)mammalian target of rapamycin (mTOR) and LC3 signaling pathways. PAA treatments also provoked ferroptosis in T-ALL cells with reduced glutathione (GSH) levels and elevated malonaldehyde (MDA) contents. Suppressing autophagy and ferroptosis almost abrogated the capacity of PAA to restrain T-ALL proliferation and growth. The effects of PAA to suppress T-ALL tumor growth were also confirmed in vivo with undetectable toxicity. Therefore, the present study highlighted the potential of PAA for T-ALL treatment mainly through inducing autophagic cell death and ferroptosis.

Expression Level and Correlation of miR-211, miR-155, C-myc in Acute T Lymphocytic Leukemia.

To investigate the expression and correlation of miR-211, miR-155, and C-myc in acute T lymphocytic leukemia (T-ALL), aiming to provide evidence for the diagnosis and treatment. A total of 96 T-ALL patients who were diagnosed and treated in Peoples Hospital of Zhengzhou from June 2014 to June 2017 were selected, and 69 healthy volunteers who had a physical examination were selected as control group in the same period. Real-time fluorescent quantitative PCR (RT-PCR) was used to determine the expression levels of miR-211, miR-155, and C-myc in peripheral blood mononuclear cells in each group. Kaplan-Meier was used to analyze the survival of T-ALL patients and correlation of miR-211, miR-155, and C-myc with prognosis. Pearson correlation analysis was used to evaluate the correlation of miR-211, miR-155, and C-myc with disease risk. The expression levels of miR-211 mRNA, miR-155 mRNA, and C-myc mRNA in T-ALL group were higher than those in the control group (P<0.01), those in non-remission group were higher than those in remission group (P<0.01), and those in high-risk group were also higher than those in low-risk group and intermediate-risk group (P<0.01). The survival time of T-ALL patients with low miR-211 expression was longer than that with high miR-211 expression (P<0.01), that with low miR-155 expression was longer than that with high miR-155 expression (P<0.01), and that with low C-myc expression was also longer than that with high C-myc expression (P<0.01). The high expression of miR-211, miR-155, and C-myc was linearly positively correlated with high risk of disease (r0.749, 0.781, 0.804). The expressions of miR-211, miR-155, and C-myc are up-regulated in T-ALL patients, closely related to prognosis, and linearly positively correlated with disease risk. 急性T淋巴细胞白血病的miR-211、miR-155、C-myc表达水平及相关性研究. 分析并探讨急性T淋巴细胞白血病（T-ALL）的miR-211、miR-155、C-myc表达及相关性，旨在为早期诊断及预后监测提供依据. 选择2014年6月-2017年6月于郑州人民医院接受诊治的T-ALL患者96例，另选同期体检健康的志愿者69例为对照组，采用实时荧光定量PCR测定各组外周血单个核细胞中miR-211、miR-155、C-myc表达水平，通过Kaplan-Meier分析T-ALL患者生存情况及miR-211、miR-155和C-myc与预后的关系，Pearson相关分析评价miR-211、miR-155和C-myc与疾病危险度的相关性. T-ALL组miR-211 mRNA、miR-155 mRNA、C-myc mRNA表达水平均明显高于对照组（P<0.01），未缓解组均明显高于缓解组（P<0.01），高危组亦明显高于低危组和中危组（P<0.01）。miR-211低表达患者生存时间明显长于高表达患者（P<0.01），miR-155低表达患者生存时间明显长于高表达患者（P<0.01），C-myc低表达患者生存时间亦明显长于高表达患者（P<0.01）。miR-211、miR-155和C-myc高表达与疾病高危呈线性正相关(r0.749、0.781、0.804). T-ALL患者miR-211、miR-155、C-myc表达上调，其表达水平与预后密切相关，且与疾病危险度呈线性正相关.

Mechanism of miR-155 Promoting Drug Resistance in Childhood Acute Lymphoblastic Leukemia by Regulating Wntβ-Catenin Signaling Pathway.

To investigate the mechanism of miR-155 promoting drug resistance of children B-ALL to Ara-C by regulating Wntβ-Catenin signaling pathway. The expression of miR-155 in bone marrow tissue and cell line of B-ALL was detected by PCR. The chemotherapy resistant strain REH Ara-C was constructed by using REH cells. REH Ara-C cells were transfected with miR-155 inhibitor. The proliferation of REHAra-C cells was detected by EdU. The apoptosis of REH Ara-C cells was detected by flow cytometry. The drug resistance of REHAra-C cells were analyzed by CCK-8 method and colony formation assay. The expression of Wntβ-Catenin signaling pathway related proteins were determined by Western blot. MiR-155 inhibitor and Wnt activator agonist were used to transfect REHAra-C cells, and their effects on cell proliferation, apoptosis and drug resistance were determined. Compared with normal tissues and cells, the expression level of miR-155 in B-ALL bone marrow tissuecell line was increased (P<0.05) Compared with drug sensitive B-ALL tissuescell lines, the expression level of miR-155 in drug resistant B-ALL tissues and cell lines was increased (P<0.05) Inhibition of miR-155 expression decreased the proliferation of REHAra-C cells (P<0.05), promoted apoptosis (P<0.05), enhanced the cytotoxicity of Ara-C (P<0.05), and inhibited Wntβ-Catenin signaling pathway related protein and MDR1 gene expression (P<0.05), which could be reversed by activating Wnt expression (P<0.05). The expression of miR-155 is up-regulated in bone marrow of children with B-ALL, which may be related to the activation of Wntβ-Catenin signaling pathway promotes the proliferation of B-ALL cells and inhibits apoptosis, which leads to chemotherapy resistance. MiR-155对小儿急性淋巴细胞白血病的耐药机制研究. 探讨miR-155通过调节Wntβ-Catenin信号通路促进小儿急性B淋巴细胞白血病（B-ALL）对阿糖胞苷（Ara-C）化疗耐药的机制. 采用PCR检测 B-ALL患儿骨髓组织与细胞系中miR-155表达情况；用REH细胞系构建化疗抵抗株REHAra-C，使用miR-155抑制剂转染REHAra-C细胞，EdU检测细胞增殖能力，流式细胞术检测细胞的凋亡率，CCK-8法与克隆形成实验分析细胞耐药性，Western blot测定Wntβ-Catenin信号通路相关蛋白的表达；用miR-155抑制剂与Wnt激活剂agonist转染REHAra-C细胞，测定其对细胞增殖、凋亡与耐药性的影响. 与正常组织及细胞相比，B-ALL骨髓组织细胞系中miR-155表达水平升高(P＜0.05）；与药物敏感B-ALL组织细胞系相比，耐药B-ALL组织与细胞系中miR-155表达水平升高(P＜0.05）；抑制miR-155表达降低了REHAra-C细胞增殖能力(P＜0.05），促进了凋亡(P＜0.05），增强了Ara-C的细胞毒性(P＜0.05），同时抑制了Wntβ-Catenin信号通路相关蛋白与耐药基因MDR1的表达(P＜0.05），通过激活Wnt表达则可逆转上述现象(P＜0.05）. B-ALL患儿骨髓组织中miR-155表达上调，可以通过激活Wnt β-Catenin信号通路促进 B-ALL细胞增殖、抑制细胞凋亡，从而导致化疗耐药.

Prognostic Value of Average Daily Platelet Increase in Childhood B-cell Acute Lymphoblastic Leukemia Patients.

To evaluate the prognosis value of average daily platelet amount increase in children with B-cell acute lymphoblastic leukemia(B-ALL) treated by CCCG-ALL-2015 regimen. 106 children with primary B-ALL were retrospective analyzed, standardized MRD test protocol was used to detect the MRD level (19 d and 46 d) after chemotherapy. The platelet count was measured by Sysmex XE-2100. Kaplan-Meier survival curve statistics was used to analyze the event free survival(EFS) rate of the children. The trend of negative correlation existed between PPC and TPR (r Ap can reflect the effect of B-ALL chemotherapy and can be used to monitor the curative effect and prognosis of B-ALL children. 定量检测平均每日血小板增长量在B细胞急性淋巴细胞白血病患儿中的预后价值. 评价平均每日血小板增长量(average daily platelet amount increase, Ap)在 CCCG-ALL-2015 方案治疗的B细胞急性淋巴细胞白血病（B-ALL）患儿预后中的价值. 回顾性分析106例初发B-ALL患儿，标准化MRD检测方案检测化疗后d 19与d 46 MRD水平，Sysmex XE-2100检测血小板计数，Kaplan-Meier生存曲线分析患儿的无事件生存(EFS）率. 相关性分析显示PPC和TPR呈负相关（r Ap增生可反映B-ALL化疗效果，可用于B-ALL患儿疗效及预后的监测.

Expression Level of SOCS3 in Acute Lymphoblastic Leukemia Cells Affects the Cytotoxicity of NK Cells.

To detect the expression level of suppressors of cytokine signaling 3 （SOCS3） in acute lymphoblastic leukemia (ALL), and to observe the effect of over-expresson of SOCS3 in Jurkat cells on the cytotoxicity of NK cells. The expression levels of SOCS3 mRNA in peripheral blood mononuclear cells of 20 children with ALL and 20 healthy children (normal control group) were detected by RT-PCR. The peripheral blood NK cells from healthy subjects were selected by immunomagnetic technique, and the purity was detected by flow cytometry. SOCS3 was overexpressed in Jurkat cells infected with lentivirus vector, and SOCS3 mRNA expression was detected by RT-PCR after lentivirus infection. The NK cells were co-cultured with the infected Jurkat, and LDH release method was used to detect the cytotoxicity of NK cells on the infected Jurkat cells. The concentrations of TNF-α and IFN-γ were determined by ELISA. The expression of NKG2D ligands MICA and MICB on the surface of Jurkat cells were detected by flow cytometry. Western blot was used to detect the effect of SOCS3 overexpression on STAT3 phosphorylation in Jurkat cells. Compared with the control group, the mRNA expression of SOCS3 in the peripheral blood mononucleated cells of ALL children was significantly decreased. The purity of NK cells isolated by flow cytometry could reach more than 70%. The expression of SOCS3 mRNA in Jurkat cells increased significantly after lentivirus infection. Overexpression of SOCS3 in Jurkat cells significantly promoted the killing ability of NK cells and up-regulated the secretion of TNF-α and IFN-γ from NK cells. The results of flow cytometry showed that the expression of NKG2D ligands MICA and MICB on Jurkat cells increased significantly after SOCS3 overexpression. Western blot results showed that overexpression of SOCS3 significantly reduced the phosphorylation level of STAT3 protein in Jurkat cells. SOCS3 mRNA expression was significantly decreased in ALL patients, and overexpression of SOCS3 may up-regulate the expression of MICA and MICB of NKG2D ligands on Jurkat cell surface through negative regulation of JAKSTAT signaling pathway, thereby promoting the cytotoxic function of NK cells. 上调急性淋巴细胞白血病中细胞因子信号传导抑制因子3的表达促进NK细胞杀伤活性的机制研究. 检测细胞因子信号传导抑制因子3（SOCS3）在急性淋巴细胞白血病（ALL）中的表达水平，并探讨NK细胞对过表达SOCS3细胞系Jurkat细胞的杀伤作用. 采用RT-PCR技术检测20例ALL患儿及20例健康体检儿童（正常对照组）外周血单个核细胞中SOCS3 mRNA表达水平。免疫磁珠分选健康人外周血NK细胞，采用流式细胞术检测其纯度。慢病毒载体感染Jurkat细胞使之过表达SOCS3，RT-PCR检测慢病毒感染后细胞中SOCS3 mRNA表达情况。将NK细胞与Jurkat细胞共培养， LDH释放法检测杀伤活性，ELISA检测TNF-α和IFN-γ浓度。流式细胞术检测过表达SOCS3后Jurkat细胞表面NKG2D配体MICA与MICB的表达。Western blot检测过表达SOCS3对Jurkat细胞中STAT3蛋白磷酸化水平的影响. ALL患儿外周血单个核细胞中SOCS3 mRNA表达水平较正常对照组显著降低。流式细胞术检测分离NK细胞纯度可达70%以上。慢病毒感染的Jurkat细胞中SOCS3 mRNA表达显著增加。过表达SOCS3的Jurkat细胞可显著促进NK细胞对其杀伤能力，且可上调NK细胞TNF-α和IFN-γ的分泌。流式细胞术检测结果显示，过表达SOCS3后Jurkat细胞表面NKG2D配体MICA与MICB表达水平均显著增加。Western blot结果显示，过表达SOCS3后可显著降低Jurkat细胞中JAKSTAT信号通路中STAT3蛋白的磷酸化水平. 在ALL中SOCS3 mRNA表达显著降低，而过表达SOCS3可能通过负性调控JAKSTAT信号通路上调Jurkat细胞表面NKG2D配体MICA与MICB的表达，进而促进NK细胞的杀伤能力.

Effect of Carvacrol on the Biological Behavior of Leukemia Cells and Its Mechanism.

To explore the effect of carvacrol on the biological behavior of leukemia cells and its regulation to circ-0008717miR-217 molecular axis. Human acute lymphoblastic leukemia cells Molt-4 were cultured in vitro, and different concentrations of carvacrol were added to the cells. si-NC and si-circ-0008717 were transfected into Molt-4 cells (si-NC group, si-circ-0008717 group). pcDNA, pcDNA-circ-0008717, anti-miR-NC, anti-miR-217 were transfected into Molt-4 cells and then added to carvacrol-treated cells (carvacrolpcDNA group, carvacrolpcDNA-circ-0008717 group, carvacrolanti-miR-NC group, carvacrolanti-miR-217 group). MTT, plate clone formation experiment, and flow cytometry were used to detect the viability of the cell, colony formation number, and apoptosis rate of cells, respectively. The RT-qPCR method was used to detect the expression levels of circ-0008717 and miR-217. The dual luciferase reporter gene experiment was used to detect the targeting relationship between circ-0008717 and miR-217. After carvacrol treatment, the cell viability decreased significantly (r-0.9405), expression level of circ-0008717 decreased (r-0.9117), colonies formed number decreased (r-0.9256), while the cell apoptosis rate increased (r 0.8464), and the expression level of miR-217 increased (r0.9468). Compared with the si-NC group, the expression level of miR-217 in si-circ-0008717 group increased (P＜0.001), the cell apoptosis rate increased (P＜0.001), while cell viability decreased (P＜0001), the number of colonies formed decreased (P＜0.001). Compared with the carvacrolpcDNA group, the cell viability of the carvacrolpcDNA-circ-0008717 group increased (P＜0.001), the number of colonies formed increased (P＜0.001), while the cell apoptosis rate decreased (P＜0.001). circ-0008717 could target miR-217. The cell viability of the carvacrolanti-miR-217 group increased (P＜0.001), and the number of colonies formed increased (P＜0.001), while the cell apoptosis rate decreased (P＜0001) as compared with the carvacrolanti-miR-NC group. Carvacrol can promote the expression of miR-217 by down-regulating the expression of circ-0008717, thereby reducing the proliferation and cloning ability of leukemia cells and promoting cell apoptosis. 香芹酚对白血病细胞生物学行为的影响及其机制. 探讨香芹酚对白血病细胞生物学行为的影响及其对circ-0008717miR-217分子轴的调控作用. 体外培养人急性淋巴细胞白血病细胞Molt-4，分别加入不同浓度的香芹酚处理细胞；si-NC、si-circ-0008717分别转染入Molt-4细胞（si-NC组、si-circ-0008717组），pcDNA、pcDNA-circ-0008717、anti-miR-NC、anti-miR-217分别转染入Molt-4细胞后加入香芹酚处理细胞（香芹酚pcDNA组、香芹酚pcDNA-circ-0008717组、香芹酚anti-miR-NC组、香芹酚anti-miR-217组）；MTT、平板克隆形成实验、流式细胞术分别检测细胞活力、集落形成数、细胞凋亡率；RT-qPCR法检测circ-0008717和miR-217的表达量；双荧光素酶报告基因实验检测circ-0008717与miR-217的靶向关系. 经香芹酚处理后，细胞活力明显降低（r-0.9405），circ-0008717的表达水平明显降低（r-0.9117），集落形成数明显减少（r-0.9256），细胞凋亡率明显升高（r0.8464），miR-217的表达水平明显升高（r0.9468）；与si-NC组比较，si-circ-0008717组miR-217的表达水平升高（P＜0.001），细胞活力降低（P＜0001），集落形成数明显减少（P＜0.001），细胞凋亡率升高（P＜0.001）；与香芹酚pcDNA组比较，香芹酚pcDNA-circ-0008717组细胞活力升高（P＜0.001），集落形成数明显增多（P＜0.001），细胞凋亡率明显降低（P＜0001）；circ-0008717可靶向调控miR-217的表达；与香芹酚anti-miR-NC组比较，香芹酚anti-miR-217组细胞活力明显升高（P＜0.001），集落形成数明显增多（P＜0.001），细胞凋亡率明显降低（P＜0.001）. 香芹酚可通过下调circ-0008717的表达而促进miR-217的表达从而减弱白血病细胞增殖、克隆形成能力及促进细胞凋亡.

Effect of Hypoxia Inducible Factor-1α on Chemosensitivity of B-ALL Cells to Vincristine and Its Mechanism.

To explore the effect of hypoxia on the chemosensitivity of B-acute lymphoblastic leukemia （B-ALL） cells to Vincristine (VCR) and the mechanisms. B-ALL cells SUP-B15, Nalm-6 and RS411 were selected as the research objects. The cells were divided into the control group and the hypoxia mimic group (CoCl CoCl Under hypoxic conditions, HIF-1α may mediate VCR resistance in B-ALL cells by downregulating the pro-apoptotic protein BAX. 低氧诱导因子-1α对B-ALL细胞长春新碱敏感性的影响及机制研究. 研究低氧条件下急性B淋巴细胞白血病（B-ALL）细胞对长春新碱（VCR）敏感性的影响及可能的作用机制. 以B-ALL细胞SUP-B15、Nalm-6及RS411为研究对象，将细胞分为对照和低氧模拟组（CoCl CoCl 低氧条件下HIF-1α可能通过下调促凋亡蛋白BAX表达导致B-ALL细胞对VCR耐药.

Establishment of An Animal Model of Acute B Lymphoblastic Leukemia with Minimal Residual Disease.

To establish an animal model of acute B lymphoblastic leukemia (B-ALL) with minimal residual disease. The transplanted tumor was formed by subcutaneous injection of 2×10 There were 2×10 The animal model of subcutaneous tumor of B-ALL was successfully established in nude mice. 急性B淋巴细胞白血病微小残留病动物模型的建立. 建立急性B淋巴细胞白血病微小残留病动物模型. 通过皮下注射2×10 裸鼠皮下注射2×10 采用裸鼠成功建立急性B淋巴细胞系白血病皮下肿瘤的动物模型.

Single Center Clinical Analysis of Bloodstream Infection Pathogens in Children with Acute Leukemia.

To investigate the clinical features, distribution of pathogenic bacteria, and drug resistance of bloodstream infection in children with acute leukemia. Clinical data of 93 blood culture-positive children with acute leukemia from January 2015 to December 2019 in Department of Pediatrics, The Second Hospital of Anhui Medical University were analyzed retrospectively. In these 93 cases, 78 cases were in the period of neutrophil deficiency. There were 54 Gram-negative bacteria (G G 急性白血病患儿血流感染单中心病原菌分析. 探讨急性白血病患儿细菌性血流感染的临床特点、病原学分布和耐药情况。方法：回顾性分析安徽医科大学第二附属医院2015年1月至2019年12月93例发生细菌性血流感染的急性白血病患儿临床资料、病原学分布特点、药敏情况及预后。结果：93例患儿中有78例处于粒细胞缺乏期。93株病原菌中以革兰氏阴性菌（G

The clinical characteristics and prognosis in adult Ph negative acute lymphoblastic leukemia with TP53 aberrations.

Very few reports elucidate the prognosis of patients with TP53 aberrations using both measurable residual disease (MRD) and the status of having undergone allogeneic hematopoietic stem cell transplantation (allo-SCT). In this study, aberrations of TP53 were analyzed using next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) in patients with Philadelphia chromosome-negative (Ph

Genomic profile of radiation-induced early-onset mouse B-cell lymphoma recapitulates features of Philadelphia chromosome-like acute lymphoblastic leukemia in humans.

Epidemiological studies have revealed a radiation-related increase in the risk of developing acute lymphoblastic leukemia (ALL). Our recent study revealed early induction and increased risk of precursor B-cell (pB) lymphomas in mice after radiation exposure. However, the genomic landscape of radiation-induced B-cell lymphomas remains unclear. To identify the relevant genetic alterations in mice, whole-exome sequencing was performed on both early-onset and late-onset B-cell lymphomas that developed spontaneously or after gamma-irradiation. In addition to multiple driver mutations, the data revealed that interstitial deletion of chromosome 4, including Pax5, and missense mutations in Jak3 are unique genomic alterations in radiation-induced, early-onset B-cell lymphomas. RNA sequencing revealed a pB-cell-type gene-expression profile with no involvement of known fusion genes for human ALLs in the early-onset B-cell lymphomas. Activation of Jak3Stat5 signaling in early-onset B-cell lymphomas was validated using western capillary electrophoresis. Those features were similar to those of Philadelphia chromosome-like ALL. Our data suggest a critical role for Pax5 loss-of-function mutations in initiating B-cell leukemogenesis coupled with activation of Jak3Stat5 signaling as a basis for the rapid development of radiation-induced pB-ALL. These molecular signatures for radiation-induced cancers will inform both risk assessment and potential targeted therapies for pB-ALL.

Cancer Recurrence and Omics Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.

A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activityinactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysisgluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valineleucineisoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular.

Molecular and Pharmacological Bladder Cancer Therapy Screening Discovery of Clofarabine as a Highly Active Compound.

The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence andor treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. We aimed to establish a model system for drug identificationrepurposing in order to identify novel therapies for the treatment of BC. A collection of commercially available BC cell lines (n 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n 8). The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.

Controversial Flow Cytometry Monitoring of a Relapse Case of Pediatric T Cell Acute Lymphoblastic Leukemia A Case Report.

Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer, with 80-85% represented by B cell ALL and only 15% by T cell ALL. T Cell ALL (T-ALL) carries a more reserved prognosis compared to B Cell ALL (B-ALL) with regard to response to treatment, risk of relapse, and overall survival. Progress made in current monitoring protocols such as

Antibody and Cellular-Based Therapies for Pediatric Acute Lymphoblastic Leukemia Mechanisms and Prospects.

Acute lymphoblastic leukemia (ALL) is one of the most commonly diagnosed cancers in children. Despite enormous efforts to treat ALL over the past decade, the intensity of conventional chemotherapeutic strategies has reached the tolerance limit. Among various recently developed therapeutic approaches, antibody and cellular-based therapies showed less toxicity and better curative effect. Due to advanced mechanistic actions, these innovative therapies have provided durable responses and long-term survival in eradicating pediatric ALL, especially patients with refractoryrelapsed ALL. Owing to these aspects, herein, we emphasize the mechanisms of action and application status of antibodies targeting tumor antigens, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells. The significant prospects and challenges are discussed, highlighting the innovative immunotherapies to deal with ALL. Together, this review will summarize the progress of antibody and cellular-based therapies for pediatric ALL, which may promote further research on antibody-based biopharmaceutics.

Digital PCR for Minimal Residual Disease Quantitation Using ImmunoglobulinT-Cell Receptor Gene Rearrangements in Acute Lymphoblastic Leukemia A Proposed Analytic Algorithm.

In minimal residual disease (MRD), where there are exceedingly low target copy numbers, digital PCR (dPCR) can improve MRD quantitation. However, standards for dPCR MRD interpretation in acute lymphoblastic leukemia are lacking. Here, for immunoglobulinT-cell receptor-based MRD, we propose an objective, statistics-based analytic algorithm. In 161 postinduction samples from 79 children with acute lymphoblastic leukemia, MRD was performed by dPCR and real-time quantitative PCR (qPCR) using the same markers and primer-probe sets. The dPCR raw data were analyzed by using an automated algorithm. dPCR and qPCR results were highly concordant (P < 0.0001) 98% (50 of 51) of qPCR positive were positive by dPCR, whereas 95% (61 of 64) of qPCR negative results were also negative by dPCR. For MRD quantitation, both qPCR and dPCR were tightly correlated (R

Primary Spindle Cell Sarcoma of the Lung with

Originally described in a rare subset of poorly differentiated squamous cell carcinomas termed NUT carcinomas,

AKR1C3 expression in T acute lymphoblastic leukemialymphoma for clinical use as a biomarker.

To investigate aldo-keto reductase 1C3 (AKR1C3) expression in T and B acute lymphoblastic leukemialymphoma (ALL) patients. Three commercial antibodies were evaluated for AKR1C3 immunohistochemistry (IHC) staining performance Polyclonal Thermofisher scientific (ClonePA523667), rabbit monoclonal Abcam EPR16726 (ab209899) and SigmaMillipore anti-AKR1C3 antibody, mouse monoclonal, clone NP6.G6.A6, purified from hybridoma cell culture. Initial optimization was performed on cell line controls HCT116 (negative control) genetically modified cell line HCT116 with AKR1C3 overexpression Nalm and TF1 cell lines. Twenty normal bone marrows from archival B and T-ALL patient samples were subsequently examined. AKR1C3 expression levels in these samples were evaluated by immunohistochemistry, Protein Wes and quantitative RT-PCR. SigmaMillipore Anti-AKR1C3 antibody (mouse monoclonal, clone NP6.G6.A6) showed higher specificity compared to rabbit polyclonal antibody by immunohistochemistry. H-score was used to quantify percent of nuclear immunoreactivity for AKR1C3 with varying disease involvement. T-ALL samples had a higher H-score (172-190) compared to B-ALL cases (H-score, 30-160). The AKR1C3 expression in peripheral blood by Protein Wes and RT-qPCR showed concordance in relapsedrefractory andor minimal residual T-ALL cases. SigmaMillipore Anti-AKR1C3 antibody and mouse monoclonal, clone NP6.G6.A6 can be used to aid in AKR1C expression of T-ALL and in cases of relapsedrefractory andor minimal residual disease.

Myeloproliferative Syndrome With Eosinophilia Associated With Translocation t(8 13) and T-cell Lymphoblastic Lymphoma A Case Report and Review of the Literature.

The 8p11 myeloproliferative syndrome (EMS) is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 tyrosine kinase gene on chromosome 8p11. We report the case of a 31-year-old man with no prior medical history who presents with two weeks of sore throat and cervical lymphadenopathy up to 5 cm. Initial peripheral blood examination showed leukocytosis with predominantly neutrophils and eosinophilia. A CT scan demonstrated mediastinal lymphadenopathies, liver enlargement and splenomegaly. An excisional biopsy of a cervical lymph node demonstrated findings consistent with a diagnosis of T-cell lymphoblastic lymphoma. Bone marrow aspirate and biopsy revealed hypercellular marrow with granulocytic predominance, left-shifted granulopoiesis, eosinophilia and the cytogenetic analysis showed the following karyotype 46, XY, t(813). The final diagnosis was a myeloproliferative syndrome with eosinophilia related to t(813) and T-cell acute lymphoblastic lymphoma (8p11 myeloproliferative syndrome). We review the relevant literature about this unusual entity.

Prognostic Observational Analysis of BMI, Leptin, and Adiponectin in Children With Acute Lymphocytic Leukemia Undergoing Remission-Induction Chemotherapy.

The survival rate of children and adolescents with acute lymphoblastic leukemia (ALL) has progressively improved. However, ALL survivors often have adverse effects after treatment, such as an increased risk of obesity. Obesity has been associated with reduced survival. We investigated the relationship between obesity, adipocytokine levels, and ALL short-term outcomes. Weight and height were measured, and body mass index (BMI) was calculated at patient diagnosis and discharge. Leptin and Adiponectin levels and Minimal Residual Disease (MRD) were measured before therapy, at days 19 of remission-induction therapy, and at the end of remission-induction therapy (days 46). The relationship between BMI, adipocytokine levels, and MRD was then determined. Compared to the normal BMI group, children with an abnormal increase in BMI had an increase in MRD at day 19 and 46 ( BMI affects the outcome of ALL patients. Early interventions such as regular weight, height monitoring, and dietary assessments should be preferably initiated during remission-induction chemotherapy.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1LMO2SPI1HOXA (G1–G6) might represent the early T cell progenitor, proprecorticalcortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3TLX1 high expression (G7–G8) could be blocked at the corticalpostcortical stage, while those with high expression of NKX2-1TAL1LMO1 (G9–G10) might correspond to corticalpostcorticalmature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3AIDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Facial Nerve Palsy in a Young Patient With Acute Lymphoblastic Leukemia Possibly Induced by Herpes Virus Reactivation in the Facial Nerve.

Facial palsy in acute lymphoblastic leukemia (ALL) patients is diagnosed as tumor cell invasion of the central nervous system (CNS) following the ALL guidelines. Facial palsy in a 6-year-old ALL patient was diagnosed as leukemia cell invasion into the CNS by hemato-oncologists. Pretreatment magnetic resonance image (MRI) revealed gadolinium enhancement of the first genu and meatal portion of the facial nerve. After chemotherapy, although the ALL tumor cells disappeared from both the blood and the cerebrospinal fluid, and the facial palsy resolved, a posttreatment MRI showed no change in terms of enhancement of the facial nerve. These findings indicated the possibility of herpetic viral reactivation in the geniculate ganglion of the facial nerve. We must be aware and discuss with hemato-oncologists the possibility that not only tumor cell invasion into the CNS, in accordance with the guidelines, but also that herpetic virus reactivation arising in the facial nerve may be causes of facial palsy.

Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia An Urgent Plea for New Treatments Is Being Answered

The treatment of acute lymphoblastic leukemia (ALL) has dramatically changed over the past three decades. However, relapsed andor refractory ALL still remains with a very low survival and high morbidity associated with its treatment. Here, we will review the outstanding progress that has been made in the treatment of relapsed andor refractory ALL and discuss future directions and challenges that require further investigation.

Mixed PhenotypeLineage Leukemia Has Anything Changed for 2021 on Diagnosis, Classification, and Treatment

Recent advances in the small field of the rare mixed phenotype acute leukemias (MPAL) are presented focusing on a better understanding of their pathophysiology and search for better therapeutic approaches. Three aspects of respective classification, therapy, and immunophenotype of MPAL are reviewed. New proposals have been made to segregate MPAL subtypes based on their genomic landscape. In parallel, it was found that a large array of therapeutic approaches has been tested in the past few years with increasingly good results. Finally, we explored the use of unsupervised flow cytometry analysis to dissect subtle variations in markers expression to better characterize the variegating aspect of MPALs. Genomic and immunophenotypic aspects more clearly link MPAL subtypes with bona fide acute myeloblastic of lymphoblastic leukemias. This is likely to impact therapeutic strategies, towards a better management and outcome.

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia.

Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of

An observational MRI study of methotrexate-treated children with acute lymphoblastic leukemia in remission and subtle cognitive decline.

For children diagnosed with acute lymphoblastic leukemia (ALL), methotrexate (MTX) treatment carries the risk of leukoencephalopathy and other treatment-related brain damage. However, earlier and more sensitive evaluation is needed to elucidate the specific effects of MTX treatment in this group. This study aimed to evaluate changes in brain metabolites, diffusion and anisotropy features, and cognitive performance in children with ALL after MTX treatment. In this observational study conducted from December 2013 to December 2015, 30 children with ALL and 30 healthy children were recruited and evaluated using baseline magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and neurocognitive tests. After MTX treatment and ALL remission, the children with ALL underwent MR examination and neurocognitive tests again. Quantitative alterations of MR and cognitive test results from the baseline data were calculated. At baseline, the ALL group (age 6.9±3.3 years 14 boys) and the healthy controls (age 6.0±3.1 years, 14 boys) had comparable neurocognitive performance and MR results. After MTX treatment, 6.7% (230) of children with ALL showed abnormalities on diffusion- and T1- and T2-weighted images. The N-acetylaspartatecreatine and N-acetylaspartatecholine values of children with ALL decreased, whereas their cholinecreatine values increased significantly. The fractional anisotropy (FA) values decreased in the frontal lobe (P0.03) and the genu of the corpus callosum (P0.01). The FA values in the genu of the internal capsule (P0.08), the occipital lobe (P0.20) and the splenium of the corpus callosum (P0.30) did not change from baseline. The apparent diffusion coefficient (ADC) values decreased in the frontal lobe (P0.03). The ADC values in the genu of the corpus callosum (P0.11), the genu of the internal capsule (P0.93), and the occipital lobe (P0.65) did not change from baseline. Due to the presence of outliers and the small sample, the ADC values in the splenium of the corpus callosum were discarded. Neurocognitive performance decreased slightly after MTX treatment, with noticeable declines in working memory and processing speed. Changes in FA values were positively correlated with the reduction in the N-acetylaspartatecreatine ratio at the genu of the corpus callosum of children with ALL aged above 6 years. MTX treatment causes subtle cognitive decline in children with ALL in remission and dramatically affects their brain metabolites, but changes in white matter diffusion features are limited to the frontal lobe and corpus callosum.

Identification of the Predictive Models for the Treatment Response of RefractoryRelapsed B-Cell ALL Patients Receiving CAR-T Therapy.

Chimeric antigen receptor (CAR) T cells for refractory or relapsed (rr) B-cell acute lymphoblastic leukemia (ALL) patients have shown promising clinical effectiveness. However, the factors impacting the clinical response of CAR-T therapy have not been fully elucidated. We here aimed to identify the independent factors of CAR-T treatment response and construct the models for predicting the complete remission (CR) and minimal residual disease (MRD)-negative CR in rr B-ALL patients after CAR-T cell infusion. Univariate and multivariate logistic regression analyses were conducted to identify the independent factors of CR and MRD-negative CR. The predictive models for the probability of remission were constructed based on the identified independent factors. Discrimination and calibration of the established models were assessed by receiver operating characteristic (ROC) curves and calibration plots, respectively. The predictive models were further integrated and validated in the internal series. Moreover, the prognostic value of the integration risk model was also confirmed. The predictive model for CR was formulated by the number of white blood cells (WBC), central neural system (CNS) leukemia, We have established predictive models for treatment response estimation of CAR-T therapy. Our models also provided new clinical insights for the accurate diagnosis and targeted treatment of rr B-ALL.

Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in

T lymphocyte acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease affecting T cells at multiple stages of their development and is characterized by frequent genomic alterations. The transcription factor LEF1 is inactivated through mutation in a subset of T-ALL cases but elevated LEF1 expression and activating mutations have also been identified in this disease. Here we show, in a murine model of T-ALL arising due to

Drug-Induced Liver Injury during Consolidation Therapy in Childhood Acute Lymphoblastic Leukemia as Assessed for Causality Using the Updated RUCAM.

The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL. Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Patients with high risk (HR) and standard risk (SR)intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SRIR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mgL, albumin ≤45 gL, and gamma-glutamyl transpeptidase (GGT) > 17 UL). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827-0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SRIR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable highly probable) were detected in 100% of HD-MTX 57% of high-dose cytarabine (HD-Ara-C), 100% of HD-MTX 20% of pegylated asparaginase (PEG-ASP), and 100% of HD-Ara-C 33.3% of PEG-ASP, respectively. Incidence of DILI in HR patients was significantly higher than that in SRIR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.

Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN).

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin-proteasome pathway.

T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T-cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T-cell cell lines and primary T-ALL cells. We provide evidence that DSF exerts anticancer activity in T-cell malignancies by targeting the NPL4-mediated ubiquitin-proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin-proteasome pathway genes, anaphase-promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T-ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1-, 3-, and 5-year OS rates for patients with T-cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T-cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T-cells via the NPL4-mediated ubiquitin-proteasome pathway and offer a potential therapeutic option for T-cell malignancies.

Osteonecrosis in paediatric acute lymphoblastic leukaemia Incidence, risk factors, radiological patterns and evolution in a single-centre cohort.

Osteonecrosis (ON) is a well-known sequela of paediatric acute lymphoblastic leukaemia (ALL) treatment. Incidence differs substantially among studies and the clinical significance of radiological findings is not fully established. We analysed 256 consecutive patients with ALL treated in our Institution between October 2010 and December 2016. Within the cohort, 41 developed ON, with a mean 5-year cumulative incidence of 18.5 (standard error, SE, 5.7)% overall. The mean (SE) 5-year cumulative incidence of ON was 12.7 (2.1)% after censoring upon stem cell transplantation (SCT) andor relapse. Patients aged ≥10 years and patients allocated to the high-risk stratum had a 10-fold and fivefold higher risk of ON respectively. The risk of ON was more than double in relapsed patients, whereas no significant impact of gender, immunophenotype and SCT was demonstrated. Multiple lesions (median four joints involved per patient) were detected by magnetic resonance imaging in all but one patient, with the knee being the most affected joint. Lesions affecting convex joint surfaces experienced the worst evolution, whereas most lesions on diaphyses and concave surfaces remained radiologically stable or disappeared during follow-up. ON has a high prevalence in paediatric ALL, presenting with multiple lesions. Lesions involving convex surfaces were at higher risk of radiological deterioration.

Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.

Chimeric antigen receptor (CAR)-modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CAR-T19) or secreting a CD19CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti-CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies.

Molecular characterization of hepatitis B virus (HBV) isolated from a pediatric case of acute lymphoid leukemia, with a delayed response to antiviral treatment a case report.

Tenofovir disoproxil fumarate (TDF) is effectively used as the first-line antiviral for chronic hepatitis B virus (HBV) infection in adults and children older than 12 years. To date, no confirmed case of virologic breakthrough (VBT) in a pediatric case has been reported. Here we describe a case of a 5-year old, asymptomatically infected with HBV infection two months after chemotherapy for precursor B acute lymphoblastic leukemia (ALL). Although the 5-year old male is South African, his family originated from Guinea. At the end of the one-year follow-up, the infection progressed to chronic HBV infection, with a high viral load. At 36 weeks (8 months) post-treatment with lamivudine (LAM), there was a partial virologic response (PVR) and after 61 weeks (14 months), he was switched to TDF rescue monotherapy. Even with TDF treatment, he still experienced VBT and subsequent PVR. The full-length genome of HBV isolated 78 weeks after the switch to rescue TDF monotherapy was sequenced and belonged to genotype E. In addition to the LAM mutations (rtS256G and rtM267L), missense mutations in B-cell, T-cell, HLA class I and II-restricted epitopes emerged, which were to evade and escape host surveillance, leading to delayed viral clearance, persistence and disease progression. Two further events of VBT occurred between weeks 113 and 141 of TDF rescue-therapy. Viral loads and liver enzymes are normalizing progressively with long-term therapy. Although the host immune reconstitution may be delayed, prolonged TDF treatment was effective in treating this pediatric case of HBV infection with VBT and PVR.

Thrombosis Complications in Pediatric Acute Lymphoblastic Leukemia Risk Factors, Management, and Prevention Is There Any Role for Pharmacologic Prophylaxis

Pediatric acute lymphoblastic leukemia (ALL) has achieved close to 90% cure rates through extensive collaborative and integrative molecular research, clinical studies, and advances in supportive care. Despite this high achievement, venous thromboembolic complications (VTE) remain one of the most common and potentially preventable therapy-associated adverse events in ALL. The majority of thromboses events involve the upper central venous system which is related to the use and location of central venous catheters (CVC). The reported rates of symptomatic and asymptomatic CVC-related VTE range from 2.6 to 36.7% and 5.9 to 43%, respectively. Thrombosis can negatively impact not only disease-free survival e.g., therapy delays andor interruption, omission of chemotherapy agents (e.g., asparaginase therapy) but also can result in long-term adverse effects that can impair the quality of life of ALL survivors (e.g., post-thrombotic syndrome, central nervous system (CNS)-thrombosis related complications seizures, neurocognitive deficits). In this review, will discuss thrombosis pathophysiology in pediatric ALL, risk factors, treatment, and prevention strategies. In addition, the recently published clinical efficacy and safety of direct oral anticoagulants (DOACs) use in thrombosis treatment, and their potential role in primarysecondary thrombosis prevention in pediatric patients with ALL will be discussed. Future clinical trials involving the use of these novel oral anticoagulants should be studied in ALL not only for primary thrombosis prevention but also in the treatment of thrombosis and its secondary prevention. These future research findings could potentially extrapolate to VTE prevention strategies in other pediatric cancer diagnoses and children considered at high risk for VTE.

T-cell lymphoblastic lymphoma as the initial presentation of myeloidlymphoid neoplasm with PDGFRA rearrangement report of a case.

伴PDGFRA、PDGFRB或FGFR1重排或PCM1-JAK2及嗜酸性粒细胞增多的髓系淋系肿瘤，是2016版WHO淋巴造血系统肿瘤分类中的独立疾病类型。在这一类别中，共同的特征是融合基因的形成导致异常酪氨酸激酶的表达。其中，伴有PDGFRA重排的髓系淋系肿瘤是最常见的肿瘤类型。现报道1例罕见的以T淋巴母细胞性淋巴瘤为初始表现，并伴PDGFRA重排的髓系淋系肿瘤。.

Characteristics of fusion gene expression in acute lymphoblastic leukemia.

Prognostic role of serum cytokines and soluble HLA-G levels in children with leukemia who undergo allogeneic stem cell transplantation.

This is the first study to have investigated the prognostic role of cytokines and soluble human leukocyte antigen-G (sHLA-G) levels in pediatric leukemia patients who have undergone allogeneic stem cell transplantation (allo-SCT). Forty-one patients with acute leukemia (n 28, acute lymphoblastic leukemia (ALL) and n 13, acute myeloblastic leukemia) were recruited. Patients were examined at diagnosis (n 26), in the pre-transplantation period (PreTx) (n 26), on the day of transplantation (Tx

In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission results from the prospective, single-arm evaluation of the UKALL14 trial.

The outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population. This was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25-65 years (BCR-ABL1-negative) or 18-65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA intravenous fludarabine 30 mgm From Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36-70), 4-year event-free survival was 46·8% (95% CI 40·1-53·2) and 4-year overall survival was 54·8% (48·0-61·2). 4-year cumulative incidence of relapse was 33·6% (27·9-40·2) and 4-year TRM was 19·6% (15·1-25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2-4 occurred in 29 (12%) of 247 patients and grade 3-4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 22% had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 95% CI 1·46-3·93) and time-to-relapse (HR 2·41 1·29-4·48). FMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes. Cancer Research UK.

Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14) a phase 3, multicentre, randomised controlled trial.

Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (11) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mgm Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n292) or standard of care plus rituximab (n294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n4, standard of care plus rituximab n5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio HR 0·85 95% CI 0·69-1·06 p0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 95% CI 0·62-1·26 p0·49). Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. Cancer Research UK and Blood Cancer UK.

Expanding diagnostic criteria Multiorgan T-Cellmyeloid mixed phenotype acute leukemia with t(v11q23)

Mixed phenotype acute leukemia (MPAL) consists of a leukemia of two different lineages (myeloid, T, andor B) co-occurring in the same tissue. KMT2A-rearrangement is rare and usually seen in Bmyeloid MPAL. We report a unique case of Tmyeloid MPAL with a t(v11q23) KMT2A-rearrangement, with acute myeloid leukemia (AML) in the bone marrow but concurrent T-cell acute lymphoblastic leukemia (T-ALL) in lymph node and skin. Genomic interrogation suggests an undifferentiated stem cells with KMT2A rearrangement as the founder mutation that acquired additional lineage-specific mutations resulting in AML in the marrow and T-ALL in other sites.

Obesity as a Prognostic Factor of Central Nervous System Relapse in Children with Acute Lymphoblastic Leukemia A Single-Centre Study and Literature Review.

Relapse as the commonest treatment failure through chemotherapy of child presented with acute lymphoblastic leukemia (ALL) is usually within 3 years of remission. Central nervous system (CNS) is expected as a site of extramedullary relapse in 3-8% of child leukemia, often leading to a poor prognosis. A few patients may have headache and vomiting and can be diagnosed without difficulty. However, most patients present with asymptomatic conditions. Obesity has become one of the greatest reported complications of children ALL survivors. Rarely, obesity presentation can be the first manifestation of CNS leukemia. Here, we present three unusual cases with B-ALL presentation of obesity as the first symptom at the time of CNS relapse after achieving remission. This highly localized presentation is unusual and would hopefully inform clinicians to have a high index of suspicion for relapse in children with ALL.

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy.

CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsedrefractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabinecyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n39), including tisagenlecleucel (n19 CD194-1BB) or on an institutional clinical trial (n20 CD194-1BB NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28 infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90 infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapyCAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.

Hepatosplenic Candidiasis in Patients With Hematological Malignancies A 13-Year Retrospective Cohort Study.

Hepatosplenic candidiasis (HSC) used to be reported in patients with acute myeloid leukemia (AML) without antifungal prophylaxis. The aim was to describe the clinical features and outcomes of HSC over the last 13 years in a single French hematology center. All patients diagnosed with HSC between 2008 and 2020 were included in a single-center retrospective cohort study. Data were collected from patient charts, and HSC was classified according to the 2020 European Organisation for Research and Treatment of CancerMycoses Study Group definitions. Sixty patients were included, with 18.3% proven, 3.3% probable, and 78.3% possible HSC according to the 2020 European Organization for Research and Treatment of Cancer Mycoses Study Group classification. Among them, 19 patients were treated for acute myeloid leukemia (AML), 21 for lymphomas, and 14 for acute lymphoblastic leukemia. HSC occurred in 13 patients after autologous stem cell transplantation for lymphoma. At HSC diagnosis, 13 patients were receiving antifungal prophylaxis. The epidemiology of HSC has changed in the last decade, with fewer cases occurring in the AML setting. A better identification of patients at risk could lead to specific prophylaxis and improved diagnosis.

Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although standard-of-care chemotherapeutics are sufficient for most ALL cases, there are subsets of patients with poor response who relapse in disease. The biology underlying differences between subtypes and their response to therapy has only partially been explained by genetic and transcriptomic profiling. Here, we perform comprehensive multi-omic analyses of 49 readily available childhood ALL cell lines, using proteomics, transcriptomics, and pharmacoproteomic characterization. We connect the molecular phenotypes with drug responses to 528 oncology drugs, identifying drug correlations as well as lineage-dependent correlations. We also identify the diacylglycerol-analog bryostatin-1 as a therapeutic candidate in the MEF2D-HNRNPUL1 fusion high-risk subtype, for which this drug activates pro-apoptotic ERK signaling associated with molecular mediators of pre-B cell negative selection. Our data is the foundation for the interactive online Functional Omics Resource of ALL (FORALL) with navigable proteomics, transcriptomics, and drug sensitivity profiles at httpsproteomics.seforall .

Anticancer Activity of Extremely Effective Recombinant L-Asparaginase from

L-asparaginase (E.C. 3.5.1.1) purified from bacterial cells is widely used in the food industry, as well as in the treatment of childhood acute lymphoblastic leukemia. In the present study, the

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia phenotypes, risk factors and genotypes.

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0-17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP n19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n797) in whom two phenotypes were evaluated diverse CNS toxicities (n103) and methotrexate-related CNS toxicity (n48). In total, 1351,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval 7.31-10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4% P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n52, 43 with seizures), sinus venous thrombosis (n28, 9 with seizures), and isolated seizures (n16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

TAL1 cooperates with PI3KAKT pathway activation in T-cell acute lymphoblastic leukemia.

TAL1 is ectopically expressed in about 30% of T-cell acute lymphoblastic leukemia (T-ALL) due to chromosomal rearrangements leading to the STIL-TAL1 fusion genes or due to non-coding mutations leading to a de novo enhancer driving TAL1 expression. Analysis of sequence data from T-ALL cases demonstrates a significant association between TAL1 expression and activating mutations of the PI3K-AKT pathway. We investigated the oncogenic function of TAL1 and the possible cooperation with PI3K-AKT pathway activation using isogenic pro-T-cell cultures ex vivo and in vivo leukemia models. We found that TAL1 on its own suppressed T-cell growth, in part by affecting apoptosis genes, while the combination with AKT pathway activation reduced apoptosis and was strongly driving cell proliferation ex vivo and leukemia development in vivo. As a consequence, we found that TAL1AKTE17K transformed cells are more sensitive to PI3K-AKT pathway inhibition compared to AKTE17K transformed cells, related to the negative effect of TAL1 in the absence of activated PI3K-AKT signaling. We also found that both TAL1 and PI3K-AKT signaling increased the DNA-repair signature in T cells resulting in synergy between PARP and PI3K-AKT pathway inhibition. In conclusion, we have developed a novel mouse model for TAL1AKTE17K driven T-ALL development and have identified a vulnerability of these leukemia cells to PI3K-AKT and PARP inhibitors.

Oncologist counseling practice and COVID-19 vaccination outcomes for patients with history of PEG-asparaginase hypersensitivity.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an effective strategy to prevent serious coronavirus disease 2019 (COVID-19) and is important for oncology patients. mRNA-based COVID-19 vaccines are contraindicated in those with a history of severe or immediate allergy to any vaccine component, including polyethylene glycol (PEG)2000. Patients with acute lymphoblastic leukemialymphoma receive asparaginase conjugated to PEG5000 (PEG-ASNase) and those with PEG-ASNase-associated hypersensitivity may be unnecessarily excluded from receiving mRNA COVID-19 vaccines. We, therefore, surveyed oncologists on COVID-19 vaccine counseling practice and vaccination outcomes in COVID-19 vaccination-eligible patients and show safe receipt of mRNA vaccines despite PEG-ASNase hypersensitivity.

Controversies in the Treatment of Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

The incidence of acute lymphoblastic leukemia (ALL) has been increasing steadily in the adolescent and young adult (AYA) population. In this review article focused on the management of AYAs with Philadelphia chromosome-negative (Ph-) B-ALL, we examine topics of clinical interest and identify areas of controversy in need of further investigation. We explore four areas of active investigation pediatric-inspired front-line treatment regimens, the optimal time of measurable residual disease (MRD) assessment, the role of hematopoietic stem cell transplant and the optimal salvage therapy for relapsedrefractory B-ALL in AYAs. There has been rapid advancement in the management of ALL in the AYA patient population, which has resulted in improved outcomes. We must build on the successes by continuing to promote multi-center innovative clinical research with clinical trial populations reflecting the AYA ALL patient spectrum. The incorporation of novel targeted immunotherapy into front-line treatment will be transformative and redefine treatment paradigms in the coming years.

RNAseqCNV analysis of large-scale copy number variations from RNA-seq data.

Transcriptome sequencing (RNA-seq) is widely used to detect gene rearrangements and quantitate gene expression in acute lymphoblastic leukemia (ALL), but its utility and accuracy in identifying copy number variations (CNVs) has not been well described. CNV information inferred from RNA-seq can be highly informative to guide disease classification and risk stratification in ALL due to the high incidence of aneuploid subtypes within this disease. Here we describe RNAseqCNV, a method to detect large scale CNVs from RNA-seq data. We used models based on normalized gene expression and minor allele frequency to classify arm level CNVs with high accuracy in ALL (99.1% overall and 98.3% for non-diploid chromosome arms, respectively), and the models were further validated with excellent performance in acute myeloid leukemia (accuracy 99.8% overall and 99.4% for non-diploid chromosome arms). RNAseqCNV outperforms alternative RNA-seq based algorithms in calling CNVs in the ALL dataset, especially in samples with a high proportion of CNVs. The CNV calls were highly concordant with DNA-based CNV results and more reliable than conventional cytogenetic-based karyotypes. RNAseqCNV provides a method to robustly identify copy number alterations in the absence of DNA-based analyses, further enhancing the utility of RNA-seq to classify ALL subtype.

Detection of

To investigate the mutation rate of the A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of Among the 120 children, 35 (29.2%) had To investigate the mutation rate of the A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of Among the 120 children, 35 (29.2%) had

Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. This study was a retrospective cohort study conducted at Wolfson Childrens Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. A total of 38 patients (50 doses in no premedication group 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

Ponatinib in pediatric patients with Philadelphia chromosome-positive leukemia a retrospective survey of the Japan Childrens Cancer Group.

Ponatinib is effective in adults with Philadelphia chromosome-positive (Ph) leukemia, resistant or intolerant to second-generation tyrosine kinase inhibitors, but there are limited data on its use in children. The clinical courses of nine pediatric patients with Ph acute lymphoblastic leukemia (Ph ALL) and four with chronic myeloid leukemia (CML) who received ponatinib therapy were retrospectively reviewed. The median age at the start of ponatinib therapy was 12 years (range 8-16 years). Nine patients were male and four were female. Six patients received ponatinib alone, three received ponatinib with prednisolone, one received ponatinib with rituximab intrathecal therapy, and one received ponatinib with conventional chemotherapy. Two patients received ponatinib both alone and in combination with chemotherapy. The median dose and duration of ponatinib were 16.9 mgm

Activity and toxicity of intramuscular 1000 ium

In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 ium

Multicenter comparison of first salvage chemotherapy versus novel therapy regimens in adult relapsedrefractory acute lymphoblastic leukemia.

Patients with relapsedrefractory (RR) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, LarsonCALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) Polymorphisms in Adult Patients with Acute B-cell Lymphoblastic Leukemia.

Neutropenia after intensive chemotherapy of acute lymphoblastic leukemia (ALL) could lead to infectious complications that affect outcome of acute leukemia patients. Many single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections. We investigated the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed B-ALL following induction chemotherapy. We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly Thr399Ile) genes using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) in a case control study of 40 precursor B-ALL patients and 50 control subjects. The risk of developing sepsis and pneumonia were assessed by multiple logistic regression analyses. The presence of the TLR-2 AG polymorphism was significantly associated with pneumonia in B-ALL patients. Furthermore, TLR4 Thr399Ile AG was a risk factor for sepsis in B-ALL patients. Moreover Significant association between TLR-2 AA, TLR-4 CC and TL-4 AA genotypes and longer OS were detected in studied B-ALL patients. We concluded that TLR-4 (AG and CT) genotypes are associated with high susceptibility to sepsis and pneumonia respectively while, TLR-2, TLR-4 AA and TLR-4 CC genotypes could predict good B-ALL patients outcome.

Changes in parents psychotropic medication use following childs cancer diagnosis A fixed-effects register-study in Finland.

Symptoms of depression and anxiety are elevated among parents of children with cancer. However, knowledge of parents psychotropic medication use following childs cancer diagnosis is scarce. We use longitudinal Finnish register data on 3266 mothers and 2687 fathers whose child (aged 0-19) was diagnosed with cancer during 2000-2016. We record mothers and fathers psychotropic medication use (at least one annual purchase of anxiolytics, hypnotics, sedatives, or antidepressants) 5 years before and after the childs diagnosis and assess within-individual changes in medication use by time since diagnosis, cancer type, childs age, presence of siblings, and parents living arrangements and education using linear probability models with the individual fixed-effects estimator. The fixed-effects models compare each parents annual probability of psychotropic medication use after diagnosis to their annual probability of medication use during the 5-year period before the diagnosis. Psychotropic medication use was more common among mothers than fathers already before the childs diagnosis, 11.2% versus 7.3%. Immediately after diagnosis, psychotropic medication use increased by 6.0 (95% CI 4.8-7.2) percentage points among mothers and by 3.2 (CI 2.1-4.2) percentage points among fathers. Among fathers, medication use returned to pre-diagnosis level by the second year, except among those whose child was diagnosed with acute lymphoblastic leukemia or lymphoblastic lymphoma. Among mothers of children with a central nervous system cancer, medication use remained persistently elevated during the 5-year follow-up. For mothers with other under-aged children or whose diagnosed child was younger than 10 years, the return to pre-diagnosis level was also slow. Having a child with cancer clearly increases parents psychotropic medication use. The increase is smaller and more short-lived among fathers, but among mothers its duration depends on both cancer type and family characteristics. Our results suggest that an increased care burden poses particular strain to the long-term mental well-being of mothers.

Adult acute lymphoblastic leukemia in a resource-constrained setting outcomes after expansion of genetic evaluation.

Acute lymphoblastic leukemia (ALL) is a challenging disease with a growing genetic landscape, even though there is substantial gap between developed and non-developed countries when it comes to availability of such new technologies. This manuscript reports a 5-year retrospective cohort of newly diagnosed ALL patients and their genetic findings and outcomes. An expanded genetic evaluation by using FISH and RT-PCR was implemented, aiming to identify Ph-like alterations. Patients were treated according to our local protocol, which allocated patients according to age and Philadelphia-chromosome status. A total of 104 patients was included, with median age of 37.5 years. Philadelphia chromosome was detected in 33 cases of B-lineage. Among 45 Ph-negative B-lineage, after excluding

Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia.

Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years median 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 ukg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two NordicBaltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iul 14 ± 2 days after the first eryaspase infusion median AEA 511 iul interquartile range (IQR), 291-780, whereas six of nine (66.7%) patients had AEA ≥100 iul 14 ± 2 days after the fourth infusion (median AEA 932 iul IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.

Identification and validation of suitable housekeeping genes for gene expression studies in BCR-ABL1 positive B-lineage acute lymphoblastic leukemia.

The stability of the housekeeping gene (HKG) expression is an absolute prerequisite for accurate normalization of target gene expression in a quantitative real-time polymerase chain reaction (RQ-PCR). In RQ-PCR, the widely used normalization approach involves the standardization of target genes to the most stable HKG control genes. According to the recent literature, in different experimental conditions the HKGs exhibit either up or down-regulation and thus affecting the gene expression profiles of target genes which leads to erroneous results. This implies that it is very important to select the appropriate HKG and verify the expression stability of the HKG before quantification of the target gene. The present study aims to analyze six different HKGs for their expression profiles and stability in BCR-ABL1 negative cases and validate them in BCR-ABL1 positive cases, detected by multiplex reverse transcribed polymerase chain reaction (RT-PCR). Six commonly used reference genes (GAPDH, ABL1, RNA18S, ACTB, GUSB, and EEF2) were selected in this study. RQ-PCR was performed on 24 BCR-ABL1 negative cases and the outcomes were validated on 24 BCR-ABL1 positive cases. RefFinder™, a web-based composite software was used to check the stability of HKG genes by different algorithms and comprehensive ranking of each HKG gene in BCR-ABL1 negative cases and finally validated in BCR-ABL1 positive cases. It was found that RNA18S, ABL1 and GUSB are good stable HKG genes, which showed minimum variability in gene expression compared to GAPDH, EEF2, and ACTB, the most commonly used HKG.

Hypersensitivity reaction to high-dose methotrexate and methotrexate-induced acral erythema in a child with acute lymphoblastic leukemia.

A 9-year-old boy with acute lymphoblastic leukemia experienced a hypersensitivity reaction (HSR) and acral erythema upon receiving high-dose methotrexate (HDMTX). Both HSR and acral erythema are uncommon adverse events of MTX therapy, and MTX has not been reported to cause HSRs in specific ethnic groups. We assessed the severity of each symptom and were successful in managing these adverse events for continuing subsequent HDMTX therapies. HSR appeared during the first and second HDMTX courses. Acral erythema occurred after the second and fourth courses. Desensitization by reducing the infusion rate and premedication allowed the continuation of HDMTX. Acral erythema improved with supportive care without dose reduction or interval lengthening. HSRs to MTX should be considered even during the first course. MTX-induced acral erythema is a self-limited reaction therefore, the chemotherapeutic regimen should not be modified unless necessary.

A Clinical Decision Support System for Increasing Compliance with Protocols in Chemotherapy of Children with Acute Lymphoblastic Leukemia.

In this survey, a protocol-based Chemotherapy Prescription Decision Support System (CPDSS) was designed and evaluated to reduce medication errors in the chemotherapy process of children with ALL. The CPDSS algorithm was extracted by the software development team based on the protocol used by doctors to treat children with ALL. The ASP.Net MVC and SQL Server 2016 programming languages were used to develop the system. A 3-step evaluation (technical, retrospective, and user satisfaction) was performed on CPDSS designed at 2 childrens hospitals in Tehran. The data were analyzed using descriptive statistics. At the technical evaluation step, users provided recommendations included in the system. In the retrospective CPDSS evaluation step, 1281 prescribed doses of the drugs related to 30 patients were entered into the system. CPDSS detected 735 cases of protocol deviations and 57 (95%, CI 1.25-2.55) errors in prescribed chemotherapy for children with ALL. In the user satisfaction evaluation, the users approved two dimensions of the user interface and functionality of the system. With the provision of alerts, the CPDSS can help increase compliance with chemotherapy protocols and decrease the chemotherapy prescribing errors that can improve patient safety.

Clinical Value of Measurable Residual Disease in Acute Lymphoblastic Leukemia.

Measurable (minimal) residual disease (MRD) status in acute lymphoblastic leukemia (ALL) has largely superseded the importance of traditional risk factors for ALL, such as baseline white blood cell count, cytogenetics, and immunophenotype, and has emerged as the most powerful independent prognostic predictor. The development of sensitive MRD techniques, such as multicolor flow cytometry (MFC), quantitative polymerase chain reaction (PCR), and next-generation sequencing (NGS), may further improve risk stratification and expand its impact in therapy. Additionally, the availability of highly effective agents for MRD eradication, such as blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapies, enabled the development of frontline regimens capable of eradicating MRD early in the treatment course. While long-term follow-up of this approach is lacking, it has the potential to significantly reduce the need for intensive post-remission treatments, including allogeneic bone marrow transplantation, in a significant proportion of patients with ALL.

Population-based targeted RNA sequencing reveals novel disease-related gene fusions in pediatric and adult T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically diverse disease characterized by a heterogeneous profile of genetic lesions. Recent transcriptome studies identified a number of new T-ALL-related gene fusions. Novel gene fusions could be employed as disease-specific molecular markers and provide a better understanding of T-ALL biology, proving the need for further omics sequencing studies. We performed a population-based analysis of 65 (26 pediatric and 39 adults) Lithuanian T-ALL patients. Targeted RNA sequencing (RNA-seq) was used to detect recurrent and novel T-ALL-related fusion transcripts and gene sequence variants. RT-qPCR was used to calculate the relative gene expression of fusion transcripts. We identified disease-related gene alterations in 5765 (87.7%) T-ALL cases, of which four patients harbored gene fusions that affect ABL-class or JAK-STAT signaling pathways. Five novel gene fusions were detected in 465 (6.2%) T-ALL cases CD99ABL2 and ZEB1GNAS in the same case, CTCFENKD1, DIAPH1JAK2, and CDK6NEK1. Novel fusion transcripts encode chimeric proteins that can potentially affect T-cell proliferation, apoptosis, and help to maintain leukemic cells. Importantly, novel fusion transcripts were not detected in the clinical remission samples attributing these fusions to the leukemic compartment. We report a similar incidence rate of recurrent gene alterations affecting T-ALL-related molecular signaling pathways in both Lithuanian T-ALL patients and other T-ALL studies. Our data suggest that newly identified gene fusions are specific to leukemic T-cells and provide new molecular insights on T-ALL pathogenesis. Further research is needed to confirm these findings.

Alternative RNA splicing defects in pediatric cancers new insights in tumorigenesis and potential therapeutic vulnerabilities.

Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing, however, a global cellular process that produces different messenger RNAprotein isoforms from a single messenger RNA transcript, has been increasingly implicated in the development of pediatric cancers. We review the current literature on the role of alternative splicing in adult cancer, cancer predisposition syndromes, and pediatric cancers. We also describe multiple splice variants identified in adult cancers and confirmed through comprehensive genomic profiling in our institutional cohort of rare, refractory, and relapsed pediatric and adolescent young adult cancer patients. Finally, we summarize the contributions of alternative splicing events to neoantigens and chemoresistance and prospects for splicing-based therapies. Published dysregulated splicing events can be categorized as exon inclusion, exon exclusion, splicing factor up-regulation, or splice site alterations. We observe these phenomena in cancer predisposition syndromes (Lynch syndrome, Li-Fraumeni syndrome, CHEK2) and pediatric leukemia (B-cell acute lymphoblastic leukemia), sarcomas (Ewing sarcoma, rhabdomyosarcoma, osteosarcoma), retinoblastoma, Wilms tumor, and neuroblastoma. Within our institutional cohort, we demonstrate splice variants in key regulatory genes (CHEK2, TP53, PIK3R1, MDM2, KDM6A, NF1) that resulted in exon exclusion or splice site alterations, which were predicted to impact functional protein expression and promote tumorigenesis. Differentially spliced isoforms and splicing proteins also impact neoantigen creation and treatment resistance, such as imatinib or glucocorticoid regimens. Additionally, splice-altering strategies with the potential to change the therapeutic landscape of pediatric cancers include antisense oligonucleotides, adeno-associated virus gene transfers, and small molecule inhibitors. Alternative splicing plays a critical role in the formation and growth of pediatric cancers, and our institutional cohort confirms and highlights the broad spectrum of affected genes in a variety of cancers. Further studies that elucidate the mechanisms of disease-inducing splicing events will contribute toward the development of novel therapeutics.

Efficacy and safety of CD19-specific CAR T cell-based therapy in B-cell acute lymphoblastic leukemia patients with CNSL.

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) because of concerns regarding poor response and treatment-related neurotoxicity. Our study included 48 patients with relapsedrefractory B-ALL with CNSL to evaluate the efficacy and safety of CD19-specific CAR T cell-based therapy. The infusion resulted in an overall response rate of 87.5% (95% confidence interval CI, 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (P .040). The treatment was generally well tolerated, with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3 to 4 neurotoxic events, which developed in 11 patients (22.9%), were associated with a higher preinfusion disease burden in CNS and were effectively controlled under intensive management. Our results suggest that CD19-specific CAR T cell-based therapy can induce similar high response rates in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for previously excluded patients with CNSL, with manageable neurotoxicity. The clinical trials were registered at www.clinicaltrials.gov as NCT02782351 and www.chictr.org.cn as ChiCTR-OPN-16008526.

Molecular Analysis of L-Asparaginases for Clarification of the Mechanism of Action and Optimization of Pharmacological Functions.

L-asparaginases (EC 3.5.1.1) are a family of enzymes that catalyze the hydrolysis of L-asparagine to L-aspartic acid and ammonia. These proteins with different biochemical, physicochemical and pharmacological properties are found in many organisms, including bacteria, fungi, algae, plants and mammals. To date, asparaginases from

Significant Roles of Notch

Notch signaling, which was initially identified in

Hidden in the Eyes-Recurrence of Systemic Hemopathies Reportedly In Remission Six Cases and Review of Literature.

Correlation of Genetic Variants and the Incidence, Prevalence and Mortality Rates of Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, representing about 30-35% of cases. Its etiology is complex and not fully understood. ALL is influenced by genetic variants, and their frequencies (Fq) vary in different ethnic groups, which consequently could influence the epidemiology of this cancer worldwide. The aim of this study was to investigate the correlation between the genetic variants and their impacts on incidence (IC), mortality (MT), and prevalence (PV) rates of ALL in different world populations. Sixty variants were selected from the literature with Genome Wide Association studies (GWAS). Information regarding allele Fq was selected from the 1000 Genomes platform. Epidemiological data were taken from the Global Burden of disease visualisations (GBD) Compare website. Statistical analyses were calculated in RStudio v.3.5.1 software. Four variants demonstrated significant results in correlations with epidemiological data for ALL. The Our study points out four important variants for understanding the IC, PV, and MT rates for ALL. The ascertainment of these data may help to choose molecular markers to investigate the susceptibility and prognosis of ALL.

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia.

Despite the rapid development of medicine, even nowadays, acute lymphoblastic leukemia (ALL) is still a problem for pediatric clinicians. Modern medicine has reached a limit of curability even though the recovery rate exceeds 90%. Relapse occurs in around 20% of treated patients and, regrettably, 10% of diagnosed ALL patients are still incurable. In this article, we would like to focus on the treatment resistance and disease relapse of patients with B-cell leukemia in the context of prognostic factors of ALL. We demonstrate the mechanisms of the resistance to steroid therapy and Tyrosine Kinase Inhibitors and assess the impact of genetic factors on the treatment resistance, especially

Tumor protein 53 ( 20 different hematological malignancy samples were tested using fluorescence in situ hybridization (FISH) technique for To the best of our knowledge, the

The Profile of MicroRNA Expression in Bone Marrow in Non-Hodgkins Lymphomas.

Non-Hodgkins lymphomas (NHLs) are a heterogeneous group of malignant lymphomas that can occur in both lymph nodes and extranodal sites. Bone marrow (BM) is the most common site of extranodal involvement in NHL. The objective of this study is to determine the unique profile of miRNA expression in BM affected by NHL, with the possibility of a differential diagnosis of NHL from reactive BM changes and acute leukemia (AL). A total of 180 cytological samples were obtained by sternal puncture and aspiration biopsy of BM from the posterior iliac spine. All the cases were patients before treatment initiation. The study groups were NHL cases (

Loss of Heterozygosity in the Tumor DNA of De Novo Diagnosed Patients Is Associated with Poor Outcome for B-ALL but Not for T-ALL.

Despite the introduction of new technologies in molecular diagnostics, one should not underestimate the traditional routine methods for studying tumor DNA. Here we present the evidence that short tandem repeat (STR) profiling of tumor DNA relative to DNA from healthy cells might identify chromosomal aberrations affecting therapy outcome. Tumor STR profiles of 87 adult patients with de novo Ph-negative ALL (40 B-ALL, 43 T-ALL, 4 mixed phenotype acute leukemia (MPAL)) treated according to the RALL-2016 regimen were analyzed. DNA of tumor cells was isolated from patient bone marrow samples taken at diagnosis. Control DNA samples were taken from the buccal swab or the blood of patients in complete remission. Overall survival (OS) analysis was used to assess the independent impact of the LOH as a risk factor. Of the 87 patients, 21 were found with LOH in various STR loci (24%). For B-ALL patients, LOH (except 12p LOH) was an independent risk factor (OS hazard ratio 3.89, log-rank

Steroid-Induced Ocular Hypertension in a Pediatric Patient with Acute Lymphoblastic Leukemia A Case Report.

Glucocorticoids play a pivotal role in therapeutic protocols in acute lymphoblastic leukemia (ALL) treatment. Systemic steroids are known to be less likely to elevate the intraocular pressure when compared to topical administration, and reports addressing hypertensive ocular response in the Asian pediatric ALL population are currently limited. We report a case of a nine-year-old girl with acute lymphoblastic leukemia (ALL) who was found to have highly elevated intraocular pressure (IOP) during maintenance treatment when taking oral dexamethasone (6 mgm

High-Throughput Drug Library Screening in Primary

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n 7) and KMT2A-rearranged ALL cell line models (n 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing.

Automated Global Longitudinal Strain Assessment in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

There is limited evidence that supports the use of the global longitudinal strain (GLS) in long-term cardiac monitoring of childhood acute lymphoblastic leukemia survivors (CLSs). Our aim was to assess the utility of automated GLS to detect left ventricular systolic dysfunction (LVSD) in long-term CLSs. Asymptomatic and subclinical LVSD were defined as LVEF < 50% and GLS < 18.5%, respectively. Echocardiographic measurements and biomarkers were compared with a control group. Inverse probability weighting was used to reduce confounding. Regression models were used to identify factors associated with LVEF and GLS in the survivors. Ninety survivors with a median follow-up of 18 (11−26) years were included. The prevalence of LVSD was higher using GLS than with LVEF (26.6% vs. 12.2%). The measurements were both reduced as compared with the controls (p < 0.001). There were no differences in diastolic parameters and NT-ProBNP. Survivors were more likely to have Hs-cTnI levels above the detection limit (40% vs. 17.2%, p 0.006). The dose of anthracycline was associated with LVEF but not with GLS in the survivors. Biomarkers were not associated with GLS or LVEF. In conclusion, LVSD detection using automated GLS was higher than with LVEF in long-term CLSs. Its incorporation into clinical routine practice may improve the surveillance of these patients.

Cytopenia after CAR-T Cell Therapy-A Brief Review of a Complex Problem.

Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as an efficacious and life extending treatment modality with high response rates and durable remissions in patients with relapsed and refractory non-Hodgkin lymphoma (NHL), follicular lymphoma, and B-cell acute lymphoblastic leukemia (B-ALL) as well as in other diseases. Prolonged or recurrent cytopenias after CAR-T therapy have increasingly been reported at varying rates, and the pathogenesis of this complication is not yet well-understood but is likely contributed to by multiple factors. Current studies reported are primarily retrospective, heterogeneous in terms of CAR-Ts used and diseases treated, non-uniform in definitions of cytopenias and durations for end points, and vary in terms of recommended management. Prospective studies and correlative laboratory studies investigating the pathophysiology of prolonged cytopenias will enhance our understanding of this phenomenon. This review summarizes knowledge of these cytopenias to date.

Pain Coping Strategies in Pediatric Patients with Acute Leukemias in the First Month of Therapy Effects of Treatments and Implications on Procedural Analgesia.

Children with leukemia experience difficulties adapting to medical procedures and to the chemotherapys adverse effects. Studys objectives were to identify which coping strategies could be associated with the treatments factors and with the dosage of sedation analgesic drugs during bone marrow aspirates. A total of 125 patients (mean 6.79 years standard deviation 3.40), majority with acute lymphoblastic leukemia (90.4%) and their parents received, one month after diagnosis, the Pediatric Pain Coping Inventory. Data on the severe treatment effects and on the dosage of drugs in sedation-analgesia were also collected. An ANCOVA model (R

Incidence, severity, and preventability of adverse events during the induction of patients with acute lymphoblastic leukemia in a tertiary care pediatric hospital in Mexico.

Healthcare-associated adverse events represent a heavy burden of symptoms for pediatric oncology patients. Their description allows knowing the safety and quality of the care processes in countries with limited resources. This study aimed to describe the incidence, types, severity, and preventability of adverse events occurring in pediatric patients with acute lymphoblastic leukemia during the induction phase in a tertiary care pediatric hospital in Mexico. This study analyzed a cohort based on medical records of between 2015 and 2017. Initially, information on patients and adverse events was collected subsequently, two pediatric oncologist reviewers independently classified adverse events, severity and preventability. Agreement between reviewers was evaluated. Adverse events incidence rates were estimated by type, severity, and preventability. One-hundred and eighty-one pediatric patients pediatric patients with acute lymphoblastic leukemia were studied. An overall adverse events rate of 51.8 per 1000 patient-days was estimated, involving 81.2% of patients during induction. Most adverse events were severe or higher (52.6%). Infectious processes were the most common severe or higher adverse event (30.5%). The presence of adverse events caused 80.2% of hospital readmissions. Of the adverse events, 10.5% were considered preventable and 53.6% could be ameliorable in severity. Improving the safety and quality of the care processes of children with acute lymphoblastic leukemia is possible, and this should contribute to the mitigation and prevention of adverse events associated morbidity and mortality during the remission induction phase.

LMO2 expression is frequent in T-lymphoblastic leukemia and correlates with survival, regardless of T-cell stage.

T- lymphoblastic leukemialymphoma (T-LL) is an aggressive malignancy of immature T-cells with poor overall survival (OS) and in need of new therapies. LIM-domain only 2 (LMO2) is a critical regulator of hematopoietic cell development that can be overexpressed in T-LL due to chromosomal abnormalities. Deregulated LMO2 expression contributes to T-LL development by inducing block of T-cell differentiation and continuous thymocyte self-renewal. However, LMO2 expression and its biologic significance in T-LL remain largely unknown. We analyzed LMO2 expression in 100 initial and follow-up biopsies of T-LL from 67 patients, including 31 (46%) early precursor T-cell (ETP)-ALL, 26 (39%) cortical and 10 (15%) medullary type. LMO2 expression was present in 50 (74.6%) initial biopsies with an average of 87% positive tumor cells (range 30-100%). LMO2 expression in ETP, medullary and cortical T-LLs was not statistically different. In patients with biopsies after initial therapy, LMO2 expression was stable. LMO2 expression was associated with longer OS (p 0.048) regardless of T-lymphoblast stage or other clinicopathologic features. These findings indicate that LMO2 is a promising new prognostic marker that could predict patients outcomes and potentially be targeted for novel chemotherapy, i.e. PARP12 inhibitors, which have been shown to enhance chemotherapy sensitivity in LMO2 expressing diffuse large B cell lymphoma (DLBCL) tumors by decreasing DNA repair efficiency.

Aberrant expression of myeloid antigens in patients of acute lymphoblastic leukaemia.

To determine the immunophenotypic pattern and aberrant expression of myeloid antigens in newly diagnosed patients of acute lymphoblastic leukaemia(ALL). This descriptive cross-sectional study was carried out in Haematology Pathology department, Army Medical College, National University of Medical Sciences (NUMS) in collaboration with Immunology and Haematology departments of Armed Forces Institute of Pathology (AFIP), Rawalpindi from 1st January, 2019 to 31st December, 2019. Seventy-three (73) recently diagnosed patients of Acute Lymphoblastic leukaemia of all age groups and both genders were included in the study. A proforma was used to note demographic data. CBC, cytochemical stains and bone marrow examinations were carried out and assessed for morphology and percentage of blasts using a microscope. Flow cytometry was used to perform immunophenotyping on samples of peripheral blood and bone marrow, using a standard panel. The most commonly expressed markers were weak CD45, TdT, CD19, CD10 and HLA-DR. Weak CD45 was present in almost all blast cells and there was no remarkable difference in its positivity among various subtypes of ALL. Myeloid expression was observed in 13 (17.8%) cases. CD13 and CD33 were aberrantly expressed in 11 and 12.3 of all cases of ALL respectively. Expression of aberrant myeloid CD markers in acute lymphocytic leukaemia has prognostic significance and should be documented during lineage assignment of acute leukaemias while performing immunophenotyping.

Intensive chemotherapy with tyrosine kinase inhibitors in philadelphia-positive acute lymphoblastic leukemia.

Before the advent of tyrosine kinase inhibitors (TKIs), patients with Philadelphia-positive Acute Lymphoblastic Leukemia (PhALL) had a poor prognosis. The association of TKIs to intensive chemotherapy (CT) improved outcome. To evaluate results of an intensive CT protocol including TKI in a public hospital in Santiago, Chile. All patients with PhALL diagnosed between January 2010 and February 2019, and who met inclusion criteria for intensive CT, received the PhALL national protocol in association with imatinib and were included in this analysis. Thirty-five patients aged 15 to 59 years received treatment. Complete response (CR) was obtained in 97%. Measurable residual disease (MRD) was negative in 61% (1931 evaluable cases) during follow-up, and 55% (1629) were MRD (-) before three months. Relapse was observed in 13 cases. Three patients underwent allogeneic hematopoietic stem cell transplant (HSCT), two in CR1. The overall survival (OS) and event-free survival (EFS) at three years were 52 and 34%, respectively. In patients who achieved MRD negativity before three months, no statistically significant differences in OS (64 and 42% respectively, p 0.15) or EFS (35 and 32% respectively, p 0.37) were observed. The prognosis of PhALL improved with the association of imatinib to intensive CT. MRD-negative status before three months in this series was not significantly associated with better outcomes. Our series suggests that the PhALL national protocol associated to TKI is a therapeutic alternative with high CR and aceptable MRD (-) rates.

Pediatric Chronic Myelogenous Leukemia in T-lineage Blast Crisis A Reminder in Relevance.

Pediatric Philadelphia chromosome positive (Ph) acute T-cell lymphoblastic leukemia can mimic chronic myelogenous leukemia (CML) in T-lineage blast crisis (BC). Differentiating the 2 is critical in guiding therapy as most children with de novo Ph acute T-cell lymphoblastic leukemia are treated with chemotherapy and tyrosine kinase inhibitors, whereas T-lineage BC of CML can include hematopoietic stem cell transplantation. We present a unique case of CML in T-lineage BC. The patient was treated with induction chemotherapy plus imatinib followed by matched unrelated donor hematopoietic stem cell transplantation. She is currently off all medications and in complete disease remission.

Preparing for CAR T cell therapy patient selection, bridging therapies and lymphodepletion.

Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed andor refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patients T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.

A novel and efficient CD22 CAR-T therapy induced a robust antitumor effect in relapsedrefractory leukemia patients when combined with CD19 CAR-T treatment as a sequential therapy.

CD19 chimeric antigen receptor (CAR) therapy has achieved impressive success in relapsed or refractory (RR) B-cell malignancies, but relapse due to antigen escape is increasingly appearing reported. As the expression profile of CD22 is similar to that of CD19, CD22 has become a candidate target when CD19 CAR-T therapy fails. A novel CD22 CAR incorporating scFv derived from an HIB22 hybridoma which bound the first and second Ig-like extracellular domains of CD22 antigen was constructed. Preclinical investigation of the CD22 CAR-T therapy against B-cell malignancies was evaluated by coculturing CD22 CAR-T cells with tumor cell lines or primary blasts from patients in vitro and using a xenograft mouse model in vivo. Further clinical study of CD22CD19 CAR-T sequential therapy was conducted in 4 RR adult B-cell acute lymphoblastic leukemia (B-ALL) patients. The novel CD22 CAR-T treatment had specific cytotoxicity to CD22 target cells, and the survival time of mice in the CD22 CAR-T treatment group was significantly prolonged. Furthermore, its validated that sequential CD22CD19 CAR-T therapy was significantly superior than single CD19 or CD22 CAR-T treatment in a relapse xenograft model. All 4 patients achieved complete remission (CR) with negative minimal residual disease (MRD), including 3 patients who had received prior CD19-related immunotherapy. The proliferation of CD19 and CD22 CAR-T cells was observed respectively in vivo, and 3 of the 4 patients experienced cytokine release syndrome (CRS) 2 of these patients had grade 1 CRS and 1 had grade 3 CRS. Long term follow-up showed that 3 of the 4 (75%) patients had sustained CR for up to 1 year. Analysis of antigen expression in the relapsed patients demonstrated that loss or diminution of CD19 and CD22 expression might cause antigen escape from CAR-T surveillance. In summary, the novel CD22 CAR-T therapy was validated with antitumor effects both in vitro and in vivo. Furthermore, our study demonstrated the safety and robust efficacy of sequential CD22CD19 CAR-T therapy in xenograft models and clinical trials, especially as the salvage treatment for RR B-ALL patients with antigen loss or in whom anti-CD19 related immunotherapy failure failed. Chinese Clinical Trial Registry (ChiCTR) ChiCTR1900025419, Supplementarily registered 26 August, 2019.

Feasibility study of a novel preparation strategy for anti-CD7 CAR-T cells with a recombinant anti-CD7 blocking antibody.

Although chimeric antigen receptor (CAR) T cell immunotherapy has shown promising significance in B cell malignancies, success against T cell malignancies remains unsatisfactory because of shared antigenicity between normal and malignant T cells, resulting in fratricide and hindering CAR production for clinical treatment. Here, we report a new strategy of blocking the CD7 antigen on the T cell surface with a recombinant anti-CD7 antibody to obtain a sufficient amount of CD7-targeting CAR-T cells for T cell acute lymphoblastic leukemia (T-ALL) treatment. Feasibility was evaluated systematically, revealing that blocking the CD7 antigen with an antibody effectively blocked CD7-derived fratricide, increased the expansion rate, reduced the proportion of regulatory T (Treg) cells, maintained the stem cell-like characteristics of T cells, and restored the proportion of the CD8

Anticancer effects of a single intramuscular dose of a minicircle DNA vector expressing anti-CD3CD20 in a xenograft mouse model.

Bispecific antibodies (BsAbs) are a class of promising anticancer immunotherapies. Among them, the US Food and Drug Administration (FDA)-approved blinatumomab (BLI) is very effective in eliminating the minimum residual disease (MRD) of acute lymphoblastic leukemia (ALL), resulting in long-term remission in many individuals. However, the need for months-long intravenous delivery and high cost limit its clinical acceptance. Here we demonstrate that these problems can be solved by a BsAb expressed by one intramuscular (i.m.) dose of a minicircle DNA vector (MC). In a human B lymphoma xenograft mouse model, when microcancers became detectable in bone marrow, the mice received an i.m. dose of the MC encoding the BsAb anti-CD3CD20 (BsAb.CD20), followed by 8 subsequent intravenous (i.v.) doses, one every other day (q2d), of human T cells to serve as effectors. The treatment resulted in persistent expression of a therapeutic level of serum BsAb.CD20 and complete regression or growth retardation of the cancers in the mice. These results suggest that the i.m. MC technology can eliminate the physical and financial burdens of i.v. delivered BLI without compromising anticancer efficacy and that cancer can be treated as easily as injecting a vaccine. This, together with other superior MC features, such as safety and affordability, suggests that the i.m. MC BsAb technology has great clinical application potential.

Predictors of thrombosis in children receiving therapy for acute lymphoblastic leukemia Results from Dana-Farber Cancer Institute ALL Consortium trial 05-001.

Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial. Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival. Of 794 patients median age 4.97 (range, 1.04-17.96) years males 441, 100 developed TE 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression the blood group impact being most evident in patients 1-5 years of age (P 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45 95% CI, 1.64-25.47 P 0.008). We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase.

Characteristics of white blood cell count in acute lymphoblastic leukemia A COST LEGEND phenotype-genotype study.

White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (ρ These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC.

Concurrent CDX2 cis-deregulation and UBTFATXN7L3 fusion define a novel high-risk subtype of B-cell ALL.

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTFATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2UBTF ALL (n 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph- B-ALL enrolled in GRAALL trials, patients with CDX2UBTF ALL (n 17723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (malefemale ratio, 0.2, P .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10-4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTFATXN7L3 fusion, representing a high-risk disease in young adults.

The role of miRNAs as a big master regulator of signaling pathways involved in lymphoblastic leukemia.

MicroRNAs (miRNAs) belong to small noncoding RNAs, which have long attracted researchers attention because of their potency in acting either as oncogenes or tumor-suppressors in cancers. acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are two known types of leukemia with high mortality rates in adults and children. On a molecular basis, various signaling pathways are active in both types, making researchers consider the potential role of miRNAs in activating or suppressing these pathways to further hinder cancer development. In this review, we summarized the potential miRNAs, especially circulating ones, involved in essential signaling pathways in the ALL and CLL patients which serve as biomarkers and valuable targets in the treatment fields.

Temporal changes in incidence of relapse and outcome after relapse of childhood acute lymphoblastic leukemia over three decades a Nordic population-based cohort study.

Relapse remains the main obstacle to curing childhood acute lymphoblastic leukemia (ALL). The aims of this study were to compare incidence of relapse, prognostic factors, and survival after relapse between three consecutive Nordic Society of Pediatric Hematology and Oncology trials. Relapse occurred as a primary event in 638 of 4 458 children (1.0-14.9 years) diagnosed with Ph-negative ALL between 1992 and 2018. The 5-year cumulative incidence of relapse was 17.3% (95% CI 15.4-19.2%) and 16.5% (95% CI 14.3-18.8%) for patients in the ALL1992 and ALL2000 trials, respectively, but decreased to 8.4% (95% CI 7.0-10.1%) for patients in the ALL2008 trial. No changes in duration of first complete remission and site of relapse were observed over time however, high hyperdiploidy, and t(1221) decreased in the ALL2008 trial. The 4-year overall survival after relapse was 56.6% (95% CI 52.5-60.5%) and no statistically significant temporal improvements were observed. Age ≥10 years, T-cell immunophenotype, bone-marrow involvement, early and very early relapse, hypodiploidy, and Down syndrome all independently predicted worse outcome after relapse. Improvements in the primary treatment of childhood ALL has resulted in fewer relapses. However, failure to improve outcome of remaining relapses suggests a selection of harder-to-cure relapses and calls for new therapeutic strategies.