The aforementioned group also reported the most favorable VAS scores for static, dynamic, and uterine cramp pain during the first 24 h after surgery. Adverse effect profiles were similar among the four groups, but a higher proportion of participants in the lumbar PCEA group (approximately 20% more than in the other three groups) reported prolonged postoperative lower extremity motor blockade (p = 0.005). In addition, the first passage of flatulence after surgery reported by the low thoracic PCEA group was approximately 8 h earlier than that of the two morphine groups (p < 0.001). Conclusions: Epidural congruency is essential to PCEA for postcesarean pain. Low thoracic PCEA achieves favorable analgesic effects and may promote postoperative gastrointestinal recovery without additional adverse effects.Patient-controlled epidural analgesia (PCEA) or epidural morphine may alleviate postcesarean pain; however, conventional lumbar epidural insertion is catheter–incision incongruent for cesarean delivery. Methods: In total, 189 women who underwent cesarean delivery were randomly divided into four groups  for postcesarean pain management. Pain intensities, including static pain, dynamic pain, and uterine cramp, were measured using a 100 mm visual analog scale (VAS). The proportion of participants who experienced dynamic wound pain with a VAS score of >33 mm was evaluated as the primary outcome. Adverse effects, including lower extremity blockade, pruritus, postoperative nausea and vomiting, sedation, and time of first passage of flatulence, were evaluated. Results: The low thoracic PCEA group had the lowest proportion of participants reporting dynamic pain at 6 h after spinal anesthesia (low thoracic PCEA, 28.8%; lumbar PCEA, 69.4%; low thoracic morphine, 67.3%; lumbar morphine group, 73.9%;  Postcesarean pain has been ranked ninth for pain severity among 179 different surgical procedures in the first 24 h after surgery ,4, interAt least two common epidural modalities may be applied for postcesarean analgesia, namely patient-controlled epidural analgesia (PCEA) with local anesthetic-based drugs and epidural morphine. However, the analgesic efficacy of PCEA versus epidural morphine for cesarean delivery remains inconclusive partly because the role of the epidural insertion site has never been examined. Epidural catheter–incision congruency is achieved when the placement of the epidural catheter corresponds to the dermatomes of the surgical incision, and it substantially influences epidural local anesthetic efficacy . In thisThis is a single-blinded randomized controlled trial of a single center. Ethical approval for this study (201902009RINC) was granted by the Research Ethics Committee of National Taiwan University Hospital, Taipei, Taiwan. This study was registered at ClinicalTrials.gov (identifier: NCT03946982). We enrolled adult women who underwent elective cesarean delivery between 8 a.m. and 12 p.m. on weekdays between June 2019 and April 2021. Study candidates were excluded if they met the following exclusion criteria: contraindication for epidural analgesia such as coagulopathy or refusal, preeclampsia status, or having received perioperative magnesium infusion  .An investigator who was independent of clinical care obtained written informed consent from each participant on the day before surgery. Additionally, a three-item preoperative screening questionnaire was administered. Designed to predict postcesarean pain, the questionnaire assessed preoperative anxiety levels , anticipated postcesarean pain , and rating of anticipated pain medication needs  . Upon arRegional anesthesia for each participant was administered in the lateral decubitus position by employing the separate space technique . The intAfter the epidural catheter was placed, spinal anesthesia was administered to each participant at L4–5 by using a 27-gauge BD Quincke spinal needle  and a combination of 12 mg of 0.5% hyperbaric bupivacaine and 15 µg of fentanyl to achieve a T6 sensory blockade ,19. AtteThe PCEA regimen comprised 0.66 mg/mL bupivacaine and 1.75 µg/mL fentanyl in the initial setting; it was designed for the delivery of a program-intermittent bolus infusion of 3 mL and demand dose of 4 mL at a lockout interval of 20 min and with a 4 h limit of 40 mL. PCEA was initiated with the first bolus infusion being performed at 1 h after surgery. Participants in the epidural morphine group received 2 mg of epidural morphine  at the end of surgery and at 9 a.m. and 9 p.m. on the 2 days that followed. Furthermore, at the end of the surgery, 4 mg of ondansetron was intravenously administered to each participant for prophylaxis of nausea, vomiting, and pruritus.1), between 9 a.m. and 10 a.m. on postoperative day 1 (T2); between 3 p.m. and 5 p.m. on postoperative day 1 (T3), and between 9 a.m. and 10 a.m. on postoperative day 2 (T4). During each assessment, the investigator and participant were blinded to the previous VAS questionnaire results. Based on a recent analysis of objective acute postoperative pain assessments that used the 100-mm VAS, a VAS position marking of ≤33 mm indicates an acceptable postoperative pain control response [1.Postcesarean pain intensity was assessed by investigators who were independent of the clinical care team; the investigators used a 100 mm visual analog scale (VAS) ,21,22 toresponse  and thatresponse . AccordiDuring the 2 days following surgery, oral analgesics were provided, including 500 mg of acetaminophen that was administered every 6 h and 500 mg of naproxen  that wasThe adverse effects of epidural analgesia include lower extremity blockade, pruritus, postoperative nausea and vomiting, and severe sedation; the evaluation of these effects was conducted concurrently with the primary outcome assessment. The adverse effects were compared with the proportion of participants in a group who experienced the most severe effects during the investigation period. Lower extremity blockade was assessed using a modified Bromage motor scale, which is a 4-point scale in which a score of 0 indicates an individual is able to lift his or her legs against gravity , 1 indicates an individual is able to flex his or her knees but not his or her legs, 2 indicates an individual is able to move his or her feet without being able to flex his or her knees, and 3 indicates an inability to move any joints  . The deg1 with a power of 0.8 and at a significance level of 0.05. Given the risk of epidural failure and frequent clinical labor force requirements for emergent cesarean procedures , 200 participants (50 in each group) were enrolled. The proportional data were compared using chi-squared tests followed by the Marascuilo procedure when appropriate. One-way analysis of variance and Tukey’s test were performed to compare the means of the four groups; repeated-measures analysis of variance (with group and time factors) and Tukey’s test were performed to compare the VAS trajectories of the four groups from T1 to T4. The incidence of moderate-to-severe postcesarean pain (unacceptable pain control) is 50%–70% ,31. Accot-test was performed for normally distributed continuous data, and the Mann–Whitney U test was performed for nonparametric ordinal data. Statistical analyses were performed using PASS 2021 Sample Size Software  and MedCalc Statistical Software version 20 .To compare analgesic consumption between two groups , Student’s Demographic characteristics and preoperative obstetric data  and preoperative questionnaires were compared among the four groups .p = 0.054); however, the requirements for intravenous fluid and norepinephrine were similar among the four groups. Furthermore, no significant difference among the four groups was observed for skin-epidural depth, time for epidural catheterization, and the number of epidural redirection attempts. Compared with the two lumber groups, those in the two low thoracic groups had a nonsignificantly higher tendency to exhibit higher spinal anesthesia sensory blockade levels  at T1, which was significantly lower than the VAS scores of 32 (1–56) and 38 (14–53) reported by the lumbar PCEA and lumbar morphine groups, respectively (p < 0.001). The beneficial analgesic effects of low thoracic PCEA on static VAS score over lumbar PCEA were observed throughout T1 to T3 . The beneficial analgesic effects of low thoracic PCEA on dynamic VAS score over lumbar PCEA were also observed at T2 and T3 , which was significantly lower than the VAS score of 61 (37–82), 45 (23–68), and 48 (24–72) reported by the lumbar PCEA, low thoracic morphine, and lumbar morphine groups (p < 0.001). The beneficial analgesic effects on uterine cramp VAS score of low thoracic PCEA over lumbar PCEA were also observed at T2 and T3  in the four groups. Compared with the other groups, a lower proportion of participants in the lumbar PCEA group scored 0 on the Bromage motor scale . The incidence and severity of pruritus and postoperative nausea and vomiting were similar among the four groups (p < 0.001). Furthermore, participants in the lumbar PCEA group revealed the worst recovery scores, and participants among the other three groups reported comparable scores  compared with those in the lumbar PCEA group ; lumbar PCEA group, 275 mL (228–308) mL, respectively; p = 0.007) and delivery ; lumbar PCEA group, 11 (7–25); p = 0.002) doses. The low thoracic PCEA group had a comparable demand/delivery ratio to the lumbar PCEA group ; lumbar PCEA group, 21 (9–37); p < 0.001; p < 0.001; In terms of rescue analgesic profile, the participants in the low thoracic PCEA and lumbar PCEA groups required, respectively, the fewest and most numbers of rescue analgesia intervention  among participants in the low thoracic morphine and lumbar morphine groups.Intrathecal morphine is considered the gold standard single-shot drug for postcesarean pain ; howeverIn this study, we observed that the incidence and severity of pruritus and PONV were similar among the four groups. Furthermore, the participants in the four groups did not report any effects of sedation during the investigation period. However, the negative influence of epidural local anesthetic infusion on maternal motility must be considered . In thisThis study has several limitations. First, this study was a single-center study, and institutional variations may limit the application of low thoracic PCEA for postcesarean pain control. Second, in the present study, experienced providers placed all catheters. Therefore, this study does not guarantee the generalizability of the study findings for inexperienced hands. Third, in the present study, PCEA was administered using a programmed intermittent bolus, which could spread more extensively than continuous infusion at a fixed rate . TherefoIn conclusion, the present study verified that epidural catheter–incision congruency profoundly influenced the effects of PCEA on postcesarean pain management. A low thoracic PCEA is associated with superior analgesic efficacy relative to lumbar PCEA and epidural morphine for postcesarean pain and is without additional adverse effects or technical difficulties. Furthermore, low thoracic PCEA may promote gastrointestinal function recovery after cesarean delivery.


Although the outcome has improved over the past decades, due to improved supportive care, a better understanding of risk factors, and intensified chemotherapy, pediatric acute myeloid leukemia remains a life-threatening disease, and overall survival (OS) remains near 70%. According to French-American-British (FAB) classification, AML is divided into eight subtypes (M0–M7), and each is characterized by a different pathogenesis and response to treatment. However, the curability of AML is due to the intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy. The treatment of childhood AML continues to be based primarily on intensive, conventional chemotherapy. Therefore, it is essential to identify new, more precise molecules that are targeted to the specific abnormalities of each leukemia subtype. Here, we review abnormalities that are potential therapeutic targets for the treatment of AML in the pediatric population. Acute myeloid leukemia (AML) is a relatively rare heterogeneous group of hematologic malignancies in children, but it causes disproportionate mortality . AML is The development of genetics, whole genome, exome, and RNA sequencing in recent years has significantly contributed to a better understanding of the molecular landscape of AML. Although many of these studies were conducted using adult AML cases, the range of mutations observed in childhood AML is similar, but differences are observed in the frequency of these changes in childhood cases ,10. AccoNPM1 and CEBPA gene mutations [Alterations associated with a favorable prognosis occur about once in ten cases of childhood AML, such as translocation , chromosome 16 inversion, utations .RUNX1::RUNX1T1 fusion gene formation, which was one of the first fusion genes to be used for minimal residual disease (MRD) monitoring [RUNX1::RUNX1T1–positive pediatric acute myeloid leukemia (AML) patients to determine risk factors for relapse. The results of the study indicate that CD19 negativity might be a distinct characteristic of the poor prognostic subgroup of RUNX1::RUNX1T1–positive AML patients. CD19-negative patients showed inferior RFS. Moreover, the results of a recent preclinical study suggest that the proteasome inhibitor bortezomib and the BCL-2 inhibitor ABT-737 can induce apoptosis and inhibit cell proliferation of RUNX1::RUNX1T1 cells in vitro and in vivo [Non-random chromosomal aberration t is one of the best-known mutations; it usually correlates with the AML M2 subtype and results in nitoring . tnitoring . Morpholnitoring ,14. Treanitoring . Recentl in vivo .CBFB-MYH11 formation. MYH11 and CBFB encode the smooth muscle myosin heavy chain (SMMHC) and β-subunit of core binding factor (CBF), respectively, and the fusion protein resulting from inv(16) contains 1–5 CBFβ exons and C-terminal region of SMMHC. It is known that oncogenic fusion protein CBFβ::SMMHC blocks the differentiation of myeloid cells and, therefore, is a potent inhibitor of leukemogenesis [Chromosome inv(16)or t, which in the majority of cases is associated with M4 subtype of pediatric AML with a specific abnormal eosinophil component (M4Eo), is a chromosome aberration that leads to a fusion gene ogenesis ,68. Patiogenesis . AML witogenesis . CBF-AMLogenesis . OS for ogenesis ,72. Ro5-NPM1 and CEBPA gene mutations [NPM1 gene, which is localized at chromosome 5q35, encodes nucleophosmin, which is predominantly localized in the nucleoli but shuttles rapidly between the nucleus and cytoplasm, and its function differs depending on cellular processes. Nucleophosmin is involved in centrosome duplication through cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylation, ribosome biogenesis, maintenance of genomic integrity, preventing aggregation of proteins in the nucleolus, and also in the ARF-p53 tumor-suppressor pathway [NPM1 occur much more frequently in adult compared to pediatric AML, or 50–60% to about 10% of cases, respectively [NPM1 mutation variants, but all of them consist of an insertion in the C-terminal region, causing aberrant movement of the protein to the cytoplasm (NPMc+), which is present in approximately one-third of adult AML cases [FLT3/ITD  mutations, high WBC, a higher percentage of blasts, and most importantly, with improved response to chemotherapy induction, but better long-term outcomes and OS were observed in NPM1 mutations without FLT3/ITD mutation, also in the pediatric population (5-year OS of 85%) [NPM1 mutations is chemotherapy. A specific feature of AML cells with NPM1 mutation is high expression of CD33; therefore, such cases can be treated with gemtuzumab ozogamicin. Adding this agent to chemotherapy improved EFS and OS. In clinical practice, allo-HSCT transplant is recommended in patients with NPM1 mutation with FLT-3 and not recommended for patients with NPM1 mutation without FLT-3. Inducing nucleolar stress could be therapeutically effective in NPM1-mutated AML. Actino-mycin D, which triggers nucleolar stress by inhibiting RNA polymerase I, induces CR in NPM1-mutated AML. Another therapeutic approach that may be effective in treating AML is blocking NPM1 oligomerization, because pentameric/decameric NPM1wt is required for proper nucleolus formation. According to other studies, targeting HOX expression may turn out to be effective in this AML [Cytogenetically normal AML (CN-AML) aberrations can also be classified as alterations associated with a favorable prognosis, and these include utations . The NPM pathway ,74,75. Mectively ,58,76,77ML cases . AML wit of 85%) ,17,79,80this AML ,82,83.CEBPA gene, which encodes CCAAT/enhancer binding protein alpha (C/EBPα), occurs in about 2.4% and 5.6% of childhood AML patients  and shows favorable prognosis with 80% 5-year OS for double mutants vs. 25% for single mutants [CEBPA gene mutations cause a selective early block of granulocyte differentiation [CEBPA promoter’s hypermethylation, resulting in CEBPA silencing, is one of the mechanisms that give an effect similar to that of mutation [FLT3/ITD, AML1-ETO and CBF-MYH11 [CEBPA mutation show high sensitivity to the effects of treatment targeting MLL1 histone-methyltransferase complex. CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Furthermore, the use of CRISPR/Cas9 to induce mutagenesis results in proliferation arrest and myeloid differentiation. The identification of dmCEBPA status in AML has major clinical importance, allowing relapse risk to be stratified properly for post-remission treatment. [Mutations in the  mutants ,24. C/EBntiation . Moreovemutation . It has BF-MYH11 ,87. Accoeatment. ,89.PML::RARA fusion gene formation is the most common mutation driving the development of acute promyelocytic leukemia (APL), which is classified as FAB-M3 AML [2 daily), and 134 to tamibarotene (6mg/m2 daily) for 14 days every 3 months for 2 years. The 7-year RFS was 84% in the ATRA arm and 93% in the tamibarotene arm . Tamibarotene has been shown to be more effective than ATRA in reducing relapses in high-risk patients [Translocation t15;17) resulting in ;17 or inv(16)(p13.3q24.3) (leads to CBFA2T3::GLIS2) [KMT2A. MLLT3 and MLLT11 together with KMT2A are associated with a good prognosis in pediatric AML, whereas the predicted outcome for AFDN, MLLT10 and ABI1 as partner genes is poorer [In addition to the genetic changes that are associated with a good prognosis and, therefore, a good response to treatment, there are also chromosome aberrations and gene mutations that lead to a poor outcome. Some of these are FLT3/ITD mutation, 11q23 rearrangements, t (leads to 16)p13.3q.3  in exons 14 and 15, which leads to ligand-independent auto-phosphorylation and activation of the receptor [FLT3/ITD mutation occurs relatively often in childhood AML; it occurs in about 10–20% of pediatric AML cases, but the frequency increases with age, from 1.5% in infants to 7% in children aged 1–5 years to nearly 17% in adolescents and young adults. In contrast to alterations with a favorable prognosis, the 5-year OS is 30–40% for patients with high allelic ratios, which means a high mutant to normal allelic ratio [FLT3/ITD is an important therapeutic target, and despite that mutation of this gene leads to a poor prognosis. Rapid FLT3/ITD diagnosis allows early intervention with targeted therapies [FLT3/ITD mutations and has a key role in tumor cell signaling, proliferation, and angiogenesis [FLT3/ITD inhibitor has been studied at 15 centers in Germany and Austria. Authors reported data from a randomized, placebo-controlled, double-blind phase II trial (SORMAIN). Adult patients with FLT3/ITD–positive AML (n = 83) in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40). The results showed that sorafenib maintenance therapy reduces the risk of relapse and death after HCT for patients with confirmed FLT3/ITD mutation [pression . The majreceptor . FLT3/ITic ratio ,25. Addiherapies . Sorafenogenesis . Early-pogenesis . Anotherogenesis . The effmutation .KMT2A gene  rearrangements, which are located in the chromosomal region 11q23 [KMT2A gene, which encodes a histone 3 lysine 4 methyltransferase, involved in the regulation of transcription and epigenetic modulations, has at least 77 fusion partners, and most of the rearrangements lead to the formation of fusion proteins, and because of that, the prognostic impact depends on the specific recombination [KMT2A rearrangements occur in 20% of childhood AML cases and most frequently in infants [KMT2A abnormality, occurring in 6–9% of pediatric patients, is t, resulting in fusion of KMT2A with the MLLT3 gene, which presents a better outcome compared with any other 11q23/KMT2A rearrangement both in adult and pediatric AML. MLLT3 is the most common partner, representing approximately 50% of all pediatric AML cases with KMT2A rearrangements, and this subtype is associated with an intermediate prognosis [ELL gene (19p13.1) or MLLT1 (ENL) gene (19p13.3), which account for 1–2% of all AML pediatric patients [KMT2A-MLLT11 fusion, also leads to favorable clinical outcomes, but there are some 11q23/KMT2A rearrangements that, independently of other prognostic factors, result in a poor prognosis, such as t and t, which involve MLLT10 and MLLT4 as fusion partners for KMT2A, respectively. MLLT10 is more common among infants , whereas MLLT4 is prevalent in older children  [PICALM::MLLT10 fusion, a rare  abnormality assigned to an intermediate risk group and that can closely resemble t in the FISH analysis [KMT2A is AFF1 (AF4/FMR2 family member 1), which encodes a member of the AF4/lymphoid nuclear proteins related to the Fragile X E syndrome (FRAXE) family of proteins. KMT2A::AFF1 fusion is rarely found in AML, but it is also known to be a molecular marker of infant acute lymphoblastic leukemia (ALL) [Some of the most frequent chromosome aberrations in AML are on 11q23 . The KMTbination . 11q23/K infants . The mosrognosis ,28,102. patients ,30. Trananalysis . Anotheria (ALL) . In addiia (ALL) .NUP98::NSD1 fusion gene creation, where NUP98 is nucleoporin 98-kDa and NSD1 is nuclear receptor-binding SET-domain protein 1 [NUP98::NSD1 also has a strong association with previously mentioned FLT3/ITD mutation [NUP98::NSD1-positive AML is often associated with other mutations similar to FLT3/ITD, NRASG12D, or MYC. Translocation t is another cytogenic abnormality involving the NUP98 gene, which fuses with the KDM5A gene. This rearrangement, initially described in M7 pediatric AML, occurs in 2% of all childhood cases, and it is associated with a poor prognosis with 5-year OS rate of around 33% [NUP98::NSD1 and NRASG12D using an in vivo mouse model. To demonstrate the leukemic potential of NRASG12D, NUP98::NSD1, and NUP98::NSD1 + NRASG12D in vivo, they transplanted transduced mouse bone marrow cells into mice. The authors reported that mice transplanted with NRASG12D transduced cells did not show any engraftment over 11 months. NUP98::NSD1 mice showed very low engraftment, while NUP98::NSD1 + NRASG12D mice showed rapidly increasing engraftment over 12 weeks. Moreover, mice that had been transplanted with NUP98::NSD1 cells developed leukemia with long latency, and mice transplanted with NUP98::NSD1+NRASG12D cells developed aggressive leukemia with short latency. The median survival was 251 vs. 54 days after transplantation, p = 0.001. Reported data might suggest that targeted inhibition of the fusion might be a potential treatment in NUP98::NSD1-positive AML patients. This appears to be a promising area for further clinical research [NUP98-fusion AML. The authors revealed CDK6 as a highly expressed, directly regulated target of NUP98-fusion proteins. Palbociclib, an inhibitor of CDK4/CDK6 that is approved for breast cancer therapy, was tested on both NUP98-rearranged cell lines and mice transplanted with NUP98::NSD1 leukemia cells. Monotherapy using a patient-derived xenograft model of NUP98::NSD1-rearranged AML caused a highly significant prolongation of survival compared to the vehicle-treated control cohort . Collected data show that NUP98-rearranged AML is sensitive towards CDK4/CDK6 inhibition in vivo and in vitro [Another chromosomal aberration associated with unfavorable outcomes in childhood AML is tq35;p15), occurring in approximately 3–4% of cases ,31. Thisrotein 1 . Translorotein 1 . It is wmutation . NUP98::ound 33% ,35,36. S;p15, occound 33%  analyzedresearch . In otheresearch  investigin vitro .MNX1 gene (previously named HLXB9) and 12p13 of the ETV6 gene, which is a motor neuron and pancreas homeobox 1, and ETS variant transcription factor 6, respectively [One of the most common chromosome aberrations in pediatric AML is t; it is present in about 30% of infant AML cases and is associated with a poor outcome . This trectively ,109,110.ectively . Due to ectively ,37.GATA2 and MECOM genes, and both result in relocation of GATA2’s enhancer to the vicinity of MECOM. As a result of these abnormalities, GATA2 is silenced, and MECOM is overexpressed [Inversion inv(3)(q21q26.2) or translocation t are abnormalities that share the same chromosomal breakpoints; both involve xpressed . In adulxpressed ,40,41.Among many chromosomal and genetic abnormalities in pediatric AML, there is still a subgroup of alterations whose presence, on the one hand, for example, may cause significant regression of the disease, but, on the other hand, may negatively impact response to therapy.MYST3 gene encoding a histone acetyltransferase is fused with CREB-binding protein (CREBBP) gene encoding nuclear receptor coactivator. Both proteins are involved in transcriptional regulation and cell cycle control [One of the examples of alterations of uncertain significance is t, whereby  control ,113. The control . This ch control ,46. t have a substantially increased risk of multiple health conditions. They have a particularly elevated risk (estimated 150-fold) of developing AML before age 5. AML-affected children develop a unique type of malignancy, referred to as myeloid leukemia of Down syndrome (ML-DS), which is recognized as a separate entity in the actual World Health Organization (WHO) classification of leukemia. Approximately 15% of pediatric AML cases occur in DS children. ML-DS demonstrates unique characteristics such as the predominance of FAB M7, an age predilection during the first 4 years of life, and higher sensitivity to chemotherapeutic agents, which translate into a good treatment response as well as increased treatment-related toxicities. . AML in K2, JAK3 .KIT is a protooncogene that encodes transmembrane glycoprotein, which is one of the type III receptor tyrosine kinase family members. KIT, upon binding with a stem cell factor, activates signaling pathways affecting proliferation, differentiation, and survival of hematopoietic stem cells. Mutations in exons 8, 10, 11 and 17, which encode extracellular, transmembrane, juxtamembrane domains and activation loop of the tyrosine kinase domain, respectively, lead to ligand-independent activation of KIT [KIT mutations may negatively impact response to therapy; therefore, KIT remains a factor of uncertain significance [n of KIT . These mn of KIT ,117. Theificance ,48.FLT3 gene (FLT3/TKD) have an incidence of 7% in childhood inv(16) AML, which is significantly less than in adult patients with the aforementioned inversion, where it accounts for 28% of cases [FLT3/TKD mutations in CBF-AML patients with a mutant allelic ratio of 10% or greater were associated with a higher cumulative incidence of relapse (CIR) compared with a lower ratio and non-mutated patients. The 5-year CIR was 58.8%, 20.0% and 31.5%, respectively [KIT and FLT3/TKD mutations highlight the multiclonality of CBF-AML and encourage investigators to delve deeper into the topic and advance the science in this area so that better identification of risk in AML patients will be possible.Mutations among tyrosine kinase domain of of cases ,49. In tBCR::ABL1 fusion gene, resulting from Philadelphia chromosome formation, is one of the most characteristic features of chronic myeloid leukemia (CML), and it has also been found in AML [BCR::ABL + AML was listed there as a provisional entity. For AML to be classified as BCR::ABL + AML, patients with de novo AML must not show any evidence of underlying CML and aberrations such as mutated NPM1 or CEBPA, t, t, or inv(16), and inv(3) must not be present, as in this case leukemia would be classified as “AML with recurrent genetic abnormalities” [BCR::ABL + AML is classified as a disease with a poor outcome [BCR::ABL + AML is classified as a high-risk disease because if the previously mentioned aberrations coexisted, the disease could not be so classified. It seems that the prediction of BCR::ABL + AML prognosis is much more complicated and depends mainly on specific genetic background, such as coexisting aberrations, rather than BCR::ABL itself.d in AML . In 2016alities” ,114. Accalities”  and curralities”  BCR::ABL outcome ,115. TheNPM1::MLF1, where NPM1 and MLF1 encode nucleophosmin and myelodysplasia/myeloid leukemia factor 1, respectively [Another aberration with uncertain significance for prognosis is t, which results in the formation of chimeric gene ectively ,116. Thiectively ,53.FUS::ERG and RUNX1::CBFA2T3, respectively. t occurs in about 0.4%, and the second one in 0.2% of pediatric AML cases; therefore, prognosis prediction is complicated, but the I-BFM Study Group indicated that the prognosis for FUS::ERG is poor with 4-year EFS of 7%, and outcome for RUNX1::CBFA2T3 is significantly better with 4-year EFS of 77% [There are two distinct abnormalities important for pediatric AML that are related to translocation between 16 and 21 chromosomes: t and t, which produce fusion proteins S of 77% ,21.RBM15 and MKL1 genes, and clinically it manifests as abnormal megakaryopoiesis, as this is characteristic for the FAB M7 subtype of AML [Another chromosome aberration that shows an intermediate outcome is translocation t. This translocation occurs only in infants and young children, with a median age of 0.7 years, and in general in 0.3% of all pediatric AML cases, mainly in the AMKL cohort ,50,51. Te of AML . PatientFLT3/ITD, KMT2A rearrangements and trisomy 19, 6 and 21. Prognostically, trisomy of chromosome 8 seems to be associated with intermediate or poor prognosis, but no molecular data were provided, and a poor prognostic impact seems to be mainly dependent on the coexisting aberrations; thus, we categorize it as an intermediate/discussed aberration (5-year EFS ~25%) [Trisomy 8 in pediatric AML may occur either as a sole cytogenetic change or it can be associated with another chromosomal aberration, and thus frequency significantly differs—trisomy 8 is generally present in about 10–14% of pediatric AML patients, but only in 3% of cases as a sole abnormality and mainly over the age of 10 ,54. The FS ~25%) .Abnormalities of chromosome 5q, primarily deletions, both in adult and pediatric AML cohorts, lead to a higher WBC and blast count at diagnosis ,118. TheKMT2Ar, and was found in 8% of pediatric AML cases as a poor risk factor [KMT2Ar, but it was detected in 15% of pediatric AML cases and showed an intermediate prognosis [A hyperdiploid karyotype can be defined as three or more numerical gains of chromosomes. According to the NOPHO-AML trial, which included 596 pediatric patients with AML, 11% were hyperdiploid cases with 48–65 chromosomes. The most frequent solely numerical gains were trisomies of 6, 8, 21 and 19. Clinically, these cases were not shown to have a poor prognosis, but on the other hand, were strongly associated with AMKL and lower WBC count ,57. Compk factor . In anotrognosis .NPM1, FLT3/ITDdm, CEBPA and mtWT1, that can significantly affect the prognosis of pediatric AML patients when they coexist with other mutations and aberrations. These anomalies were presented in Among the variety of genetic changes outlined above, there are some somatic mutations with well-established prognostic relevance, such as NPM1 encodes nucleophosmin and is translocated or mutated in several hematologic malignancies, forming a variety of fusion proteins, such as NPM::ALK, NPM::RARa, NPM::MLF1, or NPM mutant products [NPM1 along with dmCEBPA are mainly found in normal karyotype cases, assigning them to a low-risk category. It is also worth noting that the coexistence of FLT3/ITD with NPM1 mutations counteracts its negative influence on prognosis [dmCEBPA is significantly associated with GATA2 mutations, FLT3/ITD, and CBFB::MYH11, and shows a positive impact on OS [products . Nucleopproducts ,121,122.rognosis ,123. CEBct on OS ,123.FLT3/ITD, as mentioned above, is the major form of FLT3 gene mutation [FLT3/ITD co-occurs with a normal karyotype and a variety of genetic aberrations, both those associated with good and poor prognosis, but also those for which the prognosis is intermediate. Examples of secondary cytogenetic abnormalities for FLT3/ITD are as follows: t, t, inv(16)(p13.1q22) or t, t, t, which lead to formation of PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11, NUP98-NSD1, and DEK-NUP214, respectively, and furthermore trisomy 8, dmCEBPA and mutated WT1 [FLT3/ITD is a bad prognostic factor, and it worsens the outcome, which is equal to poorer OS and/or EFS [mutation . Because inv(16)p.1q22 or ated WT1 . In mostd/or EFS .WT1 gene is known to be overexpressed among leukemias including childhood AML. Mutated WT1 is often found to be a secondary aberration along with CEBPA and NPM1 gene mutations, N-RAS, and K-RAS, and it has a strong association with NUP98::NSD1 and FLT3/ITD [mtWT1, similar to FLT3/ITD, worsens the outcome [The FLT3/ITD ,123. WT1 outcome .2/dose) administered once in induction course 1 and once in intensification course 2 (Arm B). Data obtained showed GO significantly improved EFS  but not OS  [RUNX1::RUNX1T1, CBFB::MYH11, and PML::RARA rearrangements, which lead to chromosomal aberrations. These results suggest that JL1 may be a potential therapeutic target in immunotherapy for pediatric AML patients [The development of immunotherapy for the treatment of AML in the pediatric population faces many barriers. The main one is the lack of an antigen specific only to cancer cells. Furthermore, AML blasts create an immunosuppressive microenvironment. Due to the fact that the majority of surface proteins that define malignant myeloid blasts are also expressed on normal progenitors, potential therapeutic targets are mainly seen in dysregulated gene expression . However = 0.39) . Collectpatients . In the patients .In recent years, research has identified the engagement of immune checkpoint receptors as a mechanism of tumor evasion. T-cell checkpoint receptors such as CTLA-4 and PD-1 relay inhibitory signals that modulate T-cell activation. In acute myeloid leukemia, PD1 expression is observed on T-cell subpopulations, including CD4+ effector T cells, CD4+ Treg, and CD8+ T cells, both in untreated patients and in relapses. Increased PD1 expression on CD8+ T lymphocytes may be one of the factors leading to the dysfunction of this group of immune cells and a reduction in the immune response to the progressive course of AML. Blocking signaling through checkpoint receptors results in increased T-cell activation, with effector T-cell proliferation and increased cytotoxicity toward cancer cells . Inhibit+ leukemia cells. UniCar technology has been designed so that T cells do not express any characteristic antigen. Instead, they express the universal CAR (UniCAR-T) that recognizes a small linear peptide derived from the nuclear human La/SS-B protein (UniCAR epitope (UCE)). UniCART-T remains inactive until it connects with targeting modules (TMs) consisting of the UCE linked to an appropriate binding domain. The UniCAR-Ts, in combination with TM123 effectiveness and safety, will be assessed in a clinical trial [6 CART123 cells/kg, following lymphodepleting chemotherapy. The total dose administered to each subject will be based on the subject’s body weight obtained at the time of apheresis. The minimum acceptable dose for infusion is 1 × 105 CART123 cells/kg [+ targets, as a potential therapeutic agent for the treatment of CD123+ hematological malignancies [Therapy with T cells expressing chimeric antigen receptors that are specific for tumor antigens turned out to be a success in the treatment of patients with B-cell ALL . That isal trial . The useal trial ), one ancells/kg . In conccells/kg  providedgnancies .®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7 + 3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination. Thanks to this solution, the difference in the pharmacokinetics of both compounds is cancelled, and they can act simultaneously. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 h after administration. The use of a liposome allows for less exposure to tissues that are off-target tissues. CPX-351 shows high efficiency in patients with newly diagnosed high-risk/secondary AML [CPX-351 acetylation of histones, this may result in decreased or increased gene transcription, altering gene expression levels. Numerous scientific studies indicate that HDAC deregulation may lead to the development of neoplasms, including hematological neoplasms . HDAC inIDH1) and 2 (IDH2) are exceedingly rare in pediatric ALL, but are more common in pediatric AMLs, occurring in 3.5% of cases overall, and in 9.8% of pediatric AMLs with a normal karyotype. In their pediatric cohort, they could not demonstrate any significant statistical association of IDH1/IDH2 mutations with overall survival or event-free survival, although the power of this analysis is influenced by the low overall frequency of IDH1/IDH2 mutations [IDH1/2 mutation has been identified as an induction event. However, IDH1 mutations are mainly involved in early occurrences of AML. Mondesir et al. reported that IDH1 modifications are found in about 10% of AML patients and are associated with worse outcomes in patients undergoing thorough chemotherapy [ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, or TP53 were identified in 74 (21%) of 360 patients. Three DDX41 variants, 2 GATA2 variants, and a TP53 variant previously implicated in Li-Fraumeni syndrome were of germline origin [IDH2 mutations may occur in the early stages of AML leukemia development in children; their presence makes cells more susceptible to oncogenic activities of FLT3 activating mutations. It makes them a potential gene that can be studied by NGS. Germinal mutations are one of the factors conditioning the development of hematological neoplasms that gives 100% certainty of tumor development regardless of environmental conditions. An example of one such mutation is a germline 5′-end CEBPA mutation. In addition, variants identified in leukemia cells should be considered as likely germline genes that can be mutated in germline or somatic tissues, including TP53, CEBPA, RUNX1 and DDX41 [An important approach in medicine is not only the treatment of a disease entity, but also the assessment of the predisposition for the development of the disease, even before its occurrence. The World Health Organization’s latest leukemia classification scheme has included germline predisposition to myeloid malignancies as a provisional category. Predictive testing has become possible since the widespread use of next-generation sequencing (NGS). The development of NGS techniques, commercially available since 2006, allowed for cost- and time-effective sequencing . The datutations . In myelotherapy . Drazer e origin . Accordind DDX41 .In recent years, the intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy contributed to the improvement of the curability of AML patients in low-risk groups. Despite this, the curability of patients with high-risk AML in the pediatric population is still low. Many children become refractory or relapse even after successful therapy. A major challenge is the lack of specific antigens on the surfaces of tumor cells. Modern medicine has a wide range of treatment protocols, but only extending them with new therapeutic targets can provide a chance to improve the cure rate in high-risk groups. The increasing number of emerging clinical trials offers hope for new therapeutic solutions in the near future and improvement of the cure rate in the pediatric AML population.


Arabidopsis thaliana (Arabidopsis) seedlings stably expressing the bioluminescent Ca2+ reporter aequorin in the cytosol were challenged with PAW generated by a plasma torch. Ca2+ measurement assays demonstrated the induction by PAW of rapid and sustained cytosolic Ca2+ elevations in Arabidopsis seedlings. The dynamics of the recorded Ca2+ signals were found to depend upon different parameters, such as the operational conditions of the torch, PAW storage, and dilution. The separate administration of nitrate, nitrite, and hydrogen peroxide at the same doses as those measured in the PAW did not trigger any detectable Ca2+ changes, suggesting that the unique mixture of different reactive chemical species contained in the PAW is responsible for the specific Ca2+ signatures. Unveiling the signalling mechanisms underlying plant perception of PAW may allow to finely tune its generation for applications in agriculture, with potential advantages in the perspective of a more sustainable agriculture.Increasing evidence indicates that water activated by plasma discharge, termed as plasma-activated water (PAW), can promote plant growth and enhance plant defence responses. Nevertheless, the signalling pathways activated in plants in response to PAW are still largely unknown. In this work, we analysed the potential involvement of calcium as an intracellular messenger in the transduction of PAW by plants. To this aim,  The obtained results showed that Arabidopsis perception of PAW generated by two different plasma torches is mediated by rapid and sustained cytosolic Ca2+ elevations. Further studies are needed in the future to address conserved and unique features of Ca2+-mediated sensing mechanisms of PAW in phylogenetically distant plant species, as well as in plants of economic interest. A better understanding of the biochemical and molecular bases of plant perception of PAW may allow to finely tune the chemical composition of PAW for an optimal application in agriculture. To test the effect of PAW on the induction of transient changes in the cytosolic concentration of the ion  were used, both consisting of a non-transferred arc generated through a narrow nozzle less than 1 cm wide, so that a relatively high-power plasma could be generated and concentrated in a relatively narrow surface. To produce PAW, samples of 50 mL deionized H2+ signalling in the perception of PAW by plants, an Arabidopsis line stably expressing the bioluminescent Ca2+ indicator aequorin in the cytosol was used cyt elevation evoked by PAW appeared long-lasting, with sustained Ca2+ levels as high as ~1 µM after 1 h (Cafter 1 h a. Nevertfter 1 h b.3−) and nitrite/nitrous acid (NO2−/HNO2) in the PAW (4+), measured by ion chromatography, as well as the content of hydrogen peroxide (H2O2), measured through spectrophotometric analysis of TiIV/H2O2 adduct, resulted under the detection limit of the assays cyt up to 10–25 times the resting level of the ion; notably, the Ca2+ change was found to reach, after about 10 min, a plateau that is maintained for additional 20 min, before slowly decreasing. Continuous monitoring of Ca2+ showed that even after 1 h the Ca2+ elevation did not dissipate completely. However, cell viability assays demonstrated the lack of cytotoxic effects of PAW in our experimental set up. An intriguing possibility is that the unique dynamics of the PAW-activated Ca2+ signals, i.e., a sustained, long-lasting Ca2+ elevation, may be a crucial determinant of the induced “priming” condition, consisting in the activation of defence gene expression and antioxidant activities that bolster plant resistance to subsequent pathogen attacks. The lack of return of [Ca2+]cyt back to pre-stimulus resting values (about 100 nM) may lead to a state of plant alert in which the plant gets more prepared to face subsequent battles +aq was then carried out measuring the absorption at 409 nm with a double beam spectrometer Varian Cary 100 Bio , using a solution containing 0.5 mL of TiOSO4 and 9.5 mL of deionized H2O as reference. H2O2 content in PAW was also determined through the FOX1 method cyt by means of a built-in algorithm based on the calibration curve of aequorin [2+]cyt values were obtained as the sum of each instantaneous [Ca2+]cyt value for the entire duration of the experiment.Transgenic Arabidopsis seedlings (7-day-old) were incubated overnight in the dark with 5 µM coelenterazine  to reconstitute the functional aequorin probe. Prior to the start of the experiment, each seedling was gently rinsed and placed in 250 µL deionized Haequorin . Integraw/v) Evans blue (Merck), excess and unbound dye was removed by extensive washing with H2O. The dye bound to dead cells was solubilized in 1% (w/v) SDS, 50% (v/v) methanol for 30 min at 55 °C. The percentage of cell death was assessed by measuring the absorbance at 600 nm. As positive control (100% cell death), cells were incubated for 10 min at 100 °C. Cell viability was determined by the Evans blue method . Briefly


Conjunctival myeloid sarcoma (MS) as an isolated presentation of acute myeloid leukemia (AML) relapse is rare. Here, we report a case of unilateral conjunctival MS revealed as a sign of AML relapse.A 50-year-old man with a history of AML in remission visited our clinic presenting with a left conjunctival injection persisting for 1 month. Diffuse subconjunctival thickening with conjunctival vascular engorgement was observed. Ultrasound biomicroscopy revealed a hyper-reflective, thickened conjunctiva in his left eye. During the incisional biopsy, the lesion was strongly attached to the underlying sclera; histopathologic examination revealed infiltration of leukemic blasts. The relapse of AML was confirmed by a successive bone marrow biopsy. The ocular lesion disappeared after allogeneic peripheral blood stem cell transplantation (PBSCT) and concomitant salvage radiotherapy on the left eye. The patient has remained in remission for 3 years after allogeneic PBSCT.Incidental conjunctival lesions can indicate AML relapse in patients treated earlier for AML. An ophthalmologist may have a role in the early detection of AML when a patient presents with an atypical conjunctival lesion. Myeloid sarcoma (MS) is an extramedullary solid tumor composed of immature myeloblasts and other granulocytic precursor cells with or without maturation occurring at sites other than the bone marrow (BM) . The SocNPM1-mutated AML, and was in complete remission after receiving chemotherapy (CT) 2 years ago. Slit lamp examination revealed diffuse conjunctival thickening with injection in the left superior conjunctiva extending for approximately 5 clock hours (from 9 to 2 o’clock), with no abnormal findings in the cornea, anterior chamber, iris, and lens , and the relapse of AML with concurrent conjunctival MS was confirmed.The patient was treated with anti-leukemic reinduction CT , concomitant allogeneic peripheral blood stem cell transplantation (PBSCT) for the systemic relapse of AML, and salvage radiotherapy (RT) for 3 weeks (24 Gy/12 cycles) for the conjunctival MS.After 3 months, the previous conjunctival mass in the left eye had resolved Fig.  and was MS is often accompanied by hematologic malignancies, including AML, myeloproliferative neoplasm, myelodysplastic syndrome, and the blast phase of chronic myeloid leukemia. AML is the most common concomitant systemic disease, and MS has been reported to occur in 3–9% of all AML cases . In ophtThe presentation timing of MS varies: 25% occurs as isolated MS without AML, 15–35% occur concurrently with the diagnosis of AML, and up to 50% occur after or at the time of AML relapse , 15. Of The consensus for MS treatment is not well-established owing to the lack of randomized control trials. Chemotherapy is currently the mainstay of treatment, including isolated MS; other treatment options are RT and surgery. He et al. found that neither RT nor surgery delayed the transformation of MS to AML without systemic CT . Some stThis is a rare case of conjunctival MS presenting as the first sign of AML relapse, and prompt diagnosis and treatment are necessary to confer a better prognosis for this life-threatening disease. Incidental conjunctival lesions should be considered a warning sign indicating ocular involvement of the systemic disease, especially in patients with a history of cancer.


For some subgroups of AML subjects, such as patients with positive pretransplantation minimal/measurable residual disease, recent studies suggest that haplo-SCT might be superior to MSDT in decreasing relapse and improving survival. Unfortunately, for patients with AML after haplo-SCT, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes. In this review, we discuss the recent advances and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haplo-SCT protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.Haploidentical stem cell transplantation (haplo-SCT), an alternative donor source, offers a curative therapy for patients with acute myeloid leukemia (AML) who are transplant candidates. Advances in transplantation techniques, such as donor selection, conditioning regimen modification, and graft-versus-host disease prophylaxis, have successfully improved the outcomes of AML patients receiving haplo-SCT and extended the haploidentical transplant indictions for AML. Presently, treating  Allogeneic stem cell transplantation  remains a curative therapy for patients with acute myeloid leukemia (AML) –19. HoweIn the past two decades, advances in the establishment of algorithms for best haploidentical donor selection –42, optide novo AML patients in complete remission 1 (CR1), our group demonstrated that for both adults and pediatric patients  t AML cases who did not achieve major molecular remission (MMR)/MRD negativity, which were defined as >3-log reduction in RUNX1/RUNX1T1 transcripts (<0.4%) compared with the pretreatment baseline of 388% in Peking University Institute of Hematology, after the second consolidation therapy or those exhibiting the loss of MMR (defined as RUNX1/RUNX1T1 transcript levels >0.4% in MMR patients) within 6 months of achieving MMR ving MMR . iii) Foving MMR . iv) CBFving MMR . Third, ving MMR , 66–75 , cumulative incidence of relapse (CIR), and 2-year probabilities of leukemia-free survival (LFS) and overall survival (OS) to those of MSDT , suggestP=0.85), NRM , LFS , and OS  between the two transplant modalities. These results, together with other studies (P=0.27), NRM , LFS , and OS  and significantly lower chronic GVHD  than those who received MSDT (n=869). These results suggest that haplo-SCT is an alternative source for AML cases in CR1  or MSDT (n=219) . Wang et studies , 82, 91, studies  demonstrs in CR1 Table 1.vs. 42%, P<0.001) and increase the probability of 3-year GVHD and relapse-free survival  compared with those who received allografts from MSDs. These results suggest that haplo-SCT has a stronger graft-versus-leukemia (GVL) effect than MSDT in high-risk AML patients in CR1  and NRM  to those of MSDT in another meta-analysis, which included 24 studies and 11,359 cases. Overall, the literature published thus far , CIR , NRM , LFS  and OS , to those of MUDT (n=78), although higher grades II to IV acute GVHD  were observed in the haplo-SCT cohort. These preliminary data indicate that haplo-SCT could be an alternative source for patients with hematological malignancies who lack MSDs or MUDs  and lower GHVD-free relapse-free survival (GRFS)  after UCBT for subjects with AML compared to haploidentical allografts. These results indicate that haplo-SCT is associated with better GRFS and lower acute GVHD than UCBT in patients with secondary AML. For poor-risk AML patients, Versluis et al. .In 2019, Ruggeri et al.  retrospes et al.  found thvs. 18%, P=0.04), which led to higher OS after haplo-SCT compared with that of UCBT , but the PFS was comparable . Fuchs et al.  or haplo-SCT group (n=182) . Prespecs et al.  suggesteIn a recent meta-analysis, Wu et al.  found thOverall, the landscape of allografts for hematological malignancies apparently changed with the position alteration of haplo-SCT in AML treatment , 59–61. According to the CIBMTR data, relapse remains an important challenge in AML patients who undergo haploidentical allografts. Infection is another challenge following haplo-SCT-based immune tolerance induced either by G-CSF and ATG or by PTCy , 104. HeP=0.002)  , which pin vivo. They showed that haplomatching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mouse survival and reduced leukemia burden -matched transplant models were established by Guo et al.  after ina burden . The stra burden .Overall, in contrast to the traditional notion that MSDs remain the first choice, recent advances in haploidentical transplantation settings raise a new idea , 110–114Donor characteristics are important variables for transplant outcome determination. In haplo-SCT settings, we and other researchers suggest a donor selection algorithm for which the key issue is that the younger the better , 118. Re2) and Ara-c (1.5–2 g/m2 iv) on days (d) 2–6, IDA , and G-CSF (5 μg/kg d1–7). For patients in the PIB arm, VEN was administered as follows: 200 mg d1–21 (n=8), d1–14 (n=5); 400 mg d1–14 (n=3). For cases in the PIIA and PIIB arms, VEN was administered at 400 mg D1–14. After induction therapy, 67% of patients with R/R-AML  and 83% with sAML, t-AML, or ts-AML attained a CRc (CR+CRi). Eighteen (46%) R/R-AML cases, including 75% (n=6) of responding R/R patients who experienced a prior allo-SCT, were transitioned to allo-SCT. DiNardo et al. (P=0.009). This study provides a promising approach, combining FLAG-IDA+VEN with allografts, for the treatment of R/R AML.Venetoclax (VEN), a BCL-2 inhibitor, has been approved for unfit, older patients with AML , 124. Ino et al.  further + AML who relapsed after allo-SCT within 3 months and resisted multiagent chemotherapy and donor lymphocyte infusion (DLI), Yao et al. . Gao et al.  accompanied by rapid recovery of CD8+ T cells, NK cells, and regulatory T cells compared with patients in the non–G-Dec group, both of which led to higher LFS  and OS . No differences in the 2-year chronic GVHD without relapse between the two groups  were shown. The authors  DNAemia varies from 63.7 to 66.1% and remains one of the main causes of morbidity and mortality. BKV and EBV infection are also frequent in haplo-SCT and a risk factor for worse survival except for CMV infection , 145. FoCMV CTLs . These sde novo grade III or IV GVHD, graft failure, or infusion-related toxicities. BKV-CTLs were observed in patient blood samples up to 3 months postinfusion, and their in vivo expansion predicted a clinical response. This study suggests that off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after allo-SCT  and the National Key Research and Development Program of China (2017YFA0104500).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


NPM1, FLT3, DNMT3A, IDH1, IDH2, TET2, RUNX1, TP53, WT1, NRAS, and CEBPα. However, the prognostic-predictive significance of genetic mutations is more important in normal karyotype AML [Acute myeloid leukemia (AML) is a clonal disorder resulting from acquired somatic mutations in hematopoietic progenitor cells that lead to the dysregulation of differentiation and the proliferation of hematopoietic cells ,2. Theretype AML ,10,11.These aberrations might help to identify AML pathways of clonal dominance and shifts that could assist hematologists in targeting precision medicine therapies ,8,9.Cancers focuses on the novel diagnostic and therapeutic tools for the management of AML with the main aim of improving our knowledge in the field of AML [Over the last few years, there has been an increasing understanding of molecular aberrations that trigger the development of AML, and an increase in the use of novel molecular biology technologies, thus facilitating the development of investigational drugs targeting driver genetic mutations ,8,9. Basd of AML ,15,16,17Twenty years ago, the discovery of imatinib for the treatment of chronic myeloid leukemia and its remarkable activity raised hopes for similar benefits in targeted therapies for AML. Over the last few years, precision medicine has been proposed for several hematological malignancies including acute leukemia, and more than 100 different targets have been identified in AML, making it an optimal candidate for experimental clinical studies ,20,21,22Targeting fms, such as tyrosine kinase-3 (FLT-3), have been the first example of clinically actionable mutations, making them an attractive target for hematologists, as well as for pharmaceutical and biotechnology companies developing novel drugs . Over thMore recently, a great number of experimental drugs targeting single metabolic pathways have been developed and tested in phase 1, 2 and 3 clinical trials ,20,21,22Metabolism is a complex biochemical process that mammalian cells use to generate energy and maintain their growth and survival. Metabolism encompasses the generation of energy (ATP), the synthesis and breakdown of amino acids, glucose, fatty acids, and oxidative phosphorylation. In AML cells, metabolism can promote tumor growth and cellular proliferation. As a consequence, these alterations have emerged as a potential therapeutic target ,22.Some of these compounds proved to be effective in targeting altered metabolism, such as in the Krebs/citric acid cycle, hedgehog pathway (glasdegib), and the mitochondrial oxidative and carrier-associated secretory membrane proteins , making the AML therapeutic armamentarium more flexible and intriguing. The identification of actionable bioenergetic cell pathways is rapidly expanding, allowing us to hypothesize new potential therapeutic modalities in AML .More recently, the use of Bcl-2 inhibitors (venetoclax), and IDH inhibitors data have raised hopes for the benefits of targeted therapies in AML. For example, in older/unfit AML patients, hypomethylating agents (HMAs) and venetoclaxare now the new standard of care in this setting ,13,14.AML is also known to be an epigenetically heterogeneous disease. Based on this consideration, hypomethylating agents such as 5-azacitidine, decitabine, and guadecitabine; HDAC inhibitors  family protein, among others), as well as novel agents targeting the aberrant activation of gene signaling  have been tested in clinical trials.NPM1-mutated AML.Oncoprotein degradation is the basis of the curative effect of the combination of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia and has shown promising results in As far as immunotherapy is concerned, immunotherapy-based protocols have demonstrated modest activity in AML which needs to be confirmed in larger series. In contrast, encouraging results have been observed in acute lymphoblastic leukemia and in non-Hodgkin and Hodgkin lymphoma ,13,14.Interestingly, novel drugs and small compounds have been developed that can activate p53 in AML cells expressing the wild-type form of p53; the clinical implication related to the use of these molecules is under investigation .A comprehensive list of druggable genetic lesions and targeted therapy in AML is shown in The role of minimal residual disease detection for the sharper management of acute leukemia is also considered in this issue, provided that the authors include a clinical setting in which one or multiple druggable genetic lesions are presented ,8,31.Cancers is launching a collection of articles dealing with NGS data and the use of targeted therapies, as well as cellular therapies [With this background, the journal herapies ,33,34.


Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS . The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts . Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for  Genome-wide association studies (GWAS) have been successful at identifying risk loci in several hematologic malignancies, including acute myeloid leukemia AML; . RecentlIRF4, a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation, and has been previously identified in GWAS of BCM (Given the evidence of a shared genetic basis across BCM and the underlying genetic predisposition for AML and myelodysplastic syndromes (MDS) observed in family, epidemiological, and genetic association studies , we hypoS of BCM .Our study was a nested case-control design derived from the parent study DISCOVeRY-BMT  . The DISde novo AML with normal cytogenetics, de novo AML with abnormal cytogenetics and therapy-related AML (t-AML). De novo AML patients did not have precedent MDS, chemotherapy or radiation for prior cancers. MDS subtypes included de novo MDS, defined as patients without precedent chemotherapy or radiation for prior cancers, and therapy-related MDS (t-MDS). Patient cytogenetic subtypes were available, however due to limited sample sizes for each cytogenetic risk group, we consider here only broad categories. Controls were unrelated, healthy donors aged 18–61 years who passed a comprehensive medical exam and were disease-free at the time of donation. All patients and donors provided written informed consent for their clinical data to be used for research purposes and were not compensated for their participation.Acute myeloid leukemia and MDS patients were selected from the DISCOVeRY-BMT patient cohorts and used as cases and all the unrelated donors from both cohorts as controls. AMLsubtypes included P < 1.0 × 10–4).Genotyping and quality control in the DISCOVeRY-BMT cohort has previously been described in detail . Briefly1 via the Michigan Imputation server  in each cohort. European American healthy donors were used as controls. SNP meta-analyses of cohorts 1 and 2 were performed by fitting random effects models , Plink-v1.9, and SNPTEST-v2.5.4-beta3. Logistic regression models adjusted for age, sex, and three principal components were used to perform single SNP tests of association with s models . To idens models . ASSET ts models .We calculated heritability of AML and MDS combined and by independent subtypes as the proportion of phenotypic variance explained by all common genotyped SNPs, using the genome-based restricted maximum likelihood method performed with the Genome-wide Complex Trait Analysis (GCTA) software . We repode novo AML and MDS using PrediXcan (cis-regulatory variation) to inform models relating SNPs to gene expression levels in data with both gene expression and SNP genotypes available. Robust prediction models are then used to estimate the effect of cis-regulatory variation on gene expression levels. Using imputation, the cis-regulatory effects on gene expression from these models can be predicted in any study with genotype measurements, even if measured gene expression is not available. Thus, we imputed the cis-regulatory component of gene expression into our data for each individual using models trained on the whole blood transcriptome panel (n = 922) from the Depression Genes and Networks -linked genes, we carried out a gene expression tests of association of rediXcan . This merks DGN; , yieldinP < 5 × 10–6) were whole blood cis-eQTL, defined as allele specific association with gene expression (IRF4 in an independent sample of AML samples from The Cancer Genome Atlas (N = 170) and GTEx (N = 70). AML and MDS SNP associations were also placed in context of previous GWAS using Phenoscanner, a variant-phenotype comprehensive database of large GWAS, which includes results from the NHGRI-EBI GWAS catalog, the UK Biobank, NIH Genome-Wide Repository of Associations between SNPs and Phenotypes and publicly available summary statistics from more than 150 published genome association studies. Results were filtered at P < 5 × 10––8 and the R statistical software package phenoscanner2 was used to download all data for our significant variants (3 (ex vivo CD34+ hematopoietic progenitor cell lines (primary hematopoietic G-CSF mobilized stem cells and hematopoietic stem cells)  . We intem cells) .de novo (N = 1618) with normal cytogenetics (N = 543), 6% of patients had therapy-related AML (t-AML). The most frequently reported previous cancers in patients with t-AML were breast (N = 51), non-Hodgkin Lymphoma (NHL), N = 23, HL (N = 14), Sarcoma (N = 12), Gynecologic (N = 8), Acute Lymphoblastic Leukemia (N = 6), and Testicular (N = 6). Prior therapies for these patients were approximately equally divided between single agent chemotherapy and combined modality chemotherapy plus radiation. Almost half of MDS patients had Refractory Anemia with Excess Blasts (RAEB)-1 and RAEB-2. Of patients with t-MDS (∼18% of MDS patients), 65% had antecedent hematologic cancers or disorders. The most frequently reported antecedent cancers in MDS patients were NHL (N = 27), breast (N = 15), Acute Lymphoblastic Leukemia (N = 8), HL (N = 8), AML (N = 8), Sarcoma (N = 6), and CLL (N = 5)  . Overallde novo abnormal cytogenetics, de novo normal cytogenetics and t-AML) and MDS (de novo and t-MDS) are shown in P ≤ 5.0 × 10–8 with significant individual one-sided subset tests (P < 0.01), the variant association could not be driven by a single disease nor could it be both positively and negatively associated in different cohorts of the same disease (Interferon Regulatory Factor 4 (IRF4), conferred increased risk of de novo abnormal cytogenetic AML, de novo normal cytogenetic AML, MDS and t-MDS . T-AML showed no association with rs12203592. The effect allele frequency was 19% in de novo AML, MDS and t-MDS cases versus 14% in controls. ASSET analyses also identified another variant in modest linkage disequilibrium (LD), r2 = 0.7, with rs12203592 in the regulatory region of IRF4; the A allele at rs62389423, showed a putative association with de novo AML and MDS  (TAF2), associated with an increased risk of t-MDS  but not de novo MDS  (de novo MDS and 1.5% in controls.Genome-wide association studies of AML by subtype ( disease . In the  disease . The T a × 10–7) . We iden = 0.20) . The effBICRA (rs75797233) (BICRA (rs75797233) SNP may be more likely associated with cytogenetic subtypes that comprise a prognostically less severe AML. In addition, the lower frequency (MAF = 0.02) of this imputed variant (info score > 0.8 in both cohorts) possibly reduced power to detect an effect.A previous genome-wide association study of AML done in European American cases and controls reported a susceptibility variant in 5797233) . The varIRF4, as a pleiotropic susceptibility variant associated with both CLL and HL (r2 = 0.01).Multiple GWAS of healthy individuals have shown associations between the T allele at rs12203592 and higher eosinophil counts, lighter skin color, lighter hair, less tanning ability, and increased freckling . GWAS haL and HL . This SNIRF4, P = 1.48 × 10–29 in whole blood  and DEPTOR (P = 4.7 × 10–9) gene expression in whole blood . The proportion of variance in de novo AML with normal cytogenetics and de novo MDS on the liability scale had similar heritability at 9%, SE = 0.03, P = 1.9 × 10–3 and 14%, SE = 0.04, P = 1.4 × 10–4, respectively. Treatment-related AML and MDS were tested independently and estimated proportion of variance explained by all SNPs was 7% for t-AML and 4% for t-MDS, however SE were high and the heritability did not significantly differ from zero.The heritability of AML and MDS on the observed scale due to genotyped variants was 0.46 with standard error (SE) = 0.07. Transforming this to the liability scale and assuming a disease prevalence of 0.0001 resulted in a heritability of 0.10 (SE = 0.02) which differed significantly from a heritability of zero , consistent with our SNP-level findings (IRF4 expression is 1.75-fold greater in AML samples than GTEx whole blood (P < 0.01). Whole blood transcriptome models also identified two additional genes with suggestive associations with de novo AML and MDS. Increased expression of AKT Serine/Threonine Kinase 1, AKT1 at 14q32.33 was associated with risk for the development of de novo AML and MDS   (−4) were identified with limited or no evidence of biological plausibility to AML/MDS etiology (Using PrediXcan  gene expfindings . This as × 10–4) . Likewis × 10–4) . Other setiology .We performed the first large scale AML and MDS GWAS in a URD-BMT population providing evidence of novel pleiotropic risk loci associated with increased susceptibility to AML and MDS. The DISCOVeRY-BMT cohorts from the Center for International Blood and Marrow Transplant Research (CIBMTR) allow us to capture ∼99% of all AML and MDS patients who received an URD-BMT performed in the United States within the given time-frame .IRF4 and an increased risk for the development of de novo AML, de novo MDS and t-MDS in patients who had undergone URD-BMT compared to healthy donor controls. While therapy-related myeloid neoplasms have been shown to be genetically and etiologically similar to other high-risk myeloid neoplasms  in eoplasms , in our lignancy . Howeverlignancy .IRF4 transcription by physical interaction with the IRF4 promoter through a chromatin loop , plasma cell myeloma and primary effusion lymphoma  and immature fraction of reticulocytes, a blood cell measurement shown to be elevated in patients with MDS versus controls  by emailing (contactus@cibmtr.org) or Dr. Alyssa Clay-Gilmour (claygila@mailbox.sc.edu).The datasets presented in this article are not readily available because de-identified individual participant data that underlie the reported results are not available on dbGaP as informed consent is not compliant with the NIH Genomic Data Sharing Policy. Requests to access the datasets should be directed to International Blood and Marrow Transplant (JW, AC-G, LS-C, and TH designed the research, performed research and analysis, and wrote the manuscript. CH, DV, XS, and LPo performed the genotyping. SL, LPr, AW, and GB performed the quality control of genomic data. All authors reviewed and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.