Steroids are a mainstay in the treatment of acute lymphoblastic leukaemia (ALL) in children and adolescents; however, their use can cause clinically significant steroid-related neuropsychiatric symptoms (SRNS). As current knowledge on SRNS during ALL treatment is limited, we mapped the phenotypes, occurrence and treatment strategies using a database created by the international Ponte di Legno Neurotoxicity Working Group including data on toxicity in the central nervous system (CNS) in patients treated with frontline ALL protocols between 2000 and 2017. Ninety-four of 1813 patients in the CNS toxicity database (5.2%) experienced clinically significant SRNS with two peaks: one during induction and one during intensification phase. Dexamethasone was implicated in 86% of SRNS episodes. The most common symptoms were psychosis (52%), agitation (44%) and aggression (31%). Pharmacological treatment, mainly antipsychotics and benzodiazepines, was given to 87% of patients while 38% were hospitalised due to their symptoms. Recurrence of symptoms was reported in 29% of patients and two previously healthy patients required ongoing pharmacological treatment at the last follow up. Awareness of SRNS during ALL treatment and recommendation on treatment strategies merit further studies and consensus.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction remains associated with the risk of re-rupture and persisting rotational instability. Additional extraarticular anterolateral stabilization procedures stabilize the tibial internal rotation and lead to lower ACL failure rate and improved knee stability. However, data for additional stabilization of tibial external rotation is lacking and the importance of an anteromedial stabilization procedure is less well evaluated. Aim of this study is to investigate the influence of an extraarticular anteromedial stabilization procedure for the stabilization of the tibial external rotation and protection of the ACL from these rotational forces.
METHODS: Internal and external rotations of the tibia were applied to a finite element (FE) model with anatomical ACL, posterior cruciate ligament (PCL), lateral collateral ligament (LCL), medial collateral ligament (MCL) and intact medial and lateral meniscus. Five additional anatomic structures (Anteromedial stabilization/anteromedial ligament, AML, augmented superficial medial collateral ligament, sMCL, posterior oblique ligament, POL, anterolateral ligament, ALL, and popliteal tendon, PLT) were added to the FE model separately and then combined. The force histories within all structures were measured and determined for each case.
RESULTS: The anteromedial stabilization or imaginary AML was the main secondary stabilizer of tibial external rotation (90% of overall ACL force reduction). The AML reduced the load on the ACL by 9% in tibial external rotation which could not be achieved by an augmented sMCL (-1%). The AML had no influence in tibial internal rotation (-1%). In the combined measurements with all additional structures (AML, ALL, PLT, POL) the load on the ACL was reduced by 10% in tibial external rotation.
CONCLUSIONS: This study showed that an additional anteromedial stabilization procedure secures the tibial external rotation and has the most protective effect on the ACL during these external rotational forces.

CD123 \"expression\" is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin\'s lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

BACKGROUND: This study examined fatigue in patients treated for childhood acute lymphoblastic leukemia (ALL) over a 2-year period (3- to 27-months post-treatment completion), from the perspective of children and parent caregivers, compared to a healthy comparison group.
METHODS: Eighty-three patients (4-16 years at enrolment) and their parents, reported on the child\'s fatigue using the Pediatric Quality of Life Inventory- Multidimensional Fatigue Scale (PedsQL-MFS), at 3- 15- and 27-months post-treatment completion, and 53 healthy children and their parents reported on fatigue across the same timepoints.
RESULTS: Parent proxy-reporting showed that parents of ALL patients reported more total fatigue than parents of the comparison group at all time points, with all subscales elevated (general, cognitive, and sleep/rest fatigue). In contrast, patient self-report of fatigue over this period differed from the comparison children for the general fatigue subscale only. Self-reported total fatigue was worse than the comparison group at the 27-month timepoint, with cognitive and sleep/rest fatigue symptoms contributing to this difference. Expected improvements in fatigue over time were not evident in either patient or parent report and no demographic risk factors were identified. Parents and children from both groups reported significantly more fatigue at all time points compared to commonly utilised normative population data.
CONCLUSIONS: Patients treated for childhood ALL are impacted by fatigue symptoms in the post-treatment and early survivorship period. These findings highlight that patients in the 2-years following treatment require increased symptom surveillance and may benefit particularly from interventions that target cognitive and sleep/rest fatigue.

Despite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK-228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.
We conducted a single-arm multi-center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI-9775).
Sixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3-4 non-hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.
In summary, single-agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

In many organisms, including humans, the timing of cellular processes is regulated by the circadian clock. At the molecular level the core-clock consists of transcriptional-translational-feedback loops including several genes such as BMAL1, CLOCK, PERs and CRYs generating circa 24-h rhythms in the expression of about 40% of our genes across all tissues. Previously these core-clock genes have been shown to be differentially expressed in various cancers. Albeit a significant effect in treatment optimization of chemotherapy timing in paediatric acute lymphoblastic leukaemia has previously been reported, the mechanistic role played by the molecular circadian clock in acute paediatric leukaemia remains elusive.
To characterize the circadian clock, we will recruit patients with newly diagnosed leukaemia and collect time course saliva and blood samples, as well as a single bone marrow sample. From the blood and bone marrow samples nucleated cells will be isolated and further undergo separation into CD19+ and CD19- cells. qPCR is performed on all samples targeting the core-clock genes including BMAL1, CLOCK, PER2 and CRY1. Resulting data will be analysed for circadian rhythmicity using the RAIN algorithm and harmonic regression.
To the best of our knowledge this is the first study aiming to characterize the circadian clock in a cohort of paediatric patients with acute leukaemia. In the future we hope to contribute to uncovering further vulnerabilities of cancers associated with the molecular circadian clock and in particular adjust chemotherapy accordingly, leading to more targeted toxicity, and hence decreased systemic toxicities.

UNASSIGNED: To explore the functions of the polymorphisms in 5-methylcytosine (m5C) modification-related coding genes on the susceptibility of pediatric acute lymphoblastic leukemia (ALL).
UNASSIGNED: Case-control study and multinomial logistic regression analysis were performed to construct models to evaluate the susceptibility of pediatric ALL. The relationship between five functional SNPs in m5C modification-coding genes and pediatric ALL risk was analyzed. Genotyping of 808 cases and 1,340 healthy samples from South China was identified using a TaqMan assay; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and pediatric ALL susceptibility.
UNASSIGNED: Among the five analyzed SNPs, NOL1 rs3764909 and NSUN4 rs10252 variants significantly increased the susceptibility of pediatric ALL, while NSUN3 rs7653521, NSUN5 rs1880948, and NSUN6 rs3740102 variants were not associated with the risk of ALL. Stratification analyses demonstrated that NOL1 rs3764909 C>A exhibited a significant association with increased pediatric ALL risk in subgroups of common B ALL, pre-B ALL, T-cell ALL, low and middle risk, other gene fusion types, non-gene fusion, hypodiploid, normal diploid, primitive lymphocytes in marrow < 5% on week 12, and minimal residual disease (MRD) <0.01% on week 12 after induced therapy; NSUN4 rs10252 G>A was related to increased risk of ALL children in subgroups of age ≥ 120 months, normal white blood cell (WBC) number, middle risk, non-gene fusion, MRD ≥ 0.01 on days 15-19, and primitive lymphocytes in marrow < 5% on day 33 after induced therapy. Compared with the reference haplotype CAGTA, children who harbored haplotypes CCGTG and ACATA were remarkably related to increased ALL susceptibility. rs3764909 and rs10252 varieties of alleles were not associated with MRD levels after the selected chemotherapeutics.
UNASSIGNED: In conclusion, NOL1 rs3764909 and NSUN4 rs10252 variants were enhanced by pediatric ALL risk and were suggested to be potential biomarkers for pediatric ALL.

Leukemia caused by occupational risk is a problem that needs more attention and remains to be solved urgently, especially for acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphoid leukemia (CLL). However, there is a paucity of literature on this issue. We aimed to assess the global burden and trends of leukemia attributable to occupational risk from 1990 to 2019.
This observational trend study was based on the Global Burden of Disease (GBD) 2019 database, the global deaths, and disability-adjusted life years (DALYs), which were calculated to quantify the changing trend of leukemia attributable to occupational risk, were analyzed by age, year, geographical location, and socio-demographic index (SDI), and the corresponding estimated annual percentage change (EAPC) values were calculated.
Global age-standardized DALYs and death rates of leukemia attributable to occupational risk presented significantly decline trends with EAPC [-0.38% (95% CI: -0.58 to -0.18%) for DALYs and -0.30% (95% CI: -0.45 to -0.146%) for death]. However, it was significantly increased in people aged 65-69 years [0.42% (95% CI: 0.30-0.55%) for DALYs and 0.38% (95% CI: 0.26-0.51%) for death]. At the same time, the age-standardized DALYs and death rates of ALL, AML, and CLL were presented a significantly increased trend with EAPCs [0.78% (95% CI: 0.65-0.91%), 0.87% (95% CI: 0.81-0.93%), and 0.66% (95% CI: 0.51-0.81%) for DALYs, respectively, and 0.75% (95% CI: 0.68-0.82%), 0.96% (95% CI: 0.91-1.01%), and 0.55% (95% CI: 0.43-0.68%) for death], respectively. The ALL, AML, and CLL were shown an upward trend in almost all age groups.
We observed a substantial reduction in leukemia due to occupational risks between 1990 and 2019. However, the people aged 65-69 years and burdens of ALL, AML, and CLL had a significantly increased trend in almost all age groups. Thus, there remains an urgent need to accelerate efforts to reduce leukemia attributable to occupational risk-related death burden in this population and specific causes.

OBJECTIVE: Leukemia represents a serious public health concern as the incidence is increasing worldwide. In this study we aimed to describe the epidemiological profile of acute lymphoblastic (ALL) and myeloid (AML) leukemia, identify disease clusters and find association with possible risk factors.
METHODS: Data on leukemia cases were provided by the National Institute of Health of the Republic of Armenia for the period of 2012-2018. Age-standardized incidence rate was calculated using Segi World Population. SaTScan purely spatial analysis was applied to find leukemia clusters. To find association between leukemia and agricultural and mining activities and demographic data Poisson regression model was used.
RESULTS: During the studied period 259 new cases of ALL and 478 AML were recorded. The age-standardized incidence rate was 1.5 and 1.9 per 100,000 inhabitants with male to female ratio of 0.97 and 1.1 for ALL and AML, respectively. No significant changes in ALL or AML incidence trends were found. For ALL significant cluster encompassing Shirak, Lori, Tavush and Armavir provinces of Armenia was identified, while Kotayk and Ararat was provinces with the highest incidence of AML. We found significant positive association of ALL with crop density, while no elevated risk estimates were found between AML and exposure variables.
CONCLUSIONS: Altogether, our results suggested that acute leukemias incidence in Armenia follows the pattern described for developing countries.

Introduction HD-MTX is a key drug in the treatment protocols for ALL. The regimen needs to be administered with appropriate supportive measures and serum methotrexate level monitoring. A limited testing strategy is relevant in resource constraint settings since it allows a shorter duration of hospitalization. We report our experience with this strategy and its impact on the patient safety outcomes. Methods This is a retrospective study of all patients ≥ 15 years of age with newly diagnosed ALL or Lymphoblastic lymphoma (LBL) who were administered HDMTX (part of BFM-90 ALL protocol) at our institute between March 2013 to November 2013.The medical records were reviewed for clinical characteristics, disease-related details, HDMTX dose and cycles administered, leucovorin rescue and toxicities. Results A total of 423 cycles of HD-MTX were administered to 106 patients during the study period. The median duration for completion of all 4 cycles of HDMTX was 53 (IQR 49-60) days. The grade 3 or higher toxicities were anemia in 9.6%, neutropenia 19.4%, febrile neutropenia 5.7%, thrombocytopenia 4.4% and mucositis in 0.7%. There was statistically significant correlation between the levels at 42 h (≤ 1 mmol/L vs > 1 mmol/L) and toxicity- anemia, FN and mucositis observed more in the late clearance group. With limited sampling strategy whereby if the 42- hour level MTX level are < 1 mmol/L, 57% of patients could be discharged early. Conclusion HD-MTX can be safely administered to adolescent and adult ALL patients. A limited methotrexate level monitoring is a safe strategy that can optimize the resources better.