Leukemia Tumors Research Articles

Socioeconomic background and childhood cancer survival in Germany – A nationwide register study

Abstract Introduction Evidence is accumulating that not all children with cancer have benefitted equally from diagnostic and therapeutic improvements and that socioeconomic conditions are also associated with prognosis - even in high-income countries where equal access to healthcare is presumed. We investigated the association between area-based socioeconomic background and childhood cancer survival in Germany with the ultimate aim to identify groups of children that may benefit from supportive interventions. Methods We identified all children with a first cancer diagnosis before the age of 15 years in 1997-2016 from the German Childhood Cancer Registry (N = 35,443). Based on individual residential address information (at diagnosis) we applied the German Index of Socioeconomic Deprivation as measure of area-based socioeconomic background. Using Cox proportional hazards models, we assessed the association between absolute area-based socioeconomic deprivation (AASD) and ten-year overall survival (OS) to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results The Cox analysis (adjusted for diagnostic year, birth year and place of residence) revealed a null association for AASD and OS from all cancers combined (HR = 1.00, 95% CI 0.97; 1.03). Among children diagnosed with acute myeloid leukemia and germ cell tumors, a higher AASD (implying more severe levels of deprivation) was associated with worse survival, particularly pronounced in boys (HR = 1.18, 95% CI 1.01; 1.37; HR = 1.67, 95% CI 1.13; 2.45, respectively). The opposite was observed for childhood CNS tumours, yielding worse survival by decreasing AASD (HR = 0.93, 95% CI 0.88; 0.98) for both malignant and non-malignant CNS tumours. Conclusions Contrary to reports from other European countries, we found little evidence for pronounced social inequalities in childhood cancer survival in Germany based on a composite score, with inconsistent patterns across cancer types and age at diagnosis. Key messages • We found little evidence for pronounced social inequalities in childhood cancer survival in Germany on the area-based level. • Our findings indicated inconsistent patterns of social inequalities across cancer types and age at diagnosis.and age at diagnosis.

De novo design of mIDH1 inhibitors by integrating deep learning and molecular modeling

BackgroundMutations in the IDH1 gene have been shown to be an important driver in the development of acute myeloid leukemia, gliomas and certain solid tumors, which is a promising target for cancer therapy.MethodsBidirectional recurrent neural network (BRNN) and scaffold hopping methods were used to generate new compounds, which were evaluated by principal components analysis, quantitative estimate of drug-likeness, synthetic accessibility analysis and molecular docking. ADME prediction, molecular docking and molecular dynamics simulations were used to screen candidate compounds and assess their binding affinity and binding stability with mutant IDH1 (mIDH1).ResultsBRNN and scaffold hopping methods generated 3890 and 3680 new compounds, respectively. The molecules generated by the BRNN performed better in terms of molecular diversity, druggability, synthetic accessibility and docking score. From the 3890 compounds generated by the BRNN model, 10 structurally diverse drug candidates with great docking score were preserved. Molecular dynamics simulations showed that the RMSD of the four systems, M1, M2, M3 and M6, remained stable, with local flexibility and compactness similar to the positive drug. The binding free energy results indicated that compound M1 exhibited the best binding properties in all energy aspects and was the best candidate molecule among the 10 compounds.ConclusionIn present study, compounds M1, M2, M3 and M6 generated by BRNN exhibited optimal binding properties. This study is the first attempt to use deep learning to design mIDH1 inhibitors, which provides theoretical guidance for the design of mIDH1 inhibitors.

Therapeutic drug monitoring of imatinib: is there a rationale for also quantifying its active metabolite ?

Therapeutic drug monitoring of imatinib is widely performed to individualize imatinib dosage. While N-desmethyl imatinib is an active metabolite of imatinib, its concentrations are not routinely determined. Imatinib and N-desmethyl imatinib trough plasma concentrations at steady-state were obtained from 295 patients with either chronic myeloid leukemia or gastrointestinal stromal tumor to see whether N-desmethyl imatinib provided additional information. Pharmacokinetic data were analyzed using a nonlinear mixed effect approach. Correlations between several pharmacokinetic metrics of drug exposure were evaluated. The mean value of the N-desmethyl imatinib/imatinib ratio of trough concentrations was 0.31 with half of the values between 0.23-0.37. N-desmethyl imatinib and total (i.e., N-desmethyl imatinib plus imatinib) trough plasma concentrations or area-under-the curve values were closely correlated with imatinib values. The distribution of imatinib or total concentrations between patients requiring imatinib dosage adjustment, or not, were similar. These results do not clearly support routine N-desmethyl monitoring since it does not provide additional information to imatinib data.

The Effects of Having a Child with Cancer on Parental Psychology: A Cross-Sectional Study

Objective: In childhood cancers, parents are affected psychologically as well as children. We aimed to evaluate the effect of childhood cancer type and stage, as well as elapsed time from diagnosis, on the anxiety and stress indicators among parents. Materials and Methods: Patients aged between 0–18 years and diagnosed with cancer who were receiving chemotherapy (0–1 month, 1–6 month, 6–12 month) and completed treatment were included. Parents of those children (mother or father) who agreed to participate this study were also included. The personal information form and three psychological assessment scales (Beck Hopelessness Scale (PSS), Psychological Resilience Scale (PRS), Uncertainty Intolerance Scale (IUS)) were used for assessment of mental health of the parents. Scores of the scales and clinical features of the children with cancer were compared statistically. Results: The study included 84 parents (57 mothers, 27 fathers) and 84 children. The rate of children with solid tumors was 60% (n:50) and 40% of them were metastatic, which means advanced stage. The rate of the children with leukemia was 40% (n:34) and 23% of them were in high-risk group. According to the type (leukemia vs. solid tumors) and stage (high risk/advanced stage vs. others) of the cancer, there was no statistical difference among parents in the psychological scales (p > 0.05). Additionally, results of the psychological scales showed no significant difference between mothers and fathers (p > 0.05). The hopelessness scores are significantly higher among parents whose child’s treatment is terminated compared with those whose active therapy is ongoing, and resilience scores are higher among parents who have less than 1 month since diagnosis of childhood cancer than later periods. Conclusions: The regular assessment of mental health among parents of children with cancer across all the survivorship trajectory: at the time of diagnosis, during active therapy, and after treatment.

Assessment of cytotoxicity of 5-arylaminouracil derivatives

We have previously shown that 5-arylaminouracil derivatives can inhibit HIV-1, herpesviruses, mycobacteria and other pathogens through various mechanisms. The purpose of this study was to evaluate the potential of 5-arylaminouracils and their derivatives against leukemia, neuroblastoma and glial brain tumors. The cytotoxicity of 5-aminouracils with various substituents, as well as their 5’-norcabocyclic and ribo derivatives, was screened against two neuroblastoma cell lines (SH-SY5Y and IMR-32), lymphoblastic cells K-562, promyeoloblastic cells HL-60 and low-passage variants of well-differentiated glioblastoma multiforme (GBM5522 and GBM6138). As a result of assessing the cytotoxicity of the resulting compounds on the above cell lines using the standard MTT test, it was revealed that most of the compounds do not have significant toxicity. However, in the GBM-6138 cell line, 5-(4-isopropylphenylamine)uracil and 5-(4-tert-butylphenylamine)uracil exhibited a dose-dependent toxic effect, with half-maximal inhibition concentrations IC50 of 9 μM and 2.3 μM, respectively. The antitumor activity of compounds of this type has been demonstrated for the first time and can serve as a starting point for further research.

Accessibility of and Barriers to Long-Term Follow-Up Care for Childhood Cancer Survivors

Childhood cancer survivorship programs and long-term follow-up (LTFU) practices are inadequate in most regions of China. To understand the clinician and caregiver perceptions of LTFU care and to identify barriers to adherence to LTFU care in mainland China. This survey study had a 2-phase sequential mixed-methods approach, consisting of a cross-sectional survey followed by semistructured interviews. Participants included oncology clinicians recruited through an educational seminar on LTFU and caregivers recruited through convenience sampling. Data were collected from November 2022 to September 2023. The clinician survey and interview focused on the standards and resources for LTFU care at their practicing institution and barriers to the coordination of LTFU care. For caregivers, the survey and interview focused on their awareness of and participation in LTFU care and their opinions on future LTFU care visits. A total of 101 clinicians (28 [27.7%] male; 73 [72.3%] female; 46 [45.6%] aged >40 to 50 years) completed the survey (response rate: 90.2%) representing 32 institutions from 22 provinces. As for the caregivers' survey, 164 eligible participants (36 [22.0%] male; 128 [78.0%] female) were recruited (response rate: 20.2%). The majority of the caregivers had received a high school or greater education (96 [56.7%]) and were parents of CCSs diagnosed with leukemia (67 [40.9%]), lymphoma or solid tumors (47 [28.7%]), or conditions requiring hematopoietic stem cell transplantation (50 [30.5%]). Most clinicians (74 [73.3%]) reported providing late effects care, yet only 10 (13.5%) had a dedicated follow-up clinic for CCSs. Two-thirds (64 [63.4%]) reported that the LTFU plan for each survivor is solely determined by their clinical judgment. In structured interviews, all doctors admitted to deviating from published guidelines due to challenges in implementing screening recommendations in their settings. Barriers to providing LTFU services included patient-related factors (76 [75.2%]), survivor knowledge deficits (61 [60.4%]), and the absence of dedicated LTFU clinics (61 [60.4%]). Among caregivers responding to the survey, 60 (36.6%) had never heard of late effects. Overall, 22 of 26 caregivers (84.6%) who participated in the interviews were not aware of potential late effects, although 17 (68.0%) could articulate existing conditions and symptoms that their children were experiencing. In this mixed-methods study involving clinicians and caregivers, substantial disparities in the uniformity and accessibility of LTFU in China were observed, suggesting the imperative need for a standardized approach to LTFU care for survivors. This includes advocating for establishment of dedicated clinics, alongside an emphasis on enhanced education and training for both clinicians and caregivers.

Assessment of cancer predisposition syndromes in children with leukemia and solid tumors: germline-genomic profiling and clinical features in a series of cases

Cancer predisposition syndromes (CPS) are a group of genetic disorders that increase the risk of various cancers. Identifying CPS has a significant impact on the treatment plan, screening and follow-up strategy, and genetic counseling of the family. However, in children, it goes underdiagnosed in most clinical setups, especially in low- and middle-income (LMIC) countries. In the present study, we screened 60 pediatric oncology patients for a possible CPS based on pre-defined selection criteria. Six patients met the criteria, three of whom had hematological malignancy, while the remaining three had sarcoma. Whole exome sequencing was performed in the selected patients to confirm the diagnosis. Germline mutation in CPS-related genes was discovered in five of six cases, including novel mutations discovered in two. An adverse outcome was observed in all five patients with underlying cancer predisposition syndrome, with three having relapsed and two having progressive disease. Our study reflects a prevalence of 10% underlying CPS in a limited cohort of patient based on the phenotype-genotype approach in our cohort. Using pre-defined clinical selection criteria, screening can be directed to a high-risk patient cohort with high-pick up rate for CPS. The selection criteria could be utilized in any LMIC-based clinical setup for pediatric cancer patients who may benefit from modification of treatment as well as genetic counseling.

Outcome of radiotherapy for metastatic neuroblastoma

Background. Neuroblastoma (NB) is a prevalent solid extracranial tumor that primarily affects children. It is the third most common type of cancer in children, following leukemia and brain tumors. Aim. The study aimed to discuss the clinical outcomes after adjuvant radiotherapy to the primary site in case of metastatic NB after good response to chemotherapy. Methods. A retrospective clinical-dosimetric study of 25 patients metastatic NB treated with radiotherapy at Baghdad Radiotherapy and Nuclear Medicine Center, at Baghdad Medical City Complex, Baghdad, Iraq. Data collection begin from December 2023 and March 2024. Data were collected retrospectively with review of records. The following variables were studied: sex, age, date of diagnosis, site of primary tumor, site of metastasis, chemotherapy, surgery, RT, RT sites, doses of RT, fractions of RT, recurrence sites, date of relapse and survival outcome for each patient. Follow-up period include look up to metastasis, site of metastasis, recurrence, site of recurrence and survival rates. Results. In relation to sex, males (14, 56%) were more than females (11, 44%). The mean age of NB cases was 45.64±17.6 months. In NB, suprarenal masses were the most common site of primary in 21 (84%) of patients. The most common site of metastasis of NB was bone marrow in 12 (48). The multi sites of recurrence was the commonest presentation in 48%. The relapse-free survival (RFS) was 22.38 months. 5 out of 25 patients were alive whereas 20 (80%) of cases were dead. The median follow-up time was 6 years, and the OS of NB in this study after optimal treatment was 2.46 years (95%CI= 1.705-3.21) for survivors. The MS was 4.84 years. The OS was 6 yrs for those diagnosed at 2017, 2 yrs for those diagnosed at 2018, 1.5 yrs for those diagnosed at 2019, 1.75 yrs for those diagnosed at 2020, 3 yrs for those diagnosed at 2021 and 1.5 yrs for those diagnosed at 2022. There was a significant difference among doses (Log Rank (Mantel-Cox)= 11.425, p=0.044). Conclusions. This study is the first study in Iraq that examines the clinical results of radiotherapy on the primary site in cases of metastatic neuroblastoma following induction chemotherapy. The suprarenal masses of neuroblastoma are the most often occurring main site. The primary sites of metastases for neuroblastoma (NB) are the bone marrow and bones. Timely detection and proactive treatment of NB can improve overall results. Reoccurrence of skeletal issues and the infiltration of bone marrow are frequently observed. There were no significant differences observed in terms of relapse-free survival and overall survival based on factors such as sex, age, location of the main tumor, chemotherapy, radiation treatment, surgery, and radiation therapy dosages.

Targeting cellular plasticity: esculetin-driven reversion of stem cell-like characteristics and EMT phenotype in transforming cells with sequential p53/p73 knockdowns

The intricate interplay of cancer stem cell plasticity, along with the bidirectional transformation between epithelial-mesenchymal states, introduces further intricacy to offer insights into newer therapeutic approaches. Differentiation therapy, while successful in targeting leukemic stem cells, has shown limited overall success, with only a few promising instances. Using colon carcinoma cell strains with sequential p53/p73 knockdowns, our study underscores the association between p53/p73 and the maintenance of cellular plasticity. Morphological alterations corresponding with cell surface marker expressions, transcriptome analysis and functional assays were performed to access stemness and EMT (Epithelial-Mesenchymal Transition) characteristics in the spectrum of cells exhibiting sequential p53 and p73 knockdowns. Notably, our investigation explores the effectiveness of esculetin in reversing the shift from an epithelial to a mesenchymal phenotype, characterized by stem cell-like traits. Esculetin significantly induces enterocyte differentiation and promotes epithelial cell polarity by altering Wnt axes in Cancer Stem Cell-like cells characterized by high mesenchymal features. These results align with our previous findings in leukemic blast cells, establishing esculetin as an effective differentiating agent in both Acute Myeloid Leukemia (AML) and solid tumor cells.

C-Myc alone is enough to reprogram fibroblasts into functional macrophages

BackgroundMacrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases.MethodsThe composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac.ResultsHere we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models.ConclusionsOur findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining “off-the-shelf” macrophages for anti-cancer immunotherapy.

A - 58 Grit and Resilience Predict Emotional Functioning in Pediatric Cancer Survivors

Abstract Objective Grit—one’s “perseverance and passion for long-term goals” (Duckworth et al., 2007)—is distinct from resilience, one’s ability to bounce back after negative events. In healthy populations, both promote emotional well-being and quality-of-life (Datu et al., 2019; Sharkey et al., 2017). Limited research has investigated how grit and resilience affect emotional functioning after pediatric cancer. We hypothesized resilience would mediate grit’s effects on emotional functioning in pediatric cancer survivors. Methods Our clinically referred sample of 214 pediatric cancer survivors ages 4–25 years was predominantly lower- to upper-middle class (73%) and racially diverse (Caucasian = 53%, Hispanic = 25%, Black = 12%). We administered the parent-report Behavior Assessment System for Children, Third Edition (BASC-3; variables: Resiliency, Anxiety, Depression), parent-report Short Grit Scale, and self-report BASC-3 (variables: Sense of Inadequacy, Locus of Control). Multiple regression and simple mediation analyses were conducted. Results Overall, the sample demonstrated average grit and resilience. Leukemia and brain tumor survivors demonstrated greater grit and resilience than survivors of other cancers. Grit predicted Anxiety (p = 0.026), Depression (p = 0.001), and Sense of Inadequacy (p ≤ 0.001). Resiliency had a significant indirect effect on grit’s prediction of Anxiety (β = −0.107, 95% CI [−0.206, −0.011]) and Depression (β = −0.192, 95% CI [−0.271, −0.117]), but not Sense of Inadequacy (β = −0.055, 95% CI [−0.200, 0.102]). Conclusion Higher levels of grit predicted better emotional outcomes in pediatric cancer survivors. Grit affected anxiety and depression in this sample via resiliency. Exploratory analyses regarding cancer type and age at diagnosis will be described. Findings support the need for further research on “positive neuropsychology” factors affecting neuropsychological outcomes in pediatric cancer survivors.

Center-concave nanosheets of core-shell WO3@Prussian blue based handheld microchip-devices for ultrasensitive lysine determination

Lysine is one of the essential amino acids for human body, and its imbalance is a major cause to anemia, aging process, leukemia cell proliferation and tumor growth. Therefore, its monitoring is dominative to the prevention the disease progress and guidance to the clinical treatment. However, traditional in-hospital detection methods, such as colorimetry and fluorometric, often suffer the disadvantages of high cost and long time-consuming. These drawbacks show a difficulty in the home-in and dairy monitoring for the lysine regulation in body. In this study, we have proposed an ultrasensitive microchip-based portable device to achieve the onsite and precise determination of lysine within only 10 s. This microchip was functionalized through constructing a center-concave nanosheet of core-shell WO3@Prussian blue (WO3@PB) to remarkably strengthen the generation and transfer of the detection signal. In this special architecture, the core WO3 nanosheet can be exposed at the center region of this nanocomposite to effectively promote the enzymatic oxidation, while the PB shell enables to strongly reduce the H2O2 produced by the enzymatic reaction. Under above synergetic effects, a handheld device was designed to support the plug-and-play microchip, which performed an outstanding accuracy for the lysine detection in blood.

Effectiveness of Nutrition Support Team Intervention in Pediatric Patients with Cancer.

Malnutrition in children with cancer is associated with poor prognosis. This study aimed to determine whether nutritional support team (NST) interventions prevent adverse events and improve the nutritional status in pediatric patients admitted for cancer treatment. This was a historical cohort study of pediatric patients with acute lymphocytic leukemia, acute myeloid leukemia, neuroblastoma, or brain tumor who received chemotherapy or underwent hematopoietic stem cell transplantation. Patients admitted between June 2013 and October 2014 were classified into the intervention group. Those admitted between January 2011 and December 2012 were classified into the control group. We created a homogeneous probability model using the inverse probability of treatment weighting method, and compared outcomes. A total of 75 patients were included in the study (38 and 37 in the intervention and control groups, respectively). The intervention group had significantly fewer incidents of nothing by mouth (nil per os [NPO]) (p=0.037) and days of NPO (p=0.046) than the control group. There was no significant difference between the intervention and control groups regarding the change in body mass index z-score between admission and discharge (p=0.376). NST interventions for children with cancer were associated with a reduction in the number of NPO occurrences and NPO days. These findings suggest that NST interventions contribute to continued oral intake.

Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.

Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors.

Silencing of tropomodulin 1 inhibits acute myeloid leukemia cell proliferation and tumor growth by elevating karyopherin alpha 2–mediated autophagy

Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.

Reduced anti-Müllerian hormone levels in males with inherited bone marrow failure syndromes.

Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46-18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3-14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2-17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57-14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09-13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57-14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

Statistical Analysis of Features for Detecting Leukemia

In this age of digital microscopy, image processing, statistical analysis, categorization, and systems for decision-making have become essential tools for medical diagnostics research. By visualizing and analyzing images, clinicians can identify anomalies in intracellular structure. Leukemia is a cancerous condition marked by an unregulated increase in aberrant white blood cells (WBCs). Recognizing acute leukemia tumor cells in blood smear images (BSI) is a challenging assignment. Image segmentation is regarded as the most significant step in the automated identification of this disease. The innovative concavity-based segmentation algorithm is employed in this study to segment WBC in sub-images from the ALLIDB2 database. The concave endpoints and elliptical features are used in the segmentation step of convex-shaped cell images. The procedure involves the extraction of contour evidence, which detects the visible section of each object, and contour estimation, which corresponds to the final object’s contours. Following the identification of the cells and their internal structure by concavity-based segmentation, the cells are categorized based on their morphological and statistical features. The method was evaluated using a public dataset meant to test classification and segmentation approaches. The statistical tool SPSS is used to independently check the significance of derived features. For classification, significant features are passed into machine learning techniques such as support vector machines (SVM), k-nearest neighbor (KNN), neural networks (NN), decision trees (DT), and Nave Bayes (NB). With an AUC of 98.9% and a total accuracy of 95%, the neural network model performed better. We advocate using the neural network model to identify acute leukemia cells based on its accuracy.

Study of Mortality Rate and its Causes among Egyptian Children and Adolescents with Cancer

Abstract Background There is little evidence about the burden of childhood cancers in Egypt. Knowledge about the current disease burden of childhood cancers is crucial to priorities cancer control plans and improve survival. Objective To describe the frequency of deaths among children diagnosed with cancer in the last 10 years. Patients and Methods This retrospective descriptive study was conducted in Pediatric Hematology /Oncology Unit, Children's Hospital, Ain Shams University. The data of 500 patients was collected from the database in the period from 1st September 2011 to 30th September 2021. The study included 500 Children less than 18 years diagnosed as solid and hematological malignancies. Results The median age of the included patients was 4.25 years, males represented 54.4%. The most common etiology of malignancies among the included patients were: acute lymphoblastic leukemia (31.8%) and acute myeloid leukemia (714.6%). Death was evident in 71.4% of the included patients. Among the dead cases 106 (74.12%) had late death; that occurred 5 years or more after diagnosis and 37(25.4%) had early death; that occurred within 30 days after diagnosis of the first neoplasm. The higher mortality was reported among acute lymphoblastic leukemia (52; 36.4%), acute myeloid leukemia (28; 19.6%), neuroblastoma (13; 9.1%) and brain tumors (10; 7.0%). Comparison between living and dead childhood cancer patients as regards the demographic and clinical data showed no significant difference regarding; age, gender, and residence (P-value= 0.591, 0.122 &amp; 0.077, respectively). Relapse was significantly increased among dead cases representing 32.9% (P-value= 0.000). Conclusion In our institute, childhood cancer patients’ mortality rate was 28.5% in the last 10 years. Early death occurred in (25.8%) among them; infection was the leading cause of death, while primary malignancy was the main cause of death among those who died late, which is almost comparable with international studies. Furthermore, the overall survival of our childhood with cancer was (67.30%) at 5 years from diagnosis. This is relatively better than the previous published Egyptian data and reaching international figures.

Condensate-Promoting ENL Mutation Drives Tumorigenesis In Vivo Through Dynamic Regulation of Histone Modifications and Gene Expression.

Gain-of-function mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment. Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.

An Extended Flow Cytometry Evaluation of ex Vivo Expanded NK Cells Using K562.Clone1, a Feeder Cell Line Manufactured in Brazil

Natural killer (NK) cells play a crucial role in the immune system's response against cancer. However, the challenge of obtaining the required quantity of NK cells for effective therapeutic response necessitates the development of strategies for their ex vivo expansion. This study aimed to develop a novel feeder cell line, K562.Clone1, capable of promoting the ex vivo expansion of NK cells while preserving their cytotoxic potential. he K562 leukemic cell line was transduced with mbIL-21 and 4-1BBL proteins to generate K562.Clone1 cells. NK cells were then co-cultured with these feeder cells, and their expansion rate was monitored over 14 days. The cytotoxic potential of the expanded NK cells was evaluated against acute myeloid leukemia blasts and tumor cell lines of leukemia and glial origin. Statistical analysis was performed to determine the significance of the results. The K562.Clone1 co-cultured with peripheral NK showed a significant increase in cell count, with an approximate 94-fold expansion over 14 days. Expanded NK cells demonstrated cytotoxicity against the tested tumor cell lines, indicating preservation of their cytotoxic characteristics. Additionally, the CD56, CD16, inhibitory KIRs, and activation receptors were conserved and present in a well-balanced manner. The study successfully developed a feeder cell line, K562.Clone1, that effectively promotes the expansion of NK cells ex vivo while maintaining their cytotoxic potential. This development could significantly contribute to the advancement of NK cell therapy, especially in Brazil.