METHODS: A total of 25 CLL patients and 25 normal individuals were recruited in this study. The methylation status of ADAM12 was determined using Methylation-Specific PCR (MSP); whereas, DNA sequencing method was applied for validation of the MSP results.
RESULTS: Among CLL patients, 12 (48%) were partially methylated and 13 (52%) were unmethylated. Meanwhile, 5 (20%) and 20 (80.6%) of healthy individuals were partially methylated and unmethylated, respectively. There was a statistically significant association between the status of methylation at ADAM12 and the presence of CLL (p=0.037).
CONCLUSION: The aberrant methylation of ADAM12 found in this study using MSP assay may provide new exposure to CLL that may improve the gaps involved in genetic epigenetic study in CLL.
CASE REPORT: Here we report a case of a 39-year-old lady, with an incidental finding of hyperleukocytosis (white blood cells count: 139.2 x 109/L). Her peripheral blood film revealed 36% of blasts and a bone marrow aspiration showed 53% of blasts. Immunophenotyping showed a population of blasts exhibiting positivity of two lineages, myeloid lineage and B-lymphoid lineage with strong positivity of CD34 and terminal deoxynucleotidyl transferase (Tdt). A conventional karyotyping revealed the presence of Philadelphia chromosome. She was diagnosed with MPAL with t(9,22), BCR ABL1, which carried a poor prognosis. She was treated with acute lymphoblastic leukaemia (ALL) chemotherapy protocol coupled with a tyrosine kinase inhibitor and was planned for an allogeneic stem cells transplant.
CONCLUSION: This MPAL case was diagnosed incidentally in an asymptomatic patient during medical check-up. We highlight this rare case report to raise the awareness about this rare disease. Understanding the pathogenesis of the disease with the underlying genes responsible for triggering the disease, uniform protocols for diagnosis and targeted treatment will help for proper management of these patients.
CASE REPORT: Herein is an acute promyelocytic leukemia case of a 22-year-old young pregnant woman who had various social problems. The patient was diagnosed with acute promyelocytic leukemia in her the second trimester of her first pregnancy.Management and outcome: She was treated with all-trans-retinoic acid with idarubicin and successfully delivered a healthy baby. She completed induction with idarubicin but defaulted her all-trans-retinoic acid, 6-mercaptopurine and methotrexate maintenance. She relapsed after one year and was salvaged with all-trans-retinoic acid high dose cytarabine and arsenic trioxide. She went into remission and had autologous stem cells collected and was planned for an autologous stem cell transplant but she defaulted. She relapsed when she was pregnant with her second baby during her third trimester (29+weeks) 10 months later. Salvage chemotherapy with arsenic trioxide, all-trans-retinoic acid and idarubicin was given. Patient underwent an emergency lower segment caesarian section at 31 weeks of pregnancy due to abnormal fetal cardiotocography. A healthy baby was delivered.
DISCUSSION: This drug regimen is controversial during pregnancy owing to the teratogenic effects and fatal retinoic acid syndrome especially in early gestation. In this case, patient was started the induction therapy of all-trans-retinoic acid treatment at her second trimester during her first pregnancy.
CONCLUSION: Our lady demonstrated the possibility of using all-trans-retinoic acid and arsenic trioxide and chemotherapy during second and third trimester with successful pregnancy outcomes.
MATERIALS AND METHODS: Cardiovascular risk factors (CRFs) were estimated using the 30-year Framingham Risk Score in 73 childhood leukemia survivors (median age: 25; median years from diagnosis: 19) and 78 healthy controls (median age: 23). Radial arterial stiffness was measured using pulse wave analyzer, while endothelial activation markers were measured by soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). Retinal fundus images were analyzed for central retinal artery/vein equivalents (CRAE/CRVE) and arteriolar-venular ratio (AVR).
RESULTS: cALL survivors had higher CRF (P<0.0001), arterial stiffness (P=0.001), and sVCAM-1 (P=0.007) compared with controls. Survivors also had significantly higher CRVE (P=0.021) while AVR was significantly lower (P=0.026) in survivors compared with controls, compatible with endothelial dysfunction. In cALL survivors with intermediate risk for CVD, CRAE, and AVR are significantly lower, while sVCAM-1 and sICAM-1 are significantly higher when compared with survivors with low CVD risk after adjusting with covariates (age, sex, and smoking status).
CONCLUSIONS: cALL survivors have an increased risk of CVD compared with age-matched peers. The survivors demonstrated microvasculopathy, as measured by retinal vascular analysis, in addition to physical and biochemical evidence of endothelial dysfunction. These changes predate other measures of CVD. Retinal vessel analysis may be utilized as a robust screening tool for identifying survivors at increased risk for developing CVD.
OBJECTIVE: To assess, by diffusion tensor imaging, microstructural integrity of white matter in paediatric patients with acute lymphoblastic leukaemia (ALL) following intrathecal and intravenous chemotherapy.
MATERIALS AND METHODS: Eleven children diagnosed with de novo ALL underwent MRI scans of the brain with diffusion tensor imaging (DTI) prior to commencement of chemotherapy and at 12 months after diagnosis, using a 3-tesla (T) MRI scanner. We investigated the changes in DTI parameters in white matter tracts before and after chemotherapy using tract-based spatial statistics overlaid on the International Consortium of Brain Mapping DTI-81 atlas. All of the children underwent formal neurodevelopmental assessment at the two study time points.
RESULTS: Whole-brain DTI analysis showed significant changes between the two time points, affecting several white matter tracts. The tracts demonstrated longitudinal changes of decreasing mean and radial diffusivity. The neurodevelopment of the children was near compatible for age at the end of ALL treatment.
CONCLUSION: The quantification of white matter tracts changes in children undergoing chemotherapy showed improving longitudinal values in DTI metrics (stable fractional anisotropy, decreasing mean and radial diffusivity), which are incompatible with deterioration of microstructural integrity in these children.
MATERIALS AND METHODS: We searched for FL-LP in our institution from 2000 to 2018 and characterised the neoplastic cells by flow cytometry, immunohistochemistry and fluorescence in situ hybridization. Thirteen (6.1%) of 212 FL cases were FL-LP, all de novo neoplasms. The leukaemic cells were small in 12 cases and large in one. All had concurrent FL, mostly (92%; 12/13) low-grade. The single case with large leukaemic cells had a concurrent primary splenic low-grade FL and a double-hit large B-cell lymphoma in the marrow.
RESULTS: CD10 was expressed in the leukaemic cells in 38% (5/13) cases by flow cytometry and in 77% (10/13) cases in tumours (p= 0.0471). IGH/BCL2 reciprocal translocation was identified in 85% (11/13) cases. Most patients were treated with chemotherapy. In a median follow-up time of 36 months, nine patients were in complete remission. The 2- and 5-year survival rates were at 100% and 83%, respectively. In this study, we characterised a series of de novo FL-LP in Taiwan. All patients had concurrent nodal and/or tissue tumours, which might suggest that these patients seek medical help too late.
CONCLUSION: The lower CD10 expression rate by flow cytometry than by immunohistochemistry might be due to different epitopes for these assays. Alternatively, loss of CD10 expression might play a role in the pathogenesis of leukaemic change. The clinical course of FL-LP could be aggressive, but a significant proportion of the patients obtained complete remission with chemotherapy.
METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species.
RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC).
CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.
METHODS: A parallel RCT was conducted in two hospitals in Malaysia, where 129 CML patients were randomised to MMS or control (usual care) groups using a stratified 1:1 block randomisation method. The 6-month MMS included three face-to-face medication use reviews, CML and TKI-related education, two follow-up telephone conversations, a printed information booklet and two adherence aids. Medication adherence (primary outcome), molecular responses and health-related quality of life (HRQoL) scores were assessed at baseline, 6th and 12th month. Medication adherence and HRQoL were assessed using medication possession ratio and the European Organisation for Research and Treatment in Cancer questionnaire (EORTC_QLQ30_CML24) respectively.
RESULTS: The MMS group (n = 65) showed significantly higher adherence to TKIs than the control group (n = 64) at 6th month (81.5% vs 56.3%; p = 0.002), but not at 12th month (72.6% vs 60.3%; p = 0.147). In addition, a significantly higher proportion of participants in the MMS group achieved major molecular response at 6th month (58.5% vs 35.9%; p = 0.010), but not at 12th month (66.2% vs 51.6%; p = 0.092). Significant deep molecular response was also obtained at 12th month (24.6% vs 10.9%; p = 0.042). Six out of 20 subscales of EORTC-QLQ30-CML24 were significantly better in the MMS group.
CONCLUSIONS: The MMS improved CML patients' adherence to TKI as well as achieved better clinical outcomes.
TRIAL REGISTRATION: Clinicaltrial.gov (ID: NCT03090477).
METHOD AND ANALYSIS: We will conduct a systematic review of randomised controlled trials that investigate the effect and safety of GO for the treatment of patients with AML. We will search for any eligible articles from selected electronic databases. We will follow the Preferred Reporting Items for Systematic reviews and Meta-Analysis for study selection and reporting. We will use The Cochrane Handbook for Systematic Reviews of Interventions and Meta-Analysis as guidance to select eligible studies. All data will be extracted using a standardised data extraction form.
ETHICS AND DISSEMINATION: There was no patient involved in this study, therefore no ethical consideration is needed. The findings of this study will be disseminated in a peer-reviewed journal and any relevant conference presentation.
PROSPERO REGISTRATION NUMBER: CRD42019123286.
METHODS: Transfection of ANXA1 siRNA was conducted to downregulate ANXA1 expression in Jurkat, K562 and U937 cells. Apoptosis and cell cycle assays were conducted using flow cytometry. Western blot was performed to evaluate ANXA1, caspases and Bcl-2 proteins expression. Phagocytosis was determined using hematoxylin and eosin staining.
RESULTS: The expression of ANXA1 after the knockdown was significantly downregulated in all cell lines. Genistein significantly induced apoptosis associated with an upregulation of procaspase-3, -9, and - 1 in Jurkat cells. The Bcl-2 expression showed no significant difference in Jurkat, K562 and U937 cells. Treatment with phytoestrogens increased procaspase-1 expression in Jurkat and U937 cells while no changes were detected in K562 cells. Flow cytometry analysis demonstrated that after ANXA1 knockdown, coumestrol and genistein caused cell cycle arrest at G2/M phase in selected type of cells. The percentage of phagocytosis and phagocytosis index increased after the treatment with phytoestrogens in all cell lines.
CONCLUSION: Phytoestrogens induced cell death in ANXA1-knockdown leukemia cells, mediated by Annexin A1 proteins. Graphical abstract.