Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and ...clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.
An acute promyelocytic leukemia (APL) patient not demonstrating the retinoic acid receptor α (RARA) translocation is rare. A 76-year-old man was diagnosed with myelodysplastic syndrome (MDS). After a ...year, abnormal promyelocytes were detected with pancytopenia and disseminated intravascular coagulopathy. Morphologically, the patient was diagnosed with APL; however, a genetic examination failed to detect RARA translocation. Thereafter, whole-genome sequencing revealed an NRAS missense mutation c.38 G>A (p.G13D). This mutation was not detected in posttreatment bone marrow aspirate, despite residual MDS. Few reports are available on similar cases. Furthermore, the NRAS c.38 G>A mutation may be a novel pathogenic variant exacerbating RARA translocation-negative acute promyelocytic-like leukemia.
Although ATRA represents a successful differentiation therapy for APL, it is largely ineffective for non-APL AMLs. Hence combination therapies using an agent targeting ATRA-regulated molecules that ...drive cell differentiation/arrest are of interest. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, we now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest. Roscovitine upregulated ATRA-induced nuclear c-Raf phosphorylation at S259 and S289/296/301. Nuclear c-Raf interacted with RB protein and specifically with pS608RB, the hinge region phosphorylation controlling E2F binding and cell cycle progression. ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation. Part of this mechanism reflects promoting cell cycle arrest via ATRA-induced upregulation of the p27 Kip1 CDKI. Roscovitine also enhanced the ATRA-induced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular: SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1. Akin to c-Raf, Lyn bound to RB, specifically to pS608RB. Lyn-pS608RB association was greatly diminished by ATRA and essentially lost in ATRA plus roscovitine treated cells. Interestingly Lyn-KD enhanced such ATRA-induced nuclear signaling and differentiation and made roscovitine more effective. ATRA thus mobilized traditionally cytoplasmic signaling molecules to the nucleus where they drove differentiation which were further enhanced by roscovitine.
An acute promyelocytic leukemia (APL) patient not demonstrating the retinoic acid receptor α (RARA) translocation is rare. A 76-year-old man was diagnosed with myelodysplastic syndrome (MDS). After a ...year, abnormal promyelocytes were detected with pancytopenia and disseminated intravascular coagulopathy. Morphologically, the patient was diagnosed with APL; however, a genetic examination failed to detect RARA translocation. Thereafter, whole-genome sequencing revealed an NRAS missense mutation c.38G>A (p.G13D). This mutation was not detected in posttreatment bone marrow aspirate, despite residual MDS. Few reports are available on similar cases. Furthermore, the NRAS c.38G>A mutation may be a novel pathogenic variant exacerbating RARA translocation-negative acute promyelocytic-like leukemia.
Background: India ranked 2nd in the world with over 47 per cent of its children exhibiting malnutrition. The sub-schemes of ICDS are supplementary nutrition, non-formal preschool education, ...immunization, health check-up and referral services. Attainment of ICDS programme goals depends upon the effectiveness of Anganwadi workers. This study was conducted with the objectives to know the job satisfaction of Anganwadi workers. Objectives: 1) To assess the level of Job Satisfaction of Anganwadi workers. 2) To find out any significant relationship of Job Satisfaction with Age, Educational qualifications and Experience Methodology: A cross sectional study was conducted among Anganwadi workers of Thrissur District. Total 120 Anganwadi workers (AWWs) were selected by convenience sampling. The data was collected after obtaining consent from the participants using semi structured questionnaire. Data entry was performed using Google Forms and was analysed using SPSS. Results: The results showed that, 21.7% of AWWs possessed low satisfaction, 45% with moderate satisfaction and 33.3% with high satisfaction. Among study participants, 48.3% were BPL and 51.7% were APL .65% have completed SSLC, 20.0% with Pre-degree,12.5% with Degree and 2.5% with Postgraduation. It was found that, socio-economic status and education have a significant relationship with job satisfaction. Whereas, age, family size, experience and training of the respondents found to be non-significant with job satisfaction of Anganwadi workers. Conclusion: Nearly one-fourth of AWWs had low satisfaction with their job and less than half of the respondents were extremely satisfied. The job satisfaction can directly influence their work performance.
Epigenomic alterations have been associated with both pathogenesis and progression of cancer. Here, we analyzed the epigenome of two high-risk APL (hrAPL) patients and compared it to non-high-risk ...APL cases. Despite the lack of common genetic signatures, we found that human hrAPL blasts from patients with extremely poor prognosis display specific patterns of histone H3 acetylation, specifically hyperacetylation at a common set of enhancer regions. In addition, unique profiles of the repressive marks H3K27me3 and DNA methylation were exposed in high-risk APLs. Epigenetic comparison with low/intermediate-risk APLs and AMLs revealed hrAPL-specific patterns of histone acetylation and DNA methylation, suggesting these could be further developed into markers for clinical identification. The epigenetic drug MC2884, a newly generated general HAT/EZH2 inhibitor, induces apoptosis of high-risk APL blasts and reshapes their epigenomes by targeting both active and repressive marks. Together, our analysis uncovers distinctive epigenome signatures of hrAPL patients, and provides proof of concept for use of epigenome profiling coupled to epigenetic drugs to 'personalize' precision medicine.
Acute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia in childhood. It usually presents with a characteristic coagulopathy. The aim of the study was to ...determine the extent and outcome of this coagulation disorder.
This prospective observational study was conducted at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, and included PML:RAR-α (Promyelocytic Leukemia-Retinoic Acid Receptor-α) positive APL cases. At presentation, all patients were assessed with coagulation parameters and followed up clinically and hematologically while treated with ATRA (all-trans-retinoic acid)-based chemotherapy. The presence of disseminated intravascular coagulation (DIC) was determined using the DIC scoring system of the International Society on Thrombosis and Hemostasis (ISTH).
Among 20 APL cases, the mean DIC score was 5.75 ± 0.6. DIC was detected in 90% (n = 18/20) of the patients. The incidence of fatal thrombo-hemorrhagic complications was 15% (n = 3/20). Though hemorrhagic complications are common, thrombosis may also occur in pediatric APL.
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