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Pentoxifylline Added to Steroid Window Treatment Phase Modified Apoptotic Gene Expression in Pediatric Patients With Acute Lymphoblastic Leukemia.

Pentoxifylline is a xanthine that possesses antitumor properties and that can induce higher apoptosis in the leukemic cells of pediatric patients with acute lymphoblastic leukemia (ALL) during treatment with prednisone. We conducted a phase 1 pilot, controlled, randomized trial to evaluate the gene expression modified by pentoxifylline during the steroid window of induction to remission phase in patients newly diagnosed with ALL. Experimental and control treatments induced broad changes in the gene expression profile. Patients who received just prednisone upregulated 377 and downregulated 344 genes, in contrast with patients treated with the experimental treatment (combination of prednisone and pentoxifylline), who demonstrated upregulation of 1319 and downregulation of 1594 genes. The most important genes modified in this pathway are those with proapoptotic activity, the majority of these overexpressed. Thus, the addition of pentoxifylline to the treatment with prednisone during steroid window in patients with ALL modified the gene expression profile and changed different signal pathways of the leukemic cell. The combination of both drugs represents a therapeutic alternative for potentiating antileukemic therapy.

Correlation of Calcium and Magnesium Levels in the Biological Samples of Different Types of Acute Leukemia Children.

Acute leukemia (AL) is a common childhood malignancy. It is clinically and morphologically heterogeneous. The present work was intended to estimate the concentration of calcium (Ca) and magnesium (Mg) in serum and whole blood samples of children having AL 1- to 5- and 6- to 10-year-old children age group was chosen of both genders. Healthy children of the same age group were selected as controls for comparative study. For sample pretreatment, a microwave-assisted acid digestion (MAD) was carried out, to assess the concentration of Ca and Mg in biological samples of AL children. The MAD method was validated by analyzing Clinchek® Control certified samples of whole blood and serum. Ca and Mg were analyzed in the digested samples by flame atomic absorption spectrometry (FAAS). The results showed significantly higher concentration of Ca, whereas lower contents of Mg in the serum and whole blood of AL children in both genders, as compared to healthy subjects. The data provide assistance to physicianclinicians and other professional staffs to investigate the imbalance of minerals in biological samples of AL children.

Transformation of T-Cell Acute Lymphoblastic Lymphoma to Peripheral T-Cell Lymphoma A Report of Two Cases.

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Physical training interventions for children and teenagers affected by acute lymphoblastic leukemia and related treatment impairments.

A decreased physical fitness has been reported in patients and survivors of acute lymphoblastic leukemia (ALL). This is influenced by the negative effects of the disease and by the treatments of childhood cancer. In the past, children were advised to recover in bed, and to take as much relax as possible. Nowadays, it is considered that too much immobility may result in a further decrease of physical fitness and functioning. Exercise training for ALL children has frequently been reported to improve physical fitness and the well-being of the children, since it prevents the negative effects of a sedentary life-style, such as obesity and a poor skeletal health. In recent years, different studies and protocols on this subject has become available for children and young adults with cancer, both during and after treatment. The efficacy of recent physical exercise training interventions, that act on several ALL impairments in children such as skeletal, musculoskeletal, neuromuscular, cardiopulmonary and cardiovascular systems, fatigue, body balance disorders and metabolism alterations have been examined. These side effects might be prevented or significantly reduced by introducing a physical exercise program during or shortly after cancer treatment. Several interventions are discussed and presented for each impairment, reducing their level caused by the disease and thus suggesting the importance of physical training activity in ameliorating the children quality of life.

Computer-Aided Diagnosis of Acute Lymphoblastic Leukaemia.

Leukaemia is a form of blood cancer which affects the white blood cells and damages the bone marrow. Usually complete blood count (CBC) and bone marrow aspiration are used to diagnose the acute lymphoblastic leukaemia. It can be a fatal disease if not diagnosed at the earlier stage. In practice, manual microscopic evaluation of stained sample slide is used for diagnosis of leukaemia. But manual diagnostic methods are time-consuming, less accurate, and prone to errors due to various human factors like stress, fatigue, and so forth. Therefore, different automated systems have been proposed to wrestle the glitches in the manual diagnostic methods. In recent past, some computer-aided leukaemia diagnosis methods are presented. These automated systems are fast, reliable, and accurate as compared to manual diagnosis methods. This paper presents review of computer-aided diagnosis systems regarding their methodologies that include enhancement, segmentation, feature extraction, classification, and accuracy.

Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.

Prognostic Value of CD95, Active Caspase-3, and Bcl-2 Expression in Adult Patients with De Novo Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is an aggressive malignant disease with high mortality rates in adults. The expression levels of CD95, active caspase-3, and Bcl-2 were determined in 111 patients with de novo acute lymphoblastic leukemia (ALL) and correlated with overall survival (OS) and disease-free survival (DFS). The immunophenotyped ok leukemia and the expression of CD95, active caspase-3, and Bcl-2, were determined by flow cytometry. Apoptotic variables were correlated by Spearman test, and survival by Kaplan-Meier method. Log-rank test was used to compare survival curves. From a total of 111 patients, 56 cases were B-ALL, 16 T-ALL, 16 B-ALLCD33 The prognosis of ALL in adults is influenced by the expression levels of Bcl-2, active-caspase-3, and CD95.

Development and relative validation of a food frequency questionnaire for French-Canadian adolescent and young adult survivors of acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (cALL) experience cardiometabolic and bone complications after treatments. This study aimed at developing and validating an interview-administrated food frequency questionnaire (FFQ) that will serve to estimate the impact of nutrition in the development of long-term sequalea of French-Canadian cALL survivors. The FFQ was developed to assess habitual diet, Mediterranean diet score, nutrients promoting bone health and antioxidants. It was validated using a 3-day food record (3-DFR) in 80 cALL survivors (50% male) aged between 11.4 and 40.1 years (median of 18.0 years). Reproducibility was evaluated by comparing FFQs from visit 1 and 2 in 29 cALL survivors. When compared to 3-DFR, the mean values for macro- and micronutrient intake were overestimated by our FFQ with the exception of lipid-related nutrients. Correlations between nutrient intakes derived from the FFQs and the 3-DFRs showed moderate to very good correlations (0.46-0.74). Intraclass correlation coefficients assessing FFQ reproducibility ranged from 0.62 to 0.92, indicating moderate to good reliability. Furthermore, classification into quartiles showed more than 75% of macro- and micronutrients derived from FFQs 1 and 2 classified into the same or adjacent quartile. Overall, our results support the reproducibility and accuracy of the developed FFQ to appropriately classify individuals according to their dietary intake. This validated tool will be valuable for future studies analyzing the impact of nutrition on cardiometabolic and bone complications in French-speaking populations.

Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission An analysis by the Acute Leukemia Working Party of the EBMT.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs). We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph ALL in molecular remission, treated between 2007 and 2014. In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P 0.69), while overall survival rates were 70%, 70% and 69% (P 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio HR, 1.5, P 0.12) and URD-HSCT (HR, 1.6, P 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)-based regimens was associated with reduced risk of relapse (HR, 0.65, P 0.02) and overall mortality (HR, 0.67, P 0.01). In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph ALL.

Changes in pediatric DXA measures of musculoskeletal outcomes and correlation with quantitative CT following treatment of acute lymphoblastic leukemia.

We previously reported significant gains in pQCT measures of tibia trabecular bone mineral density (BMD) and cortical structure following completion of therapy in children and adolescents with acute lymphoblastic leukemia (ALL). The objective of this study was to examine changes in DXA measures used in clinical practice and expressed as Z-scores using robust national reference data. Children and adolescents, ages 5 to 18 years were enrolled within 2 (median 0.8) years of completing ALL therapy. DXA total-body less-head bone mineral content (TBLH-BMC), and spine, total hip, femoral neck, and 13rd radius areal BMD (aBMD) were assessed in 45 participants at enrollment and 12-months later. Linear regression models examined correlates of changes in DXA Z-scores. Changes in DXA outcomes were compared to changes in tibia pQCT trabecular and cortical volumetric BMD (vBMD) and cortical area. At enrollment, DXA TBLH-BMC, spine and radius aBMD Z-scores were not significantly reduced in ALL survivors however, total hip median -0.74 (IQ range -1.51 to -0.04) and femoral neck -0.51 (-1.24 to 0.14) aBMD Z-scores were lower (both p < 0.01) compared to reference data. DXA Z-scores at all skeletal sites increased over 12 months. Despite improvement, total hip Z-score remained lower at -0.55 (-1.05 to 0.18). The increases in TBLH-BMC, total hip and femoral neck aBMD Z-scores were more pronounced in those enrolled within 6 months of completing ALL therapy, compared to those enrolled at >6 months. Gains in TBLH-BMC, total hip, femoral neck and radius aBMD Z-scores were significantly associated with gains in tibia cortical area Z-scores (R 0.56 to 0.67, p ≤ 0.001). Changes in TBLH and proximal femur sites were associated with gains in trabecular vBMD Z-scores (R 0.37 to 0.40 p ≤ 0.01) these associations were not significant when adjusted for gains in cortical area. In summary, gains in DXA measures were most pronounced in total hip and femoral neck following ALL therapy. The gains in all DXA measures, with the exception of lumbar spine, reflected gains in cortical area. Overall, ALL survivors demonstrate skeletal recovery following completion of therapy a small sub-group continue to demonstrate deficits and benefit from continued observation to ensure improvement over time.

Fungal infections in hematopoietic stem cell transplantation in children at a pediatric childrens hospital in Argentina.

Our primary objective was to describe the incidence of proven or probable invasive fungal infections (IFIs), a devastating complication of hematopoietic stem cell transplant (HSCT), in HCST in a middle-income country. Secondary objectives were to describe factors associated with IFIs and outcomes. In this single center retrospective study, pediatric patients who underwent a first allogeneic or autologous HSCT from 1998 to 2016 were included. Of the 251 HSCT recipients 143 transplants were allogeneic and 108 were autologous. Overall, 23 (9%) experienced an IFI, mostly due to yeasts (83%). IFIs were more common in allogeneic HSCT (18143, 13%) than in autologous HSCT (5108, 5% P .045). Of the 23 patients with IFIs, 14 (61%) died, but only 1 directly from IFI (pulmonary aspergillosis). Overall survival at 3 years was 0.42 ± 0.11 in patients with IFIs and 0.60 ± 0.37 in those without IFIs (P .049). In Argentina, IFIs during HSCT are common. Recipients of allogeneic HSCT are at higher risk, and IFI is associated with reduced overall survival. Future work should focus on interventions to reduce and improve IFI outcomes in children undergoing transplants in low- and middle-income countries.

Hospital Based Psychosocial Support Program for Children with ALL and their Families A Comprehensive Triads Perspective.

To elucidate potential target areas of intervention and mechanisms for implementation of intervention for children with cancer during the treatment phase. Focused group discussion (FGDs) served as a primary source of providing phenomenal perspectives to explore the key objective. Eight focus groups of 45-60 min each were held with 5-9 members in each discussion. The participants were either patients, their caregivers or health care providers. The focus group audio recordings were professionally transcribed after all identifiers were removed. Employing a constructivist paradigm with a phenomenological approach, also known as emergent-systematic focus group design the study reported on families experiences of childhood cancer as construction of objective reality. Investigator triangulation method was adopted to ensure trustworthiness. Using constant comparison analysis, multistage process analysis was done which resulted in 849 codes, 32 subthemes, 20 themes and 5 domains. A total of 64 participants participated 4 FGDs with parents of children with ALL (n 31) 1 FGD with professionals working in the field of cancer (n 10) and 3 FGDs with children with ALL (n 23). Participants mean age at the time of study was 10 y (3.3) for children 37 y (4.93) for caregivers and 35 y (3.5) for professionals. The number of participants and their age range at study varied slightly between the eight focus groups. Caregivers presented care burden and compromised aspects of Quality of life (QOL). An effective and culturally sensitive psychosocial support for patients and their families during and post treatment, in addition to medical therapy, is strongly recommended.

Acute lymphoblastic leukemialymphoma of the oral and maxillofacial region.

Our objective was to describe the clinicopathologic and immunohistochemical features of acute lymphoblastic leukemialymphoma (ALLLBL) of the oral and maxillofacial region (OMF). Cases diagnosed as ALLLBL of the OMF region were retrieved from the files of 2 Brazilian and 1 Guatemalan oral pathology services from 2005 to 2017. Microscopic and immunohistochemical features of each case were reviewed and fully described, and clinical data were retrieved from the pathology reports. During the period considered, 6 cases were identified. Male patients were the most affected (42), with a mean age of 19 years old. The mandible was involved in 2 cases, the maxilla in 2, the cheek mucosa in 1, and the parotid gland in 1. Painful swelling was the most common presentation, and 3 patients also had systemic complaints. Microscopically, tumors revealed solid infiltrations of small to medium-sized immature cells. Puzzle-like and starry-sky patterns were observed, and single lane growth was also identified. Immunohistochemically, 2 cases were diagnosed as T-cell ALLLBL with the leukocyte common antigen (LCA) OMF ALLLBL is rare, but its microscopic features and immunohistochemical profiles CD3

An effective modestly intensive re-induction regimen with bortezomib in relapsed or refractory paediatric acute lymphoblastic leukaemia.

This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsedrefractory acute lymphoblastic leukaemia. Patients were randomized 11 to bortezomib (1.3 mgm

Extranodal histiocytic sarcoma in a child with acute lymphoblastic leukemia Cytomorphological features of a rare entity with brief review of literature.

Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic evidence of histiocytic differentiation. We describe a rare case of synchronous HS in a patient of B-cell acute lymphoblastic leukemia (ALL). A 16-year-old boy diagnosed as ALL also presented with a swelling over the right Achilles tendon. The cytological features of the swelling suggested a histiocytic lesion. Histological and immunohistochemical examination clinched the diagnosis of HS. The available 5-year follow-up showed no recurrence. It was a diagnostic dilemma on fine-needle aspiration. We discuss the cytological features of HS which can help in reaching a diagnosis and emphasize that it should be considered in the differential diagnosis for unexplained swellings in patients of hematological malignancies. Wide local excision of localized HS is associated with a long-term favorable outcome.

Rapid identification of BCRABL1-like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time-polymerase chain reaction clinical, prognostic and therapeutic implications.

BCRABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCRABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCRABL1-like and 26 non-BCRABL1-like cases to build a statistical BCRABL1-like predictor, for the identification of BCRABL1-like cases. By screening 142 B-lineage ALL patients with the BCRABL1-like predictor, we identified 28142 BCRABL1-like patients (19·7%). Overall, BCRABL1-like cases were enriched in JAKSTAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P 0·001), thus corroborating the validity of the prediction. Clinically, the BCRABL1-like cases identified by the BCRABL1-like predictor achieved a lower rate of complete remission (P 0·014) and a worse event-free survival (P 0·0009) compared to non-BCRABL1-like ALL. Consistently, primary cells from BCRABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCRABL1-like ALL cases at diagnosis.

Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008 The first nation-wide prospective multicenter study in China.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. The trial Chinese Children Leukemia Group (CCLG)-ALL 2008 was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first nation-wide collaborative study in China. Totally 2231 patients were recruited from ten tertiary hospitals in eight cities. The patients were stratified according to clinical-biological characteristics and early treatment response. Standard risk (SR) and intermediate risk (IR) groups were treated with a modified BFM based protocol, and there was 25%-50% dose reduction during intensification phases in the SR group. Patients in high risk (HR) group received a more intensive maintenance treatment. Minimal residual disease (MRD) monitoring with treatment adjustment was performed in two hospitals (the MRD group). Complete remission (CR) was achieved in 2100 patients (94.1%). At five years, the estimate for overall survival (OS) and event-free survival (EFS) of the whole group was 85.3% and 79.9%, respectively. The cumulative incidence of relapse (CIR) was 15.3% at five years. The OS, EFS and CIR for the SR group were 91.5%, 87.9%, and 9.7%, respectively. The outcome of the MRD group is better than the non-MRD group (5y-EFS 82.4% vs 78.3%, P .038 5y-CIR 10.7% vs 18.0%, P < .001). Our results demonstrated that the large-scale multicenter trial for pediatric ALL was feasible in China. Dose reduction in the SR group could achieve high EFS. MRD-based risk stratification might improve the treatment outcome for childhood ALL.