scholarly journals Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Q. Heydt ◽  
C. Xintaropoulou ◽  
A. Clear ◽  
M. Austin ◽  
I. Pislariu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Protein Biosynthesis ◽  
Chemotherapy Resistance ◽  
Translational Repression ◽  
Remission Induction ◽  
Cytoprotective Effect ◽  
General Control ◽  
Cell Quiescence ◽  
Cellular Quiescence

AbstractThe specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional networks and suppresses protein biosynthesis in ALL cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence thereby significantly reducing the cytoprotective effect of adipocytes against chemotherapy and other extrinsic stressors. These data establish how adipocyte driven restrictions of the ALL proteome benefit ALL tumours, preventing their elimination, and suggest ways to manipulate adipocyte-mediated ALL resistance.

Unbalanced Coagulation-Fibrinolysis Potential during L-Asparaginase Therapy in Children with Acute Lymphoblastic Leukaemia

1990 ◽  
Vol 64 (01) ◽  
pp. 038-040 ◽  
Author(s):  
N Semeraro ◽  
P Montemurro ◽  
P Giordanol ◽  
F Schettini ◽  
N Santoro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukaemia ◽  
Mononuclear Cells ◽  
Thrombus Formation ◽  
Chemotherapeutic Agents ◽  
Remission Induction ◽  
Concurrent Administration ◽  
Peripheral Blood Mononuclear ◽  
Thrombotic Complications

SummaryTreatment of acute lymphoblastic leukaemia (ALL) with L-asparaginase (L-asp) may be associated with thrombotic complications, but the pathogenetic mechanisms of thrombus formation and persistence remain unclear. We studied the procoagulant activity (PCA) of peripheral blood mononuclear cells and some components of the plasma fibrinolytic system in L0 children with ALL undergoing remission induction therapy which includes L-asp. Mononuclear cells obtained 14 days after starting L-asp treatment generated significantly higher amounts of PCA (identified as tissue factor) than cells isolated before the first dose of L-asp and 7 days after the cessation of L-asp administration (p <0.01). Augmented PCA coincided with an increase in the plasma D-dimer. The plasma levels of type 1- plasminogen activator inhibitor were found signiticantly elevated during L-asp therapy (p <0.05), whereas plasminogen levels were markedly decreased (p <0.05). These findings suggest that, during the course of L-asp treatment, the coagulation-fibrinolysis balance is shifted towards promotion of fibrin formation and deposition. Although it remains to be conclusively established whether Lasp per se or the concurrent administration of multiple chemotherapeutic agents is responsible for these changes, the latter could contribute to the thrombotic complications associated with remission induction therapy for ALL.

scholarly journals Treatment abandonment in childhood acute lymphoblastic leukaemia in China: a retrospective cohort study of the Chinese Children’s Cancer Group

2019 ◽  
Vol 104 (6) ◽  
pp. 522-529 ◽  
Author(s):  
Jiaoyang Cai ◽  
Jie Yu ◽  
Xiaofan Zhu ◽  
Shaoyan Hu ◽  
Yiping Zhu ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Lymphoblastic Leukaemia ◽  
Low Income ◽  
Lymphoblastic Leukaemia ◽  
Laboratory Data ◽  
Remission Induction ◽  
Chinese Government ◽  
Current Frequency ◽  
Cancer Group ◽  
Treatment Abandonment

ObjectivesBefore 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children’s Cancer Group ALL protocol between 2015 and 2016.MethodsDemographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government.ResultsAt a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications.ConclusionsThe rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment.Clinical trial registration numberChiCTR-IPR-14005706, pre-results.

scholarly journals Successful outcome of disseminated Candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome–positive acute lymphoblastic leukaemia-case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Lichun Xie ◽  
Qingling Long ◽  
Guichi Zhou ◽  
Sixi Liu ◽  
Fei-Qiu Wen
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Acute Lymphoblastic Leukaemia ◽  
Candida Tropicalis ◽  
Lymphoblastic Leukaemia ◽  
Philadelphia Chromosome ◽  
Remission Induction ◽  
Resonance Imaging ◽  
Successful Management ◽  
All Treatment

Abstract Background Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered. Case presentation Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel. Conclusions In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.

scholarly journals HIGH INFECTION RELATED MORTALITY IN PAKISTANI CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKAEMIA DURING REMISSION INDUCTION CHEMOTHERAPY: REVIEW OF DATA FROM A SINGLE INSTITUTION

2016 ◽  
Vol 2 (4) ◽  
Author(s):  
AUR Maaz ◽  
Farhana Badar ◽  
Tariq Mahmood ◽  
Ibrahim Al Nassir
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukaemia ◽  
Control Measures ◽  
Severe Malnutrition ◽  
Remission Induction ◽  
Symptom Duration ◽  
Treatment Related Mortality ◽  
Acinetobacter Infection ◽  
Related Mortality

Purpose: Despite advances in the treatment of acute lymphoblastic leukaemia (A.L.L.), the outcome for children living in the developing countries is still poor. This is in large part due to high treatment-related mortality (TRM). This study was carried out to review the data and analyze the factors resulting in high TRM during remission induction chemotherapy. Methods: Data for children treated at our centre during the calendar year 2007 were retrospectively analysed. Standard four-drug induction chemotherapy was used without risk strati cation. Bone marrow evaluation was carried out at days 8 and 28. Cerebrospinal uid analysis was carried out on day 1 and with each subsequent intrathecal chemotherapy injection. Modern supportive care facilities including antibiotics, nutritional support and intensive care unit were available. Results: Eighty-one children were eligible for analysis. Median age was 5 years (range 2–16), 72% were male with M:F ratio of 2.5:1. Seventy- five (92%) children had precursor B-cell A.L.L. Only 2 children had central nervous system leukaemia at presentation. Median presenting white blood cell count was 8.83 (range: 1–446). Severe malnutrition (weight <5th centile for age) was seen in 42% of children. Median symptom duration was 6 (range 1–30) weeks at the time of presentation. Induction mortality was 25%. Induction mortality was 25.6% (n = 21). Twenty were related to infections, while more than half (52%) occurred as a result of an outbreak of Acinetobacter infection. Severe malnutrition and Acinetobacter infection (due to an outbreak in our unit during the study period) were highly predictive of TRM during remission induction chemotherapy. Conclusions: Infection control measures, health education and reduction in treatment intensity may improve survival for children with A.L.L. in Pakistani population. Key words: Acute lymphoblastic leukaemia in children, malnutrition, Pakistan, treatment-related mortality

Predictive Value of Flow Cytometric MRD Analysis in Childhood Acute Lymphoblastic Leukaemia at the End of Remission Induction Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4267-4267
Author(s):  
J. Motwani ◽  
J. Jesson ◽  
E. Sturch ◽  
L. Eyre ◽  
P. Short ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukaemia ◽  
Residual Disease ◽  
Flow Cytometric Analysis ◽  
Treatment Protocol ◽  
Early Response ◽  
Response To Treatment ◽  
Remission Induction ◽  
Flow Cytometric

Abstract Patients with acute lymphoblastic leukaemia (ALL) in morphological remission may still have up to 1010 residual malignant cells. Detection of minimal residual disease (MRD) at the end of induction therapy allows better estimation of the leukaemic burden and can help selection of appropriate therapeutic strategies. Flow cytometric (FC) detection of MRD is based on the identification of immunophenotypic combinations expressed on leukaemic cells but not on normal hematopoietic cells - leukaemia associated immunophenotypes (LAIPs). We prospectively analysed bone marrow samples from 77 patients who presented with ALL to our unit between 1999–2003 and attained morphological remission. These patients were treated on a standard protocol. Multiparameter FC identification of LAIPs was performed at various time points, as dictated by the treatment protocol. Our results show that flow cytometric MRD at the end of induction therapy is an independent and the most significant predictor of relapse, both on univariate and multivariate analysis. The relapse risk was 4% if day 28 MRD was <0.01% and 50% if day 28 MRD was >0.01% (p<0.05). We conclude that flow cytometric based MRD assays can be used to assess early response to treatment and predict relapse in a similar way to molecular MRD analysis at the end of induction therapy. Flow cytometric analysis of MRD offers the advantages of being cheaper, more widely available and has quicker turnaround times.

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