Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. ...We investigated the mechanisms by which AML causes pancytopenia and suppresses patients' immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic–severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34+ progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through small-molecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis.
•AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells.•AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.
Summary
Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to ...investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.
Summary
We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3·2%) patients recruited over 5 years with 90% ...occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg‐ASP) 1000 units/m2 was used throughout. Thirty‐four children received further Peg‐ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re‐exposure to Asparaginase is feasible and safe.
AimsAudit of follow-up of neutropenia in children, in terms of blood tests, in a single institution was found to be variable. This can potentially lead to significant underlying conditions being ...missed and standardising follow-up blood tests is important. As a quality improvement project we wrote a guideline (figure 1), re-audited and present our findings.MethodsAll neutrophil counts less than 1x109/L in under 16 year olds were retrospectively collected from a single tertiary hospital over a 1-year period, as well as diagnoses and available follow-up results. Children with underlying conditions known to have haematological sequelae were excluded, as were counts requested from the haematology/oncology and neonatal units. An evidence- and locally consensus-based guideline was written and ratified, advising repeat counts within 4-6 weeks and that well children of Afro-Caribbean heritage did not require follow-up.1 A further 6 months of data were collected approximately 2 months after introduction of the guideline with the same exclusion criteria as above.Results56 children with neutropenia were identified over a 1-year period on initial analysis, with 111 full blood counts (FBC) performed between them. 36% (n=20) of children did not have a repeat FBC and 48% (n=27) did not have a normal neutrophil count (>1) recorded, even if checked more than once (figure 2). The average number of days before a ‘normal’ result was obtained was 18 in those who had repeat FBC. 3 new cases of autoimmune neutropenia (AIN) were identified in this time period; these were excluded from analysis since a normal FBC was not recorded. Following implementation of the new guideline, repeat analysis over a 6-month period was performed, with the same exclusions as the initial analysis. 36 children were identified; 25% (n=9) did not have a repeat FBC, and 36% (n=13) did not have a normal count documented. 72% had a repeat count within 6 weeks. The average number of days until normal count was recorded was 15, and 1 new case of AIN was identified, receiving a repeat FBC within the suggested 4-6 week time frame.Abstract 743 Figure 1Management and follow up of isolated neutropenia in childrenAbstract 743 Figure 2Cases of isolated neutropenia pre- and post guideline introductionConclusionLocal assessment of current practice with isolated neutropenia in children confirmed a variety of follow-up approaches, with almost 1 in 2 cases not having a normal count recorded. Introduction of a pragmatic guideline improved retesting rates (64% vs 75%). We noted a 3-5% incidence of newly identified significant diagnoses, highlighting the importance of standardising practice. The advocated 4-6 week gap before retesting FBC was supported by preliminary and repeat analysis; most counts in our datasets normalised in approximately 2-3 weeks, and although the gap could be reduced, 4-6 weeks strikes a balance between rational testing and safety. Our data however may be incomplete for those children who were from neighbouring hospitals and repatriated before repeat counts, and the re-audit was of a shorter period. More complete coding of ethnicity would also enable a better evaluation of repeat counts in different ethnic groups.ReferenceThomas AE, et al. A step-by-step approach to paediatric neutropenia. Paediatrics Child Health 2017;27:11.
AimsIt is well known that exposure to ionising radiation poses risks such as secondary cancer. We evaluated cumulative radiation exposure to a cohort of children with cancer over a 3 year period in a ...single Trust.MethodsThe OUH dose monitoring system, Radimetrics® (Bayer), was used to assess the number, type and radiation dose of the exposures received by each individual patient. Only the effective dose and organ equivalent doses from CT examinations are provided by Radimetrics®.ResultsFrom 2019-2021 there were 63 patients with leukaemia, 21 with Hodgkin lymphoma, 13 with Burkitts lymphoma, 13 with LCH, 16 with neuroblastoma, 13 with Wilms, 10 with osteosarcoma, 13 with astrocytoma, 11 with medulloblastoma, 10 with teratoma and 132 patients with rarer diagnoses with a total of 315 patients.Of the 315 patients considered, 178 (56%) received at least 1 CT examination. 27 PET scans were done, 108 CT chest abdo pelvis scans, 193 CT heads, 23 CT abdomen, CT chest.44% received 0 mSv, 50% received < 20 mSv, 5.4% received 20-50 mSv, 0.3% received 50-100 mSv and 0.3% received >100 mSv FFigure 1 shows a closer analysis of the dose distribution for the most common diseasesConclusionA recent study in the UK found that children who received an active marrow dose from CT > 30 mSv were 3.2 times more likely to develop leukaemia and children who received a brain dose > 50 mSv were 2.8 x greater risk of brain cancer. Our analysis of radiation doses in our cohort of patients showed the majority had cumulative effective doses < 20 mSv over the study period. Effective dose cannot be compared to organ doses but Radimetrics® also provides organ doses. From our data we found that the highest cumulative brain dose was 359 mSv (lens dose 421 mSv) with a corresponding effective dose of 45.5 mSv. Within the patient cohort with cumulative effective doses <20 mSv, the highest brain dose was 240 mSv (lens dose 288 mSv). The highest eye lens dose is approaching the cataract threshold dose proposed by the ICRP of 500 mSv.Abstract 538 Figure 1Shows a closer analysis of the dose distribution for the most common diseasesAbstract 538 Figure 2Average dose/examination for different age groups.In our study only 5.4% patients had cumulative whole body effective doses in the 20-50 mSv range and 2% >50 mSv. Head CT in children carries a higher lifetime cancer risk by a factor of 1.5-2 depending on sex than body scans. Body CT scanners are now more efficient and deliver up to 50% less radiation dose than older scanners,Although the risk of radiation induced cancer for the majority of patients in this study remains low (< 0.24% using a lifetime cancer risk of 12% per Sv) caution needs to be taken as more children are surviving cancer and there is a cumulative risk of secondary cancers from the treatment burden. Awareness of radiation dosing, especially with CT head is important. Alternative modalities such as MRI should be used as much as possible.
Leukaemias: a review Qureshi, Amrana K; Hall, Georgina W
Paediatrics and child health,
11/2013, Letnik:
23, Številka:
11
Journal Article
Recenzirano
Abstract Leukaemia is the most common cancer in children. Leukaemia results from clonal proliferation of stem cells and leads to bone marrow failure. Symptoms at presentation include bruising, ...bleeding, pallor due to anaemia and infection. The incidence is approximately 5 in 100 000 children. The cause is largely unknown although there is a predisposition in certain congenital conditions such as Fanconi's Anaemia and Down's syndrome and there is some understanding of how genetic mutations may cause leukaemia, but this is not thought to be a single event. The treatment of acute lymphoblastic leukaemia in children older than 1 year is extremely successful and continues to improve. Treatment is tailored according to response (minimal residual disease directed). Multi-agent immunosuppressive chemotherapy, with central nervous system prophylaxis is given over 2–3 years. Acute myeloid leukaemia is five times less common than acute lymphoblastic leukaemia and is treated intensively for 4–5 months and cure rates have remained at 60–70% for two to three decades. Survival has improved due to better supportive care. Chronic myeloid leukaemia is rare and treated with tyrosine kinase inhibitors and as in preleukemic conditions (myelodyplasia) may require allogenic bone marrow transplant.
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