Leukemia in children. Haemolytic Uraemic Syndrome (HUS).

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Leukemia in children. Haemolytic Uraemic Syndrome
(HUS).

• Sakharova Inna. Ye., MD,
• Univ. assistant

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(No Transcript)
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• Acute lymphoblastic leukaemia (ALL) is a
  malignant transformation of a clone of cells from
  the bone marrow where early lymphoid precursors
  proliferate and replace the normal cells of the
  bone marrow.

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Risk factors for the development of childhood
leukemia

• Heredity (presence of inherited genetic
  syndromes, for example Down syndrome or ataxia
  telangiectasia, presence of cytogenetic
  abnormalities )
• Environmental factors (ionizing radiation and
  electromagnetic fields, parental use of alcohol
  and tobacco)

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• The conclusion of the USA National Radiological
  Protection Board is Laboratory experiments have
  provided no good evidence that extremely low
  frequency electromagnetic fields are capable of
  producing cancer, nor do human epidemiological
  studies suggest that they cause cancer in
  general. There is, however, some epidemiological
  evidence that prolonged exposure to higher levels
  of power frequency magnetic fields is associated
  with a small risk of leukaemia in children. In
  practice, such levels of exposure are seldom
  encountered by the general public in the UK. In
  the absence of clear evidence of a carcinogenic
  effect in adults, or of a plausible explanation
  from experiments on animals or isolated cells,
  the epidemiological evidence is currently not
  strong enough to justify a firm conclusion that
  such fields cause leukaemia in children.

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According to the French-American-British (FAB)
classification, leukemic lymphoblasts in ALL
subdivide into three categories

• L1 lymphoblasts are small cells with homogeneous
  chromatin, regular nuclear shape, small or absent
  nucleolus, and scanty cytoplasm. This subtype is
  the most common in children with ALL.
• L2 lymphoblasts are large and heterogeneous
  cells, heterogeneous chromatin, irregular nuclear
  shape, and nucleolus often large. They are much
  less common than L1 cells and are sometimes
  mistaken for myeloblasts.

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• L3 lymphoblasts are large and homogeneous cells
  and cytoplasmic vacuolisation that often overlies
  the nucleus as the most prominent feature. This
  is just 1 to 2 of cases.

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Immunological classification (on the basis of
immunophenotype)

• Non-T, non-B cell ALL accounts for 80 of all
  cases
• Malignancy of B cell precursors
• B-cell ALL
• T-cell ALL.

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Shown here is bone marrow aspirate from a child
with B-precursor acute lymphoblastic leukemia.
Note that the marrow is replaced primarily with
small, immature lymphoblasts that show open
chromatin, scant cytoplasm, and a high
nuclear-cytoplasmic ratio.
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Shown here is bone marrow aspirate from a child
with T-cell acute lymphoblastic leukemia. The
marrow is replaced with lymphoblasts of varying
size. No myeloid or erythroid precursors are
seen. Megakaryocytes also are absent.
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Shown here is bone marrow aspirate from a child
with B-cell acute lymphoblastic leukemia. The
lymphoblasts are large and have basophilic
cytoplasm with prominent vacuoles.
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The first symptoms of acute leukemia are

• Tiredness, irritability
•   Intermittent fever
• Failure to thrive (poor growth)
•   Bleeding from gums/nose
•   Easy bruising
•   Bone pain
•   Headache
•   Nausea/vomiting with CNS involvement

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The signs of acute leukemia during examination
are

• Skin pallor, tachycardia and a flow murmur may be
  obvious because of anemia presence.
• Signs of infection can be non-specific like fever
  or pneumonia may be present.
• Thrombocytopenia often causes petechiae on the
  lower limbs. Disseminated intravascular
  coagulation (DIC) may aggravate the situation and
  cause larger ecchymoses. Petechiae are small
  dots, purpura is larger and ecchymoses are larger
  bruises.

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• Hepatomegaly may be found.
• Lymphomatous features massive splenomegaly,
  anterior mediastinal mass, massive
  lymphadenopathy.
• Leukaemia cutis is an uncommon condition due to
  infiltration of the skin.
• Superior vena cava syndrome is caused by
  mediastinal adenopathy compressing the superior
  vena cava. A prominent venous pattern develops
  over the upper chest from collateral vein
  enlargement. The face may appear plethoric and
  the periorbital area may be edematous.

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• Involvement of sanctuary sites 1) CNS
  involvement manifests as diffuse meningeal
  infiltration with signs of increased intracranial
  pressure 2) testes, one or both of which may be
  involved, with infiltration producing enlargement
  that is out of proportion to the childs sexual
  development

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Diagnostics of ALL

• General blood count normochromic anaemia with a
  low reticulocyte index, thrombocytopenia,
  neutropenia, different WBC count (leucopenia or
  hyperleucocytosis), presence of lymphoblasts
• Bone marrow aspiration and biopsy (sternal
  puncture) are the definitive diagnostic tests to
  confirm the diagnosis more than 25 of
  lymphoblasts prove the diagnosis of ALL

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• Bone marrow samples should undergo cytogenetics
  and flow cytometry for identification of the type
  of leukemia
• DIC may occur and this produces an elevated
  prothrombin time, reduced fibrinogen level and
  the presence of fibrin degradation products in
  coagulogram
• Lactic dehydrogenase levels (LDL) are usually
  raised and rapid cell turnover may raise uric
  acid in biochemical blood test

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• Lumbar puncture with cytospin morphologic
  analysis This is performed before systemic
  chemotherapy is administered to assess the
  presence of CNS involvement and to administer
  intrathecal chemotherapy.
• Liver and renal function (ultrasonography) must
  be checked before initiating chemotherapy
• CXR may show pneumonia or an enlarged mediastinal
  mass

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• Multiple gated acquisition (MUGA) scan is
  required because many chemotherapeutic agents
  used in treatment are cardiotoxic, ECG is also
  necessary
• Molecular techniques, including
  reverse-transcriptase polymerase chain reaction
  (RT-PCR), Southern blot analysis, and
  fluorescence in situ hybridization (FISH).

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Patients can be divided into 3 groups on the
basis of risk (The Childrens Cancer Group)

• Good prognosis (have 80 or greater chance of
  cure) age between 2 and 10 years, WBC ? 10 G/L,
  absence of L3 cells, absence of lymphomatous
  features, platelet count greater 100 G/L.
• Poor prognosis (have less than 50 chance of
  cure) age less than 1 year old or greater than
  10 years old, WBC ? 50 G/L, presence of
  chromosomes translocations, B cell ALL with L3
  cells, blasts with T-cell phenotype.
• intermediate prognosis (have 50 or greater
  chance of cure).

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Good prognosis for those who have brisk initial
response to therapy

• The Childrens Cancer Group found an improved
  prognosis in patients with less than 5 blasts
  in the bone marrow after seven days of
  chemotherapy.
• The Berlin-Frankfurt-Münster group found a
  similar prognosis in patients who had less than
  1000 blasts/ml in the peripheral blood after
  seven days of prednisone.

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• With the exception of B-cell ALL, the treatment
  of childhood ALL may be considered in three
  categories
• Induction of remission
• Consolidation of remission
• Maintenance of remission
• and all stages involve treatment with cytotoxic
  agents and steroids varying in intensity. In some
  books
• 4. The treatment of subclinical CNS leukemia
• is divided into special category also.

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• Induction is by quadruple therapy with
  vincristine, prednisolone, anthracycline, and
  cyclophosphamide or L-asparaginase or a 5-drug
  regimen of vincristine, prednisolone,
  anthracycline, cyclophosphamide, and
  L-asparaginase. Intrathecal metotrexate is used
  in proper days also. It is given over the course
  of 4 to 6 weeks. This type of therapy induces
  complete remission in more than 95 of patients.

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• The main sign of remission is less than 5 of
  blasts in bone marrow additionally it should be
  less than
• 50 of lymphocytes in peripheral blood.

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• This is usually followed by consolidation
  therapy often in the form of dexamethasone,
  vincristine, and doxorubicin, followed by
  cyclophosphamide, anthracycline, and
  6-thioguanine beginning at week 20. In this phase
  of therapy, the drugs are used at higher doses
  than during induction. Consolidation therapy,
  first used successfully in the treatment of
  patients with high-risk disease, also appears to
  improve the long-term survival of patients with
  standard-risk disease.

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• Maintenance therapy often consists of
  periodic reinduction pulses of prednisone and
  vincristin as well as
• 1) Daily oral 6-merkaptopurine and weekly oral
  methotrexate for low-risk patients
• 2) More intensive multiagent therapy for
  intermediate- and poor-risk patients.

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• Relapses still occur in 30-40 of patients.
  If relapse occurs in the CNS or testes, many
  children can still be cured with irradiation and
  additional chemotherapy. If relapse occurs in the
  marrow within 18 months of diagnosis, the chance
  of cure with either chemotherapy or stem cell
  transplantation is less than 10 .

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• Bone marrow transplantation is used rather
  more in children than in adults. If a
  first-degree relative with a HLA match is not
  available it is possible to use autologous (own)
  bone marrow rather than allogeneic (donor)
  marrow. However, the results of autologous are
  inferior to sibling donors and a study gave 3
  years survival after remission and bone marrow
  transplant of 26 with autologous bone marrow
  compared with 68 with donor marrow.

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• Primary features of tumor lysis syndrome
  include hyperuricemia (due to metabolism of
  purines), hyperphosphatemia, hypocalcemia, and
  hyperkalemia.

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• Haemolytic Uraemic Syndrome (HUS) ? a triad of
  microangiopathic haemolytic anaemia (Coombs test
  negative), thrombocytopenia and acute renal
  failure.

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• HUS has been associated with E. coli with
  somatic (O) antigen 157 and flagella (H) antigen
  7. It produces a toxin called shiga and hence
  this group is called Shiga-toxin-producing
  Escherichia coli (STEC). An alternative name is
  vero toxin-producing Escherichia coli (VTEC).

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HUS clinical features

• profuse diarrhoea that turns bloody 1 to 3 days
  later and rarely on the first day
• fever, abdominal pain and vomiting

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HUS diagnostic criteria include

• packed cell volume of less than 30
• evidence of erythrocyte destruction on peripheral
  blood smear
• platelet count less than 150 x 109/L
• serum creatinine above the upper limit for age
• haemoglobinuria

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Therapy of HUS

• Antibiotics confer no benefit, even if given
  early
• Massive intravenous infusions
• with potassium adding (under urine volume
  control)