The American Board of Pediatrics

** Subspecialty **\
**Certifying **\
**Examination**

CONTENT\
OUTLINE

Subboard of

** Pediatric Hematology-Oncology **

INTRODUCTION

This document was prepared by the American Board of Pediatrics (ABP)
Subboard of Pediatric Hematology-Oncology as a blueprint for the
subspecialty certifying examination. Each ABP subboard prepares a
similar document as a first step in preparing an examination. The
purpose is to define the knowledge a certified subspecialist should be
expected to demonstrate on an examination consisting of multiple-choice
questions.

Program directors and candidates frequently request information about
the content of subspecialty examinations. Although this document was not
prepared to respond to such requests, the Subboard believes that it may
be helpful.

Several caveats are important:

1.  \- This document is NOT intended to be a curriculum guide. There are
    many skills subspecialty trainees need to learn that cannot be
    tested in a multiple-choice examination. Also, there are many
    interesting but less important facets of knowledge that are not
    likely to be tested given the time constraints of an examination.

2.  \- This document is NOT designed to be a study guide; however,
    candidates may feel less anxious about a certifying examination if
    they know what to expect and they may be able to use this document
    to identify areas in which they are weak and need additional
    preparation.

3.  \- This document is intended to be a working blueprint. It has not
    been edited for publication.

-This document is a dynamic work-in-progress. The Subboard will be happy
to consider any comments you might have about content.

Approximate Percent in [ Examination ]{.underline}

I. Erythrocytes, Hemoglobin, Iron
Metabolism\...\...\...\...\...\...\...\...\...\...\...\...\...\...20.0

II\.
Leukocytes\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....5.0

III\.
Hemostasis\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....18.0

IV\. Pediatric Transfusion Medicine
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....8.0

V. Pediatric
Oncology\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....35.0

VI\. Immunologic
Abnormalities\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....5.0

VII\. Bone Marrow Transplantation
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...7.0

VIII\. Research
Methods\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....2.0

**I. Erythrocytes, Hemoglobin, Iron Metabolism **

**A. The normal erythron **

**1. The mature erythrocytes **

**a. Structural features **

Know the size, shape, and indices of normal erythrocytes

**b. Membrane **

Understand the role of the cytoskeleton in maintaining cell shape

Know the determinants affecting osmotic fragility

**c. Hemoglobin (hgb) structure and function **

Understand the physiologic mechanisms affecting blood oxygen affinity

Differentiate hgb A from hgb F with respect to oxygen affinity, alkali
resistance, and electrophoretic mobility

Understand the basis for the altered oxygen affinity of hgb F

Know the significance of glycosylated hgb

**d. Energy metabolism **

Understand the role of the pentose-phosphate pathway in protecting hgb
from oxidative denaturation

**2. Erythropoiesis **

**a. Stages of erythroid maturation **

Recognize the morphologic features of erythroid precursors

Understand the action of erythropoietin on terminal differentiation of
progenitors

Know the sites of fetal and post-natal erythropoietin production

**b. Regulation of erythrocyte production **

Understand the relationship between erythropoietin production, tissue
oxygenation, and anemia

**(1)**. **Iron and normal iron metabolism (a). Iron absorption **

Understand the factors that affect iron absorption

Know how iron absorption from human milk differs from that in cow milk

**(b). Cellular metabolism of iron **

Understand the regulation of iron absorption, transport, and storage

**(c). Developmental aspects **

Know the determinants of body iron at birth

**(2). Folate, vitamin B12 **

Know the dietary sources of folate and vitamin B12

Know the site of intestinal absorption of folic acid and B12

**3. Erythrocyte destruction **

**a. Life span of erythrocytes; erythrokinetics **

Be familiar with the differences in the normal erythrocyte survival of
infants and older children

**b. Mechanisms of erythrocyte destruction **

Know the laboratory basis for differentiating intravascular from
extravascular erythrocyte destruction

Know the mechanisms of erythrocyte destruction (eg, microangiopathy,
immune destruction, membranopathies, enzymopathies, hemoglobinopathies)
and methods of detecting them

**c. Hemoglobin catabolism **

Know the steps in hemoglobin degradation

Understand the biologic activity and clinical alterations of hemopexin
and haptoglobin

**4. The erythron in the fetal and postnatal periods **

**a. Embryonic hgb and characteristics of hgb switching **

Know the globin structure of embryonic, fetal, and adult hgbs

Know the relative concentrations of embryonic, fetal, and adult hgbs in
a newborn infant and variations in pathologic states Know the
chromosomal location and control mechanisms of the globin genes

**b. Distinctive features of the neonatal erythrocyte **

Know the characteristics that differentiate the erythrocytes of newborn
infants from those of adults

Know how erythrocyte antigens change during gestation and after birth

**c. Postnatal changes in erythropoiesis **

Know the changes that occur during the postnatal period in hemoglobin
concentration, reticulocytes, and bone marrow erythroblasts

**d. The anemia of prematurity **

Understand the pathophysiologic basis for the anemia of prematurity

Understand the variable treatment modalities for the anemia of
prematurity

**B. Anemias **

**1. General principles **

**a. Definitions and recognition of anemia **

Define normal ranges of hgb concentrations and erythrocyte indices at
birth and throughout childhood and adolescence

**b. Classification of anemia: morphologic, kinetic **

Correlate erythrocyte morphology with clinical syndromes

Know the origin of various erythroid inclusions seen on blood smears

Know how to classify anemias according to altered erythrocyte
production, increased erythrocyte destruction, and blood loss

Understand and interpret results of reticulocyte counts

Know how to classify anemias on the basis of cell size

Know the differential diagnosis of macrocytic anemia

Know the differential diagnosis of microcytic anemia

Know the differential diagnosis of normocytic anemia

**c. Physiologic adaptations to anemia **

Understand the physiologic adaptation of erythrocyte 2,3-DPG
concentration in response to anemia

**2. Disorders of iron metabolism **

**a. Iron deficiency anemia **

**(1). Pathogenesis **

Recognize the syndrome of milk-induced gastrointestinal bleeding and
understand its laboratory evaluation

Recognize the clinical and laboratory manifestations of pulmonary
hemosiderosis and know the appropriate diagnostic approach

Recognize the factors in medical history that predispose pediatric
patients to iron deficiency

Recognize the association between occult blood loss and iron deficiency
anemia

**(2). Clinical and laboratory features **

Know the effect of iron deficiency on hgb A2 concentration

Know the effect of iron deficiency and other microcytic anemias on
erythrocyte distribution width index (RDW)

Know the effect of iron deficiency on serum iron concentration, total
iron-binding capacity, ferritin, and free erythrocyte protoporphyrin

Know the order of appearance of laboratory abnormalities as iron
deficiency develops

Know the association of pica and iron deficiency

Know the effects on growth and development of iron deficiency

**(3). Diagnosis **

Understand the laboratory parameters that distinguish iron deficiency
anemia from the anemia of chronic inflammation

Know the laboratory studies that differentiate the anemia of lead
poisoning from that of iron deficiency

Understand the diagnostic utility of free erythrocyte protoporphyrin and
ferritin concentrations in microcytic anemias

**(4). Treatment **

Determine the proper place for dietary changes, oral iron, parenteral
iron, and erythrocyte transfusion in the treatment of iron deficiency

**(5)**. ** Prevention **

Know the indications for and types of iron supplementation

**b. Iron overloa**d\
**(1). Consequence**s

Understand the relationship between chronic iron overload and clinical
organ dysfunction (ie, cardiac, endocrine, liver, pancreas)

Know how to monitor the degree of iron overload

**(2)**. ** Diagnosis **

Be able to calculate the amount of iron in a volume of erythrocytes

Understand laboratory tests used to diagnose iron overload

Know the appropriate test for hereditary hemochromatosis

**(3)**. ** Treatment **

Know the principles for prevention and treatment, including treatment
regimens (eg, phlebotomy, iron chelators, erythrocytopheresis) of
chronic iron overload

Know the toxicity of iron chelators and appropriate monitoring of
therapy

**c. Lead intoxication **

Recognize the clinical and laboratory features of lead poisoning

**3. Anemia of chronic disease and secondary anemias **

Recognize the clinical and laboratory findings in the anemia associated
with chronic disease

Recognize the effect of acute infection on hgb concentration

Know the indications for the use of recombinant human erythropoietin in
the anemia of renal disease

Know the characteristics of anemia associated with hypothyroidism

Recognize the clinical and hematologic manifestations of cystic fibrosis
Know the mechanism of production of abnormal erythrocytes in liver
disease

Know that parvovirus B19 infection suppresses erythropoiesis by
impairing erythroid precursors

**4. Anemias due to bone marrow failure **

**a. Acquired aplastic anemia (See also VII.B.) **

Understand the hematologic toxicity of drugs in the pathogenesis of

acquired aplastic anemia Recognize the involvement of viral infections
in the pathogenesis of acquired aplastic anemia

Understand the use and toxicity of immune modulation in the treatment

of acquired aplastic anemia Recognize the involvement of immunologic
disorders in the pathogenesis of acquired aplastic anemia

Know the role of the microenvironment in marrow failure

Recognize that parvovirus can cause prolonged erythrocyte aplasia in an
immunocompromised host Understand the relative role of HSCT in acquired
aplastic anemia Understand the relationship between aplastic anemia,
paroxysmal

nocturnal hemoglobinuria, and malignant transformation

**b. Fanconi anemia **

Know the clinical and molecular features, laboratory findings, and

chromosomal abnormalities in Fanconi anemia Recognize the clinical
correlates of hereditary syndromes associated with marrow failure

Know how to differentiate acquired aplastic anemia and Fanconi

anemia in the absence of somatic anomalies Recognize the association
between Fanconi anemia and acute leukemia and other malignancies

Know the association between hepatic adenoma and androgen therapy Know
the therapeutic options for Fanconi anemia

**c. Diamond-Blackfan syndrome **

Know the relationship of Diamond-Blackfan syndrome with congenital
anomalies

Know the clinical and laboratory parameters that differentiate transient
erythroblastopenia of childhood from Diamond-Blackfan syndrome
Distinguish an aplastic crisis of a hemolytic anemia from transient
erythroblastopenia of childhood and Diamond-Blackfan syndrome

Know the various treatment modalities and their effectiveness in
Diamond-Blackfan syndrome

**d. Transient erythroblastopenia of childhood **

Recognize the clinical syndrome of transient erythroblastopenia of
childhood and know how to treat it appropriately

**e. Dyskeratosis congenita **

Recognize dyskeratosis congenita as a disorder associated with aplastic
anemia

**f. Pearson syndrome **

Know the clinical and laboratory features and underlying defects of
Pearson syndrome

**5. Hereditary hemolytic anemias **

Recognize the clinical manifestations of congenital hemolytic anemia and
correlate them with appropriate laboratory evaluation

Understand the neonatal diagnosis of hereditary hemolytic anemia

Know that Rh null phenotype is associated with a hereditary hemolytic
anemia

Know the relationship between parvovirus infection and aplastic crisis
in congenital hemolytic anemias

Recognize the role of folate supplementation in patients with hemolytic
anemia

**a. Inherited disorders of the erythrocyte membrane **

**(1). Hereditary spherocytosis **

**(a). Genetics **

Recognize the differences in the phenotypes of the autosomal dominant
and autosomal recessive variants of hereditary spherocytosis

Know the cytoskeletal defects associated with hereditary spherocytosis

Know the determinants of the severity of anemia in hereditary
spherocytosis

**(c). Evaluation **

Establish the clinical and laboratory diagnosis of a patient with
hereditary spherocytosis

Know the basis for and pattern ofabnormal osmotic fragility in
hereditary spherocytosis

Distinguish between hereditary spherocytosis and autoimmune hemolytic
anemia

**(d)**. ** Management **

Know the hematologic sequelae of splenectomy in hereditary spherocytosis

**(e). Complications **

Understand the complications seen in hereditary spherocytosis before and
after splenectomy

**(2)**. **Hereditary elliptocytosis and pyropoikilocytosis (a).
Genetics **Know the mode of inheritance of hereditary elliptocytosis and
pyropoikilocytosis

**(b)**. ** Pathophysiology **

Know the cytoskeletal defects associated with hereditary elliptocytosis
and hereditary pyropoikilocytosis

**(c). Clinical features **

Recognize hemolytic and non-hemolytic variants of hereditary
elliptocytosis

Know the clinical features of pyropoikilocytosis

**(d)**. ** Laboratory evaluation **

Recognize the morphologic characteristics and other laboratory features
of hereditary elliptocytosis and hereditary pyropoikilo- cytosis

**(e). Management **

Know the effects of splenectomy on hereditary elliptocytosis and
pyropoikilocytosis

**(3). Acanthocytosi**s\
**(a). Clinical feature**s

Recognize the erythrocyte morphologic abnormality associated with the
clinical picture of abetalipoproteinemia

**(b)**. ** Laboratory evaluation **

Know the association of acanthocytosis with abetalipoproteinemia and
with the McLeod phenotype

**b. Inherited disorders of anaerobic glycolysis **

**(1)**. **Pyruvate kinase deficienc**y\
**(a). Genetic**s

Know the inheritance pattern of pyruvate kinase deficiency

**(b)**. ** Cellular physiology **

Recognize how pyruvate kinase deficiency may lead to impaired
erythrocyte metabolism

**(c). Clinical and laboratory features **

Recognize the clinical and laboratory manifestations of pyruvate kinase
deficiency

**(d)**. ** Management **

Know the effects of splenectomy on pyruvate kinase deficiency

**(e). Complications **

Know that hemolysis and gallstone production may persist following
splenectomy

**(2)**. **Triose phosphate isomerase deficienc**y\
**(a). Genetic**s

Know that triose phosphate isomerase deficiency is an autosomal
recessive disorder

**(b)**. ** Clinical features **

Know the relationship between erythrocyte triose phosphate isomerase
deficiency and neuromuscular disease

**(3)**. **Other enzyme deficiencie**s\
**(a). Genetic**s

Know that phosphoglycerate kinase (pgk) deficiency is an X-linked
disorder, while other glycolytic disorders are autosomal recessive

**(b)**. ** Clinical features **

Know the relative frequency of the various enzymopathies

**(c). Laboratory evaluation **

Know the association of pyrimidine-5\'-nucleotidase deficiency with
basophilic stippling

Know that hemolytic anemia is associated with pyrimidine-5\'­nucleotidase
deficiency

**c. Inherited disorders of the pentose phosphate pathway **

**(1)**. **Glucose-6-phosphate dehydrogenase deficiency (a). Genetics **

Recognize that G6PD deficiency is X-linked

**(b)**. ** Cellular physiology **

Understand the pathophysiology whereby oxidant damage causes hemolysis
in G6PD deficiency

**(c). Clinical features **

Know the association of favism with the Mediterranean and Chinese forms
of G6PD deficiency

Recognize the association of naphthalene fume inhalation with acute
hemolysis in G6PD deficiency

Know the association of intermittent jaundice with G6PD deficiency

Recognize the clinical and laboratory differences between the major G6PD
variants (eg, A-Mediterranean)

Recognize the etiologic role of infection in hemolytic episodes
associated with G6PD deficiency

**(d)**. ** Laboratory evaluation **

Recognize the difficulty in making diagnosis in A-variant G6PD
deficiency during an acute hemolytic episode

**d. Structural disorders of hgb synthesis **

**(1)**. **Hgb S and the sickling syndrome**s\
**(a). Genetic**s

Know the genetic basis for the sickling syndromes

**(b)**. **Molecular and pathophysiological mechanisms **

Understand the pathophysiology of the sickling phenomenon

Understand the determinants of vaso- occlusion in the sickling syndromes
Understand the determinants of hemolysis in sickle cell disease Know the
characteristics and clinical correlates of irreversibly sickled

cells

Understand how polymerization of hgbs is influenced by other hgbs (hgb
F, A, etc) Understand the molecular abnormalities in sickle cell
syndromes

**(c). Clinical features **

Recognize the clinical and laboratory characteristics of

sickle-thalassemia syndromes Know the various clinical and laboratory
manifestations of sickle hemoglobinopathies, including sickle cell trait

Recognize the splenic sequestration syndrome in sickle cell disease Know
the central nervous system complications of sickle cell disease Know the
life expectancy in patients who have sickle cell syndromes,

including sickle cell trait Recognize aplastic crisis in sickle cell
anemia Recognize acute chest syndrome in sickle cell anemia

**(d)**. ** Laboratory evaluation **

Recognize the laboratory manifestations of sickle cell disease

Understand the utility and limits of various methodologies used to
establish the diagnosis of hemoglobinopathies Interpret hgb
electrophoresis under various conditions

Know how to differentiate the homozygous state for hgb S from doubly
heterozygous hgb S/hereditary persistence of fetal hemoglobin

Recognize differences in the hemoglobin electrophoretic patterns of
sickle cell trait and Hgb S/Beta + thalassemia

Recognize the hemoglobin patterns seen in infants with various sickle
syndromes

**(e). Management **

Understand the risk of infection in sickle cell disease and know the

appropriate preventive strategies Understand the proper therapeutic
approach to infection in patients with sickle cell disease

Know the appropriate treatment for a patient with sickle cell disease
who has a stroke

Know how to manage acute chest syndrome Know how to manage acute pain
crisis in a patient with sickle cell disease

Know the indications for and how to plan a transfusion program for a

patient with sickle cell disease Know that HSCT may be useful in a
select group of severely affected patients

Know the rationale for using different drugs to modify the propensity

for sickling Understand the risk of stroke in sickle cell disease and
know the appropriate screening and management strategies

Know how to manage priapism Know how to manage aplastic crisis Know how
to manage acute sequestration crisis Distinguish the relative advantages
and disadvantages of stem cell

transplantation and conventional therapy for sickle cell anemia

**(f). Complications **

Know the long-term complications that may occur in patients with

**(2)**. **Hgb C and hgb SC disease (a). Genetics **Understand the
relative frequency of hgb SC disease compared to other sickling
syndromes

Understand the inheritance pattern of patients with hgb SC disease

**(b)**. ** Molecular mechanisms **

Know the chemical and physical differences between hgb C and hgb S

**(c). Clinical features **

Know the relationship between hgb SC disease and retinopathy

Recognize splenomegaly and spleen infarction as common features in hgb
SC disease in older children

Recognize that aseptic necrosis of the femoral head is a common problem
in hgb SC disease

Know the clinical and laboratory manifestations of hgb C disease

**(3). Hgb E (a). Pathologic and clinical features **Know the
inheritance and clinical features of the hgb E syndromes **(b).
Laboratory evaluation **

**(4). Unstable hgbs (a). Genetics **Understand the inheritance pattern
associated with unstable hgbs **(b). Molecular mechanisms **Understand
the molecular and structural abnormalities that lead to hgb instability

**(c). Clinical features **

Recognize the association of accelerated hemolysis with intercurrent
infection in a patient with unstable hemoglobinopathy

Know the association of drug-induced hemolysis with some unstable hgbs
Know the relationship of Heinz bodies with denatured hgb

Know the laboratory approach to the diagnosis of unstable hgb disease

**(e). Management **

Know the proper management of patients with unstable hgbs

**(5)**. ** Low-affinity hgbs **

Know the relationship of low-oxygen affinity hgb with cyanosis

**e. Quantitative disorders of hgb synthesis (1). Genetic mechanisms and
molecular pathology **

Identify the molecular abnormalities associated with the various types
of thalassemia syndromes, including alpha, beta, and delta-beta
thalassemia, hgb E, and hgb Lepore

Understand the pathophysiology of anemia in disorders of globin chain
synthesis

**(a)**. ** Alpha-thalassemia **

Know the differences in the inheritance of abnormal alpha genes between
blacks and Asians with alpha-thalassemia

**(b)**. **Beta- and delta-beta-thalassemia **

Understand the basis for differences in hgb F concentrations in
delta-beta-thalassemia and hereditary persistence of fetal hgb

Know that absence of delta-chain synthesis is the basis of homozygous
hereditary persistence of hgb F

**(2)**. **Clinical and laboratory feature**s\
**(a). Alpha-thalassemi**a

Know the hematologic and hgb electrophorectic manifestations of
alpha-thalassemia minor

Identify and quantitate the major hgb fractions in alpha-thalassemia
disorders at birth and in later life

Know the clinical and laboratory features of the alpha-thalassemia
syndromes, including hgb H and hydrops fetalis

Know the association of hgb Constant Spring with an
alpha-thalassemia-like syndrome

**(b). Beta- and delta-beta-thalassemia **

Recognize the contribution of ineffective erythropoiesis to the
pathophysiology of thalassemia

Know the clinical and laboratory features of beta-thalassemia major and
minor

Know the clinical and laboratory features of delta-beta-thalassemia

Know how alpha-thalassemia modifies the clinical characteristics of
beta-thalassemia and hgb E-beta-thalassemia

**(c). Hereditary persistence of fetal hgb **

Know the clinical and laboratory features associated with hereditary
persistence of fetal hgb

**(d). Gamma-thalassemia **

Know the transient neonatal hemolytic disorders associated with
gamma-thalassemia syndromes

**(e). Beta-thalassemia/structural hgb variants **

Be able to differentiate hgb-E beta-thalassemia from homozygous hgb E

Know the clinical and laboratory features of homozygous hgb E and hgb
E-beta-thalassemia

**(3). Diagnosis **

Know which conditions can be diagnosed antenatally by means of chorionic
villus sampling

Know the indications for and limitations of prenatal diagnosis using
chorionic villus sampling

**(a). Alpha-thalassemia syndromes **

Know how to diagnose the various alpha-thalassemia syndromes

**(b). Beta-thalassemia syndromes **

Know how to differentiate beta-thalassemia minor from mild iron
deficiency

Know how to distinguish alpha-thalassemia trait from beta-thalassemia
trait

Know the characteristics which differentiate thalassemia from hereditary
persistence of hgb F

Know how to differentiate hereditary persistence of fetal hemoglobin
from other syndromes with increased hgb F concentrations

**(4)**. ** Treatment **

Recognize when splenectomy is indicated in thalassemia major

Identify the indications for chronic transfusion therapy for thalassemia
syndromes Understand the principles of iron chelation therapy and when
to initiate

it in a patient with a thalassemia syndrome

Know the beneficial effects and toxicity of ascorbic acid when given to
iron-overloaded patients with thalassemia Distinguish the relative
advantages and disadvantages of stem cell

transplantation and conventional therapy for thalassemia major
Understand the proper management of various hgb E syndromes Know how to
plan a chronic transfusion program for thalassemia major Understand the
proper management of thalassemia intermedia

**6. Acquired hemolytic anemias **

**a. Alloimmune hemolytic anemia; erythroblastosis fetalis (1).
Pathophysiology **

Understand the effect of a major blood group incompatibility on Rh
sensitization

Know the erythrocyte antigens that most frequently cause
erythro­blastosis fetalis

**(2)**. **Clinical and laboratory features **

Recognize the clinical features of erythroblastosis fetalis Know the
risk factors for the development of bilirubin encephalopathy Know that
transient conjugated hyperbilirubinemia may occur as a

complication of severe isoimmune hemolytic disease

**(3)**. ** Diagnosis **

Know the relative predictive value of tests of Rh sensitization

Differentiate fetomaternal minor blood group incompatibility from other
causes of jaundice in the neonate

Understand the appropriate laboratory evaluation of neonatal jaundice
secondary to a minor blood group fetomaternal incompatibility

Know that maternal anti-Lewis antibodies do not cause hemolytic disease
of the newborn

**(4). Treatment **

Know when to expect and how to treat the late anemia of isoimmune
sensitization Know the indications for exchange transfusion

Know what type of blood to use for exchange transfusions and delayed
simple transfusions in sensitized infants

**(5). Prevention **

Know the indications for the use of anti-D

**b. Autoimmune hemolytic anemia **

**(1). Pathophysiology **

Know the biologic properties and clinical significance of IgG and IgM
erythrocyte antibodies

Know the mechanism of erythrocyte destruction in IgG-mediated autoimmune
hemolytic anemia

Know the relationship between the response to corticosteroid therapy and
the type of autoantibody

Know the direct antiglobulin test results with warm-reactive antibodies,
cold agglutinin disease, and paroxysmal cold hemoglobinuria

**(2). Warm-antibody hemolytic disease **

Know the antigen specificity (or lack thereof) in warm autoimmune
hemolytic anemia

Know the clinical presentation and features of idiopathic autoimmune
hemolytic anemia of childhood

Know of the association of warm-reactive antibodies with other
autoimmune disorders

**(3). Cold agglutinin disease **

Know the antigen specificity of cold-reactive antibodies

Recognize the infections that are associated with cold-reactive
antibodies

Know the principles of therapy for cold agglutinin disease

**(4). Paroxysmal cold hemoglobinuria **

Identify the clinical features of autoimmune hemolytic anemia due to a
Donath-Landsteiner antibody

Know the characteristics of the Donath- Landsteiner antibody

**(5). Drug-induced immune hemolytic anemia **

Know the mechanism of hematologic toxicity of offending drugs

Recognize the examples of drug-induced immune hemolysis

**c. Anemia due to infection, chemical, physical agents **

Recognize intravascular hemolysis as a complication of recluse spider
bites

Know that thermal burns and envenomization may be complicated by
acquired spherocytic anemia

**d. Erythrocyte fragmentation syndromes **

Recognize the pathogenic mechanisms and the clinical and laboratory
features of the erythrocyte fragmentation syndromes

**e. Paroxysmal nocturnal hemoglobinuria **

Recognize the laboratory and clinical manifestations of paroxysmal
nocturnal hemoglobinuria

Know the association of paroxysmal nocturnal hemoglobinuria with
thrombosis

Understand the molecular and pathophysiologic basis for paroxysmal
nocturnal hemoglobinuria

**7. Megaloblastic anemias **

**a. Vitamin B12 deficiency (1). Pathophysiology **

Recognize anemia due to vitamin B12 deficiency in a breast-fed infant
with a vegan mother or a mother with B12 deficiency

Recognize the genetically determined disorders of vitamin B12
malabsorption

Know the association of small bowel bacterial overgrowth or surgery and
megaloblastic anemia

**(2). Clinical and laboratory features **

Know the clinical and laboratory features of pernicious anemia

Know the association of pernicious anemia with other autoimmune
phenomena

Know the clinical and laboratory features of the Imerslund-Graesbeck
syndrome Know the ages at which different disorders of vitamin B12
metabolism are first manifested

Know the morphology of peripheral blood smears and examinations of the
bone marrow in megaloblastic anemia

**(3). Diagnosis **

Know the indications for the Schilling test and how to interpret results
of the test

**(4). Treatment **

Understand the principles of treatment for the vitamin B12 deficiency
syndromes

Know the potential of folic acid to correct megaloblastic anemia but not
the neuropathy of pernicious anemia

**b. Folate deficiency **

**(1). Pathophysiology **

Understand the biochemical pathway of tetrahydrofolate metabolism that
is associated with megaloblastosis

Recognize the association of folic acid deficiency with anticonvulsant
therapy

Know that megaloblastic anemia associated with goat milk ingestion is
due to folic acid deficiency

Recognize inborn errors of folate metabolism

**(2). Clinical and laboratory features **

Understand the progression of laboratory abnormalities in folate
deficiency

Recognize the clinical and laboratory characteristics of dietary folate
deficiency

**(3). Diagnosis **

Know the limitations of measuring serum folate concentrations in the
diagnosis of folate deficiency

**(4). Treatment **

**c. Other causes of megaloblastosis **

Recognize disorders other than folate or B12 deficiency causing
megaloblastosis

**8. Blood loss anemia **

**a. Fetomaternal hemorrhage **

Recognize the clinical and laboratory characteristics of fetomaternal
hemorrhage

**b. Blood loss in the infant and child **

Recognize the clinical signs of acute hypovolemia secondary to blood
loss and differentiate them from hemolytic anemia

Recognize the need for iron therapy in hemolytic anemias associated with
intravascular hemolysis

**9. Congenital dyserythropoietic anemias **

Recognize the clinical and laboratory manifestations of congenital
dyserythropoietic anemia

Know the association of dyserythropoietic anemia type II with
multinucleated erythroblasts

**10. Congenital sideroblastic anemia **

Know the clinical and laboratory manifestations of congenital
sideroblastic anemia

**C. Other disorders affecting erythrocytes **

**1. Erythrocytosis **

Know the laboratory parameters associated with conditions characterized
by an increased hgb concentration

Correlate laboratory parameters (Hct, MCV, reticulocyte count) with
clinical situations associated with erythrocytosis

**a. Maternal-fetal and fetal-fetal transfusions **

Know how to document a maternal-fetal hemorrhage or twin-twin
transfusion causing erythrocytosis

Recognize erythrocytosis as a feature of the twin transfusion syndrome

**b. High oxygen affinity hemoglobins **

Know the relationship of high oxygen-affinity hgb with erythrocytosis

**c. Other causes of erythrocytosis **

Differentiate relative erythrocytosis from erythrocytosis due to an
increase in erythrocyte mass

Know the causes of primary and secondary erythrocytosis

**2. Methemoglobinemia **

**a. Toxic methemoglobinemia **

Know the basis for the increased vulnerability of infants to
methemoglobinemia

Know the mechanism for methemoglobin reduction in normal erythrocytes

Associate the treatment failure of methemoglobinemia with methylene blue
and G6PD deficiency

Know that consumption of well water contaminated with nitrates causes
methemoglobinemia in infants but not in older children and adults

Know the association of methemoglobinemia with diarrhea and acidiosis in
young infants

**b. Congenital cytochrome b5 reductase deficiency **

Know how to differentiate methemoglobinemia due to deficient
methemoglobin reduction from methemoglobinemia due to increased
methemoglobin production

**c. Hgb M disorders 3. Porphyrias **

Know the differential clinical characteristics of congenital
erythropoietic porphyria

**II. Leukocytes **

**A. Granulocytes **

**1. Normal granulocyte characteristics **

Know the age- and race-related normal values of granulocytes

Know the life cycle of granulocytes

Know the changes associated with systemic diseases, ie, cell numbers and
morphology

Understand and know when to order various tests of neutrophil function

**2. Myelopoiesis **

**a. Stage of myeloid maturation **

Understand progenitor cell differentiation and maturation

Recognize morphologic features of myeloid precursors

**b. Cytokine stimulation **

Understand the action of cytokines on primitive myeloid progenitors and
precursors and mature cells

**3. Granules **

Recognize the different granulocytic granules and know their content and
functions

Know the diseases associated with abnormalities of granule function and
morphology

**4. Biochemistry **

Understand the various stimulators of biochemical reactions in
granulocytes including degranulation, oxidative burst, phagocytosis, and
killing

1.  **Neutrophil kinetics **

2.  **Functional properties **

Understand the factors that regulate granulopoiesis

**a. Chemotaxis, motility, and ingestion **

Know the factors that mediate adherence in granulocyte function

Know the factors that influence the movement of phagocytes
(chemoattractants)

Know the factors that influence phagocytosis

**b. Opsonins **

Know the different opsonins and their role in neutrophil chemotaxis,
ingestion, and killing

**c. Degranulation (see II.A.2) **

Know the different stimulators and inhibitors of granulocyte
degranulation and granular fusion and the mechanism involved in
degranulation and granular fusion

**d. Killing of ingested microorganisms **

Understand the mechanisms of phagocyte-mediated oxygen toxicity

**7. Neutropenia **

**a. General **

Know the appropriate clinical and laboratory evaluation of childhood
neutropenia

Understand and differentiate the childhood presentations of neutropenia

**b. Congenital neutropeni**a\
**(1). Kostmann syndrom**e

Know the clinical presentation, molecular biology, genetics, and bone
marrow findings in Kostmann syndrome

Know the treatment options for Kostmann syndrome

Know the natural history of Kostmann syndrome

Know the risk of secondary leukemia and the role of G-CSF receptor gene
mutations

**(2)**. ** Reticular dysgenesis (3). Cyclic neutropenia **

Know the clinical presentation, molecular biology, genetics, bone marrow
findings, and therapy of cyclic neutropenia

**(4). Shwachman-Diamond syndrome **

Know the clinical presentation, molecular biology, genetics, bone marrow
findings, and therapy of Shwachman-Diamond syndrome

**(5). Benign congenital neutropenia **

Know the clinical presentation, genetics, bone marrow findings, and
therapy of benign congenital neutropenia

Understand and differentiate the childhood presentations of benign
congenital neutropenia

**(6). Myelokathexis/WHIM syndrome **

Know the clinical presentation, laboratory findings, genetics, and
treatment for the myelokathexis (WHIM) syndrome

**c. Acquired neutropenia (1). Isoimmune and alloimmune neutropenia
**Know the presentation and pathophysiology of alloimmune neutropenia in
newborn infants

Understand the role of specific antigens in alloimmune neutropenia

Know the natural history of, complications of, and therapy for
alloimmune neutropenia

**(2). Autoimmune neutropenia **

Understand the use and limitations of antineutrophil antibodies in the
diagnosis and treatment of autoimmune neutropenia

Know the natural history of autoimmune neutropenia in infancy

Understand the various therapeutic strategies for autoimmune neutropenia

Recognize autoimmune neutropenia as a manifestation of autoimmune
disorders

Know the clinical presentation of autoimmune neutropenia

**(3). Postinfectious neutropenia **

**(4).**

**(5). **

**(6). **

**(7). **

**(8). **

**(9). **

1.  ** Neutrophilia **

2.  ** Eosinophilia **

Know the viruses commonly associated with infection-related neutropenia

Know the bacteria commonly associated with postinfectious neutropenia

Know the natural history of infection-related neutropenia

** Drug-induced neutropenia **

Know the agents commonly involved in drug- induced neutropenia

Know the mechanisms of bone marrow suppression

Understand the therapeutic use of cytokines in drug-induced neutropenia

**Neutropenia associated with nutritional deficiency **

Recognize neutropenia as a feature of copper, B12, or folate deficiency

**Neutropenia associated with immune defects **

Recognize that neutropenia is a feature of immune defects

**Neutropenia associated with metabolic diseases **

Recognize neutropenia as a feature of glycogen storage disease IB and
other metabolic disorders

**Neutropenia associated with ECMO and bypass surgery and hemodialysis
**

Recognize that severe transient neutropenia is associated with ECMO,
bypass surgery, and hemodialysis and understand the mechanism

**Neutropenia associated with hypersplenism **

Recognize that hypersplenism can present with neutropenia

Know the effect of glucocorticoids on the absolute neutrophil count

Know the major causes of acute and chronic neutrophilia

Know the significance of neutrophilia in newborn infants

Know the disorders associated witheosinophilia Know the correlation of
eosinophilia with specific parasitic infestations

Know the clinical consequences of hypereosinophilia

**10. Basophils **

Know the disorders associated with basophilia

**11. Defects of neutrophil function **

**a. General **

Know the clinical features associated with various neutrophil function
disorders

**b. Chédiak-Higashi syndrome **

Associate the morphologic abnormality of neutrophil granules with the
clinical presentation of Chédiak-Higashi syndrome

Know the molecular biology and genetics of Chédiak-Higashi syndrome

Know the associated clinical and laboratory findings in Chédiak-Higashi
syndrome Understand the immunologic and hemostatic deficits associated
with Chediak-Higashi syndrome

**c. Leukocyte adhesion deficiency **

Know the genetics, clinical presentation of, and therapy for leukocyte
adhesion deficiency

Understand the molecular basis of leukocyte adhesion deficiency

Know the appropriate laboratory evaluation of leukocyte adhesion
deficiency

Know the complications of leukocyte adhesion deficiency

Know the various forms of leukocyte adhesion deficiency

**d. Chronic granulomatous disease **

Differentiate the granulocyte functional abnormalities associated with
altered killing of staphylococci

Know the current approaches to the diagnosis and treatment of chronic
granulomatous disease

Know the organisms that are poorly killed by the granulocytes of Know
the clinical manifestations, molecular biology, and inheritance patterns
of chronic granulomatous disease

**e. Hyperimmunoglobulinemia E syndrome **

Know the clinical manifestations of hyperimmunoglobulin E syndrome

Understand the laboratory evaluation and differential diagnosis of
hyperimmunoglobulin E syndrome

**f. Myeloperoxidase deficiency **

Know the genetics, clinical presentation, and laboratory evaluation of
neutrophil myeloperoxidase deficiency

**g. Hereditary/morphologic abnormalities of neutrophils (1).
Pelger-Huet anomaly **

Recognize the morphologic alteration of neutrophils associated with the
Pelger-Huet anomaly

Recognize the conditions associated with Pelger-Huet anomaly

**(2)**. ** May-Hegglin anomaly **

Know the morpholic features that characterize the May-Hegglin anomaly

**B. Monocytes, macrophages, and antigen-processing cells **

**1. Normal monocyte characteristics **

Distinguish monocytes from lymphocytes and granulocytes based on
cytochemical reactions

Know the surface markers and membrane antigens that characterize
monocyte-macrophages

Know the life cycle of normal monocyte-macrophages

Understand the factors that regulate monocyte production, including
GM-CSF and M-CSF

Recognize macrophages or neutrophils containing ingested microorganisms

**2. Function and metabolism **

Understand the role of monocyte-macrophage cells in maintaining the
integrity of the immune system

Distinguish the phagocytic behaviors of monocyte- macrophages from
neutrophils Understand the role of macrophages in the inflammatory
response

Know the secretory products of monocyte-macrophages Know the effects of
granulocyte-macrophage colony- stimulating factor on mononuclear
phagocytes

**3. Monocytosis **

Know the disorders associated with monocytosis

**4. Storage diseases **

Know the bone marrow histology of storage disorders

Understand how to diagnose Gaucher disease, including recognizing
Gaucher cells in bone marrow Know the recommended treatment for Gaucher
disease

**5. Dendritic cells **

Know the surface markers and membrane antigens that characterize
dendritic cells

Understand the function of dendritic cells

**C. Lymphocytes **

**1. Normal morphology and age-related values **

Know the normal age-related circulating blood lymphocyte values

Know the light, ultrastructure, and scanning electron microscopy
characteristics of lymphocytes and plasma cells

Know the characteristics which differentiate T lymphocytes from B
lymphocytes

**2. Surface membrane antigens and gene rearrangements **

Know the surface antigens associated with B-cell development

Know the surface antigen expression at various stages of thymocyte
differentiation

Know the surface antigen expression and T-cell receptor gene
rearrangements during T-cell ontogeny

**3. Kinetics **

Understand the circulation of T- and B-cells

Know the life history of lymphocytes

**4. Biochemistry **

**a. Interleukins **

Differentiate the effect of interleukins on T cells, B cells, monocytes,
and macrophages

Understand that granulocyte-macrophage colony- stimulating factor
augments antibody-dependent cell- mediated cytotoxicity

Understand the sequence of events in the activation and replication of
lymphocytes

**5. Function **

**a. B cell**s\
**(1). Immunoglobulin**s

Understand the regulation of immunoglobulin synthesis

Know the genetics of immunoglobulin production

Know the biological properties of human immunoglobulins

Understand the mechanisms associated with the generation of antibody
diversity

**b. T cell**s\
**(1). Recepto**r

Understand the T-cell receptor/CD3 complex

Understand the function of CD4-positive and CD8-positive lymphocytes

**(2)**. **Natural killer cells **

Know the morphology of natural killer cells

Understand the biology of natural killer cells and major
histocompatibility complex restriction

**(3). Major histocompatibility complex **

Differentiate the functions of Class I, II, and III major
histocompatibility complex proteins

Understand the process of antigen presentation

**6. Lymphocytosis **

Know the causes of lymphocytosis

**7. Lymphopenia **

Know the causes of lymphopenia

Know the relationship between skin test anergy and lymphopenia

**8. Alterations in systemic disease **

**a. Mononucleosis syndromes **

Know the etiology, pathogenesis, and clinical features of mononucleosis
syndromes

Recognize the heterophil-negative mononucleosis syndromes

Establish the diagnosis of infectious mononucleosis (Epstein-Barr virus
infection) Know the indications for use of corticosteroids in infectious
mononucleosis

Understand the pattern of immunologic response to Epstein-Barr virus
infection

Associate the morphologic abnormality of lymphocytoses with the clinical
presentation of infectious mononucleosis

**b. Congenital immunodeficiency diseases **

Differentiate between severe combined immune deficiency, adenosine
deaminase deficiency, DiGeorge syndrome, and Wiskott-Aldrich syndrome

Know the opportunistic organisms to which patients with T- and B- cell
immunodeficiency are susceptible

**c. Lipid storage disorders **

Recognize vacuoles in lymphocytes as a feature of lipid storage
disorders

**III. Hemostasis **

**A. Platelets **

**1. Normal platelet characteristics **

**a. Normal values **

Recognize spurious thrombocytopenia

Know the limitations of electronic platelet counting

Know the normal values for platelet counts in neonates and children

Understand the value of the peripheral blood smear in estimating the
platelet count

**b. Platelet production **

Know the growth factors which regulate megakaryocyte and platelet
production

Know the significance of platelet size

**c. Platelet kinetics **

Know the survival of platelets in vivo under normal conditions and in
different thrombocytopenic states

Know the mechanism of platelet destruction under normal conditions

Know the normal distribution of platelets between circulation and the
spleen

1.  **d. Platelet structure **

2.  **e. Platelet function **

Know the significance of platelet adhesion and aggregation and their
overall relationship to hemostasis

Know the content and function of substances released from platelet
granules

Know the relationship of platelet membrane receptors and their
associated ligands in platelet aggregation and adhesion

Know the relationship of von Willebrand factor, collagen, and their
receptors in platelet adhesion

Know the structural and biochemical changes that occur during platelet
activation

Know how prostaglandin metabolism in endothelial cells affects platelet
function

Know the role of cyclic adenosine monophosphate (cAMP) in platelet
activation

**f. Laboratory assessment of platelet function **

Know how to interpret the results of platelet aggregation studies

Understand the diagnostic utility and limitations of a prolonged
bleeding time

Know the relationship between platelet age and function

Know how to formulate an approach to the evaluation of a patient with
increased bleeding time

**2. Thrombocytopenia **

**a. General considerations **

Know the general mechanisms and clinical presentation of
thrombocytopenia in the setting of impaired production, increased
destruction, and abnormal distribution

Know the clinical features of bleeding associated with thrombocytopenia
as compared to those associated with coagulation factor deficiencies

Know the usefulness of the bone marrow aspirate and cytogenetics to
differentiate the mechanism of thrombocytopenia

**b. Thrombocytopenia in the newborn period **

**(1). General considerations **

Know the differential diagnosis of neonatal thrombocytopenia

Know that consumptive thrombocytopenia is seen with conditions such as
necrotizing enterocolitis (NEC), or respiratory distress syndrome (RDS)

Know the characteristics of neonatal platelet function

**(2). Infection **

Know the incidence and course of thrombocytopenia with bacterial sepsis

**(3). Neonatal alloimmune thrombocytopenia (NAIT) **

Know the major platelet antigens involved in neonatal alloimmune
thrombocytopenia

Know the risks and benefits of different therapeutic options and risk
factors associated with each option for treating bleeding in neonatal
alloimmune thrombocytopenia

Know the clinical and diagnostic features of neonatal alloimmune
thrombocytopenia

Know the fetal and maternal management of subsequent preganancies after
an initial child with neonatal alloimmune thrombocytopenia, and the role
of paternal platelet typing

Know the influence of ethnicity on the antigens involved in neonatal
alloimmune thrombocytopenia

Know the role of HLA type and other factors in maternal sensitization to
platelet alloantigens

Know the clinical presentation and timing of intrauterine intra- cranial
hemorrhage and its prognostic significance

**(4). Neonatal autoimmune thrombocytopenia **

Know the risks and proper management of an infant born to a mother with
immune thrombocytopenia

Know the issues involved in the management of an infant born to a
splenectomized mother with autoimmune thrombocytopenia

Know the clinical and diagnostic features of neonatal thrombocytopenia
due to maternal immune thrombocytopenic purpura

Know how to evaluate and manage an infant born to a mother with systemic
lupus erythematosus

Know the maternal and fetal concerns involved in the management of
pregnancy and delivery in a mother with active immune thrombocytopenic
purpura

Know the evaluation and management of an infant born to a mother with a
history of chronic idiopathic thrombocytopenic purpura

**(5). Neonatal bone marrow abnormalities **

Know the different syndromes associated with decreased platelet
production in newborn infants

Know the clinical features, inheritance patterns, treatment, and
prognosis of newborn infants with thrombocytopenia-absent-radius
syndrome

Know the clinical features, treatment, and prognosis of infants with
amegakarycytic thrombocytopenia

Know the association of thrombocytopenia with other dysmorphic syndromes

**(6). Neonatal thrombocytopenia due to perinatal drugs **

Know how maternal complications and perinatal drugs are associated with
decreased platelets in her newborn infant

**(7). Miscellaneous causes of neonatal thrombocytopenia **

Know that neonatal thrombocytopenia may be a manifestation of occult
large vessel or catheter thrombosis

Know that neonatal thrombocytopenia can occur secondary to placental
vessel hemangiomas or thrombosis

Know that neonatal thrombocytopenia can occur with hemolytic disease of
the newborn

**c. Hereditary thrombocytopenia **

Know the inborn errors of metabolism associated with neonatal
thrombocytopenia

Know that neonatal thrombocytopenia can be a manifestation of certain
chromosomal abnormalities

Know the genetics and clinical and laboratory features associated with
macrocytopenias or giant platelet syndromes

Know the differential diagnosis of hereditary thrombocytopenia

Know which hereditary thrombocytopenias are associated with normal or
with impaired platelet function

Know that thrombocytopenia may be the first sign of Fanconi aplastic
anemia

Know that thrombocytopenia may be the major clinical abnormality of the
Wiskott-Aldrich syndrome

Know that platelets in Wiskott-Aldrich syndrome are smaller than normal

Know the clinical features, immunologic abnormalities, and prognosis
Know the presentation and genetics of X-linked thrombocytopenia and its
relationship to Wiskott-Aldrich syndrome and other X-linked syndromes

**d. Acquired thrombocytopenic states **

**(1). Idiopathic thrombocytopenic purpura (ITP) **

Know the mechanisms of platelet destruction in acute idiopathic
thrombocytopenic purpura

Know the methods to measure antiplatelet antibodies

Know the clinical course, laboratory features, therapeutic options, and
complications of therapy in acute idiopathic thrombocytopenic purpura

Understand the management issues and risks of splenectomy in childhood
idiopathic thrombocytopenic purpura

Know the clinical course, laboratory features, and therapeutic options
in chronic idiopathic thrombocytopenic purpura

Know the indications for bone marrow examination in idiopathic
thrombocytopenic purpura

Know the indications and limitations of the various antiplatelet
antibody assays

**(2). Drug-induced **

Know the mechanisms of drug-induced immune thrombocytopenia

Know the treatments (eg, drugs, immunizations) associated with immune
thrombocytopenia

Distinguish thrombocytopenia due to immune destruction from
thrombocytopenia due to impaired platelet production

**(3). Infection-related thrombocytopenia **

Know the mechanisms of thrombocytopenia in various bacterial and viral
infections

Know the viral infections that should be considered as causative factors
in children with immune thrombocytopenic purpura

Know the clinical features and management of HIV-related
thrombocytopenia

**(4). Thrombocytopenia associated with intravascular coagulation **

Know that thrombocytopenia is usually an important feature of
disseminated intravascular clotting

**(5)**. **Thrombocytopenia due to impaired platelet production **

Know that thrombocytopenia is a manifestation of aplastic anemia or bone
marrow infiltrative disorders

**(6)**. **Thrombocytopenia due to increased platelet
turnover/sequestration **

Know the evaluation and management of thrombocytopenia due to
hemangioma, with or without Kasabach-Merritt syndrome

**(7). Thrombocytopenia due to nutritional deficiencies **

Know that thrombocytopenia occurs in severe iron, folate, and vitamin
B12 deficiencies

**(8)**. **Thrombocytopenia associated with cardiovascular disorders **

Know that cyanotic heart disease may be associated with thrombocytopenia
and/or a functional platelet disorder

**(9). Thrombocytopenia associated with splenomegaly **

Know that an enlarged spleen may cause thrombocytopenia due to a shift
in the distribution of platelets from the circulation to the splenic
pulp

**(10)**. ** Dilutional thrombocytopenia **

Know that dilutional thrombocytopenia can occur when large volumes of
blood are tranfused without replacing platelets, including exchange
transfusions

**(11)**. ** Post-transfusion purpura **

Know the clinical features, pathophysiology, treatment, and incidence of
thrombocytopenia due to post-transfusion purpura

**(12)**. **Thrombosis associated with ECMO **

Recognize and know the mechanism of thrombosis associated with
extracorporeal circulation

**3. Thrombocytosis **

Know the disorders associated with reactive thrombocytosis Know the
conditions under which thrombocytosis may be associated with thrombotic
complications or hemorrhage

Know how to treat patients with thrombocytosis who have a propensity for
thrombosis

Know that thrombocytosis is a sign of asplenia

**4. Abnormalities of platelet function **

**a. Hereditary disorders of platelet function **

Know the mechanism for abnormal platelet function in the hereditary
platelet function disorders

Know what platelet aggregation curves are expected in hereditary
platelet function disorders

Know the molecular basis, clinical characteristics, laboratory features,
management, and inheritance pattern associated with Glanzmann
thrombasthenia

Know the molecular basis, clinical characteristics, laboratory features,
management, and inheritance pattern associated with Bernard-Soulier
syndrome

Know the clinical characteristics, laboratory features, management,
pathophysiology, and inheritance pattern of adenosine diphosphate
storage pool defect

Know the clinical characteristics, laboratory features, management, and
inheritance of platelet alpha-granule deficiency

**b. Acquired disorders of platelet functio**n\
**(1). Drug**s

Know the specific effect and duration of the action of aspirin ingestion
on platelet function tests

Know the duration of the effect of (nonaspirin) anti-inflammatory drugs
on platelet function

Know which commonly used drugs affect platelet function

**(2)**. ** Uremia **

Understand the therapeutic options available for improving platelet
function in patients with uremia

Know the relationship of impaired platelet aggregation to collagen in

**(3). Other **

Know the management of a patient with epistaxis, prolonged bleeding
time, and normal coagulation screening tests

**c. Treatment of platelet functional disorders **

Know the clinical situations which respond to DDAVP therapy

Know the role and risks of platelet transfusions in platelet function
disorders and how to monitor for those side effects clinically

**B. Coagulation **

**1. Physiology of coagulation, fibrinolysis, and the vessel wall **

**a. Contact activation **

Know the components of the contact activation system

Know the consequences of deficiencies in the contact activation system
on the measurement of the bleeding time and coagulation assays Know the
sequence of activation of the contact activation system Know the
inhibitors which regulate the contact activation system Know the
interaction between the contact activation system and the

fibrinolytic system

Know the interaction between the contact activation system and the
complement system Know the function of Factor XI in the coagulation
cascade

**b. Factor IX **

Know the age-related changes in Factor IX concentrations Know the site
of synthesis of Factor IX Know the half-life of Factor IX Know the role
of vitamin K in the synthesis of Factor IX and Factor IX

activity Know the mechanisms of activation of Factor IX Know the
function of Factor IX in the coagulation cascade Know the consequences
of deficiency of Factor IX on the laboratory

assessment of the bleeding time and clotting assays

**c. Factor VIII **

Know that DDAVP increases plasma Factor VIII concentration Know the
natural inhibitors that regulate the activity of Factor VIII Know the
mechanism of activation of Factor VIII Know the function of Factor VIII
in coagulation Know the consequences of a deficiency of Factor VIII on
the laboratory

assessment of hemostasis Know the normal value of Factor VIII in a
newborn infant Know the half-life of Factor VIII Know that Factor VIII
circulates as a complex with von Willebrand

factor

**d. Von Willebrand factor **

Know the sites of synthesis, storage, and release of von Willebrand
factor

Know the platelet aggregation patterns associated with the different
types of von Willebrand disease

Know the laboratory methods for measuring the concentration, structure,
and function of von Willebrand factor

Know the interaction between von Willebrand factor, platelets, and the
vessel wall

Know the importance of the structure of von Willebrand factor to its
function

Know the consequences of a deficiency of von Willebrand factor on the
laboratory assessment of hemostasis

Know the factors that affect the serum concentration of von Willebrand
factor

Know the half-life of von Willebrand factor

**e. Factor VII and tissue factor **

Know the functions of Factor VII/tissue factor in coagulation

Know the consequences of a deficiency of Factor VII on the laboratory
assessment of hemostasis

Know the age-related changes in Factor VII concentration Know the site
of synthesis of Factor VII Know the role of vitamin K in the synthesis
of functional Factor VII Know the half-life of Factor VII Know the
naturally occurring inhibitors of the tissue factor/Factor VII

complex

**f. Factor X **

Know the function of Factor X in coagulation Know the mechanisms of
activation of Factor X Know the consequences of a deficiency of Factor X
on the laboratory

assessment of hemostasis Know the age-related changes in Factor X Know
the site of synthesis of Factor X Know the role of vitamin K in the
synthesis of Factor X and Factor X

activity\
Know the half-life of Factor X

**g. Factor V **

Know the mechanism of activation of Factor V Know the function of Factor
V in coagulation Know the consequences of a deficiency of Factor V on
the laboratory

assessment of hemostasis Know the normal value of Factor V in a newborn
infant Know the half-life of Factor V Know the sites of synthesis of
Factor V Know the association of Factor V with platelets and endothelial
cells Know which inhibitors regulate the activity of Factor V

**h. Prothrombin and thrombin **

Know the mechanisms of activation of prothrombin Know the function of
prothrombin and thrombin in coagulation, natural

Know the consequences of a deficiency of prothrombin on the laboratory
assessment of hemostasis Know the age-related changes in prothrombin
concentration Know the sites of synthesis of prothrombin Know the role
of vitamin K on the synthesis of prothrombin and on

prothrombin activity Know the half-life of prothrombin Know the natural
inhibitors of thrombin Know the interaction of thrombin with platelets
and with the

endothelial cells

**i. Fibrinogen and fibrin **

Know the association of decreased fibrinogen with a decreased
erythrocyte sedimentation rate Know the basic structure of fibrinogen
and its gene control

Know the function of fibrinogen and fibrin in coagulation Know the
consequences of fibrinogen deficiency on the laboratory assessment of
hemostasis

Know the normal value of fibrinogen in a newborn infant Know the sites
of synthesis of fibrinogen Know the half-life of fibrinogen Know the
interaction of fibrinogen with platelets Know the screening tests for
fibrinogen deficiency and dysfunction

**j. Factor XIII **

Know the association of Factor XIII deficiency with poor wound

healing Know the consequences of a deficiency of Factor XIII on the
laboratory assessment of hemostasis

Know the structure and mechanism of activation of Factor XIII Know the
function of Factor XIII on coagulation Know the function of Factor XIII
in fibrinolysis Know the age-related changes in Factor XIII
concentration Know the half-life of Factor XIII Know the sites of
synthesis of Factor XIII Know the laboratory test for Factor XIII
deficiency

**k. Fibrinolysis **

Know the mechanisms of activation of plasminogen Know the sites of
storage and release of plasminogen Know the effects of DDAVP on the
tissue plasminogen activator Know the natural inhibitors of plasminogen
and its activators Know the laboratory tests which measure the
fibrinolytic system Know the age-related changes in plasminogen
concentration Know the fibrinolytic and anti-fibrinolytic drugs and
their mechanisms

of action

**l. Blood vessels **

Know that von Willebrand factor is secreted and stored by vascular
endothelium

Know which connective tissue diseases are associated with bleeding Know
the clinical features, laboratory manifestations, pathophysiology, and
complications of anaphylactoid (vascular) purpura and how it relates to
the hemostatic system

Know that thrombomodulin is an endothelial cell surface protein which

binds thrombin Know the role of heparan sulfate proteoglycans on the
endothelial surface in maintaining a nonthrombogenic surface

Know that endothelial cells synthesize and secrete tissue plasminogen

activator Know that endothelial cells synthesize and secrete plasminogen
activator inhibitor

Know that endothelial cells synthesize and secrete protein S Know that
the endothelium contains surface adhesion proteins and

**2. Disorders of coagulation (diagnosis and therapy) **

**a. General **

Understand which components of hemostatic system are measured by
screening tests (prothrombin time, partial thromboplastin time, thrombin
time, bleeding time, platelet function studies)

Know the effects of specimen collection artifacts on coagulation tests
(heparin, polycythemia, inadequate specimen)

Understand the limitations of and the use of preoperative screening
tests to rule out bleeding tendencies

Know which coagulation factors are acute phase reactants

**b. Acquired defects **

**(1)**. **Introduction and overview **

**(2). Disseminated intravascular coagulation (DIC) (neonatal and later)
**

**(a)**. **Pathophysiology and clinical features **

Recognize the relationship between fibrin monomer and intravascular
thrombin activation

Recognize the underlying conditions associated with disseminated
intravascular coagulation

Recognize and know pathophysiology of purpura fulminans

Know that disseminated intravascular coagulation does not occur as a
primary illness and may occur in severely ill patients without bleeding
or thrombosis

Know the triggering events (eg, endotoxin, viruses, procoagulants
released from the tissues, toxins) that activate blood coagulation

Know the mechanism by which triggering events lead to disseminated
intravascular coagulation

Know which protective mechanisms against disseminated intravascular
coagulation are physiologically impaired in sick neonates as compared to
older infants and children

Know that the clinical features of disseminated intravascular
coagulation can include hemorrhage (localized or diffuse), thrombosis,
hemolytic anemia, and organ dysfunction

**(b). Laboratory abnormalities **

Know which tests to perform and how to interpret their results in
patients with disseminated intravascular coagulation

Know that fibrinolysis usually accompanies disseminated intravascular
coagulation as a secondary event

Know which blood coagulation factors are reduced in the plasma of
patients with disseminated intravascular coagulation

Know the significance of the measurements of fibrinogen, fibrin
production, and degradation (eg, D-dimer, fibrin monomer, and
fibrinopeptides A and B)

**(c). Treatment and outcome **

Recognize the risks and benefits of drug therapy for disseminated
intravascular coagulation

Know the risks and benefits of blood component transfusions in patients
with disseminated intravascular coagulation

Know that control of the primary disorder is the main treatment for
disseminated intravascular coagulation

**(3). Vitamin K deficiency (neonatal and later) **

**(a). Pathophysiology **

Know that acarboxyprothrombin and noncarboxylated forms of other vitamin
K-dependent proteins can be measured in the plasma of patients with
vitamin K deficiency

Know vitamin K is fat soluble

Understand how carboxylation promotes the function of vitamin
K-dependent proteins

Know the mechanisms of action of vitamin K

Know that vitamin K tissue stores are limited and that patients can
become rapidly deficient

Know that human milk contains very little vitamin K

**(b). Etiology and clinical features **

Know the clinical conditions associated with vitamin K deficiency
Recognize the clinical features of late hemorrhagic disease of the
newborn infant, ie, occurring between 4 and 12 weeks of age

Know that vitamin K deficiency and hemorrhage may occur by 24 hours of
age in infants of mothers who have taken vitamin K antagonists

**(c). Laboratory findings **

Know the laboratory features of vitamin K deficiency

**(d). Treatment and response **

Know the efficacy and response time of different vitamin K preparations

Know that the response to intravenous vitamin K therapy is rapid and why
such a rapid response occurs

Know that hemorrhagic disease of the newborn can be prevented by vitamin
K shortly after birth

**(e). Drug-induced vitamin K deficiency **

Know that certain long-acting (super) warfarin-containing rat poisons
may cause a severe and prolonged coagulopathy following their ingestion
by an infant or young child

**(4). Liver disease (a). Pathophysiology **Know the multiple mechanisms
responsible for excessive bleeding in patients with severe liver disease

Know that the liver is the site of synthesis of most clotting factors

**(b). Laboratory features **

Know the laboratory test abnormalities most commonly seen in patients
with severe liver disease and clinical bleeding

**(c). Treatment **

Know the treatment options and outcomes of various therapeutic
modalities in patients who are bleeding from liver disease

Know why the use of prothrombin complex concentrates is contraindicated
in the treatment of bleeding due to liver disease

**(5). Blood coagulation inhibitors **

**(a). Heparins and heparin-like substances **

Recognize the clinical and laboratory correlates of iatrogenic bleeding
secondary to heparin administration

Know how to screen blood samples for the presence of heparin

Understand the structure and mechanisms of action of heparin and
heparin-like substances

Know the causes of heparin resistance

Recognize the effect of heparin on coagulation assays in specimens from
plasma, including those drawn from central catheters

Know the syndrome and treatment of heparin-induced thrombocytopenia,
including its association with thrombosis

**(b). Inhibitors against specific factors **

Recognize that inhibitors against specific blood coagulation factors in
a patient without hemophilia are rare during childhood

Know which passively acquired maternal coagulation inhibitors can
adversely affect the newborn infant

Know how to differentiate inhibitor from a factor deficiency on a
standard assay curve

**(c). Lupus-type anticoagulants **

Know what hemostatic defects associated with lupus-type anticoagulants
may cause either bleeding or thrombosis

Know that lupus-type anticoagulants are often transiently observed in
healthy children following a viral infection

Know the screening and specific laboratory tests to detect the
lupus-type anticoagulant, including the 1:1 mixing study

Know that the lupus-type anticoagulant is one of the most common causes
of a prolonged partial thromboplastin time during childhood

Know the management of patients with lupus-type anticoagulant

**(6). Miscellaneous acquired bleeding disorders **

Know that children with hematophagocytic syndromes may have a severe
coagulopathy characterized by marked hypofibrinogenemia

Know the mechanisms by which L-asparaginase effects the coagulation
system and the clinical consequences

Know the coagulation abnormalities in protein-losing enteropathy and
their clinical consequences

**(7)**. ** Anti-thrombin agents **

Know the benefits and duration of anti-thrombin agents

**c. Congenital hemorrhagic disorders (1). Factors VIII and IX **

Know the mode of inheritance for Factor VIII and IX deficiency

Understand the various tests to prenatally diagnose Factor VIII and IX
deficiency Understand the various tests to diagnose the carrier state
for Factor VIII

or Factor IX deficiency Know that some hemophilia carriers are
symptomatic Know the differentiating clinical and laboratory
characteristics of mild,

moderate, and severe hemophilia A and B

Know the limitations of the partial thromboplastin time in diagnosing
plasma concentrations of Factor VIII or Factor IX Recognize the clinical
features of retroperitoneal hemorrhage in a

patient with hemophilia

Understand the optimum replacement therapy in relation to severity and
location of bleeding in a patient with hemophilia Know the indications
for and potential complications of DDAVP in

patients with hemophilia

Know the advantages and disadvantages of specific therapies for Factor
VIII deficiency Know the probable causes of therapeutic failure in
Factor VIII

deficiency Understand the Bethesda assay using human and porcine Factor
VIII

Know the therapeutic approaches to a hemophiliac patient with inhibitor
Know the management of dental extractions in hemophiliac patients
Understand the relationship between age and the sites and frequency of
Know the therapeutic approaches to a hemophiliac patient with

hematuria Know the advantages and disadvantages of specific therapies
for Factor IX deficiency

Know the proper management and appropriate pre- and postoperative

treatment for a patient with Factor VIII or IX deficiency Understand the
possible indications for and implications of prophylaxis in Factor VIII
and IX deficiencies

Understand the managment approaches to chronic arthropathy in a

patient with hemophilia Know the diagnostic and therapeutic approaches
for hepatitis in a patient with hemophilia

Understand the management principles of hemophilia in a neonate or young
infant Know the risk factors for inhibitor development

Recognize that inhibitors may be transient Know the clinical indications
for the use of human recombinant activated Factor VII concentrate

Know the risks of using human recombinant activated Factor VII
concentrate Understand the molecular basis for hemophilia

**(2). Von Willebrand disease **

Recognize the clinical features of von Willebrand disease

Know the relationship of decreased von Willebrand antigen with von
Willebrand disease Correlate the response to DDAVP with various types of
von

Willebrand disease

Know the therapeutic options for the treatment of severe von Willebrand
disease Know how to diagnose and treat subtypes of von Willebrand
disease Know the inheritance patterns of von Willebrand disease Know the
effect of blood type and other factors on von Willebrand antigen
concentration

**(3)**. **Other inherited coagulation disorders **

Know the laboratory test for alpha-2-antiplasmin deficiency

Recognize the bleeding patterns in less common coagulation defects (eg,
Factors II, V, VII, X, XI) Understand the laboratory features and
clinical patterns associated with

the following coagulopathies: Factors V, XII, XI; prekallikrein
deficiency; and high-molecular-weight kininogen

Know the appropriate therapy for Factor XIII deficiency Recognize the
clinical features of afibrinogenemias and dysfibrinogenemias

Know how to investigate the cause of a prolonged thrombin time

Know the appropriate therapy for afibrinogenemia and dysfibrinogenemia
Know the inheritance pattern for afibrinogenemia and

dysfibrinogenemia Understand that clinical bleeding does not accur with
prekallikrein

deficiency, high-molecular-weight kininogen deficiency, or Factor XII
deficiency Know the inheritance pattern for Factor XIII deficiency

**d. Hypercoagulable thrombotic states (1). General **

Know the important antithrombotic properties of vascular endothelium

Know that removal of activated coagulation factors by the liver is
important in preventing thrombosis

Know that estrogen-containing contraceptives are associated with an
increased risk of venous thromboembolism, stroke, and acute myocardial
infarction

**(2)**. ** Diagnosis **

Know how to diagnose a hypercoagulable state

For each of the known hereditary thrombotic states, know how to diagnose
the defect in infants and older children Understand the clinical
manifestations of antithrombin III and proteins

Know how to evaluate a child with established deep venous thrombosis of
unknown cause (laboratory tests, imaging)

Know how the normal concentrations of hemostatic factors in neonates
complicates the diagnosis of hypercoagulable states

Know the predisposing causes to deep venous thrombosis in infants,
children, and adolescents

Know the acquired conditions that have been associated with venous and
arterial thromboembolism

Know the clinical signs and symptoms of venous thrombosis in children

Know the clincial signs and symptoms of pulmonary embolism in children

Know the laboratory measures important in evaluating a child with venous
thrombosis and pulmonary embolism

Know the clinical presentation, laboratory features, and epidemiology of
activated protein C resistance (Factor V Leiden)

Know the problems inherent in diagnosing hypercoagulable states in
patients receiving coumadin

Know the clinical presentation and laboratory diagnosis of patients with
prothrombin mutations

Know the clinical presentation and laboratory diagnosis of patients with
MTHFR mutations

**(3). Treatment **

Know the treatment of a hypercoagulable state in a newborn infant

Know the action of anticoagulant drugs used in thrombotic states or in
patients with thrombophilia Recognize the embryopathic potential of
warfarin therapy Know the indications for and treatment of acquired
hypercoagulable

states

Know the mechanism of action of warfarin and other vitamin K antagonists
used as anticoagulants for therapeutic purposes Recognize the
association of skin necrosis with warfarin therapy in

patients with heterozygous protein C deficiency Know the indications for
use of vitamin K antagonists

Know the drugs which interact with the vitamin K antagonists Know how to
monitor heparin and low-molecular-weight heparin therapy

Know the indications for and risks of using fibrinolytic therapy Know
how to monitor fibrinolytic therapy Know the benefits, pharmakokinetics,
and monitoring of anti-thrombin

agents Know the various means to reverse vitamin K antagonists Know the
clinical presentation, diagnosis, and management of

heparin-induced thrombocytopenia

**IV. Pediatric Transfusion Medicine **

**A. Collection and storage characteristics **

**1. Erythrocytes (liquid storage) **

Know the biochemical changes and changes in oxygen affinity that

occur during erythrocyte storage Know that washed erythrocytes can be
stored for up to 24 hours before expiration

Know that erythrocytes can be stored for up to 28 days after irradiation

Know that plasma potassium concentration increases more rapidly if
erythrocytes are irradiated prior to storage Know that 2,3-DPG
concentrations in donor cells are restored within 24

hours after transfusion Know the storage time of erythrocytes

**2. Platelets **

Recognize the need for constant agitation during storage of platelets

Know the proper storage temperature for platelets

Know that single-donor platelets obtained by apheresis have the
equivalent of multiple random donor platelet units Know the storage time
of platelets

**3. Leukocytes **

Know the techniques for collecting granulocytes and the shelf-life of
granulocytes

**4. Plasma **

Understand the process of collection and separation of plasma

Know the different coagulation and anticoagulation proteins present in
fresh frozen plasma

**5. Plasma-derived products **

Understand the process of manufacturing Factor VIII concentrate,
prothrombin complex concentrate, and activated prothrombin complex
concentrate, and coagulation Factor IX

Understand the methods of viral inactivation used in the production of
the different plasma-derived products, including heat, solvent-detergent
treatment, and nanofiltration

Know the viruses that are not effectively attenuated or removed by the
various methods of treatment of plasma-derived products

Know the factor/factors present in the different plasma-derived products

Understand the methods of viral inactivation used in the production of
the different plasma-derived products

Understand the process of manufacturing cryoprecipitate

**B. Typing and crossmatching for transfusion **

**1. Erythrocytes **

Know the biochemical features of the antigens of the ABO blood group and
the Rh system

Know the effect of a positive antibody screen on same-day surgery

Recognize the consequences of major racial erythrocyte antigen frequency
differences

Know why women should be screened early in gestation for minor group
antibodies

Be able to interpret the results of direct and indirect antiglobulin
tests

Know the common alloantibodies that develop in children with sickle cell
disease receiving transfusions

**2. Platelets C. Indications for transfusion **

**1. Whole blood **

Know the indications for transfusion of whole blood (e.g., rapid blood
loss)

**2. Packed erythrocytes **

Recognize that washing erythrocytes causes loss of red cells

Know the clinical indications for leukocyte reduction (e.g., decreased
risk of HLA sensitization, CMV transmission, and febrile transfusion
reactions)

Know the indications for packed erythrocytes

**3. Cryopreserved erythrocytes **

Know the value of frozen erythrocytes for patients with rare
compatibility problems

**4. Leukocytes **

Know the indications for use of granulocyte concentrates Know the
limitations and risks of using granulocyte concentrates

**5. Platelets **

Recognize indications for use of HLA-matched platelets and

crossmatched platelets Know the risk for alloimmunization in patients
needing repeated platelet transfusions

Know how to use the platelet count in determining the need for platelet

transfusion Know the in vivo recovery and survival of transfused
platelets in situations of decreased production and increased
destruction

Know the tests and observations required to diagnose alloimmunization
Recognize the indications for platelet transfusion

**6. Irradiated blood and blood components **

Know that all blood products for exchange transfusion in a neonate who
had an intrauterine transfusion must be irradiated to prevent
graft-versus-host disease

Know that blood products from all blood relatives must be irradiated to
prevent graft-versus-host disease, even in immunocompetent recipients

Understand the reasons for irradiation of transfused blood products

Know that irradiation of blood products is necessary to prevent
graft-versus-host disease

Know that leukoreduction does not effectively prevent graft-versus­host
disease

**7. Plasma **

Know the appropriate use of fresh frozen plasma

**8. Cryoprecipitate **Know the coagulation factors present in
cryoprecipitate Know the indications for the transfusion of
cryoprecipitate

**9. Coagulation factor concentrates **

Know the risks of using prothrombin complex concentrate

Know that parvovirus is resistant to solvent detergent and heating
methods of inactivation Know the coagulation factors present in
prothrombin complex

concentrate

Know the coagulation factors present in activated prothrombin complex
concentrate Know the clinical indications for the use of activated
prothrombin

complex concentrate Know the risks of using activated prothrombin
complex concentrate

**10. Immunoglobulin intravenously **

Know the therapeutic indications for intravenous administration of
immune globulin

Know the side effects of intravenous administration of immune globulin

**11. Therapeutic pheresis **

Recognize the hematologic indications for therapeutic plasma exchange

Know the indications for leukapheresis

Know the indications for erythrocyte exchange transfusions

**12. Autologous erythrocytes **

Recognize the usefulness of autologous erythrocytes in older children
scheduled for orthopedic surgery, scoliosis repair, marrow-donor
harvest, or other conditions

Recognize the usefulness of autologous erythrocytes for individuals with
rare blood groups or compatibility problems

**13. Directed donors **

Recognize that testing requirements often make it impossible to have
directed blood donors in emergent situations

Recognize that relatives should not be used as blood component donors
for potential HSCT recipients

Recognize that first-time donors exhibit higher rates of infectious
disease markers such as HIV, hepatitis B, and hepatitis C than repeat
volunteer donors

**D. Selection of appropriate blood type **

Know the proper approach to elective transfusion in a patient with a
known erythrocyte alloantibody

Know the appropriate use of erythrocyte products in patients with
autoimmune hemolysis

**E. Computation of dose, rate of delivery, modifying conditions **

Know the in vivo recovery and survival of infused Factor VIII, Factor
IX, fibrinogen, and prothrombin

Select and calculate the value of the appropriate erythrocyte product
for treating anemia

Calculate the dose of platelet concentrate for transfusion of patients
with thrombocytopenia

**F. Complications of blood and blood product transfusions **

**1. Transfusion-transmitted disease **

Know the risk of transmission of HIV-1, hepatitis B, and hepatitis C, in
transfusion of single-donor blood components Recognize the clinical and
laboratory manifestations of

transfusion-acquired CMV infection Know that frozen or filtered
(leukocyte reduced) erythrocytes will reduce transmission of
cytomegalovirus to recipients

Recognize the significance of chronic liver disease following hepatitis
C transmission by transfusion Know the relative risks for various
complications of blood transfusion Recognize parvovirus infection in
HIV-positive recipients

Know how to identify bacterial contamination of blood products Know the
most frequent pathogens that exist in refrigerated units of packed
erythrocytes

**2. Transfusion reactions - acute and delayed **

**a. Etiology **

Recognize the major factors leading to incompatible blood transfusion

Recognize that febrile reactions in chronically transfused patients may
be due to antileukocyte, anti-platelet, or anti-HLA antibodies Know that
anaphylactic reaction to blood transfusion is associated with

IgA deficiency in the recipient Understand the indications for
leukocyte-reduced transfusions Recognize that a fever may be the first
sign of a bacterially

contaminated transfusion or an acute hemolytic transfusion reaction Know
the cause of allergic transfusion reactions

**b. Pathogenesis **

Know that a compatible crossmatch does not prevent delayed hemolytic
transfusion reaction

Recognize that anamnestic antibody production causes delayed hemolytic
transfusion reactions

Know the incidence of alloimmunization to random donor platelets and the
effect of leukoreduction

Understand the pathogenesis and clinical symptoms of transfusion-related
acute lung injury

**c. Recognition **

Recognize the clinical presentation of a delayed transfusion reaction
due to minor blood group incompatibility

Recognize the complications of massive blood transfusion

**d. Management **

Know the proper therapeutic approach to a patient refractory to platelet
transfusions

Know the proper erythrocyte types for patient with delayed hemolytic
transfusion reaction

Know what to do if an Rh-positive blood product is administered to an
Rh-negative female patient of child-bearing age or younger

Know what to do if an Rh-positive blood product is administered to an
Rh-negative male patient

Know the management of acute hemolytic transfusion reaction

Know what precautions should be taken when transfusing patients with IgA
deficiency

**e. Prevention **

Know various strategies to prevent alloimmunization to platelets

**V. Pediatric Oncology **

**A. General **

**1. Epidemiology of cancer **

**a. Age-related incidence **

Know the age distribution of childhood tumors

Know the overall annual incidence of newly diagnosed cancer in children
0-14 years of age in the U.S.

Know the relative incidence of each of the major types of childhood
tumors in the U.S. in those \< 15 years of age and those 15-19 years of
age, respectively

1.  **b. Race-related incidence **

2.  **c. Predisposing factors **

Recognize the differences in childhood cancer based on race and/or
ethnic origin

  ---------- -----------------------------------------------------------------------------------------------------------------------------------------------------
  **(1).**   ** Genetic factors **
             
             Know the chromosomal abnormalities associated with specific malignancies
             
             Know the tumors associated with congenital or acquired disorders
             Know the tumors associated with Beckwith-Wiedemann syndrome
             
             Know which oncogenes and tumor suppressor genes are associated with various malignant diseases
             
             Know which tumors are associated with genomic imprinting
             
             Know the clinical and molecular genetic features of the Li-Fraumeni syndrome
             Know which tumors are known to occur in multiple members of a family
             Know which tumors occur with increased frequency in pediatric patients with neurofibromatosis type I
             Know which malignancies occur with increased frequency in children with Down syndrome
             
             Know which tumors are associated with an increased risk of another tumor type occurring in the same patient
             
  **(2).**   ** Chemical-related **
             
             Know the drugs associated with the development of specific malignancies (eg, phenytoin and androgens)
             
             Know the relationship between chemical carcinogens and cancer
             
             Know the chemotherapy agents used in treating childhood malignancies that can increase the risk for the development of specific second malignancies
             
  **(3).**   ** Environmental **
             
             Know the association between hepatitis B and hepatocellular carcinoma
             
             Know which tumors are associated with specific viruses
             
             Know which tumors are more common after exposure to ionizing radiation
             
  **(4).**   ** Immunologic **
             
  ---------- -----------------------------------------------------------------------------------------------------------------------------------------------------

**2. Tumor molecular and cellular biology **

Understand DNA ploidy and its prognostic significance Understand the use
and interpretation of Southern blot Understand lyonization and clonality
Understand the role of transcription factors and growth Understand
apoptosis Understand the use and interpretation of reverse transcription

polymerase chain reaction (RT-PCR)

Understand the use and interpretation of fluorescence in situ
hybridization (FISH) Know the molecularly characterized fusion genes
that correspond to the

more common chromosomal abnormalities in childhood leukemias and

solid tumors Know the difference between the \"two-hit\" and sporadic
mechanisms of carcinogenesis

Understand how constitutional chromosomal abnormalities can contribute
to an increased risk of development of specific types of malignancies

**3. Oncogenesis and cell growth regulation **

Know the mechanisms of proto-oncogene activation Understand the concept
of gene amplification Know the role of protein kinases in cell growth
and transformation Understand the interaction of growth factors and cell
surface receptors

in growth control Understand the use of clonogenic assays Identify the
phases and regulation of the cell cycle Understand principles used to
measure cell cycle kinetics Know the mechanism of action of tumor
suppressor genes Know the relationship between defects in DNA repair and
oncogenesis

Understand tumor suppressor genes that, when activated or deleted can
contribute to malignant transformation

Know that the molecular abnormality in BCR-ABL leukemia alters the
tyrosine kinase gene and that targeted chemotherapy can inhibit this
activity

**4. Radiation therapy **

**a. Principles of radiobiology **

Know the effects of hypoxia on tumor and normal tissue sensitivity to
radiation Know the advantages of and indications for using brachytherapy
Know the effects of radiation on cells in different phases

Know which variables influence the response to therapeutic radiation
Know the principles underlying the use of fractionated radiation therapy

Know the tumor characteristics that make it amenable to treatment with
stereotactic radiosurgery (\"gamma knife\") Know the difference between
conformal and conventional radiotherapy Know which chemotherapy agents
act as radiation sensitizers

**b. Complications of radiotherap**y\
**(1). Earl**y

Know the effects of varying doses of radiation on normal gonads Know the
effects of varying doses of radiation on the normal thyroid Know the
effects of varying doses and types of radiation on the normal

brain Know the effects of varying doses of radiation on the normal heart
Know the clinical, laboratory, and radiologic findings of radiation

pneumonitis Know the effects of varying doses of radiation on normal
kidneys Know the effects of varying doses of radiation on normal skin

Recognize the effects of varying doses of radiation on the
gastrointestinal tract Recognize the marrow toxicity of radiation
therapy Know the effects of varying doses of radiation on normal lungs

**(2). Late (a). Specific organ damage **

Know the long-term effects of varying doses of radiation on normal
gonads

Know the long-term effects of varying doses of radiation on the normal
thyroid

Know the long-term effects of varying doses of radiation on the normal
brain at various ages

Know the long-term effects of varying doses of radiation on normal bones
at various ages

Know the long-term effects of varying doses of radiation on the normal
heart

Know the long-term effects of varying doses on radiation on normal lungs

Know the long-term effects of varying doses of radiation on normal
kidneys

Know the long-term effects of varying doses of radiation on normal skin

Know the long-term effects of varying doses of radiation on normal
gastrointestinal tract

Know the long-term effects of varying doses of radiation on normal liver

**(b). Secondary tumors **

Know the risks of second malignant neoplasms according to radiation
dosage, specific tumors, and combined therapy

Know the frequency of tumor types seen as second malignancies

**5. Chemotherapy **

**a. Principles of chemotherapy **

Know the sites of action, metabolism, and toxicities of chemotherapeutic
agents

Recognize the effect of hepatic dysfunction on chemotherapeutic drug
toxicity and efficacy

Recognize the effect of renal dysfunction on chemotherapeutic drug
toxicity

Understand the principles of tumor cell kill kinetics by
chemotherapeutic agent

Know the phases of the cell cycle in which specific chemotherapeutic
agents exert their effects

Know that specific chemotherapeutic agents, as well as pubertal status,
increase the risk of infertility

Know the age-related physiologic differences that affect drug
distribution

Understand terms used to define pharmacokinetics (eg, clearance,
half-life, AUC, volume of distribution, bioavailability and
biotransformation)

Know the classification of chemotherapeutic agents by mechanism of
cytotoxicity

Know the drugs capable of causing skin damage when extravasated and
mechanisms of prevention

**b. Specific organ damage **

Know the appropriate methods of administration of sclerosing drugs to
prevent extravasation

**c. Principles of combination chemotherapy **

Know the rationale for combination chemotherapy

Know the rationale for adjuvant combination chemotherapy

Know the rationale for primary or neoadjuvant chemotherapy

**d. Principles of drug resistance **

Know the role of the mdr gene and p-glycoprotein in the development of
drug resistance

Know mechanisms by which cells develop resistance to anticancer drugs

Know strategies to overcome drug resistance

**e. Groups of chemotherapy agents (1). Alkylating agents **

Know which chemotherapy drugs are alkylating agents

Know the potential short- and long-term toxicities of the chemo­therapy
alkylating agents

**(2)**. ** Anti-metabolites **

Know which chemotherapy agents used in children with cancer are
anti-metabolites

Know the mechanism of action of the cancer drugs that are
anti-metabolites

Know that second malignant neoplasms have not been shown to be
associated with anti-metabolite therapy

**(3)**. **Naturally derived drugs **

Know the mechanisms of action of the chemotherapy agents that are
antibiotics

**(4)**. ** Topoisomerase inhibitors **

Know which chemotherapy drugs are topoisomerase inhibitors

Know the potential short- and long-term toxicities of chemotherapy
topoisomerase inhibitors

Know the mechanisms of action of chemotherapy topoisomerase inhibitors

**(5)**. ** Vinca alkaloids **

Know which chemotherapy drugs are vinca alkaloids

Know the potential short- and long-term toxicities of chemotherapy vinca
alkaloids

Know the mechanisms of action of chemotherapy vinca alkaloids

**f. Specific agents **

**(1)**. ** 6-Mercaptopurine **

**(a)**. **Clinical pharmacology and pharmacokinetics **

Understand the mechanism of action of 6-mercaptopurine

Know the effect of allopurinol on bioavailability of 6-mercaptopurine

Understand the pharmacogenetics of 6-mercaptopurine

**(b)**. **Complications and their management **

Recognize the pattern of hepatic toxicity associated with mercaptopurine

Know the potential toxicities associated with the use of
6-mercaptopurine

**(2). 6-Thioguanine (a). Clinical pharmacology and pharmacokinetics
**Know how thioguanine differs from mercaptopurine in metabolism and
bioavailability

**(b)**. **Complications and their management **

Know how thioguanine differs from mercaptopurine in toxicity

**(3)**. **Methotrexate (conventional and high-dose) (a). Clinical
pharmacology and pharmacokinetics **Understand the mechanism of action
of methotrexate Know the kinetics and therapeutic principles of
high-dose methotrexate with leucovorin rescue

Know that oral methotrexate absorption is highly variable

Know that renal dysfunction delays methotrexate clearance

Know what drugs interfere with methotrexate clearance

Know that methotrexate has little tendency to develop cross-resistance
with other drugs

Know the potential differences in methotrexate exposure by dosage,
route, and schedule of administration

**(b)**. **Complications and their management **

Recognize the clinical features of acute methotrexate toxicity

**(4). Cytarabine (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of cytarabine Know the metabolism
of cytarabine and impact of organ dysfunction and role of cytidine
deaminase

Know the potential differences in cytarabine exposure by dosage, route,
and schedule of administration

**(b). Complications and their management **

Know the toxicities of cytarabine and the impact of organ dysfunction

Know the neurologic toxicity that can occur with high dose cytarabine

**(c). Clinical use **

Know how cytarabine is used in the treatment of childhood malignancy

Know how cytarabine is used in CNS preventive therapy and in CNS relapse
in acute leukemia

Know that intrathecal cytarabine and intravenous high dose cytarabine
given in close proximity can cause transverse myelitus

**(5). Corticosteroids (a). Clinical pharmacology and pharmacokinetics
**Know the mechanism(s) of action of glucocorticoids and the role of
glucocorticoid receptors

Understand the pharmacology of different glucocorticoids

Know that systemic dexamethasone achieves higher CNS levels, as compared
to prednisone

**(b). Complications and their management **

Know the acute and delayed toxic effects of corticosteroids and the
differences between prednisone and dexamethasone

Know how to manage hyperglycemia associated with corticosteroid
administration

Know that corticosteroid therapy can be associated with mood changes
Know that osteoporosis is a complication of corticosteroid therapy and
that schedule of administration influences the likelihood of development
of this complication

Know that corticosteroids increase the likelihood of systemic bacterial
and fungal infections

Know the difference between potential toxicities of prednisone and
dexamethasone

**(c). Clinical use **

Know the role that systemic corticosteroids play in the treatment of
ALL, non-Hodgkin lymphoma, Hodgkin disease, and histiocytoses

Know how corticosteroids can be used in managing some of the
complications of cancer (ie, nausea and vomiting, increased intra­cranial
pressure, hypercalcemia, and allergic reactions)

**(6). Hydroxyurea **

Understand the mechanism of action of hydroxyurea

**(7). Anthracyclines (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of the anthracyclines Know the
metabolism of anthracyclines and the impact of organ dysfunction

Understand the pharmacologic differences of the anthracyclines

**(b). Complications and their management **

Know the toxicities (acute and delayed) of the anthracyclines and the
impact of organ dysfunction

Know the risk factors, presentation, evaluation, and management of acute
and late anthracycline cardiotoxicity

Know that anthracyclines potentiate radiation toxicity

**(c). Clinical use **

Know the principal clinical uses for each of the anthracyclines

**(8). Dactinomycin **

Know the mechanism of action of dactinomycin

Know the metabolism of dactinomycin and the impact of organ dysfunction

**(b). Complications and their management **

Know the toxicities of dactinomycin

Know that dactinomycin is a radiation sensitizer

**(c). Clinical uses **

Know the primary ways in which dactinomycin is used in the treatment of
childhood malignancies

**(9). Bleomycin (a). Clinical pharmacology and pharmacokinetics **Know
the metabolism of bleomycin and the impact of organ dysfunction

Know the mechanism of action of bleomycin

**(b). Complications and their management **

Recognize the pulmonary complications of bleomycin and the role of total
dose

Know the toxicities of bleomycin

Know that pulmonary bleomycin toxicity is related to the cumulative dose

**(c). Clinical uses **

Know how bleomycin is used in the treatment of childhood malignancies

**(10). Vincristine (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of vincristine

Know the metabolism of vincristine and the impact of organ dysfunction

**(b). Complications and their management **

**(c). Clinical use **

Understand the use of vincristine in the treatment of various childhood
malignancies

**(11)**. **Vinblastine (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of vinblastine Know the metabolism
of vinblastine

**(b)**. **Complications and their management **

Know that the dose-limiting toxicity of vinblastine is different from
that of vincristine

Know the toxicities of vinblastine

**(c). Clinical use **

Understand the clinical use of vinblastine in treating childhood
malignancies

**(12)**. **Cyclophosphamide (a). Clinical pharmacology and
pharmacokinetics **Know the metabolism of cyclophosphamide and the
impact of organ dysfunction

Know the mechanism of action of cyclophosphamide

Know that cyclophosphamide is both myelosuppressive and
immunosuppressive

Know the potential differences in cyclophosphamide exposure by dosage,
route, and schedule of administration

**(b)**. **Complications and their management **

Know the acute and long-term complications of cyclophosphamide therapy

Know the methods (and their rationale) used to reduce the risk of
hemorrhagic cystitis associated with the use of cyclophosphamide

Know the toxicities of cyclophosphamide

**(c). Clinical use **

**(13)**. **Ifosfamide (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of ifosfamide Know the metabolism
of ifosfamide Know the pharmacologic differences between
cyclophosphamide and ifosfamide

**(b)**. **Complications and their management **

Know know to diagnose and manage renal tubular dysfunction resulting
from ifosfamide therapy

Recognize the acute and late toxicities of ifosfamide therapy

**(c). Clinical use **

Understand the clinical uses of ifosfamide in treating childhood
malignancies

**(14). Mechlorethamine (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of mechlorethamine Understand the
history of mechlorethamine in treating childhood malignancies

**(b)**. **Complications and their management **

Know the acute and late toxicities of mechlorethamine therapy

Know the precautions needed for administration of mechlorethamine via
peripheral vein

Understand the potential late toxic effects of mechlorethamine

**(15). Carmustine (a). Clinical pharmacology and pharmacokinetics **

Know the metabolism of carmustine

Know the mechanism of action of carmustine

**(b)**. **Complications and their management **

Know that prolonged thrombocytopenia can occur with carmustine

**(c). Clinical use **

Understand the clinical uses of carmustine in the management of
childhood malignancies

**(16). Lomustine (a). Clinical pharmacology and pharmacokinetics **Know
the metabolism of lomustine Know the mechanism of action of lomustine
**(b). Complications and their management **Know the acute and late
toxicities of lomustine Know the relationship between progressive renal
atrophy and cumulative doses of lomustine

**(17)**. **Asparaginase (E. coli, Erwinia, PEG-E coli) (a). Clinical
pharmacology and pharmacokinetics **Understand the mechanism of action
of asparaginase Know that asparaginase can be used to modify the toxic
effects of methotrexate and cytarabine

Know the different preparations of asparaginase and their
pharmaco­kinetics

Know how PEG asparaginase is made from E. coli asparaginase

**(b)**. **Complications and their management **

Know the hemostatic complications of asparaginase therapy

Know that asparaginase causes allergic reactions

Know the toxicities of asparaginase

Recognize acute pancreatitis as a complication of asparaginase therapy

Know the treatment options (Erwinia or PEG) for a patient who is
allergic to E. coli asparaginase

Recognize hyperglycemia due to decreased insulin production as a
Recognize hypoalbuminemia as a complication of asparaginase therapy

Know that the majority of asparaginase-associated thromboses appear to
occur in patients with underlying inherited disorders of clotting

**(c). Clinical use **

Know the uses for asparaginase in the treatment of childhood
malignancies

**(18). Cisplatin (a). Clinical pharmacology and pharmacokinetics
**Understand the mechanism of action of cisplatin Know the metabolism of
cisplatin

**(b). Complications and their management **

Understand the measures to minimize the risk of renal toxicity from
cisplatin

Know the toxicities associated with cisplatin therapy

Know the type of hearing loss that occurs with cisplatin and that this
is related to cumulative dose

Know that hypomagnesemia is common after cisplatin therapy

Know the type of hearing loss that occurs with cisplatin

**(c). Clinical use **

Understand the uses of cisplatin in the treatment of childhood
malignancies

**(19). Carboplatin (a). Clinical pharmacology and pharmacokinetics **

Understand the mechanism of action of carboplatin

Understand the metabolism of carboplatin

**(b). Complications and their management **

Know the toxicities associated with carboplatin

Differentiate carboplatin toxicity from cisplatin toxicity

Know that carboplatin can cause delayed nadirs in platelet counts and

  ------------ -------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------
  **(20). **   **Busulfan **                                                                                                                                
                                                                                                                                                            
               **(a). **                                                                                                                                    **Clinical pharmacology and pharmacokinetics **
                                                                                                                                                            
               Understand the mechanism of action of busulfan                                                                                               
                                                                                                                                                            
               Understand the metabolism of busulfan, including the role of age                                                                             
                                                                                                                                                            
               **(b). **                                                                                                                                    **Complications and their management **
                                                                                                                                                            
               Know the toxicities associated with busulfan therapy                                                                                         
                                                                                                                                                            
  **(21). **   **Epipodophyllotoxins (VP-16, VM-26) **                                                                                                      
                                                                                                                                                            
               **(a). **                                                                                                                                    **Clinical pharmacology and pharmacokinetics **
                                                                                                                                                            
               Understand the mechanism of action of the epipodophyllotoxins                                                                                
                                                                                                                                                            
               Know the metabolism of the epipodophyllotoxins                                                                                               
                                                                                                                                                            
               **(b). **                                                                                                                                    **Complications and their management **
                                                                                                                                                            
               Understand the relationship between epipodophyllotoxins and secondary AML and distinguish it from secondary AML associated with alkylators   
                                                                                                                                                            
               Know the acute and late toxicities of epipodophyllotoxins                                                                                    
                                                                                                                                                            
  **(22). **   **Camptothecans (eg, topotecan, irinotecan) **                                                                                               
                                                                                                                                                            
               **(a). **                                                                                                                                    **Clinical pharmacology and pharmacokinetics **
                                                                                                                                                            
               Understand the mechanism of action of camptothecans                                                                                          
                                                                                                                                                            
               Know the metabolism of the camptothecans                                                                                                     
                                                                                                                                                            
               **(b). **                                                                                                                                    **Complications and their management **
                                                                                                                                                            
               Know the toxicities associated with the camptothecans                                                                                        
                                                                                                                                                            
               Know how to manage the diarrhea that can be associated with irinotecan                                                                       
                                                                                                                                                            
               **(c).**                                                                                                                                     ** Clinical use **
                                                                                                                                                            
               Know the uses of toptecan and irinotecan in the treatment of pediatric malignancies                                                          
                                                                                                                                                            
  **(23).**    ** Temozolomide **                                                                                                                           
                                                                                                                                                            
  ------------ -------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------

**(a). Clinical pharamcology and pharmakokinetics **

Know the metabolism of temazolomide

**(b)**. **Complications and their management **

Know the toxicities associated with temazolomide

Know that myelosuppression is the dose-limiting toxicity of
temazolomide, but is not cumulative

**(c). Clinical use **

Know how temazolomide is used in the treatment of childhood malignancies

**(24)**. **Procarbazine (a). Clinical pharmacology and pharmacokinetics
**

Know the mechanism of action of procarbazine

**6. Biologic response modifiers and immunotherapy **

Recognize the common side effects of interferon therapy

Know the rationale for the use and toxicity of G-CSF and GM-CSF in
patients receiving chemotherapy

Know the effects of erythropoietin on chemotherapy-induced anemia

Know the common side effects of 13-cis-retimoic acid and all trans
retinoic acid

Know the potential short- and long-term toxicities of G-CSF and GM-CSF

**B. Special diagnostic tests **

**1. Bone marrow aspiration and biopsy **

Recognize normal marrow osteoclasts or osteoblasts and differentiate
from tumor cells

Know that bone marrow aspiration alone is not adequate to rule out
involvement of marrow in Hodgkin disease

Know the definitions for M1, M2, and M3 marrow in the acute leukemias

**2. Diagnostic x-ray studies/scans **

Know the uses for gallium scans in assessing pediatric malignancies

Know the indications for PET scanning in assessing pediatric
malignancies

**3. Examination of the cerebrospinal fluid **

Know the risks associated with lumbar puncture for examination of
cerebrospinal fluid

Know the definitions of CNS 1, CNS 2, CNS 3 in the acute leukemias

**4. Biochemical markers **

Know the biochemical abnormalities that characterize different neoplasms

**5. Immunologic studies **

Understand the use of tumor-specific antigens for diagnostic and
prognostic purposes

**C. Leukemia, general **

**1. Incidence and epidemiology **

Know the incidence of acute lymphoblastic leukemia and acute myelogenous
leukemia, and the peak age at which each of these occur

Know the concordance rate of acute lymphoblastic leukemia and AML in
identical twins

Know the incidence of chronic myelogenous leukemia in children

**2. Leukemogenesis **

Know which constitutional and genetic conditions predispose to the
development of leukemia

Know that Down syndrome is associated with an increased incidence of
both acute lymphoblastic and acute nonlymphoblastic leukemia

Know the mechanisms by which immunodeficiency states can have increased
risk for cancer

**3. Cell biology **

**a. Cytogenetics and oncogenes **

Know the non-random chromosomal abnormalities associated with specific
phenotypes of acute lymphoblastic leukemia and acute myeloid leukemia
Know the molecular genetic abnormalities that correlate with the
non-random chromosomal abnormalities in acute lymphoblastic leukemia and
in acute myeloid leukemia

**b. Leukemic cell proliferation in vitro **

Know the available tests to evaluate cell kinetics in acute
lymphoblastic leukemia

**c. Biologic characterization **

Identify the cytochemical staining reactions and cell morphology of
different types of leukemia

Know the immunophenotypic differences between acute lymphoid and acute
myeloid leukemia

Know how to identify lymphoid/myeloid mixed lineage acute lymphoblastic
leukemia (morphologically and by immunophenotyping)

**D. Acute lymphoblastic leukemia (ALL) **

**1. Clinical and laboratory features **

Know the clinical and laboratory features of B-lineage (non-T, non-B)
acute lymphoblastic leukemia

Know the epidemiologic, clinical, and laboratory features that
characterize B-cell (Burkitt) acute lymphoblastic leukemia

Know the epidemiologic, clinical and laboratory features that
characterize T-cell lymphoblastic leukemia

Recognize the clinical complications related to the hematologic
abnormalities in acute leukemia

Recognize hypereosinophilia as a rare presenting feature of acute
lymphoblastic leukemia

**a. Pancytopenia **

Formulate a differential diagnosis for pancytopenia in childhood

**b. Bone pain **

Know that acute lymphoblastic leukemia can mimic juvenile rheumatoid
arthritis at presentation

Recognize the changes on x-ray studies of the skeleton in association
with acute lymphoblastic leukemia

Know the differential diagnosis of bone pain in a child

**c. Organomegaly **

Know the differential diagnosis of hepatosplenomegaly and pancytopenia

**d. Purpura **

Recognize how the clinical presentation of leukemia differs from
idiopathic thrombocytopenic purpura

**e. Leukocytosis **

Recognize the complications associated with hyperleukocytosis

Know the differential diagnosis of an absolute lymphocytosis

**f. Extramedullary leukemia **

Know the criteria for the diagnosis of central nervous system leukemia

Know the clinical manifestations of central nervous system leukemia Know
the significance of an enlarged testis in acute lymphoblastic leukemia

Know the prognostic implications of the duration of first remission for
a patient with CNS or testicular relapse

**2. Biologic characterization and classification **

**a. Morphology **

Distinguish between L1, L2, and L3 acute lymphoblastic leukemia cell
morphologies (FAB)

Know how to distinguish atypical lymphocytes from lymphoblasts

Know how to recognize granular acute lymphoblastic leukemia

1.  **b. Histochemistry and Biochemistry **

2.  **c. Immunologic classification **

Know that CD10+ lymphoblasts and T-lymphoblasts both have terminal
deoxynucleotidyl transferase activity

Understand the characteristics of CD10+ and CD10- lymphoblasts

Know which types of blasts express the HLADR antigen

Know the prognostic significance of biologic markers in acute
lymphoblastic leukemia

Know the significance of myeloid markers in acute lymphoblastic leukemia
and how to differentiate from mixed lineage lymphoid/myeloid acute
leukemia

Know the relationship between the expression of surface or cytoplasmic
immunoglobulin and specific subsets of leukemia

Know which molecular abnormalities correspond with specific prognostic
translocations

**d. Gene rearrangements **

Know the gene rearrangement characteristics of acute lymphoblastic
leukemia

**3. Prognostic factors **

Know the clinical and laboratory findings that influence prognosis in
acute lymphoblastic leukemia

Know that the significance of prognostic factors varies among different
treatment regimens

Know the National Cancer Institute consensus risk stratification of
acute lymphoblastic leukemia

Know how rapidity of response can be estimated by day 8 and day 15 bone
marrow aspirations during induction treatment for acute lymphoblastic
leukemia

**a. Initial leukocyte count **

Recognize initial leukocyte count as a risk factor in acute
lymphoblastic leukemia

**b. Age **

Recognize age as a significant risk factor in acute lymphoblastic
leukemia

Recognize age subgroups as a prognostic factor within infants \< 12
months of age at diagnosis

**c. Response to therapy **

Know that rapidity of response to chemotherapy in acute lymphoblastic
leukemia is predictive of outcome

Know the methods that can be used to measure rapidity of response in
acute lymphoblastic leukemia

Know the methods for quantitating minimal residual disease (MRD)

**d. Central nervous system **

Know which acute lymphoblastic leukemia immunophenotypes are most likely
to have CNS disease at diagnosis

**e. Immune parameters **

Know the significance of decreased serum immunoglobulin concentrations
in acute lymphoblastic leukemia, before or during therapy

**f. Cytogenetics **

Know the prognostic significance of cytogenetic and molecular diagnostic
findings in acute lymphoblastic leukemia

Know the prognostic significance of hyperploidy (greater than
approximately 52 chromosomes) in acute lymphoblastic leukemia

Know the prognostic significance of Ph chromosome in acute lympho­blastic
leukemia Know the prognostic significance of DNA index (DI) ploidy, and
how it correlates with chromosome count

Know that a \"normal\" leukemic cell karyotype implies inadequate
banding

Know the prognostic significance of hypodiploidy in acute lymphoblastic
leukemia

Know how the t(1;19) and t(4;11) correlate with the outcome in acute
lymphoblastic leukemia

Know the cytogenetic/molecular abnormalities most likely to be seen in
the leukemic cells of infants less than 12 months old with acute
lymphoblastic leukemia

Know that TEL-AML 1 is the molecular counterpart of t(12;21)

Know that the occult t(12;21) is the most common non-random cytogenetic
abnormality in B-lineage acute lymphoblastic leukemia

**g. Immunophenotype **

Know the prognoses of B-precursor, T-cell, and B-cell (Burkitt) acute
lyphoblastic leukemia, respectively

Know the non-random chromosome abnormalities seen in B-precursor,
B-cell, and T-cell acute lymphoblastic leukemia, respectively

**h. Glucocorticoid receptors **

Know which cells have glucocorticoid receptors

**4. Therapy **

**a. Chemotherapy **

Identify drugs most valuable for remission induction of acute
lymphoblastic leukemia

Recognize delayed intensification as a useful strategy for standard and
high risk acute lymphoblastic leukemia

Recognize the importance of risk-adjusted therapy for acute
lymphoblastic leukemia prognostic subgroups

Recognize the importance of post-induction intensification in acute
lymphoblastic leukemia treatment

**b. Irradiation **

Plan the radiation field for prophylactic irradiation of the cranium in
acute lymphoblastic leukemia

Know the complications of intrathecal methotrexate and central nervous
system irradiation in a patient with acute lymphoblastic leukemia

Know that intrathecal chemotherapy, extended throughout most of the
maintenance period, can negate the need for CNS irradiation in most
cases

**c. Late effects of therapy **

Recognize the late complications of cranial radiation for acute
lymphoblastic leukemia

Know that brain tumor is a late complication of cranial irradiation for
acute lymphoblastic leukemia

Know the relationship between treatments for acute leukemia and late
central nervous system complications

Know the effect of age on neuropsychologic function after cranial
irradiation in acute lymphoblastic leukemia

Know the risk of secondary acute myeloid leukemia after treatment of
acute lymphoblastic leukemia with topoisomerase II inhibitors and with
alkylators

**5. Management and treatment of complications of ALL **

Plan the management of a patient with pancytopenia during induction
therapy for acute lymphoblastic leukemia

Know the clinical and laboratory features of tumor lysis syndrome and
its prophylaxis and management

**a. Central nervous system (CNS) **

Know the management of central nervous system leukemia that develops
after prophylaxis

Plan the management of central nervous system leukemia detected at the
time of diagnosis of acute lymphoblastic leukemia

Plan the diagnostic evaluation and management of a patient with ALL who
has a seizure

**b. Testicular **

Plan the management of testicular relapse of acute lymphoblastic
leukemia

**c. Bone marrow relapse **

Know the importance of the duration of first remission as a prognostic
factor after relapse

Know the role of various types of stem cell transplantation in the
management of acute lymphoblastic leukemia relapse (see also section
VII.B., #909)

**E. Acute myeloid leukemia (AML) **

**1. Clinical and laboratory features **

Know the clinical presentations and FAB classification of AML

**a. Purpura **

Recognize the association of disseminated intravascular coagulation with
M3 acute myeloid leukemia

**b. Leukocytosis **

Recognize and manage the myeloproliferative syndrome in infants with
Down syndrome and differentiate it from acute myeloid leukemia

Recognize the potential complications of hyperleukocytosis in acute
myeloid leukemia

Plan the management of hyperleukocytosis in acute myeloid leukemia

**c. Central nervous system **

Recognize that central nervous system leukemia can complicate acute
myeloid leukemia

**d. Extramedullary disease **

Recognize that leukemia cutis can be the presenting feature of acute
myeloid leukemia in infants

Recognize chloroma as a manifestation of acute myeloid leukemia

**2. Biologic characterization and classification **

**a. Morphology **

Be able to recognize acute myeloid leukemia subtypes M0 through M7

Know the relationship between myelodysplastic syndromes and acute
myeloid leukemia

**b. Histochemistry, immunologic classification **

Recognize the clinical picture, morphologic characteristics, and blast
cell surface marker characteristics of acute megakaryocytic leukemia

Know that the M7 subtype is most common in children less than 3 years of
age, especially those with Down syndrome

**c. Cytogenetics and molecular genetics **

Correlate clinical characteristics with chromosomal abnormalities in
acute myeloid leukemia

Understand the significance of rearrangements of the ATRA receptor gene
in M3 acute myeloid leukemia

Recognize specific clinical syndromes associated with t(8;21), inv (16),
t(9;11), t(15;17), and monosomy 7 or 7q- in acute myeloid leukemia

Know the molecular abnormalities with which specific and recurring
chromosomal abnormalities are associated in acute nonlymphoblastic
leukemia

Know the characteristic chromosomal abnormalities in secondary acute
myeloid leukemia resulting from topoisomerase II inhibitors and from
alkylators, respectively

Know the clinical characteristics of secondary acute myeloid leukemia
resulting from topoisomerase II inhibitors and from alkylators,
respectively

**3. Prognostic factors **

Know prognosis of various French-American-British sub-types of acute
myeloid leukemia

Know the significance of tumor burden in acute myeloid leukemia

Know the prognostic significance of the non-random cytogenetic
abnormalities in acute myeloid leukemia

Know the prognostic importance of Down syndrome in acute
nonlymphoblastic leukemia

**4. Therapy **

Know that therapy is an important prognostic factor in acute myeloid
leukemia

**a. Chemotherapy **

Plan the further chemotherapy of a patient with acute myeloid leukemia
in remission and drug-induced neutropenia and thrombocytopenia

Know that all trans-retinoic acid induces remission of M3 acute
nonlymphoblastic leukemia

Know that high-dose cytarabine is effective in the treatment of acute
myeloid leukemia Know which drug combinations are most effective in the
treatment of acute myeloid leukemia

Know the role of CNS prophylaxis in the treatment of acute myeloid
leukemia

Know the evidence against the use of extended maintenance therapy for
AML

**b. Supportive care **

Know the various components of prophylactic and acute supportive care
for children with acute myeloid leukemia receiving treatment

**c. Hematopoietic stem cell transplantation (HSCT) (see also section
VII) **

Know the indications for allogeneic HSCT in AML

**F. Chronic myeloid leukemia **

**1. Clinical and laboratory features **

Know the clinical, laboratory, and prognostic features of adult chronic
myeloid leukemia and juvenile myelomonocytic leukemia

Recognize priapism as a presenting feature of chronic myeloid leukemia

Recognize the hematologic changes associated with a blast crisis in
chronic myeloid leukemia

Know that a blast crisis in chronic myeloid leukemia can involve other
cell lines

Know the biologic properties of the malignant cells in juvenile
myelomonocytic leukemia

Recognize the clinical and laboratory findings in monosomy 7 syndrome

Know the criteria for the diagnosis of juvenile myelomonocytic leukemia

**2. Biologic characterization and classification **

Know the association of bcr-Ab1 oncogene with chronic myeloid leukemia

Know the molecular difference in Ph+ chronic myeloid leukemia and Ph+
acute lymphoblastic leukemia in children

**3. Therapy **

**a. Chemotherapy **

Know the principles of chemotherapy to treat chronic myeloid leukemia

Plan the treatment of a blast crisis in a patient with chronic myeloid
leukemia

Know the principles of therapy for juvenile myelomonocytic leukemia and
for monosomy 7 syndrome

**b. Immunotherapy **

Know the therapeutic effects and side effects of alpha interferon in
treatment of chronic myeloid leukemia

**c. HSCT (See also section VII) **

Know the indications for and timing of HSCT in a patient with chronic
myeloid leukemia

Know the therapeutic options for a patient who has a recurrence of
chronic myeloid leukemia after HSCT

**G. Lymphomas **

**1. Hodgkin disease **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
Hodgkin disease

Know the epidemiologic, clinical, and laboratory features of Hodgkin
disease in children

Recognize that Hodgkin disease may occur in families

**b. Pathology **

Recognize the pathologic subtypes of Hodgkin disease relative to
prognosis

Know the biologic characteristics of the Reed-Sternberg cell

Know the incidence of each of the pathologic subtypes of Hodgkin disease
in children

Recognize the morphologic characteristics of Reed-Sternberg cells and of
Reed-Sternberg cell variants

**c. Clinical presentation **

Recognize the clinical presentation and pattern of spread of Hodgkin
disease by anatomic site

Know the differential diagnosis of acute lymphadenopathy and chronic
lymphadenopathy simulating malignant lymphoma

Recognize impaired cellular immunity in a patient with Hodgkin disease

Interpret results of immunologic studies in a patient with Hodgkin
disease

Know the most common clinical presentation of Hodgkin disease in
children

Know the laboratory abnormalities that may be seen in children with
Hodgkin disease at the time of diagnosis

**d. Diagnosis and staging **

Utilize imaging modalities appropriately to determine the extent of
primary disease and metastatic spread of Hodgkin disease

Know the advantages and limitations of computed tomography in staging a
patient with Hodgkin disease

Know the advantages and limitations of radionuclide scans in staging a
patient with Hodgkin disease

Know the advantages and limitations of magnetic resonance imaging in
staging a patient with Hodgkin disease

Know the appropriate indications for surgical staging of Hodgkin disease
in children and adolescents

Know the advantages and limitations of gallium scanning in staging and
in follow-up of a patient with Hodgkin disease

**e. Treatment (See also VII.B.) **

Know the role of radiation therapy in the treatment of Hodgkin disease
in children and adolescents

Know the role of chemotherapy in the treatment of Hodgkin disease in
children and adolescents

Be able to monitor appropriately the response to treatment of Hodgkin
disease

Plan the treatment of a relapse in a patient with Hodgkin disease

Understand the principles of radiation therapy in a pediatric patient
with Hodgkin disease

**f. Prognosis **

Know the prognostic features of Hodgkin disease

Know the prognosis of Hodgkin disease according to stage and histology
Know the effect of \"B\" symptoms on prognosis of Hodgkin disease Know
the effect of a large mediastinal mass on prognosis of Hodgkin

disease

**g. Complications/late effects **

Evaluate and manage a febrile patient with Hodgkin disease who has
previously undergone splenectomy

Recognize the clinical manifestations of recurrent Hodgkin disease
Recognize the effects of irradiation on bone growth in a patient with
Hodgkin disease

Recognize the effects of irradiation on cardiac function in a patient
with Hodgkin disease

Recognize the effects of irradiation on pulmonary function in a patient
with Hodgkin disease

Know which treatments influence the development of second malignancies
in patients with Hodgkin disease

Recognize the significance of persistent mediastinal widening after
therapy

Know that solid tumor second malignant neoplasms are most likely to
occur within the irradiated field, after treatment for Hodgkin disease

Know the increased risk for the development of breast cancer in women
who were treated for Hodgkin disease as children or adolescents

**2. Non-Hodgkin lymphoma **

**a. Epidemiology/predisposing factors/genetics **

Know the association of Epstein-Barr virus and human

immunodeficiency virus with non-Hodgkin lymphoma Know that the African
type Burkitt lymphoma is associated with Epstein-Barr virus

Know the cytogenetic and molecular genetic abnormalities associated with
non-Hodgkin lymphoma Know the association of c-myc oncogene with Burkitt
lymphoma

Know the chromosomal alterations associated with Burkitt lymphoma Know
the gene rearrangement patterns which distinguish monoclonal and
polyclonal lymphoproliferative processes

Understand the relationship of oncogenes to structural genes in

chromosome 8:14 translocation Recognize the clinical and epidemiologic
characteristics that distinguish \"endemic\" from \"sporadic\" Burkitt
lymphoma

Know that Wiskott-Aldrich syndrome and other immunodeficiency states
predispose to the development of non-Hodgkin lymphoma Understand that
transplant recipients are at risk for non-Hodgkin lymphoma

**b. Histopathology and immunophenotype **

Recognize the pathologic subtypes of non-Hodgkin lymphoma in children
and adolescents

Recognize the pathologic subtypes of non-Hodgkin lymphoma relative to
primary site and pattern of spread

Know the characteristic immunophenotype of Burkitt and Burkitt-like
lymphomas

Know the relative importance of heavy and light chain immunoglobulin
expression in the diagnosis of Burkitt or Burkitt-like lymphomas

Know the characteristic immunophenotype of T-cell lymphoblastic NHL

Know that, immunophenotypically, Burkitt and Burkitt-like lymphomas are
identical to B-cell ALL, and T-cell lymphoblastic lymphomas are
identical to T-cell ALL

Know the variety of immunophenotypes which may be seen in large cell
lymphomas in children

**c. Clinical presentation **

Recognize the clinical presentation of non-Hodgkin lymphoma by anatomic
site

Know the sites of involvement of African type and non- African type
Burkitt lymphoma

Recognize the superior vena cava syndrome as a presentation of
lymphoblastic lymphoma

Know the clinical presentation and laboratory findings of Burkitt
lymphoma

Recognize when tumor lysis syndrome can be present in non-Hodgkin
lymphoma

Know that large B-cell lymphomas can arise in the anterior mediastinal

**d. Diagnosis and staging **

Utilize appropriate imaging modalities to determine the extent of
non-Hodgkin lymphoma

Know that diagnosis of non-Hodgkin lymphoma can be made on pleural
effusion or ascitic fluid

Recognize CNS involvement in a patient with non-Hodgkin lymphoma

Know how to use the degree of bone marrow involvement to distinguish
stage IV non-Hodgkin lymphoma and acute leukemia of similar
immunophenotype

Recognize that advanced stage T-cell lymphoblastic lymphoma and T-cell
acute lymphoblastic leukemia represent different stages of the same
disease

Recognize that advanced sage Burkitt lymphoma or Burkitt-like
non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia represent
different stages of the same disease

**e. Treatment (See also VII.B.) **

Know the role of surgery in the treatment of non-Hodgkin lymphoma

Know the role of radiation therapy in the treatment of non-Hodgkin
lymphoma

Know the role of chemotherapy in the treatment of specific types of
non-Hodgkin lymphoma

Know the emergency management of a large mediastinal mass in non-Hodgkin
lymphoma

Know the emergency management of tumor lysis syndrome in non-Hodgkin
lymphoma

Know the emergency management of spinal cord compression in non-Hodgkin
lymphoma

Appropriately monitor the response to treatment of non-Hodgkin lymphoma

Plan the treatment for a patient with advanced stage Burkitt lymphoma or
Burkitt-like non-Hodgkin lymphoma

**f. Prognosis **

Know the prognostic features of non-Hodgkin lymphoma

Know the prognosis of non-Hodgkin lymphoma according to stage and
histology and immunophenotype

**g. Complications/late effects **

Know the complications and late effects of irradiation in the treatment
of non-Hodgkin lymphoma

Know the complications and late effects of chemotherapy in the treatment
of non-Hodgkin lymphoma

**H. Malignant solid tumors **

**1. Bone tumors **

**a. Osteosarcoma (1). Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
osteosarcoma Know the epidemiology of osteosarcoma

Know that osteosarcoma can occur as a late effect of radiation therapy
Know that patients with hereditary retinoblastoma are at increased risk
for osteosarcoma

**(2)**. ** Pathology **

Recognize the pathologic subtypes of osteosarcoma and their effect on
prognosis

Know that the histiopathologic basis for making the diagnosis of
osteosarcoma is finding osteoid-producing malignant cells

**(3)**. ** Clinical presentation **

Recognize the most common skeletal locations for primary osteosarcoma

Be able to evaluate a patient for pulmonary metastasis in osteosarcoma
Recognize the predilection of osteosarcoma for the metaphysis of long
bones

Know the most common metastatic sites in osteosarcoma

**(4)**. **Diagnosis and staging **

Utilize appropriate imaging modalities to determine the extent and
metastatic spread of osteosarcoma Identify the radiologic appearance of
osteosarcoma of long bones Know the differential diagnoses for a primary
bone lesion suspected of

**(5)**. ** Treatment **

Know the role of surgery in the treatment of primary osteosarcoma and in
the treatment of metastatic osteosarcoma

Know the role of chemotherapy in the treatment of osteosarcoma Know the
role of preoperative chemotherapy in the treatment of osteosarcoma

Know the role of postoperative chemotherapy in the treatment of
osteosarcoma Know the available surgical options for treatment of
osteosarcoma Plan the treatment of parosteal and periosteal variants of
osteosarcoma

**(6)**. ** Prognosis **

Know the laboratory findings that have prognostic importance in
osteosarcoma Know the prognostic features of osteosarcoma

Know the prognosis of osteosarcoma according to stage and histology Know
how the location of the primary tumor in osteosarcoma influences the
prognosis

Know that the histopathologic response (% necrosis) in osteosarcoma

to preoperative chemotherapy is of prognostic significance Know how
tumor size at diagnosis of osteosarcoma influences prognosis

**(7)**. ** Complications/late effects **

Know the complications and late effects of osteosarcoma

Know the complications and late effects of surgery performed in the
treatment of osteosarcoma

Know the complications and late effects of chemotherapy in the treatment
of osteosarcoma

**b. Ewing sarcoma (1). Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
Ewing sarcoma

  ---------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------------------------------------
  Know the association of t(11:22) with both Ewing sarcoma and primitive neuroectodermal tumor   
                                                                                                 
  **(2).**                                                                                       ** Pathology **
                                                                                                 
                                                                                                 Formulate a differential diagnosis of small round cell tumors of bone based on pathologic characteristics
                                                                                                 
                                                                                                 Recognize the pathologic similarities and differences between Ewing sarcoma and primitive neuroectodermal tumor
                                                                                                 
                                                                                                 Understand the use of molecular assays in the diagnosis of Ewing sarcoma and primitive neuroectodermal tumor
                                                                                                 
  **(3).**                                                                                       ** Clinical presentation **
                                                                                                 
                                                                                                 Recognize the clinical presentation of Ewing sarcoma by anatomic site and know the most common primary sites
                                                                                                 
                                                                                                 Know the clinical and laboratory features of extraosseous Ewing sarcoma
                                                                                                 
  **(4). **                                                                                      **Diagnosis and staging **
                                                                                                 
                                                                                                 Utilize appropriate imaging modalities to determine the extent and metastatic spread of Ewing sarcoma
                                                                                                 
                                                                                                 Recognize the radiologic findings of Ewing sarcoma
                                                                                                 
                                                                                                 Know the laboratory studies that have prognostic significance in Ewing sarcoma
                                                                                                 
  **(5). **                                                                                      **Treatment (see also section VII.B) **
                                                                                                 
                                                                                                 Know the role of surgery in the treatment of Ewing sarcoma
                                                                                                 
                                                                                                 Know the role of irradiation in the treatment of Ewing sarcoma Know the role of chemotherapy and preoperative chemotherapy in the treatment of Ewing sarcoma
                                                                                                 
                                                                                                 Be able to appropriately monitor the response to treatment of Ewing sarcoma
                                                                                                 
  **(6).**                                                                                       ** Prognosis **
                                                                                                 
                                                                                                 Understand the prognostic variables in Ewing sarcoma
                                                                                                 
  **(7).**                                                                                       ** Complications/late effects **
                                                                                                 
                                                                                                 Know the complications and late effects of surgery performed in the treatment of Ewing sarcoma
                                                                                                 
                                                                                                 91 Know the complications and late effects of irradiation in the treatment
                                                                                                 
  ---------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------------------------------------

Know the complications and late effects of chemotherapy in the treatment
of Ewing sarcoma

Know the complications and late effects of treatment of Ewing sarcoma
according to primary tumor site, eg, pelvis, spine, extremities

Know the association of specific chemotherapy drugs used in treating
Ewing sarcoma with the development of cytogenetic/molecular changes
leading to secondary acute myeloid leukemia

**2. Retinoblastomas **

**a. Epidemiology/predisposing factors/genetics **

Understand the inheritance pattern of bilateral retinoblastoma

Know the cytogenetic and molecular genetic abnormalities associated with
retinoblastoma

Know the epidemiologic, genetic, and clinical features of unilateral and
bilateral retinoblastoma

Understand the limitations and use of DNA-based diagnoses in genetic
counseling of patients with retinoblastoma

**b. Pathology **

Recognize the importance of pathologic examination relative to the
extent of primary tumor and pattern of spread in retinoblastoma

**c. Clinical presentation **

Recognize the clinical presentation of retinoblastoma Recognize the
clinical manifestations of trilateral retinoblastoma

**d. Diagnosis and staging **

Know the differential diagnosis of retinoblastoma

Be able to appropriately utilize imaging modalities to determine the
extent and metastatic spread of retinoblastoma Stage retinoblastoma
according to the intraocular extent of the tumor Stage retinoblastoma
according to the pathologic findings after

enucleation Know that the central nervous system and bone marrow are the
most common metastatic sites of retinoblastoma

**e. Treatment **

Know the role of surgery in the treatment of retinoblastoma Know the
role of irradiation in the treatment of retinoblastoma Know the role of
chemotherapy in the treatment of retinoblastoma Know the role of
photocoagulation in the treatment of retinoblastoma Appropriately
monitor the response to treatment of retinoblastoma Plan the treatment
according to disease stage of a patient with bilateral

retinoblastoma Know the management of unilateral retinoblastoma Know the
treatment modalities available for retinoblastoma Know the proper
follow-up monitoring of an infant who has had

enucleation for unilateral retinoblastoma Know the proper screening and
follow-up for children who are siblings of a patient with retinoblastoma

**f. Prognosis **

Know the prognostic features of retinoblastoma Know the prognosis of
retinoblastoma according to stage and histology

**g. Complications/late effects **

Know the complications and late effects of retinoblastoma

Understand the risks for the development of secondary malignant
neoplasms in unilateral or bilateral retinoblastoma

Know the complications and late effects of surgery performed in the
treatment of retinoblastoma

Know the indications for, complications of and late effects of
irradiation in the treatment of retinoblastoma

Know the complications and late effects of chemotherapy in the treatment
of retinoblastoma

**3. Neuroblastic tumors **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
neuroblastoma

  --------- ------------------------------------------------------------------------------------------------------------------------------------------
  **b. **   **Pathology **
            
            Recognize the characteristic pathologic features of neuroblastomic tumors
            
            Know the relationship of pathologic classification to prognosis and outcome in patients with neuroblastoma
            
  **c.**    ** Clinical presentation **
            
            Recognize the clinical presentation of neuroblastoma by anatomic site
            
            Know the association of myoclonic encephalopathy with neuroblastoma
            Recognize the clinical presentation of metastatic neuroblastoma
            Recognize the clinical and laboratory findings of neuroblastoma
            
            Know the association of intractable secretory diarrhea with neuroblastomic tumors, and the natural history of patients with these tumors
            
  **d. **   **Diagnosis and staging **
            
            Distinguish neuroblastoma in bone marrow from other abnormal cells by histochemical analysis
            
            Utilize appropriate imaging modalities to determine the extent and metastatic spread of neuroblastoma
            Utilize appropriate laboratory studies to determine the extent and metastatic spread of neuroblastoma
            
            Know the biologic markers of neuroblastoma
            
  **e. **   **Treatment (See also VII.B.) **
            
            Know the principles of treatment for various stages of neuroblastoma
            
            Know the role of surgery in the treatment of neuroblastoma
            
            Know the role of irradiation in the treatment of neuroblastoma
            
            Know the role of chemotherapy in the treatment of neuroblastoma
            
            Know the role of biologic response modifiers in the treatment of neuroblastoma
            
            Be able to appropriately monitor the response to treatment of neuroblastoma
            
  **f.**    ** Prognosis **
            
  --------- ------------------------------------------------------------------------------------------------------------------------------------------

Know the prognosis of neuroblastoma according to stage

Know the prognostic significance of tumor pathology in patients with
neuroblastoma

Know the clinical variables of prognostic significance in patients with
neuroblastoma

Know the genetic variables of prognostic significance (such as DNA
index, MYCN amplification, 1p detection) in patients with neuroblastoma

Know the serum markers of prognostic significance (such as ferritin,
neuron-specific enolase, lactic dehydrogenase, etc) in patients with
neuroblastoma

**g. Complications/late effects **

Know the complications and late effects of neuroblastoma and its
treatment

Know the neurologic complications and late effects of neuroblastoma
presenting with myoclonic encephalopathy

**4. Peripheral neuroectodermal tumors **

**a. Clinical presentation **

Recognize the clinical presentation of peripheral neuroectodermal tumors
by anatomic site

**b. Diagnosis and staging **

Recognize esthesioneuroblastoma

Utilize appropriate imaging modalities to determine the extent and
metastatic spread of peripheral neuroectodermal tumors

Utilize appropriate laboratory studies to determine the extent and
metastatic spread of peripheral neuroectodermal tumors

Know the chromosomal and molecular alterations characteristic of
peripheral neuroectodermal tumor

**c. Treatment **

Know the role of surgery in the treatment of peripheral neuroectodermal
tumors

Know the role of irradiation in the treatment of peripheral Know the
role of chemotherapy in the treatment of peripheral neuroectodermal
tumors

Be able to appropriately monitor the response to treatment of peripheral
neuroectodermal tumors

**d. Prognosis **

Know the prognosis of primitive neuroectodermal tumors

**e. Complications/late effects **

Know the complications and late effects of primitive neuroectodermal
tumors and their treatment

**5. Brain tumors **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
brain tumors

Recognize the association between brain tumors and heritable syndromes
(eg, neurofibromatosis, tuberous sclerosis)

Know the association between pineoblastoma and retinoblastoma

**b. Pathology **

Recognize the pathologic subtypes of brain tumors relative to prognosis

Recognize the pathologic subtypes of brain tumors relative to primary
tumor site and pattern of spread

Recognize the relationship between histologic grade of gliomas and
prognosis

**c. Clinical presentation **

Recognize the clinical presentation of brain tumors by anatomic site
Understand the clinical and pathologic characteristics of pediatric
brain tumors

Know the clinical and laboratory manifestations of different central
nervous system tumors Know the clinical and laboratory features of
medulloblastoma Know the clinical and laboratory features of cerebellar
astrocytoma Know the clinical and laboratory features of brain stem
glioma

Know the clinical and laboratory features of pineal tumors Know the
clinical and laboratory features of ependymoma Know the clinical and
laboratory features of primitive neuroectodermal

tumors Know the clinical and laboratory features of optic pathway
gliomas Recognize the relationship between age and anatomic site in the
clinical

presentation of brain tumors

**d. Diagnosis and staging **

Utilize appropriate imaging modalities to determine the extent and

metastatic spread of brain tumors Know which central nervous system
tumors are associated with spinal cord metastases

Know the cerebrospinal fluid findings associated with medulloblastoma

Know how to utilize imaging modalities to characterize medulloblastoma
Know how to utilize imaging modalities to characterize astrocytoma Know
how to utilize imaging modalities to characterize brain stem

glioma

Know how to utilize imaging modalities to characterize pineal cell
tumors Know how to utilize imaging modalities to characterize ependymoma
Know how to utilize imaging modalities to characterize primitive

neuroectodermal tumors

Know the patterns of metastasis and spread characteristic of
medulloblastoma Know the patterns of metastasis and spread
characteristic of low grade

astrocytoma

Know the patterns of metastasis and spread characteristic of ependymoma
Know the patterns of metastasis and spread characteristic of primitive

neuroectodermal tumors Know which central nervous system tumor is most
likely to metastasize outside the central nervous system

Know the patterns of metastasis and spread characteristic of
glioblastoma multiforme

**e. Treatment (see also section VII.B) **

Know the role of surgery in the treatment of brain tumors Recognize that
surgery alone is curative for cerebellar astrocytoma Know the role of
irradiation in the treatment of brain tumors Know the role of
chemotherapy in the treatment of brain tumors Monitor the response to
treatment of brain tumors using clinical

modalities

Monitor the response to treatment of brain tumors using imaging
modalities Monitor the response to treatment of brain tumors using
biochemical

markers

Monitor the response to treatment of brain tumors using histologic
markers Know the principles of management for patients with
medulloblastoma Know the principles of management for patients with low
grade

astrocytoma Know the principles of management for patients with brain
stem glioma Know the principles of management for patients with pineal
tumors Know the principles of management for patients with ependymoma
Know the principles of management for patients with primitive

neuroectodermal tumors

Know the principles of management for patients with high grade gliomas
(anaplastic astrocytoma and glioblastoma multiforme) Know the principles
of management of patients with central nervous

system germ cell tumors

**f. Prognosis **

Know the prognostic features of brain tumors Know the natural history of
medulloblastoma Know the natural history of low grade astrocytoma Know
the natural history of brain stem glioma Know the natural history of
pineal cell tumors Know the natural history of ependymoma Know the
natural history of central nervous system primitive

neuroectodermal tumors Identify the prognostic factors in patients with
medulloblastoma Identify the prognostic factors in patients with
astrocytoma Identify the prognostic factors in patients with brain stem
glioma Identify the prognostic factors in patients with pineal cell
tumors Identify the prognostic factors in patients with ependymoma
Identify the prognostic factors in patients with primitive

neuroectodermal tumors Know the natural history of high grade gliomas
Identify the prognostic factors in patients with central nervous system

germ cell tumors

**g. Complications/late effects **

Know the complications and late effects of brain tumors

Know the late effects of brain tumors and their treatment in patients of
various ages

Know the secondary malignancies associated with treatment of brain
tumors

Know the potential neurologic sequelae of brain tumors and their
treatment Know the potential endocrine sequelae of brain tumors and
their treatment

Know the potential intellectual sequelae of brain tumors and their
treatment

Know the complications and late effects of surgery performed in the
treatment of brain tumors Know the complications and late effects of
chemotherapy in the treatment of brain tumors, eg, secondary
malignancies

**6. Hepatoblastoma and hepatocellular carcinoma **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
hepatoblastoma and hepatocellular carcinoma

Know the association of familial polyposis coli with hepatoblastoma and
hepatocellular carcinoma

Know which congenital conditions are associated with an increased risk
of hepatoblastoma

Know the association of hepatocellular carcinoma with inborn errors of
metabolism causing cirrhosis

**b. Pathology **

Recognize the pathologic subtypes of hepatoblastoma and hepato­cellular
carcinoma relative to prognosis and pattern of spread

**c. Clinical presentation **

Recognize the clinical presentation of hepatoblastoma and hepatocellular
carcinoma

Know that hepatoblastoma is a disease of infancy and early childhood

**d. Diagnosis and staging **

Utilize appropriate imaging modalities to determine the extent and
metastatic spread of hepatoblastoma and hepatocellular carcinoma

Utilize appropriate laboratory studies to determine the extent and
metastatic spread of hepatoblastoma and hepatocellular carcinoma

**e. Treatment **

Know the role of surgery in the treatment of hepatoblastoma and
hepatocellular carcinoma

Know the role of irradiation in the treatment of hepatoblastoma and
hepatocellular carcinoma

Know the role of chemotherapy in the treatment of hepatoblastoma and
hepatocellular carcinoma

Appropriately monitor the response to treatment of hepatoblastoma and
hepatocellular carcinoma

**f. Prognosis **

Know the prognosis of hepatoblastoma and hepatocellular carcinoma
according to stage and histology

**g. Complications/late effects **

Know the complications and late effects of hepatoblastoma and
hepatocellular carcinoma and their therapy

**7. Renal tumors **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
renal tumors

Know the somatic abnormalities associated with Wilms tumor

**b. Pathology **

Recognize the pathologic subtypes of renal tumors relative to primary
tumor and pattern of spread

Recognize that a mesoblastic nephroma is not a malignancy

Know the relationship between histologic pattern of Wilms tumor and
prognosis

Know the significance of the presence of nephroblastomatosis in a
patient with Wilms tumor

Know the biologic characteristics and clinical management of mesoblastic
nephroma

**c. Clinical presentation **

Recognize the clinical presentation of renal tumors

Know the congenital anomalies that are associated with an increased risk
of Wilms tumor

1.  **d. Diagnosis and staging **

2.  **e. Treatment **

Utilize appropriate imaging modalities to determine the extent
metastatic spread of renal tumors

Know the procedures necessary to stage Wilms tumor (stages I-V)

Know the complications of radiation therapy in patients with Wilms tumor

Know the role of surgery in the treatment of renal tumors

Plan the management of an infant with a mesoblastic nephroma

Know the role of irradiation in the treatment of renal tumors

Know the role of chemotherapy in the treatment of renal tumors

Be able to appropriately monitor the response to treatment of renal
tumors

Understand the therapy of pulmonary metastases of Wilms tumor

Know the appropriate treatment of Wilms tumor in relation to stage and
histologic subtype

Plan the management of a patient with recurrent Wilms tumor

**f. Prognosis **

Know the prognostic features of renal tumors

**g. Complications/late effects **

Know the complications and late effects of renal tumors and their
treatment

**8. Rhabdomyosarcoma **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
rhabdomyosarcoma

**b. Pathology **

Recognize how rhabdomyosarcoma is differentiated from similar tumors by
immunohistochemical tests

Recognize the pathologic subtypes of rhabdomyosarcoma relative to
prognosis and patterns of presentation and spread

**c. Clinical presentation **

**(1). Head/neck (parameningeal vs nonparameningeal) **

Recognize the clinical presentation of rhabdomyosarcoma affecting the
head and neck (parameningeal versus nonparameningeal)

**(2). Orbit and nasopharynx **

Recognize the clinical presentation of orbital rhabdomyosarcoma

Recognize the clinical presentation of nasopharyngeal rhabdomyo­sarcoma

**(3). Trunk **

Recognize the clinical presentation of rhabdomyosarcoma affecting the
trunk

**(4). Genitourinary syste**m\
**(a). Bladde**r

Recognize the clinical presentation of rhabdomyosarcoma affecting the
bladder

**(b). Prostate gland **

Recognize the clinical presentation of rhabdomyosarcoma affecting the
prostate gland

**(c). Vagina **

Recognize the clinical presentation of vaginal rhabdomyosarcoma

**(5). Extremities **

Recognize the clinical presentation of rhabdomyosarcoma affecting the
extremities

**d. Diagnosis and staging **

Be able to appropriately utilize imaging and laboratory modalities to
determine the extent and metastatic spread of rhabdomyosarcoma

**e. Treatment **

Know the role of surgery in the treatment of rhabdomyosarcoma

Know the role of irradiation in the treatment of rhabdomyosarcoma

Know the role of chemotherapy in the treatment of rhabdomyosarcoma

**f. Prognosis **

Know the prognosis of rhabdomyosarcoma according to stage and histology
and anatomic site of the primary tumor

Know the relationship between site of metastasis and prognosis in
rhabdomyosarcoma

Know the prognostic significance of tumor recurrence in rhabdomyosarcoma

**g. Complications/late effects **

Know the complications and late effects of rhabdomyosarcoma and its
therapy

**9. Soft tissue sarcomas other than rhabdomyosarcoma **

**a. Epidemiology/predisposing factors/genetics **

Recognize the cytogenetic and molecular genetic abnormalities associated
with soft tissue sarcomas other than rhabdomyosarcoma

**b. Pathology **

Recognize the pathologic subtypes of soft tissue sarcomas other than
rhabdomyosarcoma relative to prognosis and pattern of spread

**c. Clinical presentation **

Recognize the clinical presentation of soft tissue sarcomas other than
rhabdomyosarcoma by anatomic site

**d. Diagnosis and staging **

Utilize appropriate imaging modalities and laboratory studies to
determine the extent and metastatic spread of soft tissue sarcomas other
than rhabdomyosarcoma

**e. Treatment **

Know the role of surgery in the treatment of soft tissue sarcomas other
than rhabdomyosarcoma

Know the role of irradiation in the treatment of soft tissue sarcomas
other than rhabdomyosarcoma

Know the role of chemotherapy in the treatment of soft tissue sarcomas
other than rhabdomyosarcoma

**f. Prognosis **

Know the prognostic features of soft tissue sarcomas other than
rhabdomyosarcoma

**g. Complications/late effects **

Know the complications and late effects of soft tissue sarcomas other
than rhabdomyosarcoma and their treatment

**10. Gonadal/Germ cell tumors **

**a. Epidemiology/predisposing factors/genetics **

Know the cytogenetic and molecular genetic abnormalities associated with
gonadal/germ cell tumors

Know the age distribution of patients with gonadal/germ cell tumors

**b. Pathology **

Recognize the pathologic subtypes of gonadal/germ cell tumors relative
to prognosis and patterns of spread

**c. Clinical presentation **

Recognize the clinical presentation of gonadal/germ cell tumors by
anatomic site

Know the biologic markers and clinical correlates of germ cell tumors

**d. Diagnosis and staging **

Utilize appropriate imaging modalities and laboratory studies to
determine the extent and metastatic spread of gonadal/germ cell tumors

**e. Treatment **

Know the role of surgery in the treatment of gonadal/germ cell tumors

Know the role of radiation therapy in the treatment of gonadal/germ cell
tumors

Know the role of chemotherapy in the treatment of gonadal/germ cell
tumors

Be able to monitor appropriately the response to treatment of
gonadal/germ cell tumors

**f. Prognosis **

Know the clinical, radiologic, and prognostic features of sacrococcygeal
germ cell tumors

**g. Complications/late effects **

Know the complications and late effects of gonadal/germ cell tumors and
their treatment

**I. Histiocytic disorders **

**1. Epidemiology/predisposing factors/genetics **

Know the inheritance pattern of familial erythrophagocytic
lymphohistiocytosis

**2. Pathology **

Know the pathologic classification of childhood histiocytosis

Recognize histiocytosis in bone marrow

**3. Clinical presentation **

Recognize the clinical and laboratory features of Langerhans cell
histiocytosis

Know the clinical and laboratory features of infection-associated
hemophagocytic syndrome

Recognize the clinical and laboratory features of sinus histiocytosis
with massive lymphadenopathy

Recognize the clinical and laboratory features of familial
erythrophagocytic lymphohistiocytosis

**4. Diagnosis and staging **

Recognize erythrophagocytosis in bone marrow

Know the appropriate laboratory and imaging studies to determine the
extent of Langerhans cell histiocytosis

**5. Treatment **

Know which types of chemotherapy are effective in the treatment of
Langerhans cell histiocytosis

Plan appropriate management of Langerhans cell histiocytosis based on
disease effects, location and extent

Know the role and limitations of chemotherapy in the treatment of Plan
appropriate management of infection-associated hemophagocytic syndrome

**6. Prognosis **

Know the clinical and pathologic features of the histiocytoses that
impact prognosis

Know the prognosis of Langerhans cell histiocytosis

Know the prognosis of viral associated hemophagocytic syndrome, familial
erythrophagocytic lymphohistiocytosis,

Know the prognosis of sinus histiocytosis

**7. Complications/late effects **

Know the complications of Langerhans cell histiocytosis and its
treatment

**J. Supportive care **

**1. Nutrition **

Know the nutritional needs of patients of different ages undergoing
antineoplastic therapy

Understand the principles and complications of total parenteral
nutrition

Know the role of nasogastric feeding and gastrostomy in the care of
patients

**2. Dental care and oral hygiene **

Know the importance of dental hygiene in patients receiving
antineoplastic treatment

Know the importance of prophylactic dental treatment in patients
receiving radiation therapy to the head and neck

Know how to treat buccal ulceration in a patient receiving
antineoplastic therapy

Know the importance of dental hygiene in patients undergoing bone marrow
transplant

**3. Central venous access **

Know the indications for and the complications of central venous
catheterization

Know the indications for removing a central venous access

**4. Pain control **

Know which factors predispose children to narcotic addiction in the
management of pain

Understand the principles of pain control, including pain assessment
Know the various analgesic and narcotic drugs and their routes of
administration and side effects

Know the treatment for opioid overdose and the attendant risks of such
treatment Understand the management approach to procedural pain

**5. Fatal illness and terminal care **

Know how to arrange for terminal home care for a child with cancer

Know how to counsel family members at times of diagnosis, relapse, and
terminal illness

Know the effect of fatal illness and its treatment on the patient\'s
family members, including siblings

Know the community resources available to assist the family of a child
with cancer

**6. Antiemetics **

Know the mechanism of action of various classes of antiemetics Know how
to manage acute and delayed therapy-induced vomiting Know how to prevent
and treat side effects of a phenothiazine

antiemetic

**7. Schooling **

Know how to achieve appropriate and optimal school re-entry for patients
receiving antineoplastic therapy

Know how to utilize community and school-based resources in maintaining
educational continuity for the child receiving antineoplastic treatment

**VI. Immunologic Abnormalities A. Infections in immunocompromised
patients **

**1. Prophylaxis **

**a. Bacterial **

**(1). Indications for antimicrobials **

Know the role of prophylactic antibiotics in preventing bacterial
infection in an immunocompromised patient

Know the indications for and risks and benefits of trimethoprim with
sulfamethoxazole for prophylaxis against bacterial infections in an
immunocompromised patient

Know the indications for and benefits of antibiotic prophylaxis for
patients with anatomic or functional asplenia

**b. Fungal **

Know the indications and alternative topical and systemic methods of
achieving antifungal prophylaxis in an immunocompromised patient

**c. Viral **

**(1). Rubeola **

Know the management of rubeola exposure in a nonimmunized
immunocompromised patient

Know the clinical manifestations of rubeola in immunocompromised
patients

**(2). Cytomegalovirus (CMV) **

Know the association of CMV disease with reduced T-lymphocyte mediated
immunity in the post-transplantation period

Understand the use of CMV-negative blood products in the prevention of
CMV infection

Understand the issues surrounding leukocyte depletion by filtration of
cellular blood products in prevention of CMV infection in an
immunocompromised host

Understand that CMV disease in the immunocompromised patient may occur
by either primary exposure or reactivation of latent infection

Understand the effective strategies for prevention of CMV disease using
ganciclovir in patients following allogeneic marrow transplantation

Know the clinical manifestations of CMV disease in immunocompromised
patients Understand the difficulties in demonstrating that clinical
symptoms are causally related to the diagnosis or severity of CMV
disease

Know the alternative CMV treatment in an HSCT patient with graft failure
secondary to ganciclovir therapy

**(3). Herpes zoster, varicella, and herpes simplex **

Know the management of varicella exposure in a patient who has recently
completed therapy for malignancy

Plan the management of a child with malignancy who is exposed to
varicella during chemotherapy

Understand that prophylaxis can prevent herpes simplex virus and
varicella zoster virus reactivation in immunocompromised patients

Know the clinical manifestations of herpes simplex infection in
immunocompromised patients

Know the risk, presentation, and management of varicella zoster virus
dissemination in the immunocompromised host who has chickenpox

Know the risk, presentation, and management of varicella zoster virus
dissemination in the immunocompromised host who has shingles

Understand the risk factors for herpes simplex reactivation in the
immunocompromised patient

**d. Other **

**(1). Pneumocystis carinii **

Know the alternative medications for prophylaxis against P. carinii in
patients unable to tolerate trimethoprim with sulfamethoxazole

**2. Treatment of infection in immunocompromised patients **

**a. Bacterial **

Know the common and uncommon bacteria causing infections in the
immunocompromised host

Know the appropriate antimicrobial therapy for treatment of suspected or
proven bacterial infection in an immunocompromised patient

**(1). Indications for antimicrobials **

Investigate the cause of and initiate treatment of fever in a patient
with

**(2). Complications of antimicrobials **

Recognize the interaction of antibiotics and chemotherapeutic agents

**b. Fungal **

Know the common and uncommon fungi causing infections in the
immunocompromised host

Know the appropriate antimicrobial therapy for treatment of suspected or
proven fungal infection in an immunocompromised patient

Know the indications for empiric anti-fungal therapy in the febrile,
neutropenic patient

**c. Viral **

Know the common and uncommon viruses causing infections in the
immunocompromised host

Know the appropriate antimicrobial therapy for treatment of suspected or
proven viral infection in an immunocompromised patient

Recognize potential therapies for EBV lymphoproliferative disorders in
immunocompromised patients

**d. Protozoal infections **

Know the common and uncommon protozoans causing infections in the
immunocompromised host

Know the appropriate antimicrobial therapy for treatment of suspected or
proven protozoan infection in an immunocompromised patient

Know the indications for and dosage of trimethoprim with
sulfamethoxazole for P. carinii infection

**e. Other **

Know the indications for the use of immunoglobulin and interferon in the
prevention or treatment of infections in an immunocompromised patient

**B. Immunodeficiency states (congenital and acquired) **

**1. Congenital immune deficiencies **

**a. Clinical features and inheritance patterns **

Know the cellular basis for transient hypogammaglobulinemia of infants

Evaluate the child with recurrent infections for possible congenital
immunodeficiency diseases Know the patterns of inheritance of
immunologic disorders

Understand the relationship of specific organisms to disruption of
normal defense systems

Know which metabolic disorders are associated with altered defense
mechanisms

Know the laboratory manifestations of disorders associated with altered
defense mechanisms

**b. Treatment (See also VII.B.) **

Know the therapeutic options for patients with congenital immune
deficiencies

**c. Relationship between immunodeficiency and cancer **

Understand which immune deficiencies lead to lymphoproliferative disease

Understand which immunodeficiency states are associated with increased
incidence of cancer

Know the mechanisms by which immunodeficiency states can have increased
risk for cancer

**d. Specific congenital immune deficiencies **

**(1). Wiskott-Aldrich syndrome **

Understand that thrombocytopenia, infections, and eczema are
manifestations of Wiskott-Aldrich syndrome

Know the typical X-linked recessive inheritance pattern of
Wiskott-Aldrich syndrome

Know that small platelets are associated with Wiskott-Aldrich syndrome

Know the relationship of skin test anergy to Wiskott-Aldrich syndrome

Know the humoral immunologic abnormalities associated with
Wiskott-Aldrich syndrome

Know that T-lymphocyte dysfunction is associated with Wiskott-Aldrich
syndrome

Know the role of splenectomy in managing thrombocytopenia in

**(2). DiGeorge syndrome **

Recognize that DiGeorge syndrome is associated with hypocalcemia,
cardiac disorders, dysmorphic facial features, and decreased T-cell
numbers or function

Know that inheritance of DiGeorge syndrome is usually sporadic Recognize
the variable natural history of DiGeorge syndrome Know the molecular
basis of DiGeorge syndrome

**(3). Common variable immune deficiency **

Know that common variable immune deficiency is associated with
autoimmune processes

Recognize that common variable immune deficiency is associated with
decreased total and specific immunoglobulin concentrations and recurrent
sinopulmonary infections

Know that inheritance of common variable immune deficiency can be
X-linked or autosomal recessive

**(4). Severe combined immune deficiency (SCID) **

Recognize the clinical picture of SCID

Know that some patients with SCID may have panhypogammaglobulinemia and
increased lymphocyte counts Know the characteristics of maternal
lymphocyte engraftment in SCID Know that inheritance of SCID is either
X-linked or autosomal

recessive Associate very low IgG with SCID Know the clinical
presentation and laboratory features of adenosine

deaminase deficiency compared to other forms of SCID

Appreciate the risk of transfusion-associated graft-versus-host disease
in SCID Associate marked lymphopenia (\< 2000 lymphocytes/cu mm) in

infancy with adenosine deaminase deficiency Recognize that untreated
patients with SCID have markedly reduced or absent in vitro T-lymphocyte
responses to mitogens

Recognize that live virus vaccines are contraindicated in patients with
SCID

**(5). X-linked lymphoproliferative disease **

Know the association of hypogammaglobulinemia with X-linked
lymphoproliferative disease

Know the hematologic disorders associated with X-linked
lymphoproliferative disease

Recognize the importance of a family history of lymphoproliferative
disease, bone marrow failure, and immunodeficiency in male maternal
relatives

Know the abnormal response of patients with X-linked lymphoproliferative
disease to Epstein-Barr virus

Know the laboratory methods available to aid in diagnosis of X-linked
lymphoproliferative disease

**(6). Complement defects **

Recognize the clinical manifestations of congential abnormalities of the
complement system

Know the laboratory methods used to diagnose complement defects

**(7). X-linked agammaglobulinemia **

Distinguish between the various kinds of agammaglobulinemia

Know the clinical presentation of patients with X-linked
agammaglobulinemia

Know that the techniques of linkage analysis and molecular genotyping
can be used to diagnose prenatal X-linked agammaglobulinemia

Recognize the absence of specific antibody responses to vaccination in
untreated children with X-linked agammaglobulinemia

Recognize the increased susceptibility of patients with X-linked
agammaglobulinemia to vaccine-acquired poliomyelitis, viral hepatitis
and central nervous system enterovirus infections

Recognize that live virus vaccines are contraindicated in patients with
X-linked agammaglobulinemia

Recognize that T-lymphocyte numbers and function are normal in X-linked
agammaglobulinemia

Recognize that patients with X-linked agammaglobulinemia have complete
absence of mature B-lymphocytes and plasma cells in blood, lymph nodes
and other tissues

b.)

**2. Acquired immunodeficiency syndrome (AIDS) **

**a. Features **

Recognize the clinical features of AIDS in pediatric patients Know the
effects of HIV on mononuclear cells Know the effects of HIV on immune
function Associate panhyperimmunoglobulinemia with AIDS Recognize the
clinical manifestations of HIV infection Know the hematologic
abnormalities associated with HIV infection Know the immunologic
abnormalities associated with HIV infection Know the hematologic
abnormalities associated with therapy for HIV

infection Recognize the infectious complications of AIDS Know the proper
laboratory methods for diagnosing HIV infection in

both the young infant (\< 6 months of age) and the older child
Understand the epidemiology and pathogenesis of HIV infection Know the
malignancies that can occur in patients with HIV infection Know when to
do HIV testing in children with malignancies

**b. Risk factors **

Recognize the risk factors for AIDS in the pediatric population

**c. Treatment **

Recognize available HIV anti-viral therapies Know proper supportive care
measures for patients with HIV infection

**VII. Hematopoietic Stem Cell Transplantation (HSCT) A. Biologic
Principles **

**1. Types of hematopoietic stem cell transplantation **

Know the definitions of allogeneic, syngeneic, and autologous
hematopoietic stem cell transplantation

**2. Hematopoietic stem cells for transplantation **

Know from which tissues hematopoietic stem cells may be harvested

Know the biologic features of hematopoietic stem cells

**3. HLA system **

Recognize the difference between class I and class II antigens

Know the laboratory methods currently in use for HLA typing, the results
each method provides, and their appropriate uses in evaluation of marrow
transplant candidates and donors

Know the inheritance pattern of human HLA antigens and how this pattern
applies to selection of allogeneic marrow transplant donors

**4. Graft versus host disease (GVHD) **

Recognize that GVHD represents an injury of recipient tissues by donor
cells

Recognize that GVHD is mediated by T-lymphocytes, natural killer cells,
and cytokines

Recognize that GVHD represents a donor response directed against major
and/or minor HLA disparities in the host

**5. Graft rejection **

Recognize that allogeneic marrow graft rejection is mediated by residual
host T-lymphocytes responding to histocompatibility differences in the
donor cells

**B. Indications **

Know the causes of poor outcome of patients undergoing HSCT for acute
lymphoblastic leukemia in second remission (see also section V.D.5.c)

Know the role of HSCT in the treatment of Hodgkin disease (see also
section V.G.1.e)

Know the role of HSCT in the treatment of non-Hodgkin lymphoma (see also
section V.G.2.e)

Know the possible role of HSCT in the treatment of Ewing sarcoma

Know the possible role of HSCT in the treatment of neuroblastoma (see

also section V.H.3.e)\
Know the possible role of HSCT in the treatment of brain tumors (see\
also section V.H.5.e)

Recognize the possible indications for HSCT in patients with leukemia
Recognize the possible indications for HSCT in patients with solid
tumors

Recognize the possible indications for HSCT in patients with

non-malignant hematologic disorders Recognize the possible indications
for bone marrow transplantation in patients with metabolic storage
diseases (eg, Hurler syndrome)

Recognize the possible indications for HSCT in patients with

immunodeficiencies Recognize the possible indications for HSCT in
patients with aplastic anemia

Know the indications for HSCT in ALL Know which conditions may preclude
HSCT in ALL Know the indications for HSCT in ANLL (see also section
V.E.4) Know the possible role of HSCT in the treatment of Wilms tumor
Understand the rationale for HSCT in patients with genetic disorders

**C. Methods **

**1. Donor selection **

Judge the suitability of a donor-recipient match, given the HLA-A, B,
and DR typing

Understand the advantages and disadvantages of allogeneic HSCT as
compared with autologous HSCT in various disorders

Recognize pertinent factors besides HLA typing that should be considered
in selection of allogeneic HSCT donors

Understand the advantages and disadvantages of the various available
hematopoietic stem cell sources

**2. Preparative therapy **

Recognize appropriate preparative regimens for patients with Fanconi
Understand the rationale for preparative therapy in HSCT for different
clinical indications and using differnet donor types

Understand that preparative therapy may not be necessary in some
patients with SCID

Understand the role of submyeloablative therapy in HSCT

**3. Hematopoietic stem cell collection **

**a. Peripheral blood stem cells **

Know the potential indications for the use of peripheral blood stem
cells

Understand the methods of collecting and preserving peripheral blood
stem cells

**b. Umbilical cord stem cells **

Understand collection and storage methods of umbilical cord stem cells

**4. Marrow processing **

**a. T cell **

Understand the risks and benefits of lymphocyte depletion for
graft-versus-host disease prophylaxis

Recognize the methods by which T-lymphocytes can be separated and/or
removed from marrow or peripheral blood stem cells

**b. Tumor cell **

Know the methods for purging autologous marrow or peripheral blood of
malignant cells (positive and negative selection)

**D. Outcomes **

**1. Graft versus host disease **

Recognize the clinical and laboratory manifestations of acute
graft-versus-host disease

Recognize the clinical and laboratory manifestations of chronic
graft-versus-host disease

Evaluate a patient who has undergone HSCT and differentiate between
infection and graft-versus-host disease

Know which drugs are useful for prevention and/or treatment of Recognize
risk factors for acute graft-versus-host disease following HSCT

Recognize risk factors for chronic graft-versus-host disease following
HSCT

Recognize which histocompatibility antigens are most influential in the
causation of graft-versus-host disease

Understand the importance of CD34 quantification on HSCT product
preparation and selection

**2. Graft rejection **Know the factors associated with graft rejection
Know the options for management of graft rejection

**3. Complications **

**a. Infections **

Recognize the spectrum of infectious complications that may occur

following HSCT Know which infectious complications are expected
following allogeneic HSCT

Know how post-transplant immune reconstitution influences the pattern
and frequency of infection

Recognize risk factors for infection following HSCT Recognize the
factors that influence the rate of immune reconstitution following HSCT

Know the microorganisms that cause pneumonia following HSCT

Know the infectious complications and their management following
autologous HSCT Know the strategies available for the prevention of
infection following

HSCT

1.  **b. Non-infectious complication**s\
    **(1). Early onse**t

2.  **c. Other **

Recognize the unique problems of patients with Fanconi anemia, and other
DNA-repair defects, undergoing HSCT

**(2).**

**4. Survival **

Know what factors increase the risk of post HSCT EBV lymphoproliferative
disease

Recognize the causes of interstitial pneumonitis following HSCT

Recognize the signs, symptoms, and diagnostic findings of hepatic
veno-occlusive disease following HSCT

Recognize the risk of and factors associated with cardiac failure
following HSCT

Recognize the risk of and factors associated with renal dysfunction
following HSCT

Know the toxicities associated with hematopoietic stem cell infusion

Know the clinical presentation, laboratory findings, and treatment of
thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome associated
with HSCT

Recognize the risk of and factors associated with hepatic dysfunction
following HSCT

** Late sequelae **

Know the risk for the development of cataracts in patients who have
undergone HSCT

Know the risk of infertility after HSCT Know the risk for development of
endocrinopathies in patients who have undergone HSCT

Know the risk of impaired growth in patients who have undergone

HSCT Know the relationship of the conditioning regimen and the
complications of HSCT

Recognize the risk of second malignancies following HSCT Recognize the
risk of and factors associated with chronic lung disease following HSCT

Know the complications associated with unrelated donor transplantation

Recognize relapse potential following HSCT for leukemias Recognize the
factors influencing post-transplant survival

Know the anticipated outcome and disease-free survival for HSCT based on
donor, source of hematopoietic stem cells, and primary diagnosis

**VIII. Research Methods **

**A. Biostatistics **

**1. Description of population **

**a. Central value and dispersion **

Know the difference between the mean value and median value of a
population and when each is applicable

**b. Standard deviation **

Know when to use standard deviation and when to use standard error

Know that standard deviation gives an estimate of the variation of
individuals within the population

**c. Standard error **

Know standard error of the mean given an estimate of the precision with
which the mean value of the population is known

**2. Statistical significance **

**a. Parametric **

Know when to use a paired and unpaired Student t-test

**b. Non-parametric **

Know that non-parametric tests must be used when the populations being
compared do not have a normal distribution and when the outcomes are
measured on an ordinal or categorized scale

**c. Type I error **

Know the definition of type I or alpha error or p value

Know inappropriateness of repeated t-tests without appropriate
correction (eg, Bonferroni correction)

**d. Type II error **

Know the definition of a type II error

**3. Correlation **

Know the definition of correlation coefficient

Know the inappropriateness of determining the correlation between an
independent variable and a dependant variable when that independent
variable is a component of the dependent variable

Know that the correlation coefficient by itself does not indicate the
statistical significance of changes in the dependent variable that were
related to changes in the independent variable

Know that r2 (correlation coefficient squared) illustrates the amount of
the change in the dependant variable resulting from the change in the
independent variable

**4. Analysis of variance **Know the assumptions underlying the use of
analysis of variance Know when to use a two-way analysis of a variance

**5. Proportions **

Know that the chi-square test is used to compare proportions in paired
or independent samples

Understand the results of a chi-square analysis

**6. Research design **Know the importance of stratification and when it
should be utilized Know the meaning of the \"null hypothesis\" Know the
importance of \"washout\" period in crossover studies Select the proper
statistical test for data analysis Know the importance of \"power\" in
planning a prospective study or

interpreting the literature Know the basic principles of informed
consent for a research protocol Know the meaning of a positive
predictive, and a negative predictive

index sensitivity, and specificity in evaluating diagnostic tests
Determine the sensitivity of a test given a true positive and false
positive ratio

**7. Clinical trials **

Know the differences between a case control, cohort, and randomized

controlled study in regard to their design and validity Understand how
to interpret results from survival/event analysis, Kaplan-Meier curves,
confidence limits, and log rank comparisons

Know the rationale behind randomized trials

Know the importance of establishing a margin of difference when
determining size Know the importance of a randomized clinical trial in
establishing a

causal relationship Know indications for utilizing a factorial design of
a randomized trial Know the indications for and hazards of meta-analysis
Know the definitions of terminology used in evaluating clinical trials

and patient entries

Know the definitions of event-free survival and of continuous complete
remission Understand Phase I, II, and III clinical trials in new drug
development

**B. Responsible conduct of research **

Know the most common forms of scientific misconduct Know the
contributions warranted for authorship on a manuscript Know the
appropriate steps to take when suspected fraudulent data are

encountered in the clinic or laboratory Recognize when an investigator
has a conflict of interest during the course of a study Last revised
03/06