Haematology Flashcards

Question

Essential thrombocythemia

Answer 1

Epidemiology Median age at diagnosis: 60 years ♀ > ♂ (2:1) Genetics: JAK2 mutation in 50% of cases Clinical features 50% asymptomatic Thromboembolic events Increased risk of fetal loss Vasomotor symptoms (headache, visual disturbances, acral paresthesias) Acute gouty arthritis Petechial bleeding Diagnostics ET is a diagnosis of exclusion; all other causes of thrombocytosis must be ruled out before the diagnosis can be made. Thrombocytosis (> 600,000/μL) ↑ LDH and uric acid Bone marrow aspiration: hyperplasia of megakaryocytes Differential diagnosis Reactive thrombocytosis: platelet proliferate as a reaction to a certain condition, and not because of an intrinsic defect Can be particularly severe in children, with platelet counts reaching 1,000,000/μL. Etiology Inflammation, infection Iron deficiency Malignancy Increased cellular turnover following acute blood loss Pregnancy Following cytostatic therapy Treatment Prevent thromboembolisms: low dose aspirin Reduce thrombocyte count: hydroxyurea or interferon alpha

Answer 2

Description: leukemia with monoclonal proliferation of eosinophilic granulocytes, that causes peripheral eosinophilia and tissue damage Clinical features Hepatosplenomegaly Anemia and/or coagulation disorders Diagnosis CBC: ↑↑↑ eosinophilic granulocytes Peripheral blood smear and bone marrow aspiration: monoclonal blast cells or cytogenetically abnormal eosinophils

Answer 3

Insufficient nucleus maturation relative to cytoplasm expansion due to Defective DNA synthesis Defective DNA repair. ``` Ddx: Megaloblastic anemia: impaired DNA synthesis and/or repair with hypersegmented neutrophils Vitamin B12 deficiency Folate deficiency Medications Phenytoin Sulfa drugs Trimethoprim Hydroxyurea MTX 6-mercaptopurine Fanconi anemia Orotic aciduria Nonmegaloblastic anemia: normal DNA synthesis without hypersegmented neutrophils Liver disease Alcohol use Diamond-Blackfan anemia Myelodysplastic syndrome Multiple myeloma Hypothyroidism. ``` Both iron deficiency anemia and anemia of chronic disease can manifest with normocytic anemia in the initial phase and microcytic anemia later on. Bone marrow failure (e.g., due to myeloproliferative malignancy, myelodysplastic syndrome) can manifest with microcytic, normocytic, or macrocytic anemia. The causes of microcytic anemia can be remembered with IRON LAST: IRON deficiency, Lead poisoning, Anemia of chronic disease, Sideroblastic anemia, Thalassemia.

Answer 4

MCV (fL) = 80-100 | Mechanism: Decreased blood volume and/or decreased erythropoiesis

Answer 5

MCV (fL) <80. | Insufficient hemoglobin production.

Answer 6

``` D: Definition: a decrease in the absolute number of circulating RBCs; exact cutoffs vary from source to source. WHO criteria for anemia [1] Men: Hb < 13 g/dL Women: Hb < 12 g/dL Revised WHO/National Cancer Institute [2] Men: Hb < 14 g/dL Women: Hb < 12 g/dL American Society of Hematology [3] Men: Hb < 13.5 g/dL Women: Hb < 12 g/dL ``` R: D: E: A: ``` C: Asymptomatic Pallor (e.g., on mucous membranes, conjunctivae) Exertional dyspnea and fatigue Pica (craving for ice or dirt) Jaundice (in hemolytic anemia) Muscle cramps Worsening of angina pectoris Features of hyperdynamic state Bounding pulses Tachycardia/palpitations Flow murmur Pulsatile sound in the ear Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g., thalassemia, myelofibrosis). Hepatosplenomegaly Paravertebral mass Widening of diploic spaces of the skull. Pulse acceleration is often the first sign of hemodynamically relevant blood loss. ``` P: I: Reticulocyte count, peripheral blood smear, bone marrow biopsy, imaging (if bleeding is suspected). Haemoglobin electrophoresis, M: Identify and treat the underlying cause Blood transfusion with RBCs for severe anemia: Hb ≤ 7 g/dL Hb ≤ 8 g/dL if the patient either has a preexisting cardiovascular disease or is undergoing cardiac or orthopedic surgery See transfusion for further details Bone marrow transplantation may be indicated in certain cases (e.g., aplastic anemia). P:

Answer 7

D: Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia. Based on the defective globin chain, they are classified as either alpha or beta subtypes. Thalassemias are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in patients of Asian or African origin, whereas beta thalassemias are predominant in patients of Mediterranean descent. Beta thalassemia can be further divided into a heterozygous minor and a homozygous major variant. The minor variant features only a low risk of hemolysis; however, the major variant presents with severe anemia as early as infancy and often causes growth retardation. The severity of alpha thalassemias varies as well, with significant anemia generally first arising with a deletion of three of the four alleles (HbH disease). Deletion of all four α-globin alleles (Hb Bart disease) is usually fatal in utero or shortly after birth. In all forms of thalassemia, insufficient erythropoiesis can lead to extramedullary hematopoiesis as well as bone marrow hyperplasia. The latter frequently results in periosteal reactions that are observed as the classic "hair-on-end" sign on skull radiographs. Diagnosis is confirmed via electrophoresis or DNA analysis. If a patient with thalassemia requires transfusion therapy, it is important to consider the possible development of secondary iron overload, which should be treated with chelating agents (e.g., deferoxamine). R: D: E: Beta thalassemia: most commonly seen in people of Mediterranean descent Alpha thalassemia: most commonly seen in people of Asian and African descent Thalassemia provides partial resistance against malaria. Alpha thalassemia is common in Asia and Africa. A: General Cause: gene mutations Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites β-globin locus - short arm of chromosome 11 Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles The α-globin gene cluster is located on chromosome 16 Inheritance pattern: autosomal recessive Beta thalassemia In a normal cell, the β-globin chains are coded by a total of two alleles Thus, there are two forms of the disease. Beta thalassemia minor (trait): one defective allele Beta thalassemia major (Cooley anemia): two defective alleles Sickle cell beta-thalassemia: a combination of one defective β-globin allele and one defective HbS allele Alpha thalassemia In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles. Silent carrier (minima form): one defective allele (-α/αα) Alpha thalassemia trait (minor form) Two defective alleles (-α/-α or --/αα) Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart. Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results in excessive production of pathologically altered HbH Hemoglobin Bart disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers)). C: Beta thalassemia Minor variant (heterozygous): unremarkable symptoms (low risk of hemolysis, rarely splenomegaly) Major variant (homozygous) Severe hemolytic anemia that often requires transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis Hepatosplenomegaly Growth retardation Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla) Transient aplastic crisis (secondary to infection with parvovirus B19) Sickle cell beta thalassemia Features of sickle cell disease Severity depends on the amount of β-globin synthesis. Alpha thalassemia Silent carrier: asymptomatic Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW Hemoglobin H disease Jaundice and anemia at birth Chronic hemolytic anemia that may require transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis Hepatosplenomegaly Skeletal deformities (less common) Compared to thalassemia beta, symptoms in adults are generally less severe. Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia) Intrauterine ascites and hydrops fetalis, severe hepatosplenomegaly, and often cardiac and skeletal anomalies Incompatible with life (death in utero or shortly after birth). P: Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype. Inefficient erythropoiesis → anemia Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2. HbF protects infants up to the age of 6 months, after which HbF production declines and symptoms of anemia appear. Alpha thalassemia intermedia (HbH disease) and Bart disease: faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb-Bart's In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia. Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities. I: Blood sample: microcytic hypochromic anaemia: Iron deficiency anaemia usually presenting with a low RBC count and a high RDW. Blood smear: target cells, teardrop cells, anisopoikilocytosis. Bone marrow biopsy: reactive hyperplaia. Confirmatory tests: Hb-electrophoresis: alpha thalassemia can usually be detected if >3 alleles are defective. Abnormal pattern depends on the exact subtype. Diagnosis of beta-thalassemia minor is confirmed by HbA2> 3.5%. DNA analysis: to test for alpha thalassemia minor and minima (<3 alleles defective). Can do imaging: skseletal deformaties (e.g high forehead, prominent zygomatic bones and maxilla, referred to as 'chipmunk facies' can be seen on all imaging modalities. X-ray: hair on end ('crew cut') sign. Family history plays an important role in diagnosing patients with clinically silent thalassemia. The possibility of thalassemia in these patients may only be investigated once a family member is diagnosed with a more severe form! Suspect thalassemia in a patient with microcytic anemia that is nonresponsive to iron supplementation! M: Minor and minima variants Usually no therapy required Supplementation of iron or folic acid may be indicated in some patients. Major variants and hemoglobin H disease Curative: allogeneic stem cell transplantation Symptomatic treatment Transfusion of erythrocyte concentrate Indication: Hb < 7–8 g/dL or marked clinical symptoms Target: Hb > 10 g/dL Chelating agents (e.g., deferoxamine) in patients with Serum ferritin concentration > 1000 μg/L Secondary iron overload Folic acid supplementation Splenectomy P:

Answer 8

D: Sickle cell syndromes are hereditary hemoglobinopathies. Homozygous sickle cell anemia (HbSS, autosomal recessive) is the most common variant of the sickle cell syndromes and occurs predominantly in individuals of African and East Mediterranean descent. Sickle cell trait occurs in heterozygous carriers (HbSA). Other rare variants of sickle cell syndrome occur in individuals with one HbS allele and one other allele (HbC or Hb-β thalassemia). A point mutation in the beta chain of hemoglobin leads to substitution of glutamic acid by valine, thus changing the structure (and properties) of hemoglobin. Abnormal hemoglobin polymerizes when deoxygenated, resulting in sickle-shaped erythrocytes, which cause vascular occlusion and ischemia. Sickle cell anemia manifests in early childhood with symptoms associated with vascular occlusion and hemolytic anemia. Infarctions in the spleen, kidneys, bone, CNS, and other organs are common and cause progressive loss of organ function and acute and chronic pain in affected parts of the body. Acute, painful vaso-occlusive crises are provoked by conditions associated with reduced oxygen tension. Neonatal screening for sickle cell anemia has been implemented across the U.S., allowing the diagnosis to be made before the first manifestation of the disease. In older children and adults, hemoglobin quantification tests are used to diagnose the condition. The cornerstones of treatment involve the management of painful vaso-occlusive crises, hemolytic anemia, and disease complications as well as prevention of infection. Allogeneic bone marrow transplantation is the only curative treatment option. R: D: E: Predominantly affects individuals of African and East Mediterranean descent Africa has the highest prevalence of the disease (30% heterozygote prevalence). HbS gene is carried by 8% of the African American population. [1] Sickle cell anemia is the most common form of intrinsic hemolytic anemia worldwide. A: C: Sickle cell trait Often asymptomatic Painless gross hematuria due to renal papillary necrosis: often the only symptom Hyposthenuria: nocturia, enuresis Recurrent urinary tract infections Renal medullary carcinoma Very rarely, symptoms of sickle cell disease may occur as a result of severe oxygen deficiency. Sickle cell disease Onset ∼ 30% develop symptoms in the first year of life; > 90% by age 6 years Manifests after 6 months of age as the production of HbF decreases and HbS levels increase Acute symptoms Acute hemolytic crisis (severe anemia) Splenic sequestration crisis Splenic vaso-occlusion → entrapment and pooling of large amounts of blood in the spleen → acute left upper quadrant pain, anemia, reticulocytosis, and signs of intravascular volume depletion (e.g., hypotension) Aplastic crisis Aplastic anemia with an acute, severe drop in hemoglobin and associated reticulocytopenia due to an infection with parvovirus B19 Dysmorphic erythrocytes in sickle cell disease and hereditary spherocytosis are susceptible to parvovirus B19 infection, which can temporarily suppress bone marrow erythropoiesis. Hyperhemolysis: intravascular and extravascular hemolysis triggered by mild oxygen deficiency (rare) Infection Pneumonia Meningitis Osteomyelitis (most common cause: Salmonella spp., Staphylococcus aureus) Sepsis (most common cause: Streptococcus pneumoniae) Vaso-occlusive events Vaso-occlusive crises (painful episodes, painful crisis): recurrent episodes of severe deep bone pain and dactylitis → most common symptom in children and adolescents Acute chest syndrome Priapism Stroke (common in children) Infarctions of virtually any organ (particularly spleen) and avascular necrosis with corresponding symptoms (see “Complications” below) Chronic symptoms Chronic hemolytic anemia: fatigue, weakness, pallor; usually well-tolerated Chronic pain Cholelithiasis (pigmented stones) Symptoms of other forms of sickle cell syndrome (HbSC disease and HbS/beta-thalassemia) are similar to sickle cell anemia but less severe. P: Genetics Heterozygotes (HbSA): carry one sickle allele and one other (usually normal) → sickle cell trait Homozygotes (HbSS): carry two sickle alleles → sickle cell anemia Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine (single amino acid substitution) → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS). Glutamic acid can also be replaced with a lysine, creating hemoglobin C. Hemoglobin SC disease Heterozygosity for hemoglobin S and hemoglobin C Results in a phenotype more severe than sickle cell trait but not as severe as sickle cell disease (e.g., fewer acute sickling events). Pathomechanism HbS polymerizes when deoxygenated, causing deformation of erythrocytes (“sickling”). This can be triggered by any event associated with reduced oxygen tension. Hypoxia (e.g., at high altitudes) In homozygotes, up to 100% of the hemoglobin molecules are affected, leading to sickle cell formation under minimally decreased oxygen tension. In heterozygotes, sickling only occurs due to severe reduction in oxygen tension. Infections Dehydration Acidosis Sudden changes in temperature Stress Pregnancy Sickle cells lack elasticity and adhere to vascular endothelium, which disrupts microcirculation and causes vascular occlusion and subsequent tissue infarction. Extravascular hemolysis and intravascular hemolysis are common and result in anemia. Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency. The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease. I: Prenatal testing: may be conducted in select cases: chorionic villus sampling and DNA analysis at 8–12 weeks of gestation Neonatal screening (mandatory in all states) If positive: Repeat hemoglobin electrophoresis (gold standard) confirms the diagnosis and distinguishes between heterozygotes and homozygotes and other forms of sickle cell syndrome (e.g., HbSC disease) Migration towards the anode: HbA > HbF > HbS > HbC Older children and adults Liquid chromatography and isoelectric focusing to quantify hemoglobin subtypes (best tests) Sickle cell test: detects sickle cells in a blood smear under anaerobic conditions. Peripheral blood smear Sickle cells (drepanocytes): crescent-shaped RBCs Target cells Possibly Howell-Jolly bodies Reticulocytosis Imaging: X-ray of the skull shows hair-on-end (“crew cut”) sign due to periosteal reaction to erythropoietic bone marrow hyperplasia (also present in thalassemia). Disease monitoring Laboratory analysis See “Laboratory signs of hemolysis” in hemolytic anemia. Liver and kidney function tests Pulmonary function tests Transcranial Doppler ultrasound is used to identify and monitor children with a high risk of stroke. M: Longterm management Prevent infections Pneumococcal vaccines Meningococcal vaccines Daily penicillin prophylaxis (at least until the age of 5 years) If sepsis is suspected, treat with IV third-generation cephalosporin (e.g., ceftriaxone) If meningitis is also suspected: add vancomycin Second-line therapy (e.g., due to allergy): levofloxacin, clindamycin Prevent vaso-occlusive crises and manage anemia Avoid triggers Hydroxyurea: first-line treatment Indications Frequent, acute painful episodes or other vaso-occlusive events Severe symptomatic anemia Effect: stimulates erythropoiesis and increases fetal hemoglobin → sickled hemoglobin is proportionally reduced → red blood cell polymerization decreases → fewer vaso-occlusive episodes Possible adverse effects: myelosuppression (beneficial in patients with myeloproliferative disease, e.g., polycythemia vera) Can cause an atypical form of macrocytosis (nonmegaloblastic anemia) If the response to hydroxyurea alone is not adequate Combine with erythropoietin Blood transfusions Folic acid supplementation Cholecystectomy to treat cholelithiasis Management of acute sickle cell crisis Prompt and adequate supportive treatment Hydration Pain management with nonsteroidal anti-inflammatory agents and opioids Thromboembolic prophylaxis Nasal oxygen Bed rest Blood transfusions Indications Acute, severely symptomatic anemia (e.g., aplastic crisis) Secondary prophylaxis of acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure) Surgery (preoperative transfusions) Pregnancy Exchange transfusions (erythrocytapheresis): automated removal of erythrocytes containing HbS and simultaneous replacement with HbS free erythrocytes Indication: acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure) Advantages Rapid effect! Allows precise control of HbS levels and iron accumulation Disadvantages Expensive and equipment not readily available Requires experienced practitioner Curative therapy Allogeneic bone marrow transplantation Indications: homozygotes, children < 16 years with severe disease. P: Organ damage Recurrent vascular occlusion and disseminated infarctions lead to progressive organ damage and loss of function. In homozygotes, this progress is associated with high morbidity and mortality. In heterozygotes, organ damage is very rare.

Answer 9

``` Brain 26% Leukaemias 31% Lymphomas 13% SNS STS Other ```

Answer 10

``` Brain 13% Carcinomas 9% Germ cell tumours 27% Leukaemias 10% Lymphomas 22% Other 19% ```

Answer 11

Brain 28% Leukaemias 29% Lymphomas 7%

Answer 12

Brain 14% Carcinomas 31% Leukaemias 7% Lymphomas 20%

Answer 13

Leukaemias --> most common liquid tumour in both male and female (0-14) Brain tumour --> 2nd most common in male and female 0-14 Germ cell testicular tumours in boys (15-24) Carcinomas in girls. (15-24)

Answer 14

``` Abdominal masses distended. Swollen lymph nodes. Back pain. Bruises --> on areas you do not expect. Weight loss Headaches --> brain tumour. Haematuria --> could be kidney Vomiting White pupil --> retinol blastoma in eye. ```

Answer 15

Exposure to infections (EBV), Exposure to radiations (atomic radiation radiotherapy). Secondary cancers due to previous chemotherapy (Etoposide). Inheritance (retinoblastoma) or certain genetic syndromes like down syndrom (have increased risk). Fanconi anaemia have increased risk of malignancies. More research evidence of genetics involved in certain leukaemias.

Answer 16

Bone marrow infiltration by blast cells --> spill into the blood, normal cells will not be produced. Anaemia -->pallor, lethargy. Thrombocytopenia -->bleeding, petechiae. Neutropenia --> fevers and infections. Bone pain --> limp, irritability. Repeating histories, recurrent infections as WBC not matured/produced. Irritable child because of bony pains. Enlarged lymph nodes, hepatosplenomegaly, orthopnea, mediastinal mass, . This is because of extramedullary spread of blasts which are in bone marrow, then go out from blood and infiltrate/accumulate in other areas. tracheal compression, testicular enlargement, gingival hypertrophy.

Answer 17

Diagnosis -FBC: blood test to look for FBC and blood film. -Bone marrow: aspiration and trephine biopsy. Needle procedure, take tissues and aspirate. -Lumbar puncture to test for CSF and blasts, as leukaemia cells can go into CSF and testes. -Chest x-ray to look for mediastinal mass  lymph nodes can be enlarges in chest which can cause pressure on trachea. -coagulation tests  myeloid leukaemia can present with coagulopathy. LDH,ESR, lectic dehydrogenase, high in malignancies, sign of tissue breakdown.

Answer 18

Age: -low risk 109 years. -children below 1 year or above 10 years have a high risk. WBC: -if below 50k  low risk -If above 50k  high risk Cytogenetics to look at leukaemic cells/blast cells: -high hyperdiploidy good risk/prognosis. -philaldelphia chromosome/near haploidy  low number of chromosomes  leukaemia or blast cell cutogenetocs high risk. Monosomy 7;5  high risk. Minimal residual disease  special test that we do. marker done in initial BM test, then again after 1 month of treatment of leukaemia, and we compare it. This allows us to see the response to chemotherapy. If mrd is low then that means a low risk and good prognosis if there is a high risk than mrd will be high and that means we may need to intensify the treatment.

Answer 19

there are five phases of treatment for ALL Number one induction treatment for one  induce remission: Vincristine/Daunorubicin/dexamethasone/asparaginase Number two consolidation (6months) , interim maintenance and delayed intensification: Cyclophosphamide/Cytarabine Number three maintenance for 2-3 years: Vincristine/Dexamethasone/Mercaptopurine/Methotrexate -Will give CNS prophylaxis via intrathecal methotrexate. Overall treatment for ALL: Girls 2 years aand 3 months Boys 3 years and 3 months, as leukaemia can also travel to testes.

Answer 20

Daunorubicin.

Answer 21

Intrathecal methotrexate.

Answer 22

less common 16% Treatment more intense and shorter given over 4-6 months as compared to ALL (2-3 years). However, AML treatment is all based in hospital (inpatient due to side effects of treatment) whereas for ALL treatment it is mainly outpatient based, eventhough it is 2-3 years. Targeted therapy with Gemtuzamab in AML. If high risk cytogenetics, require allogenic stem cell transplant.

Answer 23

AML with characteristic cytogenetic translocations. AML with multilineaage dysplasia. AML and myeloidysplasia syndromes, secondary to therapy. AML not otherwise categorised.

Answer 24

Targeted therapy in AML which we give and it is antiCD33 --> one of the markers of AML is CD33. GO--> Gemchoosal map --> the other name of mylotaarg. It is a targeted therapy in myeloid leukaemia. So GO is latest new treatment to give, in addition to other chemotherapy.

Answer 25

2-3% of leukaemia in children. CLL does not occur in children. -older children -hyperleucocytosis Three phases: 1. chronic phase, asymptomatic, sitting in body with high white cell count for a long time, incidental diagnosis. 2. Accelerated phase: a lot of blasts produced. 3. Blast crisis (transformation to ALL or AML). Plentiful of blasts, can be lymphoid blast crisis or myeloid blast crisis, then treated accordingly. Diagnostic via translocation of chromosome 9 & 22 (BCR-ABL) Treatment of CML Initial cytoreduction with hydroxycarbamide (hydroxyurea) --> same drug used in sickle cell anaemia, it causes cytoreduction and reduces the white cell count. -Targeted treatment with TKIs (tyrosine kinase inhibitors). -Imatinib, dasatinib to achieve cytogenetic and morphological remission. -Blast crisis: treatment for ALL/AML and allogenic SCT (matched related donor) --> transplant.

Answer 26

If BM involvement >25% iit is lymphoblastic leukaemia. If some cells in BM but less than 25% it is lymphoblastic lymphoma.

Answer 27

Burkitt lymphoma.

Answer 28

``` Adolescents > younger children. Painless lymphadenopathy-->long history of weight loss, night sweats, lymph nodes are painless. Mediastinal mass SVC: superior vena cava syndrome. SMS: superior mediastinal syndrome. Oncology emergency ```

Answer 29

Stage one: neck Stage two: neck and axillary sTAGE 3: under diaphraam, spleen/liver, genitourinary track. Stage 4: all areas including pelvis

Answer 30

Second most common lymphoma we see in children. - -B-cell origin -Abdomen or nasopharynx: we can see EBV involvement esp if nasopharyngeal. -can present with intussusception, if present in absomen. This is acute abdominal emergency. -aggressive chemotherapy, as it is an aggressive lymphoma, very rapidly proliferating, limited time emergency. -It is a long inpatient stay, but is short treatment 6-8 weeks, children do have time to go home. -outcome is very good and treatments are successful. -excellent treatment success -we also have good targeted treatment in addition to chemotherapy in Burkitt lymphoma --> Rituximab, targeted at anti CD20, becaause CD20 is a marker for burkitt lymphoma. -There is a high risk of tumour lysis syndrome, because it is rapidly proliferating, cells also lyse or breakdown very rapidly, and this causes tumour lysis.

Answer 31

Infant: Neuroblastoma, Wilms tumour, hepatoblastoma. 2-6 years: neuroblastoma, Wilms tumour, hepatoblastoma, York cell tumours. 7-10years: NHL, germ cell tumours. 10-16 years: lymphoma, hepatocellular carcinoma, ovarian.

Answer 32

Tumour markers -AFP and Hcg for liver tumours and germ cell tumours Urine catecholamines for neuroblastoma Scans : CT/MRI/PET/MIBG (MIBG only for neuroblastoma) Biopsy for tissue diagnosis /histology Bone marrow/trephine (as solid tumours can spread to BM aswell) /Lumbar puncture PET scan: tells us if any other site of body is invplved or not, esp bone involvement (metastatic spread).

Answer 33

Increase number of myeloblasts, that are normally supposed to differentiate into basophils, neutrophils, eosinophils, and macrophages. However it does not therefore you get increased myeloblasts, reduced wbc of neutrophils and basophils therefore more infections.

Answer 34

1. Febrile neutropenia and sepsis 2. Tumour lysis syndrome 3. Hyperleucocytosis 4. SVCS due to mediastinal mass 5. Thrombosis usually central catheter related 6. Gastrointestinal issues/Typhilits 7. Spinal cord compression

Answer 35

Temperature > 38 Neutrophils < 0.5 Risk criteria –Low risk or high risk for sepsis Broad spectrum antibiotics –Tazocin/Gentamicin. Need to start antibiotics within an hour as there is a high risk for septicaemia. When giving chemotherapy, compromising immunity -->fever.

Answer 36

Most commonly seen in first 5 days. Most commonly seen in leukaemia. When cancer cells break, they release potassium and phosphate. When potassium is released, this can cause massive levels and can cause heart failure and death. Increased phosphate causes decreased calcium and this can cause seizures due to hypocalcaemia. But at the same time, when they are together in the blood, then they can precipitate at certain places, esp the kidneys, and this can cause renal failure. DNA also broken down, released purines, makes uric acid. Uric acid will be high, can be toxic to kidneys, precipitate renal failure. So we have 2 types of treatment for high uric acid: allopurinol which we start all the time from the beginning. BUT, if massive white cell count: large liver, spleen, lymph nodes, give nrsburicase: breaks down uric acid to allatoin. But ideally/usually start with allopurinol. Chemotherapy for rapidly proliferating tumours (leukaemia, lymphoma, myeloma). This leads to cell death and increase urate, increase potassium, increase phosphate and decrease calcium. This causes risk of arrhythmia and renal failure. Management is to prevent with hydration and uricolytics, eg rasburicase, allopurinol.

Answer 37

Hyperleucocytosis Mediastinal mass Bulky abdominal disease High LDH and uric acid Reduced urine output and renal dysfunction Renal involvement by lymphoma or leukaemia

Answer 38

Leucocytosis: sticky, blocking blood vessels and stopping flow of blood. ``` Ischaemia to vital organs, the symptoms related to that. WBC > 100 ( Admission needs discussion with PICU) 5-10% of leukaemic pts at diagnosis ALL > AML Risk of complications more with AML Complications: -Tumour Lysis -Stasis: Cerebrovascular , Pulmonary ```

Answer 39

• SVCS: signs and symptoms resulting from compression, obstruction , or thrombosis of the superior vena cava. • Flow to upper face is congested, look swollen. • Symptoms result from compression, obstruction or thrombosis of superior vena cava. • SMS: tracheal compression also occurs 45 degrees angle, Commonest causes: B & T NHL, Hodgkin lymphoma. T-ALL Less common teratoma,neuroblastoma or rhabdomyosarcoma

Answer 40

* Direct pressure effect from tumour | * Commonest in neuroblastoma, Ewing’s, RMS, sarcomas; lymphoma, germ cell tumours; any metastatic tumour.

Answer 41

``` Nausea, vomiting Hair loss--> chemotherapy acts on rapidly dividing cells --> gut, mouth, bone marrow cells. Bone marrow suppression Febrile neutropenia and septic shock Constipation/diarrhoea Mucositis ```

Answer 42

Cardiotoxicity: Doxorubicin, Daunorubicin Deafness: Cisplatin Renal toxicity: Cisplatin, Peripheral neuropathy: Vincristine, Cisplatin Haemorrhagic cystitis: Cyclophosphamide, ifosfamide Neurotoxicity :High dose methotrexate/intrathecal methotrexate Ifosfamide

Answer 43

``` Growth Fertility Endocrine Cardiac Cataracts Neuro-psychological sequele Second cancers ```

Answer 44

Non-hodgkin's lymphoma. CLL can transform to high-grade lymphoma (Richter's transformation) making patients suddenly unwell The rapid onset of the symptoms above suggest Richter's transformation; a transformation of CLL into a fast-growing diffuse large B cell non-Hodgkin's lymphoma which occurs in 2-10% of people with CLL (Cancer Research UK) and carries a poor prognosis. CLL may rarely transform into Hodgkin's lymphoma or ALL (0.5% and <1% of patients respectively), making these much less likely than Richter's transformation. CLL to myeloma transformation is extremely uncommon and the symptoms above aren't typical of myeloma. CLL is a cancer of the lymphoid cell line, whilst AML and CML are cancers of the myeloid cell line. As these

Answer 45

Myelofibrosis. It's tear-drop shaped because the bone marrow is fibrosed. So the RBC's are being 'pushed' out through a solid, unforgiving gap, and as such become squeezed like a tear drop. Myelofibrosis usually presents with an isolated low Hb with a raised/normal white cell/platelet count. Initial symptoms are usually insidious and non-specific but a massive splenomegaly +/- lymphadenopathy +/- hepatomegaly is common. As disease progresses there may be a pancytopoenia due to progressive marrow fibrosis. The blood film changes are characteristic of myelofibrosis and to distinguish this from CML, which can present similarly, you would look for an absent Philadelphia chromosome and 'dry' bone marrow aspiration.

Answer 46

Myelofibrosis would have normal cell maturation, whereas myelodysplasia would have abnormal maturation and give you an accumulation of blasts. Myelodysplasia would only give you a deficiency in two blood lines. Myelodysplasia is characterised by dysplastic (abnormal) cells found in the marrow, leading to deficient production in usually one (or more) cell lines. In only some cases does it give blasts (RAEB). For example, the most common form is refractory anaemia (RA). Myelofibrosis is characterised by fibrosis seen in the marrow, with a dry bone marrow aspirate and loss of cellularity on trephine biopsy. It eventually results in pancytopenia.

Answer 47

To diagnose tumour lysis syndrome, you require either increased serum creatinine, a cardiac arrhythmia or a seizure to have occurred. This question is asking about a man with known lymphoma. He starts chemotherapy and then begins to deteriorate. Any deterioration in a patients state within 7 days of starting chemotherapy is indicative of tumour lysis syndrome (TLS) and in this case, this is what the patient was suffering with. To diagnose tumour lysis syndrome you require both a positive laboratory TLS and positive clinical TLS. ``` Positive laboratory TLS requires 2 or more of the below within 7 days of chemotherapy or 3 days before: uric acid > 475umol/l or 25% increase potassium > 6 mmol/l or 25% increase phosphate > 1.125mmol/l or 25% increase calcium < 1.75mmol/l or 25% decrease ``` Positive clinical TLS requires any one of: increased serum creatinine (1.5 times upper limit of normal) cardiac arrhythmia or sudden death seizure

Answer 48

Age: -low risk 1-9 years. -children below 1 year or above 10 years have a high risk. WBC: -if below 50k  low risk -If above 50k  high risk Cytogenetics to look at leukaemic cells/blast cells: -high hyperdiploidy good risk/prognosis. -philaldelphia chromosome/near haploidy  low number of chromosomes  leukaemia or blast cell cutogenetocs high risk. Monosomy 7;5  high risk. ``` Poor prognostic factors age < 2 years or > 10 years WBC > 20 * 109/l at diagnosis T or B cell surface markers non-Caucasian male sex ```

Answer 49

Leukaemia: abnormal cells in blood.  Acute and chronic. Leukaemia is a clonal abnormality with one stem cell growing out of control. Lymphoma: may or may not involve BM, and it may or may not be in blood.--> Hodgkin lymphoma and non-hodgkin lymphoma. Myeloproliferative Myelodysplastic disorders Myeloma and immunoglobulin disorders.

Answer 50

Inherited factors: - Down syndrome - Fanconi anaemia - Wiskott-Aldrich syndrome Environmental factors: -chemicals eg. Benzene Drugs: cytotoxic drugs, radiation: previous treatment with chemotherapay/radiation to increase chance of developing cancer again. Infection: EBV causes Burkitt's lymphoma (aggressive tumour but can be cured by chemotherapy). HTLV-1: adult T-cell leukaemia/lymphoma. Bacteria: Helicobacter pylori, -->gastric cancer (MALT) Protozoa: malaria --> Burkitt's lymphoma

Answer 51

Because testes are also a site of metastasis for leukaemic cells. Some chemotherapeutic drugs don't easily go to testes, therefore need more treatment. Radiation however gets everywhere.

Answer 52

Lumbar puncture, to find out if CSF is involved. Even if CSF is not involved, you inject intrathecal chemotherapy into the CSF to prevent leukaemia settling in. If it is involved, you need much more intensive treat,ent to erradicate the CSF/brain, a lot of intrathecal therapy.

Answer 53

ALL and CML. It is diagnostic in CML.

Answer 54

-having this chromosome means poorer response to chemotherapy and higher response to relapse. --> may want to do transplantation. In philaldelphia chromosome, the fusion gene causes a fusion protein which drives proliferation of cells. This drive can be blocked by blocking that fusion protein.

Answer 55

Blocks that fusion protien. Tyrosine kinase inhibitor. Add it to treatment, and this can help targeted therapy in treatment of cancer.

Answer 56

Systemic effects of cytokines: malaise, fatigue, nausea, fever. Bone marrow infiltration: tenderness on bones. Anaemia: Pallor, lethargy, shortness of breath, dizziness, palpitations, reduced exercise tolerance. Neutropenia: fever, infection in general, recurrent infection, unusual interactions (opportunistic). Thrombocytopenia: bruising, petechiae, epistaxis. Reticuloendothelial infiltration: hepatosplenomegaly, lymphadenopathy symptoms due to mediastinal compression. Other organ infiltration: CNS: headaches, vomiting, cranial nerve palsies, convulsions. Testes: testicular enlargement. Leucostasis: headache, stroke, shortness of breath, heart failure. Bone/joint pain--> because bone marrow that is infiltrated will give thoracic pain. ``` Fever, fatigue bleeding, enlarged lymph nodes, can obstruct major vessels --> superior vena cava obstruction/invasion of vital structures. Lymphadenopathy Hepatomegaly Splenomegaly Mediastinal mass CNS leukaemia Testicular leukaemia Presence of marrow failure is very common. ```

Answer 57

1. Remission induction (4-6weeks) 2. Consolidation and CNS therapy (usually prophylactic) (4-12 weeks) (8-12 weeks 3. Intensification 4. Continuation (maintenance) therapy 2-3 years. 5. Allogeneic bone-marrow transplantation.

Answer 58

Mechanism and complication Neutropenia: infection (Gm-negative sepsis), DIC. Thrombocytopenia: Bleeding, stroke, pulmonary haemorrhage. Gastrointestinal haemorrhage. Electrolyte imbalance: hyperkalaemia & hyperphosphataemia (TLS). AC. renal failure-hyperuricaemic nephropathy. RE infiltration: Ac airway obstruction-mediastinal mass. Leucostasis: stroke, ac. pulmonary oedema, heart failure.

Answer 59

The RES is responsible for phagocytosis and the removal of organic and inorganic material from blood and tissues The lymphoid organs are responsible for immunity and specifically the production and activation of lymphocytes in order to generate immune responses to microbes

Answer 60

The primary lymphoid organs generate lymphocytes from immature progenitor cells (haemopoietic stem cells) to give rise to lymphoid stem cells which are committed to lymphocyte lineage. The primary lymphoid organs provide the environment for T and B cells to develop T lymphocytes develop in the thymus B lymphocytes develop in the bone marrow.

Answer 61

The Secondary Lymphoid Organs (SLOs) are filters where foreign invaders e.g. microbes, are captured, and lymphocytes are activated. Lymph nodes Mucosa-associated lymphoid tissue (MALT) e.g. tonsils, Peyer’s patches of the small bowel Spleen SLOs represent ‘meeting places’ where antigen and lymphocytes interact to generate an immune response. SLOs particularly lymph nodes are strategically positioned to intercept invaders which penetrate the first line barrier defences. Lymph nodes police tissues MALT polices mucosa (moist internal epithelial surfaces) - nasal associated lymphoid tissue NALT e.g. the tonsils police the upper respiratory tract - gut associated lymphoid tissue GALT e. g. Peyer’s patches police the gut. - Bronchial associated lymphoid tissue BALT police the lower respiratory tract The spleen polices the blood

Answer 62

Tertiary lymphoid organs (TLOs) are basically acquired lymphoid organs that develop in tissues in response to chronic immune-mediated inflammation stimulated by persistent infections, chronic graft rejection, autoimmunity, and cancer TLOS are loose lymph node-like immune cell clusters with defining features the same as SLOs, namely: High Endothelial Venules, lymphoid stromal cells, and lymphoid follicles Defining features of TLOs are those that define SLOs: High Endothelial Venules (HEV) Lymphoid stromal cells Separate T-lymphocyte and B-lymphocyte-rich compartments Follicular dendritic cell (FDC)-containing germinal centres Antigen-presenting cells, including dendritic cells (DCs). TLOs can be detrimental to the health of tissues by perpetuating chronic inflammation. For example in Crohn’s disease TLOs can be helpful by discouraging tumour growth and can often convey an improved prognosis in cancer. TLOs serve as the functional immune organs to recruit and activate T cells in the tumour site so mediating an effective anti-tumour immune response. Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Focus has been on T cells but it is likely the effect of tertiary lymphoid structures in general that determines the response to ICB treatment,

Answer 63

``` Mesenteric fat (creeping fat) is a characteristic feature of Crohn’s disease (CD) In areas of creeping fat, which associates with inflammation-affected areas of the bowel in CD, TLOs are positioned along collecting lymphatic vessels in a manner expected to affect delivery of lymph to LNs. Blockage of afferent mesenteric lymphatics by TLOs causes backflow of lymph all the way back to the gut wall. Lymphatic pressures are higher. Mesenteric backflow may facilitate the creeping fat. Tertiary lymphoid structures have a key role in the immune microenvironment in cancer, by conferring distinct T cell phenotypes. ```

Answer 64

``` Primary (congenital) immunodeficiencies: a condition resulting from a genetic or developmental defect. The defect is present from birth and is mostly inherited (result of a mutation). Some people may not be clinically observed until later in life  present later. Deficiency may be in innate or adaptive immune function, or both. Recurrent infections (normal <6-8 URI/year for the 1st 10 years; 6 Otitis media and 2 gastroenteritis/year for the 1st 2-3 years). Mostly infections associated with the mucosa. Appear in first months of life or early malignancies. ``` Secondary immunodeficiencies: originate as a result of malnutrition, cancer, drug treatment or infection. Most common and well-known = Aids. -A result of a condition that causes immunodeficiency. It is much more common. Causes include: -HIV infection (depletion of CD4+ T cells) -Protein calorie malnutrition (metabolic derangements inhibit lymphocyte malnutrition and function). -Irradiation and chemotherapy for cancer (Decreased bone marrow lymphocyte precursors). -cancer metastases and leukaemia involving bone marrow (reduced site of leukocyte development). -immunosuppression for transplants, autoimmune disease (reduced lymphocyte activation, cytokine blockade, impaired leukocyte trafficking). -removal of spleen (decreased phagocytosis of microbes)