Oncology/Haematology Flashcards
1
Q
Poor prognostic signs in ALL
A
WCC>50
<2 and >9 years age
Boys do less well than girls
Chromosomal abnormalities eg t(4:11) and t(9:22)
Hypodiploidy <44
CNS disease
Poor response to induction chemo with minimal residual disease
2
Q
Ifosfamide side effects
A
Metabolic acidosis
3
Q
Wilm’s tumour is associated with which conditions?
A
- WAGR syndrome 30%, WT1 deletion- Wilms tumour; aniridia; genitourinary abnormalities; retardation
- Denys-Drash syndrome 90%, WT1 missense mutation - pseudohermaphroditism; mesangial renal sclerosis, Wilms tumour.
- Fanconi Anaemia (20%)
- Beckwith-Wiedemann syndrome 5%, 11p15
Hemihypertrophy
Cryptorchidism
Hypospadias
4
Q
Risk factors for development of sarcoma?
A
- Li-Fraumeni syndrome (p53 mutation)
- NF1
- Hereditary retinoblastoma (500x risk osteosarcoma)
- Prior treatment with radio/chemotherapy (inc osteosarcoma risk)
5
Q
Side effects of methotrexate?
A
Mucositis
Hepatitis
Decr renal function
Neurocognitive effects
6
Q
Side effects of cisplatin?
A
Ototoxicity (can use sodium thiosulfate to decrease hearing loss risk)
Nephrotoxicity
Delayed nausea
7
Q
Side effects of ifosfamide and cyclophosphamide?
A
Haemorrhagic cystitis
Leukaemia/lymphoma
Infertility
Lung fibrosis
8
Q
Side effects of vincristine?
A
Peripheral neuropathy Abdominal pain, constipation Jaw and bone pain Ptosis Extravasation injury
9
Q
Side effects of anthracyclines/doxorubicin?
A
AML
Cardiomyopathy
Radiation-recall dermatitis
Necrosis on extravasation
10
Q
Side effects of etoposide?
A
Leukaemia (AML)
11
Q
Side effects of L-asparaginase?
A
Hyperglycaemia
Pancreatitis
Coagulopathy
Encephalopathy
12
Q
Side effects of bleomycin?
A
Pulmonary fibrosis
13
Q
Chemotherapy drugs causing an increased risk of secondary malignancy?
A
- Cyclophosphamide (alkalising agent)
- Etoposide (topoisomerase II inhibitor)
- Doxorubicin and danorubicin (anthracyclines, topoisomerase II inhibitors)
14
Q
Side effects of radiotherapy?
A
Neurocognitive
Endocrine: growth hormone deficiency, hypotyhroidism
Malignancy: breast, thyroid, sarcoma, lymphoma
MSK atrophy
Organ damage: cardiac, lung, GI
15
Q
Describe the types of Non-Hodgkin’s lymphoma
A
- Burkitt’s lymphoma with majority of B cells
- Lymphoblastic lymphoma with 80% T cells and 20% B cells
- Diffuse large B cell lymphoma with B cells
- Anaplastic large cell lymphoma with 70% T cells, 20% null cells and 10% B cells
16
Q
Describe veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)
A
- Obstruction of small veins in the liver as a complication of high-dose myeloablative chemotherapy given before a bone marrow transplant
- Due to injury to hepatic venule, dilation of sinusoids and hepatocyte necrosis, sclerosis, collagen deposition -> obliteration and necrosis, fibrous tissue replacement of normal liver
- Triad of: weight gain, painful RUQ hepatomegaly, jaundice
- Onset within 30 days of SCT, occurs in 10-60%
- Ascites and hyperbilirubinaemia
- Image with doppler USS or CT
- Can treat with defibrotide (anti-thrombus, anti-inflamm). High mortality rates when associated with multiorgan failure
17
Q
Target cells and tear drop cells are consistent with?
A
Thalassaemia trait
18
Q
What is haemoglobin made up of and how is it made?
A
4 globin chains + haem Fetal = a2 + y2 Adult = a2 + b2 Haem is developed in the mitochondria of developing erythroblasts. Haem = porphyrin (from Vit B6) + iron. 90% of EPO comes from kidney.
19
Q
Which factors shift the oxygen dissociation curve to the left?
A
Shift to left = increased affinity for oxygen
Alkalosis, low CO2, low temp, low 2,3 DPG, HbF
20
Q
Which factors shift the oxygen dissociation curve to the right?
A
Shift to right = decreased affinity for oxygen
Acidosis, hight CO2, high temp, high 2,3 DPG, Hb S, exercise
i.e. shifts to right when tissues need more oxygen
“Right Raised Reduced affinity”
21
Q
What is Hb Barts?
A
4 x fetal gamma chains due to 4 x alpha deletions
22
Q
Describe the types and consequences of alpha thalassaemia
A
1 alpha missing - silent carrier, normal FBC
2 missing - alpha thalassaemia trait: mild anaemia
3 missing - HbH disease/alpha thalassaemia intermedia: mod anaemia, mild haemolysis, not transfusion dependant, HSM and skeletal changes
4 missing - Hb Barts: hydrops fetalis, newborn death due to severe anaemia, congestive heart failure. Can do IU transfusions and then BMT postnatally
BF: hypochromic, microcytic, target cells, golf-ball like
- Leads to excess b or y chains, abnormal O2 dissociation curves
23
Q
Describe the types and consequences of beta thalassaemia
A
- Autosomal recessive, B+ (partial function), Bo (no function)
- Minor- B/Bo or B/B+. Mild microcytic anaemia, no Tx
- Intermedia - B+/B+ or B+/Bo. Mod haemolysis, mod-severe anaemia, not transfusion dependant, splenomegaly
- Major - Bo/Bo. Severe haemolysis from 3-6m life (after HbF decreases) transfusion-dependent, HSM, iron overload, bony deformities, “hair on end” skull x-ray, may need splenectomy
- Inc HbA2% (>3.5% in minor) and HbF%, inc RBC distribution width
- BF: microcytic hypochromic, target cells
- High Fe, transferrin, ferritin
24
Q
Management of thalassaemia
A
If Hb <60 for ?3/12 then need regular transfusions
Iron chelation therapy (deferiprone or deferasirox)
May requite BMT, splenectomy
Gene therapy in future
25
Describe the mechanism of sickle-cell disease
- Single base mutation A->T which changes valine to glutamic acid on B-globin chain
- HbS is insoluble, forms crystals when exposed to low O2 tensions.
- Shifts O2 dissociation curve to right
- Presents >6m age when HbF-> HbA
- Sickle cell trait usually asymptomatic as long as well-oxygenated
26
Risks of sickle-cell disease
- Crisis: vaso-occlusion with ischaemia-reperfusion injury
- Haemolytic anaemia
- Above precipitated by infection, acidosis, dehydration, deoxygenation
- Infection risk: pneumococci, haemophilus, salmonella (due to impaired splenic function, defective complement activation, tissue ischaemia, micronutrient deficiencies)
- Stroke - progressive vasculopathy, moyamoya-like syndrome, acute IH when older, cognitive defects due to silent brain infarcts
- Aplastic crisis, often associated with parvovirus
- Acute chest syndrome - pulmonary infiltrate, infection, embolism, vaso-occlusion
27
Management of sickle-cell disease
- Penicillin prophylaxis + conjugate vaccines
- Hydroxyurea - increases HbF concentration
- RBC transfusions - decr HbS synthesis
- BMT is curative (inc morbidity and mortality)
- Opiates for acute pain in crisis
28
What are the causes of asplenia?
Surgical resection
Autosplenectomy (infarct e.g. sickle-cell)
Congenital asplenia syndromes
Iatrogenic/treatment for diseases (ITP, spherocytosis, thalassaemia)
29
What is hypersplenia?
High number of WCC, RCC, plts in spleen - get destroyed.
Due to infection (EBV, TB, hepatitis), alcohol, cirrhosis.
Splenomegaly.
Treat: underlying cause +/- splenectomy
30
Side effects of transfusion?
ABO-incompatibility - haemolysis, DIC, renal failure
Bacteria-contaminated infusion
Transfusion-related acute lung injury (TRALI) - ARDS-like picture
Fever, rigors - cytokine production
Anaphylaxis, IgE
31
Side effects of massive transfusion protocol
```
Coagulopathy (relative decr platelets)
Volume overload
Hypothermia
Hypokalaemia
Hypocalcaemia
```
32
Describe transient erythroblastopenia of childhood
Pure red blood cell defect: low Hb, low retics, normal MCV
6m - 5y/o
Due to viral illness, spontaneous recovery
Expectant transfusion for symptomatic anaemia
33
Causes of anaemia
- Decreased substrate (Fe, B12, folate)
- Abnormal production (aplastic BM, malignancy, drugs, liver/renal disease, haemoglobinopathies)
- Increased destruction (haemolysis, congenital, autoimmune, infection, hypersplenism)
34
Causes of aplastic anaemia
- Constitutional: Fanconi anaemia, Dyskeratosis congenita, Schwachman-Diamond syndrome
- Acquired: idiopathic, drugs (acetazolamide, chloramphenicol), infections (EBV, parvovirus, viral hepatitis), toxins (glues), paroxysmal nocturnal haemoglobinuria
- Tx: HSCT or immunosuppression (cyclosporin)
35
Causes of iron deficiency anaemia
```
Early weaning to cow's milk, cow's milk excess
Coeliac disease
Malabsorption
Chronic blood loss
Menstrual losses
```
36
What are the causes of microcytic anaemia?
Iron deficiency
Thalassaemia (beta or alpha)
Lead poisoning
Sideroblastic anaemia (iron present but cannot be utilised to make Hb)
Anaemia of chronic disease (infection, malignancy) - can be normocytic
37
Describe Fanconi Anaemia
- AR, mean onset age 8y. Defect in DNA-repair, increased chromosomal breakage.
- Marrow aplasia - all lines affected. Macrocytic anaemia
- Microcephaly, absent thumbs + radii, cafe au-lait, short stature, cutaneous hyperpigmentation, decreased fertility (hypogonad), develop delay
- Increased risk AML (30%) and solid tumours (25%)
- Tx: androgens (inc RBC synthesis), steroids, HSCT
38
Describe Dyskeratosis Congenita
- X-linked recessive, mean age 10 for skin, 17 for anaemia
- Associated with short telomeres (repair regions), similar to premature ageing
- Pancytopenia, hyperpigmentation, dystrophic nails, oral leukoplakia, pulmonary and liver fibrosis
- Tx: androgens (inc RBC synthesis), splenectomy, HSCT
- Inc risk oral, nasopharyngeal, vulvul cancers
39
Describe Shwachman-Diamond Syndrome
- Neutropenia +/- anaemia + thrombocytopenia
- Exocrine pancreatic insufficiency
- Skeletal abnormalities (esp hip and knee)
- Short stature
- Can progress to marrow aplasia or AML
40
Diamond-Blackfan Syndrome
- Newborn, 90% present <1yo. AR
- Pure RBC aplasia, elevated HbF, inc RBC adenosine deaminase activity
- Macrocytic, absent red cell precursors in marrow
- Short stature, webbed neck, cleft lip, triphalangeal thumb
- Late onset leukaemia
- Tx: steroids (80% respond, 20% remit), transfusion, HSCT
41
Describe hereditary spherocytosis
- Autosomal dominant
- Blood film: spherocytes, polychromasia (inc immature RBC)
- Bloods: DAT-ve, inc bili/retics/LDH, low Hb
- Splenomegaly
- EMA binding test (decr) + osmotic fragility test (inc fragility)
- Tx: folic acid, splenectomy, cholecystectomy
- Range from asymptomatic with mild anaemia to poor growth, jaundice, chronic transfusion requirement
42
Describe G6PD deficiency
- X-linked, African/Mediterranean/SE Asian
- Usually asymptomatic or prolonged jaundice
- Acute haemolysis triggered by meds (aspirin, antimalarials, cotrimox, nitrofurantoin), infections, acidosis, fava beans
- Decr NADPH (may be normal in acute haemolysis), low Hb, high retics
- Tx: supportive (hydration, transfusion)
43
Heinz bodies + bite cells on blood film
G6PD (bite cells are where the Heinz body has been "bitten" out/phagocytosed by splenic macrophages)
44
Describe pyruvate kinase deficiency
- Low PK level leads to low ATP which impairs RBC survival
- Tolerate low Hb due to inc in 2,3DPG and shift O2 curve to R - increased O2 availability
- AR
- Haemolysis secondary to infections e.g. parvovirus, not aggravated by stress
- Splenectomy to stop RBC destruction
- Can get chronic haemolytic anaemia, unconjugated jaundice
45
Causes of DAT/Coombs+ve
ABO incompatibility/ haemolytic disease of newborn
AIHA
Drug-induced HA
Haemolytic transfusion reactions
46
Causes of polycythaemia
- Primary (rare in childhood) - familial or congenital, polycythaemia vera
- Secondary - heart disease (ToF, CHD), lung disease, high altitude, congenital methaemoglobinaemia, neonates, delayed cord clamping. All are a response to hypoxia with increased EPO production
47
Describe autoimmune haemolytic anaemia
- Acute, self-limiting, often presents post virus (EBV, mycoplasma)
- DAT/Coombs +ve, low Hb, high retics
- Jaundice, splenomegaly, anaemia
- Causes: infections, drugs (penicillin, quinidine), SLE/RA, lymphoprolif disease (Hodgkin's)
- Tx: supportive with folic acid, occ steroids, splenectomy, transfusions (but haemolyse), occ rituximab
48
Is beta thalassaemia associated with hydrops?
Not associated with fetal hydrops, as fetal haemoglobin (α2γ2) compensates
49
Most commonly implicated antigen in NAIT?
In Caucasian women it is Human Platelet Antigen 1a (HPA1a) which accounts for 85% of cases
50
Most commonly implicated antigen in NAIT?
In Caucasian women it is Human Platelet Antigen 1a (HPA1a) which accounts for 85% of cases. 3% population negative.
51
Abnormal thrombin time but normal reptilase time suggests?
Heparin (reptilase is resistant to inhibition by antithrombin III, thus is not prolonged in blood samples with heparin)
52
Causes of spherocytes on blood film?
Spherocytosis - reduced EMA binding
| AIHA (usually warm HA)- normal EMA binding
53
What is Evan's Syndrome?
Evans syndrome is an autoimmune haemolytic anaemia and thrombocytopenia. Coombs+ve.
54
Which factor stimulates eosinophil production?
IL-5
55
Causes of congenital neutropenia?
- Kostmann syndrome (recurrent infection, ELANE or HAX1 mutation, cognitive defects and seizures)
- Shwachman-Diamond syndrome (SS, pancreatic insuff, skeletal abnorm)
- > significant infection history (pneumonia, abscess, gingivitis)
56
Describe chronic benign neutropenia
Autoimmune, can be post viral infection, at risk minor infections, usually ANA+ve, 95% remit in 6-24m. Can usually mount inc neutrophil response with infections (make neuts but destroyed by antibodies)
57
Causes of raised neutrophils
```
Infection
Stress
Exercise
Seizures
Toxic agents
Steroids
```
58
Causes of chronic neutrophilia
```
Malignancy
JIA
Kawasaki
Burns
Uraemia
Post-op
Splenectomy
```
59
What cells do platelets develop from?
Megakaryocytes. Under control of thrombopoeitin and IL-6
60
Causes of thrombocytopenia?
- Impaired production - thrombocytopenia + absent radius syndrome, Fanconi anaemia, Wiskott-Aldrich, aplastic anaemia
- Decreased survival
- Immune mediated: ITP, NAIT, SLE, drug-induced, malignancy
- Non immune mediated: DIC, HUS, TTP, cyanotic CHD, Kasabach-Merrit
61
What percentage of ITP becomes chronic?
20%, usually older girls. Chronic = >6m duration
62
What is the risk of severe bleed in ITP?
<3%
63
When do you treat ITP, and what with?
IVIG, platelet transfusion (for ICH/surgery), tranexamic acid, steroids 2/52 (need BM first to r/o malignancy as steroids can mask this)
Treat if: mucosal bleeding, haematuria, ICH/head trauma, retinal haemorrhage, urgent surgery required
64
Causes of low platelets in neonate
Alloimmune (NAIT) - maternal antibodies to father's platelet antigen. HPA1 most common (85%). Can occur in firstborn. If plts <20 urgent transfuse due to risk ICH first few days life +/- IVIG
Isoimmune (ITP) - mother will have low platelets
Sepsis
TORCH infection
65
What drugs can cause thrombocytopenia?
```
Sodium valproate
Phenytoin
Carbamazepine
Cotrimoxazole
Rifampicin
Heparin
```
66
Signet rings within cells
Malaria
67
Howell-Jolly bodies
Hyposplenism
| nuclear remnants in RBC that haven't been removed as spleen is not working
68
Basophilic stipling
Lead poisoning
69
Auer rods
AML, needle-like
70
Blue cytoplasm with pink/red granules
AML
71
Vitamin-K dependant clotting factors
10, 9, 7, 2
72
Extrinsic coagulation cascade activated by?
Tissue thromboplastin
73
Prothrombin time measures?
Extrinsic pathway + common pathway
| Factor 7, 5, 10, 2
74
APTT measures?
Intrinsic pathway + common pathway
| Factor 8, 9, 11, 12, 5, 10, 2
75
Thrombin time measures?
Final part of common pathway (thrombin, fibrinogen -> fibrin). Prolonged by lack of fibrinogen, and inhibitors (heparin, fibrin degradation products)
76
Natural anticoagulants
Antithrombin III - most potent inhibitor, heparin potentiates its effect
Protein C - inhibits 5a, 8a, promotes fibrinolysis. Protein S enhances protein C action
77
Describe haemophilia A
- X-linked, 30% new mutations
- Carriers have variable F8 levels
- Neonate - IVH, haematoma, excessive bleeding
- Inc APTT, N PT + bleeding time, F8 decr
- Mild: DDAVP (releases vWF from endothelial cells, incr FVIII)
- Tranexamic acid for mucosal bleeds
- Mod+severe: recombinant F8, up to 20% develop inhibitors (low titre give inc doses F8. High titre use F7a to
bypass)
- Mild 5-50% F8, mid 1-5%, severe <1%
78
Role of vWF?
Stabilises and protects F8 from proteolytic enzymes, mediates platelet adhesion. Produced by endothelial cells and platelets
79
Describe vWD
- F8 decr, vWF decr, bleeding time N or inc, plt count N, ristocetin cofactor activity decr (c.f. normal in Haemophilia A)
- T1: AD, 70%, partial def of vWF
- T2: abnormal vWF function, AD
- T3: complete absence, AR, present similarly to Haemophilia A
- Tx: DDAVP, tranexamic acid, type2b+3 require plasma-derived factor 8 concentrate (recombinant factor contains no vWF)
80
Describe Vit K deficiency of infancy
- Early, within 24 hrs, maternal warfarin or anticonvulsants
- Classic, 1-7d, idiopathic or BF babies
- Late, >8d, peaks several weeks, idiopathic or due to BFing, malabsorption, diarrhoea
- APTT inc, PT inc, plt + fibrinogen N. PT prolonged only when <50% prothrombin
- Tx: IV Vit K, works within 20 min, don't given IM. FFP +/- transfusion
81
Presentation of F13 deficiency
Delayed bleeding from umbilicus/cord in up to 80%.
AR. Decr F13 level. Clots lyse in 5M urea solubility test.
Causes inability to cross-link fibrinogen. Lifelong risk ICH. Tx: fibrogammin.
Abnormalities of fibrinogen also present as cord oozing
82
Li Fraumeni predisposes to?
Soft tissue sarcoma, brain tumours
83
Von Hippel-Lindau predisposes to?
Cerebellar haemangioblastomas, renal cell carcinoma, pheochromocytoma
84
Beckwith-Wiedemann predisposes to?
Hepatoblastoma, neuroblastoma. rhabdomyosarcoma. adenocortical carcinoma
85
Ataxia telangectasis predisposes to?
Leukaemia, B-cell lymphoma
86
Which chemotherapy drugs does not interact with DNA directly?
Vincristine
87
Describe lupus anticoagulant
- Acquired inhibitors that may produce a prolonged APTT
- Common, frequently associated with recent viral infections
- Transient
- They are not a risk for bleeding. Increased risk thrombosis
88
Highest risk for testicular relapse in leukaemia is in?
T cell ALL > B cell ALL
89
Describe Kasabach-Merritt syndrome
- Giant haemangioma leading to localised form of DIC
- Lesions at birth in approximately 50% of patients
- Severe thrombocytopaenia, hypofibrinogenemia, elevated fibrin degradations products and fragmentation of red blood cells
- Consumptive coagulopathy
- Tx: corticosteroids, interferon alpha, surgery, embolisation and chemo (vincristine, cyclophosphamide and actinomycin D)
90
What does cryoprecipitate contain?
Factor 8, fibrinogen, vWF, factor 13
91
What is the composition of ALL?
>80% B-cell (pre-B or common ALL), 15% T-cell, 2% mixed
92
What is the most powerful adverse prognostic factor in ALL?
Poor response to induction chemo
93
Significance of presenting WCC count?
If high then poor prognosis in B-cell ALL
| Not prognostic in T-cell ALL
94
What is the Philadelphia translocation, and what can improve its prognosis?
t(9;22), improved by tyrosine kinase inhibitors (imatinib)
95
Why do you give IT chemo?
As CNS lymphoblasts protected from systemic chemotherapy by blood-brain barrier
96
What is the current cure rate for ALL?
>90%
97
Describe AML
- Poorer prognosis than ALL, 5yr survival 60-65%, T21
- Cytarabine-based chemo over 6m, intensive
- Skin involvement (purple spots), HSM, bleeding, masses (chloroma), gum hypertrophy
- Chromosomal abnorm in 80%. t(8;21) has good prognosis
- FLT3-ITD poor, NPM1 favourable, CEBPA favourable
- Film: blasts, auer rods, basophilic (blue) cytoplasm with pink granules
- APML can be treated with arsenic + retinoic acid
98
Significance of acute promyelocytic leukaemia?
May present with DIC. Induction chemo with retinoic acid and arsenic (if presenting WCC <10). Good prognosis if survive induction.
99
Where do NHL and HL originate from?
NHL from B or T lymphocytes, whereas HL from B lymphocytes
100
What are B symptoms?
Paraneoplastic phenomena.
| Night sweats, weight loss (>10% in 6m), fever >38
101
What are the pathognomonic cells in Hodgkin's lymphoma?
Reed-Sternberg cells - large cell, multiple nuclei, "owl-like" appearance
102
Describe Hodgkin's lymphoma
- Inc 2nd decade life, F>M (except <10y), can be EBV-driven
- Painless cervical LAN most frequent symptom
- May have prolonged history, mediastinal mass, itch, rash, B-symptoms
- Ann Arbor staging. PET scan v. useful
- Usually >90% survival
103
Describe non-Hodgkin's lymphoma
- Group of conditions including Burkitt and lymphoblastic
- Burkitt most common NHL in childhood - fast growing
- Lymphoblastic 80% T cell, 20% B cell
- Abdomen (B cell) > mediastinum (T-cell) > head/neck
- St-Judes staging
- More rapid onset than HL
- B cell malignancy use rituximab (binds to CD20+ve B cells, destroys them) and intensive chemo
104
Describe Burkitt lymphoma
- Commonest NHL in childhood, fast-growing, usually high stage at presentation, prognosis >85% even for stage 4
- Often present with abdominal mass
- Usually short history, doubling time = hours
- Burkitt cells = dark blue cytoplasm with white vacuoles
105
Who is at most risk of tumour-lysis syndrome?
High count ALL (esp T cell)
B cell NHL (esp Burkitt)
Elevated uric acid/LDH pre-treatment
As have potential for bulky disease - a high cell mass that undergoes lysis with treatment.
Risk peaks at 24-48hrs post starting treatment.
106
What are the findings in tumour-lysis syndrome?
Uric acid and phosphate crystals leading to acute renal failure, fluid overload, high phos, high K, high urea, high creat, low calcium
107
Treatment of tumour-lysis syndrome?
Hyperhydration (2 x maint)
Urate oxidase (rasburicase, increases urinary excretion) or allopurinol (give in G6PD)
Treat hyperkalaemia
May need dialysis
Avoid calcium replacement while phosphate is rising as causes complexes that worsen renal damage
108
What is the most common brain tumour in children?
Low-grade glioma (astrocytoma)
109
What is the classic finding on histology of low-grade glioma?
Rosenthal fibres
110
What is the most common type of astrocytoma?
Juvenile pilocytic astrocytoma
2/3rds found in posterior fossa
Most tumours involving optic pathway are JPA
111
Treatment of low grade glioma?
Observation, may regress/have indolent course. May require surgery +/- chemo (vincristine, carboplatin).
Intervene if visual deterioration.
(B_RAF pathway aberration.
Better prognosis in children with NF1.
112
Describe high grade glioma
Locally infiltrative astrocytic tumours
Glioblastoma multiforme, poor prognosis, no recent change in survival outcomes
Surgery + chemoradiation. Temozolamide standard of care in adults
113
Most common malignant brain tumour?
Medulloblastoma, makes up 20% of brain tumours.
| Highly malignant primitive neuroectodermal tumour
114
Location of medulloblastoma
Typically arise from vermis of cerebellum. Up to 1/3rd metastasised at presentation.
115
Prognosis of medulloblastoma?
Depends on stage, histology, molecular markers
PF survival 75-80% at 5 years.
Most favourable = desmoplastic/nodular subtype
Least favourable = large cell/anaplastic
Infants <3y - high risk/poor prognosis as cannot have radiotherapy to brain
116
Treatment of medulloblastoma?
Surgery, craniospinal irradiation with boost, adjuvant chemotherapy (vincristine, cisplatin, cyclophos)
Spinal MRI + LP for CSF cytology 2/52 post surgery to check for residual cells.
117
Describe atypical teratoid/rhabdoid tumours
- Highly malignant, short history
- Usually <3y/o
- Disseminated disease in 20%, anywhere along brain and spine, often short clinical history
- Median survival 9-12 months
- Biallelic inactivation of SMARCB1 in majority (prev hSNF5), INI loss in tumour
- Tx: surgery, chemo, radiation
118
What gene mutation is associated with atypical teratoid/rhabdoid tumours?
- Biallelic inactivation of SMARCB1 in majority (prev hSNF5), INI expression loss in tumour
- Screen family, at risk of renal and soft tissue tumours if germline mutation present
119
Describe ependymomas
- Arise from wall of ventricle or spinal canal
- Not chemosensitive. Use surgery and radiotherapy
- Poor prognosis if: <3y/o, anaplastic, posterior fossa primary, metastasis
120
Describe brainstem gliomas
- 10-20% of brain tumours, 80% are diffuse brainstem gliomas
- Poor prognosis, <10% survival
- Cannot resect. Chemo nil benefit. Use radiotherapy
- Avoid biopsy as high risk (diagnosis via MRI)
121
Presenting signs of diffuse intrinsic pontine glioma?
- Cerebellar signs (ataxia, dysarthria)
- CN palsies
- Long tract signs (hypertonic, hyperreflexic, upgoing plantars, motor deficit)
- MRI: T2 hyperintense, T1 hypointense, >50% pons, basilar artery encasement
122
Describe craniopharyngiomas
- Suprasellar region
- Raised ICP, visual disturbances, pituitary dysfunction, GH insufficiency, bitemporal hemianopia
- Usually benign but morbidity due to tumour and treatment (endocrine)
- Often calcified on imaging
- Tx surgery and chemo
123
What can cause posterior reversible encephalopathy syndrome?
Chemotherapy + hypertension
- Headache, confusion, seizures
- Often visual loss due to occipital lobe involvement
- Usually vasogenic oedema, lack of diffusion restriction on MRI
124
Describe diencephalic syndrome
- Failure to thrive associated with hypothalamic/optic chiasm tumours, usually pilocytic astrocytoma
- Severe emaciation despite normal caloric intake
- Nystagmus, occ blindness, raised ICP
- Possible hyperactivity, hyperalertness, euphoria and vomiting
125
Describe the inheritance of retinoblastoma
- 60% sporadic, unifocal, onset ~18m
- 40% hereditary, AD, multifocal, onset ~10m. Deletion of tumour suppressor gene, germline RB1 mutation in Ch13q14. Still requires inactivation of remaining allele at cellular level.
126
Describe retinoblastoma
- Presents with leukocoria (white eye reflex), strabismus, nystagmus, red eye
- 60% sporadic, 40% hereditary
- Hereditary - can have trilateral tumour (inc pineal region)
- Tx: laser, cryotherapy, chemo (vincristine, carboplatin). If poor prognostic features (such as anterior segment) then enucleation.
- Cure > globe salvage > vision
127
RB1 mutation
- Retinoblastoma, trilateral tumour (bilateral retinoblastoma + pineal gland)
- AD
- Increased risk osteosarcoma, soft tissue sarcoma, breast cancers
- Avoid CT scans and unnecessary radiation
128
What cells does neuroblastoma arise from?
Primordial neural crest cells in adrenal medulla and sympathetic chain
129
Discuss neuroblastoma
- Average age 18m
- FHx in 1-2% (PHOX2B gene, central hypoventilation, Hirschprung's)
- Can have raccoon eyes (bony invasion), metabolic symptoms due to catecholamine secretion (sweating, pallor, diarrhoea, hypertension), bone pain/refusal to walk, Horner's syndrome, Opsoclonus/myoclonus, blue subcutaneous nodules
- MRI, iodine 123 MIBG scan (uptake in 90%), urinary catecholamines (HVA and VMA)
130
Where are neuroblastoma located?
65% abdomen, 35% adrenal glands, 20% chest, pelvis 4%, neck 1%
131
Factors associated with poor prognosis in neuroblastoma
Increased age, increased stage, molecular biology (diploid, 11q abnormality, MYCN amplification - growth oncogene)
132
Dinutuximab use and mechanism
Anti-GD2 antibody (Ch14.18) used for high risk neuroblastoma.
Kills cells expressing GD2 including peripheral nerves and CNS cells, ciliary eye muscles - severe neuropathic pain, sensory/motor neuropathy. Often need morphine. Sepsis-like picture with fever, oedea.
133
Treatment of neuroblastoma
Depends on risk.
Observe (some involute spontaneously), surgery, chemo, radiotherapy, may need stem cell rescue, dinutuximab (anti-GD2 antibody) for high risk
134
Describe Wilm's tumour (nephroblastoma)
- 90% of all renal tumours
- Predisposed by nephrogenic rest (foetal tissue persisting into infancy)
- Abdo mass (75%), haematuria, constipation, pain, HTN
- Metastasises to lungs and IVC tumour thrombus
- Low risk - surgery+observe. Other risk - surgery + chemo +/- radiotherapy
- Overall survival >90% for favourable disease
135
Describe osteosarcoma
- Most common bone tumour, peak 2nd decade life
- 80% lesions extremity (distal femur, prox tibia, humerus), 50% in knee joint
- Rapid bone growth/metaphysis areas
- Pain and mass
- Inc risk with radiation, RB1 gene, Li-Fraumeni
- 15-20% metastasis, esp lungs
- May have inc LDH and ALP
- Pathology: osteoblastic, chondroblastic
- Radiotherapy not used. Surgery + chemo (micrometastatic disease)
136
Describe Ewing's sarcoma
- Small, round cell tumour of neuroectodermal origin
- Bone or soft tissue (extraskeletal ES), equal distribution axial (pelvis, ribs, vertebra) + long bones, diaphysis
- Pain, soft tissue mass, constitutional symptoms (fever, weight loss, high WCC+ESR)
- Recurring translocation involving EWSR1 gene (22q12, t11;22)
- 25% present with mets (<30% EFS)
- Sensitive to radiotherapy. Surgery + chemo.
137
Side effects of steroids
```
Immunosuppression
Weight gain
Weakness
Psychosis or mood swings
Stomach ulcers
Elevated blood pressure
Sleep problems
Hyperglycaemia
Osteoporosis
Avascular necrosis
```
138
Describe the features of Langerhans Cell Histiocytosis
- Presents with cutaneous lesions (trunk and scalp) resembling cradle cap, which is caused by infiltrates of Langerhans cells
- Hepatosplenomegaly, lymphadenopathy, pulmonary lesions, destructive osteolytic bone lesions (punched out xray)
- Anaemia, thrombocytopenia
- Recurrent infections such as otitis media and mastoiditis
- Bilateral proptosis due to retro-orbital accumulation of granulation tissue
139
Describe the blood film in haemolytic uraemic syndrome
Films characteristically show schistocytes/helmet cells as well as thrombocytopenia.
Triad of microangiopathic haemolytic anaemia, thrombocytopenia, acute renal failure.
140
Describe the x-ray differences between osteosarcoma and Ewing's sarcoma
Osteosarcoma - lytic and sclerotic lesion, "sunburst"
| Ewing's sarcoma - lytic lesion with periosteal reaction, "onion skin"
141
What is the half life of F8 and F9?
F8 - 12 hours
| F9 - 24 hours
142
Causes of acquired methaemaglobinaemia
Lidocaine/lignocaine, nitrous oxide, metoclopramide.
Methaemoglobin is formed when the iron in haemoglobin is oxidised to its ferric state. This reduces the oxygen carrying capacity of haemoglobin.
Inc risk infants.
143
What is the most common prothrombotic abnormality:
- Acquired
- Familial
```
Acquired = antiphospholipid antibodies (lupus anticoagulant and cardiolipin antibodies)
Familial = Factor V Leiden mutation = activated protein C resistance. Heterozygotes also have inc. risk clotting by 3-8%
```
144
What is the difference between embryonal and alveolar rhabdomyosarcoma?
- Embryonal - more common, younger, better prognosis
- Alveolar - less common, older, worse prognosis. Fusion gene is pathognomonic (PAX7 better prognosis than PAX3-FOXO1, t(1;13), 2(2;13))
145
Where are malignant germ cell tumours located?
Gonadal (30%) or extra-gonadal (70%) - sacrococcygeal, retroperitoneal, mediastinum, neck, pineal region
146
Describe malignant germ cell tumours
- Gonadal 30%, extra-gonadal 70%
- Range from undifferentiated embryonal carcinoma to mature teratoma (pure teratoma has no metastatic potential)
- Gonadal: testicular swelling, pelvic pain, ovarian torsion, abnormal or precocious puberty
- Inc risk with undescended testes
- Ix: AFP and b-HCG
- Can metastasise to lungs, liver lymph nodes
- Tx depends on type/location. Chemo is cisplatin and carboplatin
147
Risk factors for hepatoblastoma
Premature infants with IUGR, Beckwith-Wiedemann syndrome, FAP, congenital retinal pigmentation
148
Hepatoblastoma vs. HCC
Hepatoblastoma - underlying normal liver, much higher AFP than in HCC. Usually <2y/o
HCC - usually underlying liver disease, metastatic HCC is incurable but can have palliative chemo
149
Presentation and treatment of hepatoblastoma
Usually painless abdominal mass
Treatment with chemo (cisplatin, carboplatin) and surgery (resection or transplant)
Overall survival 70-80%
150
What is a Langerhans cell?
A potent antigen presenting cell.
151
Describe the process of Langerhans cell histiocytosis
- Clonal accumulation and proliferation of abnormal Langerhans cells in bone marrow. Forms damaging infiltrates with eosinophils, lymphocytes and normal histiocytes.
- Can affect any age
- Localised disease (skin, bone, lymph nodes) or multi-system (worse prognosis)
- Unpredictable course, can rapidly progress
- Can develop diabetes insipidus
- Tx: steroids, vinblastine, methotrexate, mercaptopurine
152
What are the symptoms of haemophagocytic lymphohistiocytosis?
Fever, hepatosplenomegaly, cytopenia, high lipids, coagulopathy, high fibrinogen and ferritin, liver dysfunction, neuro symptoms, inc CD25
153
What is the difference between primary and secondary HLH?
- Primary/familial - AR, defect in NKC and cytotoxic T cell function, results in phagocyte and inflammation activation - multi-system pathology
- Secondary = macrophage activation syndrome - usually precipitated by infection, rheumatological, malignancy, immune deficiency
154
Treatment of HLH
Steroids, chemotherapy, bone marrow transplant as definitive treatment
155
What are the indications for a bone marrow transplant?
- Malignancy - high risk leukaemia, or rescue due to high dose chemo e.g. neuroblastoma, brain tumours
- Metabolic - to replace missing/defective enzyme e.g. mucopolysaccharidosis
- Immunodeficiency e.g. SCID
- Bone marrow failure e.g. aplastic anaemia, Fanconi anaemia
- Haemoglobinopathy e.g. Sickle cell, thalassaemia major
156
Name the cancer predisposition syndromes
- Familial retinoblastoma - germline RB1 mutation
- Li-Fraumeni - mutation in tumour suppressor TP53
- Neurofibromatosis 1 - mutation of NF-1 gene on Ch 17
- Beckwith-Wiedemann - mutation in 11p15.5
- Trisomy 21
157
Cancer predisposition: retinoblastoma
- Germline RB1 mutation, Ch13q14, deletion of tumour suppressor gene
- AD, high penetrance
- Requires double hit
- Trilateral tumour (bilat retino + pineal pNET)
- In risk osteosarcoma, soft tissue sarcoma, breast cancer
158
Cancer predisposition: Li-Fraumeni
- Mutation in TP 53 gene, tumour suppressor gene
- AD, FHx early-onset cancers
- Soft tissue sarcoma, osteosarcoma, breast cancer, leukaemia, brain cancers
159
Cancer predisposition: neurofibromatosis 1
- Mutation of NF-1 on Ch17, unable to produce neurofibromin
- AD, variable expression
- Neurofibroma, schwannoma, optic glioma, astrocytoma, pheochromocytoma, malignant tumour from plexiform neurofibroma
160
Cancer predisposition: Beckwith-Wiedemann
- 85% sporadic, mutation in 11p15.5 causing over-reactivity of IGF2 gene
- From abnormal methylation or uniparental disomy
- 10-20% develop malignancy - hepatoblastoma, neuroblastoma, Wilm's, rhabdomyosarcoma, adrenocortical tumour
- Abdo USS 3-monthly until age 8, AFP every 6 weeks until age 4
161
Cancer predisposition: Trisomy 21
- ALL (inc 20x), acute megakaryoblastic leukaemia (inc 500x)
- Transient myeloproliferative disease
- 10-20% of these develop AMKL within 3 years
162
Describe transient myeloproliferative disease
- Trisomy 21, occurs in first 3m life in 10% (develops in utero), resolves spontaneously in 1-3m.
- Anaemia, thrombocytopenia, hepatosplenomegaly. Inc WCC and blasts.
- Inc risk (10-20%) of then developing acute megakaryoblastic leukaemia
163
Acquired causes of thrombophilia
- Central line e.g. neonates - renal vein thrombosis
- Trauma, surgery, nephrotic syndrome, malignancy
- Lupus anticoagulant (in APTT) e.g. SLE, antiphospholipid syndrome
164
Inherited causes of thrombophilia
- Factor V Leiden mutation - activated protein C resistance
- Protein S, protein C deficiency - AD, infants with homozygous protein C def present like DIC, can cause purpura fulminans and blindness. FFP only source of protein C. When out of neonatal period, use warfarin
- Prothrombin gene mutation - inc prothrombin levels
165
Factor V Leiden mutation
- Activated protein C resistance, so factor 5+8 become more resistant to inactivation by protein C
- Inc risk VTE, no inc risk arterial thrombosis
- Heterozygotes 5x inc risk, homozygotes 50x inc risk
- 4% Caucasians carriers
166
When and why does the nadir of Hb occur?
Around 2 months age, due to decr EPO (inhibited by inc O2 after birth, once Hb is at nadir get decr O2 therefore EPO stimulated again and get rise in Hb).
167
Extrinsic vs intrinsic haemolysis
- Extrinsic (acquired)
| - Intrinsic (congenital)
168
Rod cells on blood film
= pencil cells
| Iron deficiency anaemia
169
Causes of macrocytosis
B12/folate deficiency
Newborn
Hypothyroidism
Down syndrome
Massive reticulocytosis (recticulocytes are larger than RBC)
Liver disease
Megaloblastic anaemia - nutritional, IEOM, drug e.g. azathioprine
170
B12/folate deficiency
Macrocytic anaemia
Mild thrombocytopenia +/- neutropenia (hypersegmented)
- Dietary deficiency, defective absorption (small intestine, intrinsic factor), inc requirement (growth, skin disease)
171
Causes of extra-vascular haemolysis
- Immune, DAT+ve - auto or alloimmune. Get splenomegaly
| - Non-immune (congenital) e.g. thalassaemia, haemoglobinopathy, hereditary spherocytosis, G6PD def
172
Cold agglutination
- Antibodies bind to RBC causing haemolysis, IgM, DAT-ve. - Usually lab phenomenom only, not clinically relevant in body as warmer.
- Post-viral, can be associated with mycoplasma
- C3 coating on FBCs
- Intravascular haemolysis
- Spurious macrocytosis
- Doesn't respond to steroid
173
Causes of intra-vascular haemolysis
- Infection - malaria, sepsis, burns
- Cardiac e.g. prosthetic valves
- Microangiopathic - TTP, HUS, Kasabach Meritt, calcineurin inhibitors (ciclosporin, tacrolimus), malignancy, DIC
174
HbF
HbA
HbA2
HbF - alpha 2, gamma 2
HbA - alpha 2, beta 2
HbA2 - alpha 2, delta 2
175
Unfractionated heparin vs LMW heparin
- Unfractionated - short 1/2 life, based on APTT ratios, infants metabolise UFH faster, reversed by protamine sulphate. ADRs bleeding, HIT, osteporosis
- LMWH - less monitoring required (anti-X1 levels), decr risk HIT and osteoporosis, effect not readily reversed by protamine sulphate
176
Side effects of warfarin
Bleeding, tracheal calcification, hair loss
| - Management of bleeding with IV Vit K, FFP, recombinant F7a
177
Threshold for acute leukaemia on bone marrow?
Need >20% blasts (normal number blasts <5%), but often is >85%. High nucleus:cytoplasm ratio
178
Good prognosis in ALL?
Hyperdiploid >50
Trisomy 4, 10
ETV6-RUNX1 t(12;21) translocation - 99% cure rate
179
Significance of Philadelphia Chromosome?
t(9;22) balanced translocation resulting in fusion of BCR and ABL1 creating a novel tyrosine kinase resulting in unregulated cell proliferation.
- Imatinib /dasatinib (TK inhibitor) has dramatically improved outcome.
- Survival >70%
180
Discuss the use of Blinatumomab
- Early phase studies, promising results for multiple relapse/refractory B-ALL. BiTE molecule - binds CD19+ve B cells and T cells at each end. Non cytotoxic, T cell kills B cell
- Can lead to cytokine release syndrome (similar to MAS) and neurotoxicity
181
Infant ALL
Often high WCC at presentation, MLL (11q23) rearrangements, rare disorder, poor outcome, inc treatment-related toxicity
182
Describe risks of hyperleukocytosis
- WCC>100 (or >50 in AML). More frequent AML, higher mortality
- Leukostasis in brain and lungs, like pulm oedema
- DIC
- Tumour lysis syndrome
- Tx: hyperhydration, rasburicase, may need leukapheresis, manage DIC, avoid transfusion (inc viscosity)
183
Differentials of mediastinal masses - ant, middle, post
- Anterior: lymphoma, germ cell tumour
- Middle: lymph nodes, TB, fungal, osteosarcoma
- Posterior: neuroblastoma, neurofibroma, schwannoma
- 80% of mediastinal masses are malignant
184
Describe superior mediastinal compression syndrome
- SVC obstruction - facial plethora, oedema, collaterals chest wall
- Airway obstruction
- Horner's syndrome
- T cell leukaemia, lymphoma, GCT
- Tx: avoid GA/lying flat, MDT involvement, steroids to shrink tumour/swelling, may need anticoagulation
185
Symptoms and treatment of spinal cord compression (3-5% of children at diagnosis)
- Local or radicular pain
- Motor weakness, sensory loss, incontinence
- Paraplegia/quadriplegia can progress rapidly
- Emergency MRI, surgery/radio/chemo +/- dexamethasone
186
Anaphylaxis most commonly with which chemotherapies?
- L'Asparaginase/PEG asparaginase
- Etoposide
- Carboplatin
- Amifostine
- Platelet transfusions
+ newer moncolonal antibodies
- Premedications given to reduce risk
187
Drugs that are high risk if extravasation occurs?
Doxorubicin, dactinomyin, danorubicin, vinblastine, vincristine
188
Febrile neutropenia and shock.. organism is?
Gram-ve sepsis until proven otherwise (e.g. E.Coli, pseudomonas, Klebsiella).
If shocked use tazocin + vancomycin + amikacin
(if cisplatin exposure then avoid amikacin due to hearing loss, can use meropenem instead).
189
Febrile neutropenia in on high dose cytarabine...organism is most likely?
Alpha haemolytic strep (strep mitis/strep pleuridans)
| Always treat these patients with tazocin + vancomycin
190
Anti-emetics used in oncology
```
Ondansetron, metoclopramide
Scopoderm patch
Arepitant
Cyclizine
Lorazepam
Dexamethasone (half dose if using arepitant. Don't use if on immunotherapy)
```
191
Drugs associated with mucositis?
Methotrexate, doxorubicin
192
Risk of cardiomyopathy with?
Doxorubicin (anthracyclines) + thoracic radiation
- worse with puberty, pregnancy, high intensity exercise
- Give dexrazoxane (iron chelator) prior to anthracycline in high risk patients
193
Risk of pulmonary penumonitis/fibrosis with?
Bleomycin, lung irradiation
194
Highest risk of infertility with which cancer?
Ewing's sarcoma
195
Risks of second malignancy post cancer treatment
- Radiation exposure: sarcoma
- Etoposide/alkylator (cyclophos, ifosfamide) exposure: AML, sarcoma
- Hodgkin (mantle irradiation): breast (30-40% risk by age 50) and thyroid cancer
196
Risk of high frequency hearing loss with which chemo?
Cisplatin (up to 70%), worse if had gentamicin, amikacin, frusemide treatment. 30% require hearing aids.
197
Environmental factors linked to cancer development in children
- Treatment for previous cancers (radiotherapy, etoposide + alkylating chemo)
- Lack of infection exposure may play a role in ALL
- EBV in nasopharyngeal carcinoma
198
MYC is associated with?
| MYCN is associated with?
```
MYC = Burkitts lymphoma
MYCN = neuroblastoma
```
199
Klinefelters have an increased risk of?
Mediastinal germ cell tumour
| Breast cancer
200
Primary function of a checkpoint inhibitor is?
Activation of T-cells and dendritic cells
201
Familial adenomatous polyposis (FAP)
AD cancer predispostion syndrome caused by germline mutations in the tumour suppressor gene APC. Inc risk bowel cancer and hepatoblastoma
202
Types of cancer mutations
Errors in:
- Oncogenes promote healthy growth-> cause constant activation
- Tumour suppressor genes suppress excess growth -> excess growth
- DNA repair genes proof read and repair mutations -> don't fix errors
203
Which malignancies can metastasise to bone marrow?
Ewing's, alveolar rhabdomyosarcoma, neuroblastoma
204
Side effects of 6-mercaptopurine?
Hepatic necrosis
| Myelosuppression
205
Posterior fossa syndrome
- Delayed neuro changes after tumour resection
- Cerebellar mutism, irritability, difficulty verbalising, emotional lability, nystagmus
- 20% incidence after resection medulloblastoma
- Mutism resolves ~1m, other neuro symptoms persist
206
CNS manifestations of Tuberous Sclerosis
- Supependymal giant cell astrocytoma (5-15%) - benign, slow growing, wall lateral ventricles
- Cerebral cortical tubers (90-100%), associated with seizures
- Subependymal hamartomatous nodules
- Everolimus is the standard of care for unresectable lesions
207
Describe the mechanism of methotrexate
- Competitively inhibits the enzyme folic acid reductase
- Interferes with tissue cell reproduction
- Main effect is directed to the S phase of cell division. - Actively proliferating tissues such as malignant cells, bone marrow, buccal and intestinal mucosa are sensitive to the effects of methotrexate
- Need normal kidney function to excrete the drug adequately and avoid excessive toxicity
208
What mutation is implicated in the majority of hereditary spherocytosis cases?
Mutations in the ANK1 gene is implicated in more than 50% of cases of HS
209
What is the life-span of WBC, RBC, neuts, platelets?
RBC 120 days, WBC 13-20 days, platelets 10 days, neuts 5 days
210
How does rasburicase work?
Oxidation of uric acid to allantoin
211
Prognostic factors in neuroblastoma?
Good prognostic factors:
Age <1
Hyperdiploidy
Whole chromosome gains
Poor prognostic factors:
Amplification of the N-myc proto-oncogene
Segmental chromosome abnormalities
212
Describe transfusion-related GvHD
- Is a result of donor T lymphocytes directed against recipient tissue antigens.
- Fever, rash, diarrhoea, LFT derangement and pancytopenia.
- It has a very poor prognosis and is almost universally fatal
- Prevent by using irradiated blood.
213
What are schistocytes?
Schistocytes are seen in microangiopathic haemolytic anaemia (such as haemolytic uraemia syndrome). They are caused by damage in the vessels. Schistocytes are always an abnormal finding on a blood film.
214
What are haemophilia factor inhibitors?
- High affinity IgG antibodies
- 30% Haem A, 5% Haem B (may have anaphylaxis)
- Decrease the response to factor infusions and also delay maturation (bone age, puberty, growth).
- Tx: switch from prophylactic factor to on demand factor.
- Immune tolerance induction may also be performed. - Activated FVII can used to bypass inhibitors but it is less effective (misses thrombin amplification) and can predispose to thrombosis
- If there is upcoming surgery then use recombinant FIIa q2hourly for the preceding 48 hours.
- New medication emicizumab is a monoclonal AB that can bridge IX and X to bypass VIII and may be used as a prophylaxis alternative.
215
By how much do platelets and Hb rise after transfusion?
Each unit of platelets will raise the platelet count by 20x10g/L.
Each unit of red cells will raise the count by 10x10g/L
216
How much iron does each unit of RBC contain?
- Each unit of RBC contains 250mg of iron
- Clinically significant iron overload is thought to occur after 10 units in children
- Iron chelator such as desferroxamine can be used.
The RDI for iron is
- 11mg/day infants
- 7-10mg/day children
217
Intra vs extravascular haemolysis
- Intra: higher LDH and haemoglobinuria, low hapto (HUS, DIC, transfusion reaction, PNH, prosthetic valve hemolysis)
- Extra: higher bilirubin, lower LDH, low hapto (alloimmune haemolysis, thalassaemia, inc RBC turnover).
218
What is Bernard Soulier Syndrome?
- AR disorder
- Absence or severe deficiency of the VWF receptor (GPIb complex) on the platelet membrane
- Extremely large platelets and thrombocytopenia, prolonged bleeding time
- Defect in ristocetin induced agglutination, but platelets will agglutinate in response to other agonists (collagen, ADP)
219
What are the findings in sideroblastic anaemia?
- Hypochromic, microcytic red cells mixed with normal red cells = dimorphic population
- Extremely high red cell distribution width
- Serum iron elevated, transferrin saturation increased
- Impaired heme synthesis leads to retention of iron within the mitochondria
- Sideroblasts on film with ferritin iron deposits (blue stained) in the mitochondria of erythroid precursors, forming an apparent ring around the nucleus
220
What is the only known heritable risk factor for brainstem gliomas?
NF1
221
What are types of small round blue cell tumours?
- Medulloblastoma
- Neuroblastoma
- Ewings
- Wilms
- Hepatoblastoma
- Retinoblastoma
222
What syndromes are associated with medulloblastoma?
Gorlin (nevoid basal cell carcinomas), Li-Fraumeni (TP53, wide range of cancers), Turcot (adenomatous colon polyps), Gardner (FAP), Cowden (multiple hamartomas)
223
Discuss the use of Car-T cell therapy
- Engineered autologous T cells transfected using viral vector, target CD19+ve B cells + destroys them
- Currently used in CD19+ve ALL, rationale for use in B-cell lymphoma
- Cells are autologous, therefore rejection minimal, can persist in circulation leading to prolonged remission, can penetrate into CSF
- Can cause cytokine release syndrome in up to 50% cases, long-term B cell depletion requiring immunoglobulin
224
What are the different MHC Class I antigens?
HLA-A, HLA-B, HLA-C
| Found on nearly all cells (except erythrocytes and corneal endothelium)
225
What are the different MHC Class II antigens?
HLA-DR, HLA-DQ, HLA-DP
| Found on antigen-presenting cells (e.g. dendritic cells, B-lymphocytes, monocytes, macrophages, Langerhans cells)
226
Discuss parent/sibling relationship with HLA markers for HSCT
- Parents are haploidentical matches to patient (i.e. patient shares 50% with Dad, 50% with Mum)
- 1/4 chance of having a complete HLA matched sibling
227
What are the different types of HSCT?
- Autologous (self) vs allogeneic (foreign)
- Related vs unrelated
- Matched vs mismatched/unmatched
228
What does a haploidentical transplant mean?
- Refers to the use of a parent or non-matched sibling as the donor
- A child by definition will have at worst 50% of a parent's HLA type
229
In what conditions will excess haematopoietic stem cells be produced in the body?
- Umbilical cord blood (physiological)
- Marrow regeneration following myelosuppressive chemotherapy
- Following GCSF stimulation
230
What are the advantages and disadvantages of cord blood for HSCT?
+ve: risk-free collection, less requirement for HLA matching, low risk infection, low incidence GvHD, rapid availability, better for metabolic syndromes + AML
-ve: low volume/dose, slow engraftment, no possibility of donor lymphocyte infusion
231
What are the advantages and disadvantages of bone marrow for HSCT?
+ve: moderately brisk engraftment, moderate risk GvHD, donor lymphocyte infusion available
-ve: increased risks of collection, contains all marrow cells including RBC
232
What are the advantages and disadvantages of peripheral blood stem cells for HSCT?
+ve: rapid engraftment, low risk during collection, only CD34+ cells collected, donor lymphocyte infusion available
-ve: increased rates GvHD, especially chronic GvHD, not a practical procedure on small patient
233
What is the order of preference for allo-SCT sources?
- Matched sibling donor - marrow
- Matched sibling donor - PBSC
- Matched unrelated donor - marrow
- Matched unrelated donor - cord
- Mismatched family donor (haploidentical) - marrow
234
Waiting time for stem cell transplants depending on type used?
- Matched unrelated donor - 4-6 weeks
- Cord bloods - 7-14 days
- Haploidentical donors (parents) - immediately
235
What is the role of transplant conditioning?
- Allows treatment of underlying condition (in malignancy)
- Immunosuppression to allow engraftment (in allotransplant)
- Can be: myeloablative (higher risk of toxicity) or reduced intensity conditioning (higher risk of graft failure)
236
Discuss cause and management of graft versus host disease
- Acute = <100 days post transplant
- 1: damage to host tissues by inflammation from preparative chemo/radio regime
- 2: recipient and donor APC trigger activation of donor-derived T cells
- 3: T-cell mediated cytotoxicity against target host cells. Production of cytokines and TNFa causing further inflammation and damage
- Signs: rash, jaundice, diarrhoea = all correlate with severity of GvHD
- Tx: optimise immunosuppression - cyclosporine, steroids, sirolimus/tacrolimus
- Chronic GvHD very difficult to manage, rare complication
